Current Challenges in Proton Therapy

**65**

**Chapter 7**

**Abstract**

infrastructure

**1. Introduction**

Proton Therapy in

Lower-Middle-Income Countries:

From Facts and Reality to Desire,

*Sandra Ileana Pérez Álvarez, Francisco Javier Lozano Ruiz,* 

Around 50% of cancer patients will require radiotherapy (RT) and 10–15% of these patients could be eligible for proton beam radiotherapy (PBT). Dosimetric advantages are undeniable, mainly in pediatric and reirradiation scenarios. Though, PBT facilities are scarce worldwide and the IAEA has reported 116 functional particle facilities, of which 98 are PBT, virtually absent in low- and middle-income countries (LMIC). The Latin America and Caribbean region represent a unique opportunity for a PBT center, as there are currently no functional facilities and current RT needs are significant. The challenges can be summarized as high initial investment and maintenance, geographic coverage, required baseline technology and certification, over-optimistic workload, unclear rates and reimbursement, unmet business plan and revenue expectations, and lack of trained human resources. Investment costs for a PBT facility are estimated to be at around 140 million euros; therefore, this seems unsuitable for LMIC. Mexico's geographical advantage, GDP, baseline technologies and high demand for RT makes it an ideal candidate. Nevertheless, a PBT center would account for a third of Mexico's annual health expenditure for 2020. Enormous efforts must be made by both the private

Challenges and Limitations

*Federico Maldonado Magos and Aida Mota García*

sector and governmental authorities to provide funding.

**Keywords:** proton therapy, cost-effectiveness, low-to-middle-income countries,

Radiotherapy (RT) is an integral component of contemporary cancer treatment, both as curative and palliative therapy. Around 50% of patients will, at some point during their cancer history, require RT. Its contribution to cancer survival is estimated at around 40% versus 49% for surgery and 11% for systemic treatment modalities. [1] In the past decade, ongoing research in systemic therapies has broadened the indications for RT, since as long-term survival increases so does the prevalence of the disease. Oligometastatic cancer recurrence is increasingly managed with RT, as well as oligoprogressive disease. This in addition to its more common applications, such as local control in curable or metastatic settings. However,

#### **Chapter 7**

## Proton Therapy in Lower-Middle-Income Countries: From Facts and Reality to Desire, Challenges and Limitations

*Sandra Ileana Pérez Álvarez, Francisco Javier Lozano Ruiz, Federico Maldonado Magos and Aida Mota García*

#### **Abstract**

Around 50% of cancer patients will require radiotherapy (RT) and 10–15% of these patients could be eligible for proton beam radiotherapy (PBT). Dosimetric advantages are undeniable, mainly in pediatric and reirradiation scenarios. Though, PBT facilities are scarce worldwide and the IAEA has reported 116 functional particle facilities, of which 98 are PBT, virtually absent in low- and middle-income countries (LMIC). The Latin America and Caribbean region represent a unique opportunity for a PBT center, as there are currently no functional facilities and current RT needs are significant. The challenges can be summarized as high initial investment and maintenance, geographic coverage, required baseline technology and certification, over-optimistic workload, unclear rates and reimbursement, unmet business plan and revenue expectations, and lack of trained human resources. Investment costs for a PBT facility are estimated to be at around 140 million euros; therefore, this seems unsuitable for LMIC. Mexico's geographical advantage, GDP, baseline technologies and high demand for RT makes it an ideal candidate. Nevertheless, a PBT center would account for a third of Mexico's annual health expenditure for 2020. Enormous efforts must be made by both the private sector and governmental authorities to provide funding.

**Keywords:** proton therapy, cost-effectiveness, low-to-middle-income countries, infrastructure

#### **1. Introduction**

Radiotherapy (RT) is an integral component of contemporary cancer treatment, both as curative and palliative therapy. Around 50% of patients will, at some point during their cancer history, require RT. Its contribution to cancer survival is estimated at around 40% versus 49% for surgery and 11% for systemic treatment modalities. [1] In the past decade, ongoing research in systemic therapies has broadened the indications for RT, since as long-term survival increases so does the prevalence of the disease. Oligometastatic cancer recurrence is increasingly managed with RT, as well as oligoprogressive disease. This in addition to its more common applications, such as local control in curable or metastatic settings. However,

dose-limiting toxicity remains the main problem for RT, especially for in-field recurrences where reirradiation is a bigger concern.

Proton beam radiotherapy (PBT) is a novel technique with endless possibilities. Different simulation models have estimated that 10–15% of all radiated patients from various European countries could be eligible for PBT, but only less than 1% receive it. [2] Since toxicity and dosimetry advantages are undeniable, and although there is still scarce clinical practice, indications and applications are on the rise mainly in pediatric and reirradiation scenarios, without excluding common indications for radiation treatments, especially when dose constraints are an issue. Still, PBT remains non-existent in Latin America and virtually absent in low- and middle-income countries (LMIC). The following chapter will focus on how a PBT can be suitable for proven clinical indications in LMIC, particularly in Latin America and Mexico, where cancer and epidemiology registries—although insufficient—present a broader view of current RT needs when compared to other LMIC across Africa and Asia. A general overview of the facts and realities of RT, as well as the challenges and limitations expected for a proton facility in these countries, will be presented.

The Latin America and Caribbean (LAC) region represents a unique clinical opportunity for a proton radiation therapy center, as there are currently no functional facilities and because current radiotherapy needs are significant. Nevertheless, auxiliary diagnostic facilities required for a functional PBT center, such as computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI) and pathology departments, although insufficient, are found in some LAC cities, meeting the highest quality requirements and the most rigorous international certifications. There is an upcoming PBT center in Buenos Aires, Argentina with operations due to start in 2022. Even with this center, availability for this type of treatment is evidently not enough for the 629 million inhabitants living/distributed in the 192 million km<sup>2</sup> of Latin American territory. [3]

#### **2. Proton therapy in low- and middle-income countries**

#### **2.1 Facts and reality**

According to the IAEA Directory of Radiotherapy Centres, there are 116 functional proton/ion facilities (107 in high-income countries, 8 in uppermiddle-income countries and 1 in LMIC) around the world, out of which 98 are PBT. Most are located in high-income countries in North America, Europe and Asia, countries that coincidentally have the highest number of photon radiotherapy equipment, and none in LAC. [4] **Figure 1** shows available PBT facilities according to their operation status. Even LAC has RT available only in 70% of its countries, with approximately 1 megavoltage machine per 650,000 inhabitants. Distribution varies according to income groups, creating an unequal environment for adequate cancer care, particularly from a radiotherapy standpoint. [5]

Cancer accounts for 10% of the global healthcare budget, out of which RT takes up only about 5%; therefore, RT expenditure is about 0.25–1% of the total healthcare budget. [6] This represents a very small fraction of the total healthcare budget if we consider that up to 25% of the population is expected to go through radiation treatment at some point in their life. [7] Although RT is regarded as the cheapest cancer treatment modality, limited resources are available in Latin America due to absence of domestic and international funding. Approximately 90% of the population in these countries will lack access to RT.

**67**

implemented. [8]

**Figure 1.**

*proton facility*

*Proton Therapy in Lower-Middle-Income Countries: From Facts and Reality to Desire…*

Insufficient detailed information about attainability for radiotherapy and auxiliary diagnostic tools in LMIC is a constant. Currently very few countries in LAC have submitted recent data. Thus, planning for a PBT center requires data regarding general availability, not only for radiotherapy but also for auxiliary diagnostic tools, such as PET, MRI, CT scans and pathology laboratories, many of which are either partially or completely unavailable across the LAC region. Developing a PBT center with full access to all therapeutic and diagnostic tools involved in proton therapy must therefore be contemplated in at least one of the main cities of the region; otherwise, PBT center usage could be suboptimal. LAC presents a complex paradox, where most of childhood cancer and reirradiation scenario candidates for PBT are much more frequent than in developed countries—where most PBT centers exist—but is simultaneously the region facing the most difficulties for a functional PBT center, not due to the obvious economic challenges, but because of the lack of

*Available proton therapy facilities in clinical operation and under construction.*

Another issue is that currently around 8% of LAC residents are 65 years or older, which represents the population with the highest risk for malignant neoplasms. By 2050, this figure is expected to double to 17.5% and to exceed 30% by the end of the century. In 2018, this represented over 1.3 million new cancer cases and over 660,000 cancer-related deaths; therefore, at least twice this number will reflect cancer deaths by 2050 unless international efforts to reduce mortality are effectively

*2.1.1 Adult tumors suitable for PBT in Latin America and their relevance for a* 

The LAC region encompasses 33 countries and 15 dependencies or territories with a total population of 646 million in 2019. [9] With a combined gross domestic product (GDP) of United States dollars (USD) 5.7 trillion, LAC is a region of growing importance to the world economy. [10, 11] GDP per capita ranges from USD 754 in Haiti to USD 85,477 in the Cayman Islands. Haiti is considered the only low-income country in the region; 7%, 49% and 41% are considered lower-middle-, upper-middle- and high-income countries, respectively. [12] According to Bishr

complementary and auxiliary tools required for it.

*DOI: http://dx.doi.org/10.5772/intechopen.95984*

*Proton Therapy in Lower-Middle-Income Countries: From Facts and Reality to Desire… DOI: http://dx.doi.org/10.5772/intechopen.95984*

*Proton Therapy - Current Status and Future Directions*

be presented.

territory. [3]

**2.1 Facts and reality**

recurrences where reirradiation is a bigger concern.

dose-limiting toxicity remains the main problem for RT, especially for in-field

Proton beam radiotherapy (PBT) is a novel technique with endless possibilities. Different simulation models have estimated that 10–15% of all radiated patients from various European countries could be eligible for PBT, but only less than 1% receive it. [2] Since toxicity and dosimetry advantages are undeniable, and although there is still scarce clinical practice, indications and applications are on the rise mainly in pediatric and reirradiation scenarios, without excluding common indications for radiation treatments, especially when dose constraints are an issue. Still, PBT remains non-existent in Latin America and virtually absent in low- and middle-income countries (LMIC). The following chapter will focus on how a PBT can be suitable for proven clinical indications in LMIC, particularly in Latin America and Mexico, where cancer and epidemiology registries—although insufficient—present a broader view of current RT needs when compared to other LMIC across Africa and Asia. A general overview of the facts and realities of RT, as well as the challenges and limitations expected for a proton facility in these countries, will

The Latin America and Caribbean (LAC) region represents a unique clinical

of Latin American

opportunity for a proton radiation therapy center, as there are currently no functional facilities and because current radiotherapy needs are significant. Nevertheless, auxiliary diagnostic facilities required for a functional PBT center, such as computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI) and pathology departments, although insufficient, are found in some LAC cities, meeting the highest quality requirements and the most rigorous international certifications. There is an upcoming PBT center in Buenos Aires, Argentina with operations due to start in 2022. Even with this center, availability for this type of treatment is evidently not enough for the

629 million inhabitants living/distributed in the 192 million km<sup>2</sup>

**2. Proton therapy in low- and middle-income countries**

According to the IAEA Directory of Radiotherapy Centres, there are 116 functional proton/ion facilities (107 in high-income countries, 8 in uppermiddle-income countries and 1 in LMIC) around the world, out of which 98 are PBT. Most are located in high-income countries in North America, Europe and Asia, countries that coincidentally have the highest number of photon radiotherapy equipment, and none in LAC. [4] **Figure 1** shows available PBT facilities according to their operation status. Even LAC has RT available only in 70% of its countries, with approximately 1 megavoltage machine per 650,000 inhabitants. Distribution varies according to income groups, creating an unequal environment

for adequate cancer care, particularly from a radiotherapy standpoint. [5]

Cancer accounts for 10% of the global healthcare budget, out of which RT takes up only about 5%; therefore, RT expenditure is about 0.25–1% of the total healthcare budget. [6] This represents a very small fraction of the total healthcare budget if we consider that up to 25% of the population is expected to go through radiation treatment at some point in their life. [7] Although RT is regarded as the cheapest cancer treatment modality, limited resources are available in Latin America due to absence of domestic and international funding. Approximately 90% of the population in

**66**

these countries will lack access to RT.

Insufficient detailed information about attainability for radiotherapy and auxiliary diagnostic tools in LMIC is a constant. Currently very few countries in LAC have submitted recent data. Thus, planning for a PBT center requires data regarding general availability, not only for radiotherapy but also for auxiliary diagnostic tools, such as PET, MRI, CT scans and pathology laboratories, many of which are either partially or completely unavailable across the LAC region. Developing a PBT center with full access to all therapeutic and diagnostic tools involved in proton therapy must therefore be contemplated in at least one of the main cities of the region; otherwise, PBT center usage could be suboptimal. LAC presents a complex paradox, where most of childhood cancer and reirradiation scenario candidates for PBT are much more frequent than in developed countries—where most PBT centers exist—but is simultaneously the region facing the most difficulties for a functional PBT center, not due to the obvious economic challenges, but because of the lack of complementary and auxiliary tools required for it.

Another issue is that currently around 8% of LAC residents are 65 years or older, which represents the population with the highest risk for malignant neoplasms. By 2050, this figure is expected to double to 17.5% and to exceed 30% by the end of the century. In 2018, this represented over 1.3 million new cancer cases and over 660,000 cancer-related deaths; therefore, at least twice this number will reflect cancer deaths by 2050 unless international efforts to reduce mortality are effectively implemented. [8]

#### *2.1.1 Adult tumors suitable for PBT in Latin America and their relevance for a proton facility*

The LAC region encompasses 33 countries and 15 dependencies or territories with a total population of 646 million in 2019. [9] With a combined gross domestic product (GDP) of United States dollars (USD) 5.7 trillion, LAC is a region of growing importance to the world economy. [10, 11] GDP per capita ranges from USD 754 in Haiti to USD 85,477 in the Cayman Islands. Haiti is considered the only low-income country in the region; 7%, 49% and 41% are considered lower-middle-, upper-middle- and high-income countries, respectively. [12] According to Bishr

et al., there is a total of 593 RT centers in 28 countries, with up to 983 megavoltage machines, of which 23.9% are telecobalt machines. Twelve countries (30%), containing 2% of the LAC population (estimated population of 12.5 million), lack RT facilities. [13]

Although the number of needed radiotherapy machines varies between reports and despite underestimation due to lack of cancer registries, the overall conclusion is that around 50% of cases requiring radiotherapy in LMIC never receive treatment, and this goes up to 90% in low-income countries. [7] Additionally, the economic burden of lost productivity due to morbidity and premature death from cancer accounts for nearly 60% of the total economic burden associated with cancer in European Union countries. [14]

#### *2.1.2 Pediatric tumors in Latin America and their relevance for a proton facility*

Although pediatric cancers represent 10–13% of patients treated with PBT in the US, PBT has proven clinical applications, especially for pediatric brain tumors since important toxicities such as growth deficiencies, hearing loss, intelligence quotient impairment, learning disabilities and secondary malignant neoplasms will potentially be avoided in childhood survivors. Among potential tumors treated with PBT, medulloblastoma and other pediatric central nervous system (CNS) malignancies in people under 21 are highly prevalent in LAC. LMIC countries have younger populations; for example, according to UNICEF, there are over 193 million minors registered in LAC. [15] Therefore, the expected number of children with cancer is larger. It is estimated that around 84% of childhood cancer occurs in these countries, simply because nearly 90% of the world's children population lives in LMIC. Moreover, 45% suffer from child poverty, which limits their access to RT.

GLOBOCAN estimates the incidence of childhood cancer varies between 50 and 200 cases per million children each year in different LMIC. However, this data is not reliable due to many undiagnosed childhood cancers, especially in rural areas of LAC, where diagnostic tools, such as MRI or even CT scanning, are not available [16]. Under-recording is another main issue since LMIC have weaker epidemiology networks and death certificates may be incomplete or absent. All of these factors contribute to inaccurate data.

Childhood cancer survival rates vary widely by region, particularly in LMIC, where lack of access to diagnoses is just the tip of the iceberg. Access to optimal treatments is often limited to private and selected tertiary public institutions. These out-of-pocket expenditures are often prohibitive for most of the LMIC population and, among many other factors, are essential components for this foreboding result. A simulation-based analysis for global childhood cancer survival estimates shows large variation by region, ranging from 8.1% (4.4–13.7) in low-income countries in Eastern Africa to 83% in high-income countries in North America, placing Latin America central nervous system cancer survival estimates at around 50%. [17]

#### *2.1.3 Advantages and limitations of PBT*

PBT has been used for almost seven decades. Even so, indications of PBT for cancer treatment have had an alarmingly slow development, often being displaced by other radiotherapy techniques, such as stereotactic body RT (SBRT) or intensitymodulated RT (IMRT) /volumetric arc therapy (VMAT). PBT has an important and undeniable radiobiological advantage over SBRT and VMAT techniques, [18] since it significantly reduces the absorbed dose by normal tissue and lowers whole body integral radiation doses due to the requirement of fewer treatment fields, [14, 19] which means there is overall less acute and late toxicity. This has been

**69**

*Proton Therapy in Lower-Middle-Income Countries: From Facts and Reality to Desire…*

otherwise would not be optimal candidates for photon therapy. [2]

lack of investment, not a limitation of PBT per se. [20]

*2.1.4 Realities of radiotherapy attainability in Latin America and/or Mexico*

country or the whole LAC region for patient recruitment and referral.

ongoing PBT project running in Buenos Aires, Argentina.

Starting a PBT center is an enormous challenge and many variables should be accounted for, not only the obvious limitations such as economic capabilities and preexisting infrastructure. But also more subjective and complex variables, such as amenable workforce, solid governmental facilities for diagnosis and oncologic treatment like a national cancer institute, national and international private sector funding, and an organized radiation oncologist society committed to and involved in providing all necessary means for a comprehensive workforce network across the

Viability of a PBT center is only possible if a continuous flow of patients is guaranteed, either from locoregional cases or from a referral-based system, and this can only be done by few LAC countries. Based on published information about current demographics, radiotherapy capabilities and diagnostic workup auxiliaries, this might only be possible in few countries. Economic capabilities are fundamental for such type of investment. Even with international support, only cities with a high population and GDP should be considered. **Table 1** ranks the 5 top cities by population and GDP amenable for any PBT projects. As stated before, there is already an

It is estimated that two thirds of cancer-related deaths will occur in LMIC and treatment related-morbidity and mortality cause an enormous economic burden, especially in developing countries. Taking into account a PBT center is projected to start soon in Argentina, geographic location, gross domestic income, RT capabilities and diagnostic auxiliary tools available, a following PBT center could be feasible in Mexico. Particularly in the metropolitan area, where most oncology centers in the country are located. Mexico is currently the 14th most powerful world economy and 11th in purchasing power parity, second biggest economy in LAC and 4th in the continent, and is currently classified as an upper-middle-income country with a median age of 28 years old, 7.3% of its population being 65 years or older. [12, 21] Mexico is an exceptionally young country for its economic capabilities, with an incidence of childhood and teenage cancer of 89.6 per million inhabitants (111.4 in children aged 0–9 and 68.1 for teenagers aged 10–18) in 2017 and a prevalence of 18,000 annual

proven in multiple clinical trials, particularly in pediatric cancer and specific adult malignancies (skull base, head and neck, hepatocellular, central nervous system, breast, lung, prostate, testicular and ocular tumors), among other fewer common scenarios, such as reirradiation, where it allows for dose escalation in patients who

Challenges for investment in particle therapy treatment centers reported by the European Investment Bank can be summarized in a) PBT is currently indicated for only a small number of cancers; b) treatment is very costly and time consuming; c) geographic coverage; d) limited research activity. Main issues for project implementation include a) delays and problems with technology specifications and certification; b) overflow of patients seeking treatment and over-optimistic workload; c) unclear rates and reimbursement schemes; d) unmet business plan and revenue expectations; e) limited number of trained human resources. Surprisingly, limitations for PBT are mainly economical, not only because of the high initial investment but also due to the yearly increases in the cost of cancer care, often above inflation rates. This raises the concern that a PBT facility that was once sustainable will not be so in the future due to operational costs, quality assurance, maintenance and continuous training and/or medical education. Lack of high-quality clinical data on outcome and long-term toxicity for PBT contributes to mistrust, but this is a symptom that reflects

*DOI: http://dx.doi.org/10.5772/intechopen.95984*

#### *Proton Therapy in Lower-Middle-Income Countries: From Facts and Reality to Desire… DOI: http://dx.doi.org/10.5772/intechopen.95984*

proven in multiple clinical trials, particularly in pediatric cancer and specific adult malignancies (skull base, head and neck, hepatocellular, central nervous system, breast, lung, prostate, testicular and ocular tumors), among other fewer common scenarios, such as reirradiation, where it allows for dose escalation in patients who otherwise would not be optimal candidates for photon therapy. [2]

Challenges for investment in particle therapy treatment centers reported by the European Investment Bank can be summarized in a) PBT is currently indicated for only a small number of cancers; b) treatment is very costly and time consuming; c) geographic coverage; d) limited research activity. Main issues for project implementation include a) delays and problems with technology specifications and certification; b) overflow of patients seeking treatment and over-optimistic workload; c) unclear rates and reimbursement schemes; d) unmet business plan and revenue expectations; e) limited number of trained human resources. Surprisingly, limitations for PBT are mainly economical, not only because of the high initial investment but also due to the yearly increases in the cost of cancer care, often above inflation rates. This raises the concern that a PBT facility that was once sustainable will not be so in the future due to operational costs, quality assurance, maintenance and continuous training and/or medical education. Lack of high-quality clinical data on outcome and long-term toxicity for PBT contributes to mistrust, but this is a symptom that reflects lack of investment, not a limitation of PBT per se. [20]

#### *2.1.4 Realities of radiotherapy attainability in Latin America and/or Mexico*

Starting a PBT center is an enormous challenge and many variables should be accounted for, not only the obvious limitations such as economic capabilities and preexisting infrastructure. But also more subjective and complex variables, such as amenable workforce, solid governmental facilities for diagnosis and oncologic treatment like a national cancer institute, national and international private sector funding, and an organized radiation oncologist society committed to and involved in providing all necessary means for a comprehensive workforce network across the country or the whole LAC region for patient recruitment and referral.

Viability of a PBT center is only possible if a continuous flow of patients is guaranteed, either from locoregional cases or from a referral-based system, and this can only be done by few LAC countries. Based on published information about current demographics, radiotherapy capabilities and diagnostic workup auxiliaries, this might only be possible in few countries. Economic capabilities are fundamental for such type of investment. Even with international support, only cities with a high population and GDP should be considered. **Table 1** ranks the 5 top cities by population and GDP amenable for any PBT projects. As stated before, there is already an ongoing PBT project running in Buenos Aires, Argentina.

It is estimated that two thirds of cancer-related deaths will occur in LMIC and treatment related-morbidity and mortality cause an enormous economic burden, especially in developing countries. Taking into account a PBT center is projected to start soon in Argentina, geographic location, gross domestic income, RT capabilities and diagnostic auxiliary tools available, a following PBT center could be feasible in Mexico. Particularly in the metropolitan area, where most oncology centers in the country are located. Mexico is currently the 14th most powerful world economy and 11th in purchasing power parity, second biggest economy in LAC and 4th in the continent, and is currently classified as an upper-middle-income country with a median age of 28 years old, 7.3% of its population being 65 years or older. [12, 21] Mexico is an exceptionally young country for its economic capabilities, with an incidence of childhood and teenage cancer of 89.6 per million inhabitants (111.4 in children aged 0–9 and 68.1 for teenagers aged 10–18) in 2017 and a prevalence of 18,000 annual

*Proton Therapy - Current Status and Future Directions*

RT facilities. [13]

in European Union countries. [14]

contribute to inaccurate data.

*2.1.3 Advantages and limitations of PBT*

et al., there is a total of 593 RT centers in 28 countries, with up to 983 megavoltage machines, of which 23.9% are telecobalt machines. Twelve countries (30%), containing 2% of the LAC population (estimated population of 12.5 million), lack

*2.1.2 Pediatric tumors in Latin America and their relevance for a proton facility*

Moreover, 45% suffer from child poverty, which limits their access to RT.

GLOBOCAN estimates the incidence of childhood cancer varies between 50 and 200 cases per million children each year in different LMIC. However, this data is not reliable due to many undiagnosed childhood cancers, especially in rural areas of LAC, where diagnostic tools, such as MRI or even CT scanning, are not available [16]. Under-recording is another main issue since LMIC have weaker epidemiology networks and death certificates may be incomplete or absent. All of these factors

Childhood cancer survival rates vary widely by region, particularly in LMIC, where lack of access to diagnoses is just the tip of the iceberg. Access to optimal treatments is often limited to private and selected tertiary public institutions. These out-of-pocket expenditures are often prohibitive for most of the LMIC population and, among many other factors, are essential components for this foreboding result. A simulation-based analysis for global childhood cancer survival estimates shows large variation by region, ranging from 8.1% (4.4–13.7) in low-income countries in Eastern Africa to 83% in high-income countries in North America, placing Latin America central nervous system cancer survival estimates at around 50%. [17]

PBT has been used for almost seven decades. Even so, indications of PBT for cancer treatment have had an alarmingly slow development, often being displaced by other radiotherapy techniques, such as stereotactic body RT (SBRT) or intensitymodulated RT (IMRT) /volumetric arc therapy (VMAT). PBT has an important and undeniable radiobiological advantage over SBRT and VMAT techniques, [18] since it significantly reduces the absorbed dose by normal tissue and lowers whole body integral radiation doses due to the requirement of fewer treatment fields, [14, 19] which means there is overall less acute and late toxicity. This has been

Although pediatric cancers represent 10–13% of patients treated with PBT in the US, PBT has proven clinical applications, especially for pediatric brain tumors since important toxicities such as growth deficiencies, hearing loss, intelligence quotient impairment, learning disabilities and secondary malignant neoplasms will potentially be avoided in childhood survivors. Among potential tumors treated with PBT, medulloblastoma and other pediatric central nervous system (CNS) malignancies in people under 21 are highly prevalent in LAC. LMIC countries have younger populations; for example, according to UNICEF, there are over 193 million minors registered in LAC. [15] Therefore, the expected number of children with cancer is larger. It is estimated that around 84% of childhood cancer occurs in these countries, simply because nearly 90% of the world's children population lives in LMIC.

Although the number of needed radiotherapy machines varies between reports and despite underestimation due to lack of cancer registries, the overall conclusion is that around 50% of cases requiring radiotherapy in LMIC never receive treatment, and this goes up to 90% in low-income countries. [7] Additionally, the economic burden of lost productivity due to morbidity and premature death from cancer accounts for nearly 60% of the total economic burden associated with cancer

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*Abbreviations: B: billion; GDP: gross domestic product; M: million; PPP: purchasing power parity; US\$: american dollars.*

#### **Table 1.**

*Top 5 cities by population and GDP amenable for any PBT projects.* 

cases in persons under 18 years of age. [22] The estimated incidence and prevalence of all cancers was 195,499 and 530,602 in 2020, respectively. [23] A busy PBT center is feasible. Mexican radiotherapy demographics have been recently published and this information is not only crucial for any investment on PBT, but also sets a necessary precedent for adequate development.

According to the Mexican radiotherapy certification board, the country lies on an alarmingly low density of radiotherapy facilities, with a density of 1.19 linear accelerators per million inhabitants. [24] Mexico stands out because of this, since it's not only one of the few countries in LAC that could divert health expenditures to a PBT project, but it also currently has an enormous need for radiotherapy facilities. The need for RT centers is huge and will rise in the following years in conjunction with the increasing age of its population and the number of pediatric cancer patients requiring RT (due to its high pediatric population).

#### **2.2 Challenges**

#### *2.2.1 Cost evaluation*

Van Dyk (2017) evaluated the annual cost of 4 fully independent centers with two linear accelerators each. They reported that capital costs, operational costs per year and cost per treatment course in high-income countries (HIC) are approximately \$41,175,000, \$18,309,00 and \$5,350, respectively; whereas for LMIC, it's \$32,035,000, \$6,911,000 and \$2,020, respectively. [25] In 2003, Goiten estimated that particle therapy was about 2.4 times more expensive than most sophisticated RT techniques, and that this could be reduced to 1.7–2.1 over a decade. [26] The investment costs are estimated to be about 140 million euros or 150–200 million dollars for a 4 to 5-room PBT facility and 40 million for a single-room center, which represent a more affordable option even for high-income countries [26, 27]. The former represents a small, but important, fraction of Mexico's health expenditure (which is approximately 31,700 million USD in 2020) [28].

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treatment machines.

*Proton Therapy in Lower-Middle-Income Countries: From Facts and Reality to Desire…*

Lifespan of a PBT facility should also be considered. Although the cost of a 4- or 5-room PBT center can reach several hundred million dollars, a large portion of the cost is attributable to the cyclotron or synchrotron and the huge rotational gantries with a lifespan of more than 30 years. Which is significantly longer than the 7-year average lifespan of a linear accelerator. The direct cost of a modern 4-gantry PBT center is similar to that of a linear accelerator facility with 16 machines over its 30-year lifespan (4 linear accelerators replaced 3 or 4 times over this period). [29]. Several US PBT centers had to accept a reference price as payment for PBT instead of no payment or coverage. In this case, payment is made based on the next most expensive alternative, which does not cover the real cost of delivering the treatment. [30] Additionally, some payers are complaining that they pay for a therapy with no clear evidence of benefit. [31] A focus only on direct up-front costs at the time of the treatment is inaccurate because the indirect costs of managing and surviving with the late adverse effects of radiotherapy could be reduced

Investment in high-cost RT facilities will also lead to an increase of the mean treatment cost; however, the cost-effectiveness of PBT may improve if the rate of patients with indications expected to benefit from this innovation increases. [32] PBT cost-effectiveness studies should include costs associated with intervention and secondary benefit comparisons. In summary, all potential costs saved from morbidity and/or mortality reduction versus all possible expenses should be considered. It is very difficult to include and assess every direct and indirect cost related to intervention. This should include construction of the PBT facilities, operational or procedural cost (personnel costs, electricity and maintenance, beam delivery time, number of patients treated). In addition, it should consider potential toxicities and their related costs, such as support medication and/or hospitalization related to RT-induced toxicities, both potentially more frequent in patients with a long life expectancy, close anatomical relationships to organs at risk (OAR), advanced tumor stage, histopathology and pre-existing comorbidities. Others factors that affect cost-effectiveness are treatment volume, treatment fields, treatment duration, total dose and fractionation. [2] A country's health system organization also influences economic cost. Since public (complete coverage versus adjusted-socioeconomical payment) and private services (with or without insurance company, and percentage of reimbursement) differ significantly in availability, reimbursement and cost, this must be considered in the analysis. And even more important is the availability of

PBT use in pediatric cancer is based on integral dose advantages of protons over photon RT. It modulates dosage to avoid OAR when the dose is high and OAR are close and with integral dose minimization. [33] Verma (2016) reported a 2.4-fold increase in initial cost of PBT versus conventional or IMRT in pediatric cancers. However, total costs of adverse effects showed an 8-fold decrease in favor of PBT. This yields a 2.6-fold reduction of overall costs in favor of PBT. [2] Currently, PBT is the most cost-effective option for several pediatric brain tumors. [34] Especially in craniospinal irradiation (CSI) with high dose boost requiring more conformation, such as in medulloblastoma, in which associated adverse effects related to radiotherapy are IQ decline, hearing loss and growth hormone deficiency. In atypical cases, such as high-grade glioma and sarcoma or retreatment of spine lesions, the doses achieved treat less normal tissue and can avoid internal OAR better. [35, 36] Other pediatric tumors suitable for PBT are intracranial and skull base tumors, spine tumors, Hodgkin Lymphoma and retreatment. As such,

*DOI: http://dx.doi.org/10.5772/intechopen.95984*

significantly or even completely with PBT. [29].

*2.2.2 Cost-effectiveness analysis and limitations*

#### *Proton Therapy in Lower-Middle-Income Countries: From Facts and Reality to Desire… DOI: http://dx.doi.org/10.5772/intechopen.95984*

Lifespan of a PBT facility should also be considered. Although the cost of a 4- or 5-room PBT center can reach several hundred million dollars, a large portion of the cost is attributable to the cyclotron or synchrotron and the huge rotational gantries with a lifespan of more than 30 years. Which is significantly longer than the 7-year average lifespan of a linear accelerator. The direct cost of a modern 4-gantry PBT center is similar to that of a linear accelerator facility with 16 machines over its 30-year lifespan (4 linear accelerators replaced 3 or 4 times over this period). [29].

Several US PBT centers had to accept a reference price as payment for PBT instead of no payment or coverage. In this case, payment is made based on the next most expensive alternative, which does not cover the real cost of delivering the treatment. [30] Additionally, some payers are complaining that they pay for a therapy with no clear evidence of benefit. [31] A focus only on direct up-front costs at the time of the treatment is inaccurate because the indirect costs of managing and surviving with the late adverse effects of radiotherapy could be reduced significantly or even completely with PBT. [29].

#### *2.2.2 Cost-effectiveness analysis and limitations*

Investment in high-cost RT facilities will also lead to an increase of the mean treatment cost; however, the cost-effectiveness of PBT may improve if the rate of patients with indications expected to benefit from this innovation increases. [32] PBT cost-effectiveness studies should include costs associated with intervention and secondary benefit comparisons. In summary, all potential costs saved from morbidity and/or mortality reduction versus all possible expenses should be considered. It is very difficult to include and assess every direct and indirect cost related to intervention. This should include construction of the PBT facilities, operational or procedural cost (personnel costs, electricity and maintenance, beam delivery time, number of patients treated). In addition, it should consider potential toxicities and their related costs, such as support medication and/or hospitalization related to RT-induced toxicities, both potentially more frequent in patients with a long life expectancy, close anatomical relationships to organs at risk (OAR), advanced tumor stage, histopathology and pre-existing comorbidities. Others factors that affect cost-effectiveness are treatment volume, treatment fields, treatment duration, total dose and fractionation. [2] A country's health system organization also influences economic cost. Since public (complete coverage versus adjusted-socioeconomical payment) and private services (with or without insurance company, and percentage of reimbursement) differ significantly in availability, reimbursement and cost, this must be considered in the analysis. And even more important is the availability of treatment machines.

PBT use in pediatric cancer is based on integral dose advantages of protons over photon RT. It modulates dosage to avoid OAR when the dose is high and OAR are close and with integral dose minimization. [33] Verma (2016) reported a 2.4-fold increase in initial cost of PBT versus conventional or IMRT in pediatric cancers. However, total costs of adverse effects showed an 8-fold decrease in favor of PBT. This yields a 2.6-fold reduction of overall costs in favor of PBT. [2] Currently, PBT is the most cost-effective option for several pediatric brain tumors. [34] Especially in craniospinal irradiation (CSI) with high dose boost requiring more conformation, such as in medulloblastoma, in which associated adverse effects related to radiotherapy are IQ decline, hearing loss and growth hormone deficiency. In atypical cases, such as high-grade glioma and sarcoma or retreatment of spine lesions, the doses achieved treat less normal tissue and can avoid internal OAR better. [35, 36] Other pediatric tumors suitable for PBT are intracranial and skull base tumors, spine tumors, Hodgkin Lymphoma and retreatment. As such,

*Proton Therapy - Current Status and Future Directions*

**millions**

1 Brazil 3,078,901 14,562 Sao Paulo US\$

2 Mexico 2,424,511 18,804 Mexico city US\$

3 Argentina 924,539 20,369 Buenos Aires US\$ 118

4 Colombia 719,251 14,136 Bogota

5 Chile 456,394 23,454 Santiago

**GDP (PPP) per capita**

**Highest GDP (city)**

> 699.2 B (2017)

411 B (2011)

B (2008)

US\$ 221.7 B (2016)

US\$ 175 B (2014)

**Highest population (city)**

Sao Paulo 21.3 M (2015)

Mexico city 8.85 M (2015)

Buenos Aires 2.8 M (2010)

> Bogota 8.08 M (2017)

Santiago 7.3 M (2015)

**Rank Country GDP (PPP) in** 

sary precedent for adequate development.

*Top 5 cities by population and GDP amenable for any PBT projects.* 

patients requiring RT (due to its high pediatric population).

(which is approximately 31,700 million USD in 2020) [28].

cases in persons under 18 years of age. [22] The estimated incidence and prevalence of all cancers was 195,499 and 530,602 in 2020, respectively. [23] A busy PBT center is feasible. Mexican radiotherapy demographics have been recently published and this information is not only crucial for any investment on PBT, but also sets a neces-

*Abbreviations: B: billion; GDP: gross domestic product; M: million; PPP: purchasing power parity; US\$: american* 

According to the Mexican radiotherapy certification board, the country lies on an alarmingly low density of radiotherapy facilities, with a density of 1.19 linear accelerators per million inhabitants. [24] Mexico stands out because of this, since it's not only one of the few countries in LAC that could divert health expenditures to a PBT project, but it also currently has an enormous need for radiotherapy facilities. The need for RT centers is huge and will rise in the following years in conjunction with the increasing age of its population and the number of pediatric cancer

Van Dyk (2017) evaluated the annual cost of 4 fully independent centers with two linear accelerators each. They reported that capital costs, operational costs per year and cost per treatment course in high-income countries (HIC) are approximately \$41,175,000, \$18,309,00 and \$5,350, respectively; whereas for LMIC, it's \$32,035,000, \$6,911,000 and \$2,020, respectively. [25] In 2003, Goiten estimated that particle therapy was about 2.4 times more expensive than most sophisticated RT techniques, and that this could be reduced to 1.7–2.1 over a decade. [26] The investment costs are estimated to be about 140 million euros or 150–200 million dollars for a 4 to 5-room PBT facility and 40 million for a single-room center, which represent a more affordable option even for high-income countries [26, 27]. The former represents a small, but important, fraction of Mexico's health expenditure

**70**

**2.2 Challenges**

*dollars.*

**Table 1.**

*2.2.1 Cost evaluation*

PBT is more cost-effective for pediatric cancer due to the decrease in long-term toxicity, long life expectancy after cancer treatment and more remaining years of economic-productive life. Therefore, although the number of cancers that are cured is generally very low, treatment of curable childhood cancer is highly cost-effective. Some issues to be considered include limited data, lack of long-term follow-up and contraindications for PBT (Wilms' tumor classic fields, whole lung classic fields and palliative RT). [2] By contrast, a Brazilian patient volume-based analysis showed that PBT was not cost-effective for pediatric medulloblastoma treatment. [37].

Other outcomes that can be measured include total life-years gained or lost, and quality-adjusted life years (QALYs). [2] For pediatric brain tumor, the incremental cost-effectiveness ratio was \$21,716 to 26,419 dollars per QALY, depending on the study. [34].

In adult cases, PBT as standard treatment for breast cancer has not been shown to be cost-effective and is associated with a minimal increase in QALYs. However, specific subgroups that may benefit include patients with high-risk late cardiac toxicity, such as left-sided tumors or internal mammary node irradiation and those with double baseline risk of non-radiotherapy-related cardiac disease. [34, 38] For locoregionally advanced non-small cell lung cancer (NSCLC), PBT increased QALYs compared to conformal or IMRT, and was probably more cost-effective than for early-stage NSCLC. [34, 39, 40] In locally advanced head and neck cancer, intensity-modulated PBT (IMPT) reduces xerostomia and dysphagia rates compared to IMRT; however, cost was increased, [41] with an incremental cost-effectiveness ratio of \$4,254 to 143,229 US dollars per QALY, depending on study and radiation technique. [34] In another Chinese study, IMPT was more cost-effective and provided an extra 1.65 QALYs for paranasal sinus and nasal cavity cancers compared to IMRT. [42] For prostate cancer, PBT showed increased costs without increasing QALYs compared to IMRT; in this case, life expectancy determines cost-effectiveness. [43] However, PBT is currently not considered medically necessary for the treatment of lung, prostate, breast, gastro-esophageal, hepatocellular, head and neck, gynecologic cancer or Hodgkin and non-Hodgkin Lymphoma. [44] A review of PBT concluded that no clinical data had shown superiority over advanced RT for treatment of central nervous system lesions. It is only medically necessary for cases with adjacent structures. [45] Given the excellent long-term results with PBT, it is considered medically necessary for the treatment of base skull and sacral chordomas and chondrosarcomas, [46] and uveal melanoma due to lower local recurrence rate, retinopathy and cataract formation. [47] PBT is appropriate for reirradiation where the dose tolerance of adjacent normal structures would be exceeded with conformal or IMRT. [44].

Limitations of cost-effectiveness analyses are short-term follow-up of clinical and toxicity evidence, and lack of standard indications. Therefore, a subgroup of patients that will clinically benefit and gain most QALYs may be identified for an adequate distribution of limited access and availability of PBT facilities.

#### *2.2.3 Human resources*

As currently there are no functional PBT centers in LAC, adequate training for radiation oncologists, medical physicists, dosimetrists and radiation therapy technicians is imperative. Although this topic is popular in medical conferences and webinars, the lack of clinical experience is an issue. If a PBT center is considered for LAC, training in all levels of attention will be necessary and this represents an enormous challenge by itself since long term fellowships are required, at least for physicists and radiation oncologists. Periodic supervision from experienced

**73**

*Proton Therapy in Lower-Middle-Income Countries: From Facts and Reality to Desire…*

personal or remote assistant and continuous medical education are two alternatives

PBT project management requires planning (construction design, permits, functional set-up), implementation (regulatory frame, technical expertise during construction) and operation (treatment planning time, patient logistics, nuclear safety, business plan, financial sustainability). Current PBT facilities require a space the size of a football field. This space is unavailable at or near the main hospitals and could be highly expensive in many capital cities. Therefore, future PBT units that are smaller (single-room PBT), more efficient and less expensive (even as low as

The margins for protons are larger due to range uncertainties, which contribute

to less conformality and larger higher dose volumes that include nearest OAR. Techniques to reduce clinical-to-planning target volume (CTV-to-PTV) margin include beam-specific PTV and in-vivo range verification; however, this approach is more expensive. [50, 51] Another limitation is image guidance and adaptive radiotherapy, since this modern technology is lacking in most PBT facilities. [2] Daily reproducibility, setup and anatomical changes are important determinants of dose distribution and thus in tumor control and complications. The treatment time per fraction with proton therapy is longer than for IMRT (22 versus 14 minutes). [52] The ideal PBT facility should have daily volumetric imaging for correct patient setup and identification of anatomical changes, adaptative replanning to compensate variations and setup with respiratory motion management. [53] It is expected that advances will give rise to more compact PBT facilities (1 or 2 treatment rooms)

with volumetric image guidance and with a lower cost over time. [2].

no proven benefits compared to other modern techniques.

PBT has been approved for cancer treatment by the FDA since 1988. Uniform federal government regulations with rigorous evaluation of useful and vital versus inefficient and unworthy technology are necessary since uncontrolled and unregulated healthcare spending on new technology without adequate determination of its effectiveness will eat up funds that could be spent efficiently. It should be considered that private insurers have declined to reimburse PBT for common cancer with

Currently there are virtually no PBT centers in LMIC, and none in LAC. Disparities on PBT distribution around the globe go further than just the obvious—lack of appropriate oncological treatments to alleviate human suffering—but are partially responsible for the slow development of PBT worldwide. At present, most patients amenable for PBT treatments are in LMIC countries, and clinical trials has been halted at least partially because of a lack of recruitment. There is a negative paradox, wherein patients in need of PBT have no access to it and PBT centers around the world with all dosimetric advantages represent less than 1% of all RT treatments. However, a PBT center in any LMIC is economically unviable and requires extensive sociodemographic studies. Mexico could be a strong candidate, not only due to its geographical advantages and total population, but because of its exceptionally young population for its economical capabilities, detailed published

*DOI: http://dx.doi.org/10.5772/intechopen.95984*

*2.2.4 Technical needs and limitations*

\$30 million dollars) are expected. [49].

*2.2.5 Initial investment*

**3. Conclusions**

if intercountry fellowships are not feasible. [48].

personal or remote assistant and continuous medical education are two alternatives if intercountry fellowships are not feasible. [48].

#### *2.2.4 Technical needs and limitations*

*Proton Therapy - Current Status and Future Directions*

treatment. [37].

study. [34].

PBT is more cost-effective for pediatric cancer due to the decrease in long-term toxicity, long life expectancy after cancer treatment and more remaining years of economic-productive life. Therefore, although the number of cancers that are cured is generally very low, treatment of curable childhood cancer is highly cost-effective. Some issues to be considered include limited data, lack of long-term follow-up and contraindications for PBT (Wilms' tumor classic fields, whole lung classic fields and palliative RT). [2] By contrast, a Brazilian patient volume-based analysis showed that PBT was not cost-effective for pediatric medulloblastoma

Other outcomes that can be measured include total life-years gained or lost, and quality-adjusted life years (QALYs). [2] For pediatric brain tumor, the incremental cost-effectiveness ratio was \$21,716 to 26,419 dollars per QALY, depending on the

In adult cases, PBT as standard treatment for breast cancer has not been shown to be cost-effective and is associated with a minimal increase in QALYs. However, specific subgroups that may benefit include patients with high-risk late cardiac toxicity, such as left-sided tumors or internal mammary node irradiation and those with double baseline risk of non-radiotherapy-related cardiac disease. [34, 38] For locoregionally advanced non-small cell lung cancer (NSCLC), PBT increased QALYs compared to conformal or IMRT, and was probably more cost-effective than for early-stage NSCLC. [34, 39, 40] In locally advanced head and neck cancer, intensity-modulated PBT (IMPT) reduces xerostomia and dysphagia rates compared to IMRT; however, cost was increased, [41] with an incremental cost-effectiveness ratio of \$4,254 to 143,229 US dollars per QALY, depending on study and radiation technique. [34] In another Chinese study, IMPT was more cost-effective and provided an extra 1.65 QALYs for paranasal sinus and nasal cavity cancers compared to IMRT. [42] For prostate cancer, PBT showed increased costs without increasing QALYs compared to IMRT; in this case, life expectancy determines cost-effectiveness. [43] However, PBT is currently not considered medically necessary for the treatment of lung, prostate, breast, gastro-esophageal, hepatocellular, head and neck, gynecologic cancer or Hodgkin and non-Hodgkin Lymphoma. [44] A review of PBT concluded that no clinical data had shown superiority over advanced RT for treatment of central nervous system lesions. It is only medically necessary for cases with adjacent structures. [45] Given the excellent long-term results with PBT, it is considered medically necessary for the treatment of base skull and sacral chordomas and chondrosarcomas, [46] and uveal melanoma due to lower local recurrence rate, retinopathy and cataract formation. [47] PBT is appropriate for reirradiation where the dose tolerance of adjacent normal structures would be exceeded with

Limitations of cost-effectiveness analyses are short-term follow-up of clinical and toxicity evidence, and lack of standard indications. Therefore, a subgroup of patients that will clinically benefit and gain most QALYs may be identified for an

As currently there are no functional PBT centers in LAC, adequate training for radiation oncologists, medical physicists, dosimetrists and radiation therapy technicians is imperative. Although this topic is popular in medical conferences and webinars, the lack of clinical experience is an issue. If a PBT center is considered for LAC, training in all levels of attention will be necessary and this represents an enormous challenge by itself since long term fellowships are required, at least for physicists and radiation oncologists. Periodic supervision from experienced

adequate distribution of limited access and availability of PBT facilities.

**72**

conformal or IMRT. [44].

*2.2.3 Human resources*

PBT project management requires planning (construction design, permits, functional set-up), implementation (regulatory frame, technical expertise during construction) and operation (treatment planning time, patient logistics, nuclear safety, business plan, financial sustainability). Current PBT facilities require a space the size of a football field. This space is unavailable at or near the main hospitals and could be highly expensive in many capital cities. Therefore, future PBT units that are smaller (single-room PBT), more efficient and less expensive (even as low as \$30 million dollars) are expected. [49].

The margins for protons are larger due to range uncertainties, which contribute to less conformality and larger higher dose volumes that include nearest OAR. Techniques to reduce clinical-to-planning target volume (CTV-to-PTV) margin include beam-specific PTV and in-vivo range verification; however, this approach is more expensive. [50, 51] Another limitation is image guidance and adaptive radiotherapy, since this modern technology is lacking in most PBT facilities. [2] Daily reproducibility, setup and anatomical changes are important determinants of dose distribution and thus in tumor control and complications. The treatment time per fraction with proton therapy is longer than for IMRT (22 versus 14 minutes). [52] The ideal PBT facility should have daily volumetric imaging for correct patient setup and identification of anatomical changes, adaptative replanning to compensate variations and setup with respiratory motion management. [53] It is expected that advances will give rise to more compact PBT facilities (1 or 2 treatment rooms) with volumetric image guidance and with a lower cost over time. [2].

#### *2.2.5 Initial investment*

PBT has been approved for cancer treatment by the FDA since 1988. Uniform federal government regulations with rigorous evaluation of useful and vital versus inefficient and unworthy technology are necessary since uncontrolled and unregulated healthcare spending on new technology without adequate determination of its effectiveness will eat up funds that could be spent efficiently. It should be considered that private insurers have declined to reimburse PBT for common cancer with no proven benefits compared to other modern techniques.

#### **3. Conclusions**

Currently there are virtually no PBT centers in LMIC, and none in LAC. Disparities on PBT distribution around the globe go further than just the obvious—lack of appropriate oncological treatments to alleviate human suffering—but are partially responsible for the slow development of PBT worldwide. At present, most patients amenable for PBT treatments are in LMIC countries, and clinical trials has been halted at least partially because of a lack of recruitment. There is a negative paradox, wherein patients in need of PBT have no access to it and PBT centers around the world with all dosimetric advantages represent less than 1% of all RT treatments. However, a PBT center in any LMIC is economically unviable and requires extensive sociodemographic studies. Mexico could be a strong candidate, not only due to its geographical advantages and total population, but because of its exceptionally young population for its economical capabilities, detailed published

data on current needed access to radiotherapy and a modest but sufficient number of the required auxiliary diagnostic tools, such as PET, MRI and pathology services. Enormous efforts must be made by the private sector (national and international alike) and governmental authorities to provide funding and a comprehensive referral system for the PBT center. As stated previously, following the ALARA principle, PBT provides a clinical benefit to certain patients that is not achievable with photons.

### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Sandra Ileana Pérez Álvarez1 \*, Francisco Javier Lozano Ruiz2 , Federico Maldonado Magos1 and Aida Mota García1

1 National Cancer Institute, Mexico City, Mexico

2 Medica Sur, Mexico City, Mexico

\*Address all correspondence to: sandraileana@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**75**

*Proton Therapy in Lower-Middle-Income Countries: From Facts and Reality to Desire…*

Available from http://scioteca.caf.com/

Development Organization [Internet].

handle/123456789/1652

LAC\_Region\_0.pdf

and-the-Caribbean.pdf

[11] The World Bank Group

[Internet]. 2020. World Development Indicators. Available from: https:// databank.worldbank.org/reports. aspx?source=2&country=LCN

[12] The World Bank Group [Internet]. 2020. World Bank Country and Lending Groups. Available from: https://datahelpdesk.worldbank.org/ knowledgebase/articles/906519-worldbank-country-and-lending-groups

[13] Bishr, M. K., Zaghloul, M. S. (2018) Radiation Therapy Availability in Africa andLatin America: Two Models of Low and Middle-Income Countries. Int J Radiat Oncol Bio

[14] The economic burden of cancer [Internet]. 2020. Available from: https:// canceratlas.cancer.org/taking-action/

[15] Children in Latin America and the Caribbean. Overview 2019

[Internet]. 2019. Available from: https:// www.unicef.org/lac/media/7131/ file/PDF%20Children%20in%20 Latin%20America%20and%20the%20

Phys;102(3):490-498

economic-burden/

[9] United Nations Industrial

2015. Inclusive and Sustainable Industrial Development in Latin America and Caribbean Region. Available from: https://www.unido.org/ sites/default/files/2015-07/UNIDO\_in\_

[10] Organisation for the Economic Co-operation and Development. OECD [Internet]. 2017. Active with Latin America and the Caribbean. Available from: http://www.oecd.org/latinamerica/Active-with-Latin-America-

*DOI: http://dx.doi.org/10.5772/intechopen.95984*

[1] Levitt SH, Leer JW. The role of radiotherapy in Swedenda landmark study by the Swedish Council on Technology Assessment in Health Care.

[2] Verma V., Shah C., Rwigen J-C. M., Solberg T., Zhu X., Simone II C.B. Cost-comparativeness of proton versus photon therapy. Chin Clin Oncol

[3] UBA New Technologies Cancer Treatment Center [Internet]. 2020. Available from: https://www.ibaasiapacific.com/zh-hans/node/2511

[4] IAEA DIRAC Directory of RAdiotherapy Centres. Status of Radiation Therapy Equipment

the-caribbean-population/

10.1016/j.clon.2016.11.011

[8] Álvarez F., Brassiolo P.,

Toledo M., Allub L., Alves G., De la Mata D. [Internet]. 2020. RED 2020: Los sistemas de pensiones y salud en América Latina. Los desafíos del envejecimiento, el cambio tecnológico y la informalidad. Caracas: CAF.

[Internet]. 2020. Available from: https:// dirac.iaea.org/Query/Map2?mapId=2

[5] Latin America and the Caribbean Population [Internet]. 2020. Available from: https://www.worldometers.info/ world-population/latin-america-and-

[6] Gonzales, Selena, Cox, Cynthia. What are recent trends in cancer spending and outcomes? [Internet]. 2016. Available from: https://www. healthsystemtracker.org/chartcollection/recent-trends-cancerspending-outcomes/#item-start

[7] Zubizarreta E., Van Dyk J., Lievens Y. Analysis of Global Radiotherapy Needs and Costs by Geographic Region and Income Level. Clin Oncol (R Coll Radiol) 2017;29(2):84-92. DOI:

Acta Oncol 1996;35:965-966

**References**

2016;5(4):56-65

*Proton Therapy in Lower-Middle-Income Countries: From Facts and Reality to Desire… DOI: http://dx.doi.org/10.5772/intechopen.95984*

#### **References**

*Proton Therapy - Current Status and Future Directions*

The authors declare no conflict of interest.

data on current needed access to radiotherapy and a modest but sufficient number of the required auxiliary diagnostic tools, such as PET, MRI and pathology services. Enormous efforts must be made by the private sector (national and international alike) and governmental authorities to provide funding and a comprehensive referral system for the PBT center. As stated previously, following the ALARA principle, PBT provides a clinical benefit to certain patients that is not achievable

**74**

**Author details**

with photons.

**Conflict of interest**

Sandra Ileana Pérez Álvarez1

Federico Maldonado Magos1

2 Medica Sur, Mexico City, Mexico

provided the original work is properly cited.

1 National Cancer Institute, Mexico City, Mexico

\*Address all correspondence to: sandraileana@gmail.com

\*, Francisco Javier Lozano Ruiz2

and Aida Mota García1

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

,

[1] Levitt SH, Leer JW. The role of radiotherapy in Swedenda landmark study by the Swedish Council on Technology Assessment in Health Care. Acta Oncol 1996;35:965-966

[2] Verma V., Shah C., Rwigen J-C. M., Solberg T., Zhu X., Simone II C.B. Cost-comparativeness of proton versus photon therapy. Chin Clin Oncol 2016;5(4):56-65

[3] UBA New Technologies Cancer Treatment Center [Internet]. 2020. Available from: https://www.ibaasiapacific.com/zh-hans/node/2511

[4] IAEA DIRAC Directory of RAdiotherapy Centres. Status of Radiation Therapy Equipment [Internet]. 2020. Available from: https:// dirac.iaea.org/Query/Map2?mapId=2

[5] Latin America and the Caribbean Population [Internet]. 2020. Available from: https://www.worldometers.info/ world-population/latin-america-andthe-caribbean-population/

[6] Gonzales, Selena, Cox, Cynthia. What are recent trends in cancer spending and outcomes? [Internet]. 2016. Available from: https://www. healthsystemtracker.org/chartcollection/recent-trends-cancerspending-outcomes/#item-start

[7] Zubizarreta E., Van Dyk J., Lievens Y. Analysis of Global Radiotherapy Needs and Costs by Geographic Region and Income Level. Clin Oncol (R Coll Radiol) 2017;29(2):84-92. DOI: 10.1016/j.clon.2016.11.011

[8] Álvarez F., Brassiolo P., Toledo M., Allub L., Alves G., De la Mata D. [Internet]. 2020. RED 2020: Los sistemas de pensiones y salud en América Latina. Los desafíos del envejecimiento, el cambio tecnológico y la informalidad. Caracas: CAF.

Available from http://scioteca.caf.com/ handle/123456789/1652

[9] United Nations Industrial Development Organization [Internet]. 2015. Inclusive and Sustainable Industrial Development in Latin America and Caribbean Region. Available from: https://www.unido.org/ sites/default/files/2015-07/UNIDO\_in\_ LAC\_Region\_0.pdf

[10] Organisation for the Economic Co-operation and Development. OECD [Internet]. 2017. Active with Latin America and the Caribbean. Available from: http://www.oecd.org/latinamerica/Active-with-Latin-Americaand-the-Caribbean.pdf

[11] The World Bank Group [Internet]. 2020. World Development Indicators. Available from: https:// databank.worldbank.org/reports. aspx?source=2&country=LCN

[12] The World Bank Group [Internet]. 2020. World Bank Country and Lending Groups. Available from: https://datahelpdesk.worldbank.org/ knowledgebase/articles/906519-worldbank-country-and-lending-groups

[13] Bishr, M. K., Zaghloul, M. S. (2018) Radiation Therapy Availability in Africa andLatin America: Two Models of Low and Middle-Income Countries. Int J Radiat Oncol Bio Phys;102(3):490-498

[14] The economic burden of cancer [Internet]. 2020. Available from: https:// canceratlas.cancer.org/taking-action/ economic-burden/

[15] Children in Latin America and the Caribbean. Overview 2019 [Internet]. 2019. Available from: https:// www.unicef.org/lac/media/7131/ file/PDF%20Children%20in%20 Latin%20America%20and%20the%20

Caribbean%20-%20Overview%20 2019.pdf

[16] Howard SC, Metzger ML, Wilimas JA, et al. Childhood cancer epidemiology in low-income countries. Cancer 2008; 112: 461-72.

[17] Ward ZJ, Yeh JM, Bhakta N, Frazier AL, Girardi F, Atun R. Global childhood cancer survival estimates and priority-setting: a simulationbased analysis. Lancet Oncol 2019;20(7):972-983.

[18] Uhl M, Herfarth K, Debus J. Comparing the use of protons and carbon ions for treatment. Cancer J 2014;20:433-9.

[19] Jones B. (2017). Proton radiobiology and its clinical implications. ecancer 11;777

[20] Goossens M. E., Van den Bulcke M., Gevaert T., Meheus L., Verellen D., et al. (2019). Is there any benefit to particles over photon radiotherapy? ecancer; 13:982.

[21] INEGI. Datos epidemiológicos [Internet]. 2019. Available from: https://www.gob.mx/cms/uploads/ attachment/file/520501/LSDM2019\_ OK\_23DIC19.pdf

[22] Programa sectorial de salud [Internet]. 2014. Programa de acción específico. Cáncer en la infancia y la adolescencia 2013-2018. Available from http://www.censia.salud.gob.mx/ contenidos/descargas/transparencia/ especiales/PAE\_Cancer.pdf

[23] World Health Organization [Internet]. 2020. Cancer today. International Atomy for Research on Cancer. Available from https://gco.iarc. fr/today/home

[24] Maldonado Magos F., Lozano Ruiz F. J., Pérez Álvarez S. I., Garay Villar O., Cárdenas Pérez C, et al.

(2020). Radiation oncology in Mexico: Current status according to Mexico's Radiation Oncology Certification Board. Reports of Radiation Oncology & Radiotherapy;25(5):840-845

[25] Van Dyk J., Zubizarreta E., Lievens Y. (2017). Cost evaluation to optimise radiation therapy implementation in different income settings: A time-driven activity-based analysis. Radiother Oncol 125:178-185.

[26] Goiten M. Jermann M. (2003) The relative costs of proton and X-ray radiation therapy. Clinical Oncol 15:S37-S50

[27] Kerstiens J., Johnstone G. P., Johnstone P. A. (2018). Proton Facility Economics: Single-Room Centers. J Am Coll Radiol

[28] Dirección General de Finanzas [Internet]. 2019. Recursos destinados al Sector Salud en el Proyecto de Presupuesto de Egresos de la Federación 2020. Available from: http://bibliodigitalibd.senado.gob.mx/ bitstream/handle/123456789/4685/1%20 Publicación%20Sector%20Salud\_2020. pdf?sequence=1&isAllowed=y

[29] Salama J. K., Willet C. G. (2014). Is proton beam theray better than standard radiation therapy? A paucity of practicality puts photons ahead of protons. Clinical Advances in Hematology & Oncology 12(2):861-868.

[30] Bekelman JE, Hahn SM. (2014). Reference pricing with evidence development: a way forward for proton therapy. J Clin Oncol;32:1540-1542.

[31] Zietman A. L. (2018). Too Big to Fail? The Current Status of Proton Therapy in the USA. Clinical Oncol 30:271-273.

[32] Pommier P., Lievens Y., Feschet F., Borras J. M., Baron M. H., et al. (2010) Simulating demand for innovative

**77**

*Proton Therapy in Lower-Middle-Income Countries: From Facts and Reality to Desire…*

a cost-effective alternative to photon radiotherapy in Belgium? J Thorac

[41] Ramaekers BL, Grutters JP, Pijls-Johannesma M, et al. Protons in head-and-neck cancer: bridging the gap of evidence. Int J Radiat Oncol Biol Phys

[42] Li G., Qiu B., Huang Y-X, Doyen J., Bondiau P-Y, et al. Bekelman JE, Hahn SM. (2014). Reference pricing with evidence development: a way forward for proton therapy. J Clin Oncol;32:1540-1542.

[43] Yu JB, Soulos PR, Herrin J, et al. Proton versus intensity- modulated radiotherapy for prostate cancer: patterns of care and early toxicity. J Natl

[44] AIM Specialty Health. (2018). Clinical Appropriateness Guidelines: Radiation Oncology. Proton Beam

[45] Combs SE. Does proton therapy have a future in CNS tumors? Curr Treat

Pedlow FX, et al. Long-term results of Phase II study of high dose photon/ proton radiotherapy in the management of spine chordomas, chondrosarcomas, and other sarcomas. J Surg Oncol.

[47] Wang Z, Nabhan M, Schild SE, et al. Charged particle radiation therapy for uveal melanoma: a systematic review and meta-analysis. Int J Radiat Oncol

Options Neurol. 2017;19(3):12.

[46] DeLaney TF, Liebsch NJ,

Cancer Inst 2013;105:25-32.

Therapy Guidelines.

2014;110(2):115-22.

Biol Phys. 2013;86(1):18-26.

action. Luxembourg.

[48] Subgroup on Proton Therapy. (2018). EIB support to investments in proton therapy: Key issues and proposed

[49] Klein AA, Bradley J. (2016). Singleroom proton radiation therapy systems:

Oncol 2013;8:S839-40.

2013;85:1282-8.

*DOI: http://dx.doi.org/10.5772/intechopen.95984*

radiotherapies: an illustrative model based on carbon ion and proton radiotherapy.

[33] Buchsbaum J. C. (2015). Pediatric proton therapy in 2015: Indications, applications and considerations. Applied Radiation Oncology:4-11

Mehta M. P. (2016) A Systematic Review of the Cost and Cost-Effectiveness Studies of Proton Radiotherapy. Cancer;122(10):1483-501.

Radiother Oncol 96(2):243-249.

[34] Verma V., Mishra M. V.,

[35] Pediatric proton therapy in 2015: Indications, applications and considerations. Applied Radiation

[36] Hirano E, Fuji H, Onoe T,

Kumar V, Shirato H, Kawabuchi K. Costeffectiveness analysis of cochlear dose reduction by proton beam therapy for medulloblastoma in childhood. J Radiat Res (Tokyo). 2014;55(2):320-327.

[37] Alves Fernandes R. R., de Mello Vianna C. M., Leborato Guerra R., de Camargo Cancela M., de Almeida L. M. (2019). Cost-Effectiveness of Proton Versus Photon Therapy in Pediatric Medulloblastoma Treatment: A Patient Volume-Based Analysis. Value in Health

[38] Lundkvist J, Ekman M, Ericsson SR, et al. Economic evaluation of proton radiation therapy in the treatment of breast cancer. Radiother Oncol

[39] Grutters JP, Pijls-Johannesma M, Ruysscher DD, et al. The costeffectiveness of particle therapy in non-small cell lung cancer: exploring decision uncertainty and areas for future research. Cancer Treat Rev

[40] Lievens Y, Verhaeghe N, De Neve W, et al. Proton radiotherapy for locallyadvanced non-small cell lung cancer,

Regional;20:122-128.

2005;75:179-85.

2010;36:468-76.

Oncology:4-11.

*Proton Therapy in Lower-Middle-Income Countries: From Facts and Reality to Desire… DOI: http://dx.doi.org/10.5772/intechopen.95984*

radiotherapies: an illustrative model based on carbon ion and proton radiotherapy. Radiother Oncol 96(2):243-249.

*Proton Therapy - Current Status and Future Directions*

(2020). Radiation oncology in Mexico: Current status according to Mexico's Radiation Oncology Certification Board. Reports of Radiation Oncology & Radiotherapy;25(5):840-845

[25] Van Dyk J., Zubizarreta E., Lievens Y. (2017). Cost evaluation to optimise radiation therapy implementation in different income settings: A time-driven activity-based analysis. Radiother Oncol 125:178-185.

[26] Goiten M. Jermann M. (2003) The relative costs of proton and X-ray radiation therapy. Clinical Oncol

[27] Kerstiens J., Johnstone G. P., Johnstone P. A. (2018). Proton Facility Economics: Single-Room Centers. J Am

[28] Dirección General de Finanzas [Internet]. 2019. Recursos destinados

al Sector Salud en el Proyecto de Presupuesto de Egresos de la Federación 2020. Available from: http://bibliodigitalibd.senado.gob.mx/ bitstream/handle/123456789/4685/1%20 Publicación%20Sector%20Salud\_2020.

pdf?sequence=1&isAllowed=y

[29] Salama J. K., Willet C. G. (2014). Is proton beam theray better than standard radiation therapy? A paucity of practicality puts photons ahead of protons. Clinical Advances in

Hematology & Oncology 12(2):861-868.

[30] Bekelman JE, Hahn SM. (2014). Reference pricing with evidence development: a way forward for proton therapy. J Clin Oncol;32:1540-1542.

[31] Zietman A. L. (2018). Too Big to Fail? The Current Status of Proton Therapy in the USA. Clinical Oncol

[32] Pommier P., Lievens Y., Feschet F., Borras J. M., Baron M. H., et al. (2010) Simulating demand for innovative

30:271-273.

15:S37-S50

Coll Radiol

Caribbean%20-%20Overview%20

[16] Howard SC, Metzger ML, Wilimas JA, et al. Childhood cancer epidemiology in low-income countries.

[17] Ward ZJ, Yeh JM, Bhakta N, Frazier AL, Girardi F, Atun R. Global childhood cancer survival estimates and priority-setting: a simulationbased analysis. Lancet Oncol

Debus J. Comparing the use of protons and carbon ions for treatment. Cancer J

[19] Jones B. (2017). Proton radiobiology

[20] Goossens M. E., Van den Bulcke M., Gevaert T., Meheus L., Verellen D., et al. (2019). Is there any benefit to particles over photon radiotherapy?

[21] INEGI. Datos epidemiológicos [Internet]. 2019. Available from: https://www.gob.mx/cms/uploads/ attachment/file/520501/LSDM2019\_

[22] Programa sectorial de salud [Internet]. 2014. Programa de acción específico. Cáncer en la infancia y la adolescencia 2013-2018. Available from http://www.censia.salud.gob.mx/ contenidos/descargas/transparencia/

especiales/PAE\_Cancer.pdf

[23] World Health Organization [Internet]. 2020. Cancer today. International Atomy for Research on Cancer. Available from https://gco.iarc.

[24] Maldonado Magos F., Lozano Ruiz F. J., Pérez Álvarez S. I., Garay Villar O., Cárdenas Pérez C, et al.

Cancer 2008; 112: 461-72.

2019;20(7):972-983.

2014;20:433-9.

ecancer 11;777

ecancer; 13:982.

OK\_23DIC19.pdf

fr/today/home

[18] Uhl M, Herfarth K,

and its clinical implications.

2019.pdf

**76**

[33] Buchsbaum J. C. (2015). Pediatric proton therapy in 2015: Indications, applications and considerations. Applied Radiation Oncology:4-11

[34] Verma V., Mishra M. V., Mehta M. P. (2016) A Systematic Review of the Cost and Cost-Effectiveness Studies of Proton Radiotherapy. Cancer;122(10):1483-501.

[35] Pediatric proton therapy in 2015: Indications, applications and considerations. Applied Radiation Oncology:4-11.

[36] Hirano E, Fuji H, Onoe T, Kumar V, Shirato H, Kawabuchi K. Costeffectiveness analysis of cochlear dose reduction by proton beam therapy for medulloblastoma in childhood. J Radiat Res (Tokyo). 2014;55(2):320-327.

[37] Alves Fernandes R. R., de Mello Vianna C. M., Leborato Guerra R., de Camargo Cancela M., de Almeida L. M. (2019). Cost-Effectiveness of Proton Versus Photon Therapy in Pediatric Medulloblastoma Treatment: A Patient Volume-Based Analysis. Value in Health Regional;20:122-128.

[38] Lundkvist J, Ekman M, Ericsson SR, et al. Economic evaluation of proton radiation therapy in the treatment of breast cancer. Radiother Oncol 2005;75:179-85.

[39] Grutters JP, Pijls-Johannesma M, Ruysscher DD, et al. The costeffectiveness of particle therapy in non-small cell lung cancer: exploring decision uncertainty and areas for future research. Cancer Treat Rev 2010;36:468-76.

[40] Lievens Y, Verhaeghe N, De Neve W, et al. Proton radiotherapy for locallyadvanced non-small cell lung cancer,

a cost-effective alternative to photon radiotherapy in Belgium? J Thorac Oncol 2013;8:S839-40.

[41] Ramaekers BL, Grutters JP, Pijls-Johannesma M, et al. Protons in head-and-neck cancer: bridging the gap of evidence. Int J Radiat Oncol Biol Phys 2013;85:1282-8.

[42] Li G., Qiu B., Huang Y-X, Doyen J., Bondiau P-Y, et al. Bekelman JE, Hahn SM. (2014). Reference pricing with evidence development: a way forward for proton therapy. J Clin Oncol;32:1540-1542.

[43] Yu JB, Soulos PR, Herrin J, et al. Proton versus intensity- modulated radiotherapy for prostate cancer: patterns of care and early toxicity. J Natl Cancer Inst 2013;105:25-32.

[44] AIM Specialty Health. (2018). Clinical Appropriateness Guidelines: Radiation Oncology. Proton Beam Therapy Guidelines.

[45] Combs SE. Does proton therapy have a future in CNS tumors? Curr Treat Options Neurol. 2017;19(3):12.

[46] DeLaney TF, Liebsch NJ, Pedlow FX, et al. Long-term results of Phase II study of high dose photon/ proton radiotherapy in the management of spine chordomas, chondrosarcomas, and other sarcomas. J Surg Oncol. 2014;110(2):115-22.

[47] Wang Z, Nabhan M, Schild SE, et al. Charged particle radiation therapy for uveal melanoma: a systematic review and meta-analysis. Int J Radiat Oncol Biol Phys. 2013;86(1):18-26.

[48] Subgroup on Proton Therapy. (2018). EIB support to investments in proton therapy: Key issues and proposed action. Luxembourg.

[49] Klein AA, Bradley J. (2016). Singleroom proton radiation therapy systems: no small change. Int J Radiat Oncol Biol Phys;95:147-148.

[50] Park PC, Zhu XR, Lee AK, et al. A beam-specific planning target volume (PTV) design for proton therapy to account for setup and range uncertainties. Int J Radiat Oncol Biol Phys 2012;82:e329-36.

[51] Li Y, Niemela P, Liao L, et al. Selective robust optimization: A new intensity-modulated proton therapy optimization strategy. Med Phys 2015;42:4840-7.

[52] *Goiten M. Jermann M. (2003) The relative costs of proton and X-ray radiation therapy. Clinical Oncol 15:S37-S50.*

[53] Liu W, Liao Z, Schild SE, et al. Impact of respiratory motion on worst-case scenario optimized intensity modulated proton therapy for lung cancers. Pract Radiat Oncol 2015;5:e77-86.

Section 5

Future Directions and

Management

**79**

Section 5

## Future Directions and Management

*Proton Therapy - Current Status and Future Directions*

no small change. Int J Radiat Oncol Biol

[50] Park PC, Zhu XR, Lee AK, et al. A beam-specific planning target volume (PTV) design for proton therapy to account for setup and range uncertainties. Int J Radiat Oncol Biol

[51] Li Y, Niemela P, Liao L, et al. Selective robust optimization: A new intensity-modulated proton therapy optimization strategy. Med Phys

[52] *Goiten M. Jermann M. (2003) The relative costs of proton and X-ray radiation therapy. Clinical Oncol* 

[53] Liu W, Liao Z, Schild SE, et al. Impact of respiratory motion on worst-case scenario optimized intensity modulated proton therapy for lung cancers. Pract Radiat Oncol

Phys;95:147-148.

Phys 2012;82:e329-36.

2015;42:4840-7.

*15:S37-S50.*

2015;5:e77-86.

**78**

**Chapter 8**

*and Javier Aristu*

**Abstract**

**1. Introduction**

**81**

Proton Cancer Therapy:

Synchrotron-Based Clinical

*Santiago M. Martin, Javier Serrano, Mauricio Cambeiro,*

*Diego Azcona, Daniel Zucca, Borja Aguilar, Alvaro Lassaletta*

Proton therapy is an efficient high-precision radiotherapy technique. The number of installed proton units and the available medical evidence has grown exponentially over the last 10 years. As a technology driven cancer treatment modality, specific subanalysis based on proton beam characteristics and proton beam generators is feasible and of academic interest. International synchrotron technology-based institutions have been particularly active in evidence generating actions including the design of prospective trials, data registration projects and retrospective analysis of early clinical results. Reported evidence after 2010 of proton therapy from synchrotron based clinical results are reviewed. Physics, molecular, cellular, animal investigation and other non-clinical topics were excluded from the present analysis. The actual literature search (up to January 2020) found 192 publications, including description of results in over 29.000 patients (10 cancer sites and histological subtypes), together with some editorials, reviews or expert updated recommendations. Institutions with synchrotronbased proton therapy technology have shown consistent and reproducible results along the past decade. Bibliometrics of reported clinical experiences from 2008 to early 2020 includes 58% of publications in first quartile (1q) scientific journals classification and 13% in 2q (7% 3q, 5% 4q and 17% not specified). The distribution of reports by cancer sites and histological subtypes shown as dominant areas of clinical research and publication: lung cancer (23%), pediatric (18%), head and neck (17%), central nervous system (7%), gastrointestinal (9%), prostate (8%) and a miscellanea of neplasms including hepatocarcinoma, sarcomas and breast cancer. Over 50% of lung, pediatric,

Experiences 2020 Update

*Felipe Angel Calvo Manuel, Elena Panizo,*

head and neck and gastrointestinal publications were 1q.

**Keywords:** cancer, proton therapy, synchrotron, oncology, radiotherapy

**1.1 Cancer medicine: precision, interdisciplinary and personalization**

Proton beam therapy (PBT) is developing in the context of a substantial increase in the incidence of cancer, the enormous advances made in our understanding of

#### **Chapter 8**

## Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update

*Felipe Angel Calvo Manuel, Elena Panizo, Santiago M. Martin, Javier Serrano, Mauricio Cambeiro, Diego Azcona, Daniel Zucca, Borja Aguilar, Alvaro Lassaletta and Javier Aristu*

### **Abstract**

Proton therapy is an efficient high-precision radiotherapy technique. The number of installed proton units and the available medical evidence has grown exponentially over the last 10 years. As a technology driven cancer treatment modality, specific subanalysis based on proton beam characteristics and proton beam generators is feasible and of academic interest. International synchrotron technology-based institutions have been particularly active in evidence generating actions including the design of prospective trials, data registration projects and retrospective analysis of early clinical results. Reported evidence after 2010 of proton therapy from synchrotron based clinical results are reviewed. Physics, molecular, cellular, animal investigation and other non-clinical topics were excluded from the present analysis. The actual literature search (up to January 2020) found 192 publications, including description of results in over 29.000 patients (10 cancer sites and histological subtypes), together with some editorials, reviews or expert updated recommendations. Institutions with synchrotronbased proton therapy technology have shown consistent and reproducible results along the past decade. Bibliometrics of reported clinical experiences from 2008 to early 2020 includes 58% of publications in first quartile (1q) scientific journals classification and 13% in 2q (7% 3q, 5% 4q and 17% not specified). The distribution of reports by cancer sites and histological subtypes shown as dominant areas of clinical research and publication: lung cancer (23%), pediatric (18%), head and neck (17%), central nervous system (7%), gastrointestinal (9%), prostate (8%) and a miscellanea of neplasms including hepatocarcinoma, sarcomas and breast cancer. Over 50% of lung, pediatric, head and neck and gastrointestinal publications were 1q.

**Keywords:** cancer, proton therapy, synchrotron, oncology, radiotherapy

#### **1. Introduction**

#### **1.1 Cancer medicine: precision, interdisciplinary and personalization**

Proton beam therapy (PBT) is developing in the context of a substantial increase in the incidence of cancer, the enormous advances made in our understanding of

the biological basis and clinical implications of the disease, and the need to improve the therapeutic index: tumor control promotion and minimal clinically relevant toxicity. PBT is an accessible precision high-energy particle radiation technology, adapted to the therapeutic demands tendencies in health care and health budget of modern clinical practice [1]. Other radiotherapy (RT) solutions using hadron beams (hadron therapy) are too costly in the medium term in most clinical settings [2].

PBT is now firmly established the era of precision medicine [3]. In oncology, the principles of medicine must be well defined: Interdisciplinarity and molecular individuation. Technological excellence will only be achieved when it encompasses the different medical specialties involved in treating each individual patient. Multidisciplinary Tumor Boards (MTD) are an essential part of an efficient approach to cancer management [4]. Personalized cancer treatment is characterized by a detailed analysis of the molecular configuration and evolution of each patient's tumor (gene expression profile and nanobiology) [5]. The latest evidence suggests that tumors are probably unique to each patient, and that each tumor within the same patient (metastasis, primary site or recurrence) has its own biological pattern of progression and host adaptation pathway [6].

#### **1.2 Vectors in radiation oncology: individualized, functional, accurate and precise therapy**

RT currently helps to achieve cure over half of all patients that require this treatment; it relieves symptoms in 2 out of every 3 patients, and in general terms is a crucial therapeutic component in 3 out of every 4 cancer patients [7]. Furthermore, RT preserves organs and tissue structures (in contrast to the status resulting from radical extended surgery) and can be used in the context of radical treatment for oligometastatic and oligo-recurrent disease [8, 9]. Forecasts in healthcare systems in countries like the US suggest that by 2020, indications for RT in all types of cancer will have increased by 25%, and by 35% in the case of gastrointestinal malignancies [10].

The foregoing estimations are based on the enormous technological advances made in RT in the last 30 years. If medical advances in clinical oncology have ushered in the era of precision medicine, interdisciplinary approach in recent decades in oncological RT (which specifically uses ionizing radiation to treat cancer) have ushered in the era of accurate precise RT.

Precision RT is very efficient in promoting the local control (LC) of macroscopically identifiable cancer lesions (targeted by image-guided RT), and has an excellent therapeutic index, in other words, minimal, toxicity in normal radiationsensitive tissue [11]. Because accurate precise RT has minimum effect on the function of the organs, systems (blood, liver, lungs, etc.) and tissues where the tumor is located, it has allowed clinicians to explore the radiobiological effects of hypofractionation, heterogeneous dose distribution within target volumes (adjusted for bioheterogeneity), and of immunomodulatory, radiation-enhancing, radiationsensitive and radiation-protective drug interactions [12]. Finally, one of the most promising aspects of accurate precise RT is the potencial of radiation-induced immunogenicity induced by hypofractionated (>8 Gy) RT [13]. Checkpoint inhibitors and other inmunomodulators allow clinicians to explore the potential of combining systemic immunotherapy effects with precision local and atoxic RT [14].

precision of PBT compares favorably with photon therapy and, guided by beam homogeneity in the delivery and imaging systems for precision control (4D and quasi-real-time control), its results in clinical practice will be equivalent and

*Clinical practice-based example of dose distribution in a craneospinal irradiation represented in 2D and 3D images. Treatment planning implementation in PBT enhances the perception of clinical benefit expected by*

*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update*

*DOI: http://dx.doi.org/10.5772/intechopen.94937*

morbidities that can occur years to decades after RT is completed.

The value of a treatment is defined as the outcomes obtained divided by the cost, measured over the entire cycle of care [15]. The clinical potential of proton cancer therapy requires sophisticated and realistic assessment of integral cost of care estimations including "costicity" (the cost of toxicity and general health-related supportive care). A collaborative effort between clinicians, patients, and policy makers is needed to design clinical trials with meaningful patient engagement. In particular, patients may help to identify and refine approaches that will lead to improved enrollment and retention in clinical trials as evidence generators sources. One crucial element in arriving at meaningful conclusions from such analyses is the need to account for the costs of managing not only acute RT toxicity but also long-term

In 2016, Mishra et al. reviewed the context of developing evidence in cancer proton therapy [16]. PBT clinical trials identified from clinicaltrials.gov and the

reproducible (**Figure 1**).

*protecting normal anatomy from unnecessary irradiation.*

**Figure 1.**

**83**

#### **2. Developing proton beam therapy clinical evidence**

In the next decade, technological advances in PBT will bring further technological developments in precision RT into mainstream clinical practice. The dosimetric *Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update DOI: http://dx.doi.org/10.5772/intechopen.94937*

#### **Figure 1.**

*Clinical practice-based example of dose distribution in a craneospinal irradiation represented in 2D and 3D images. Treatment planning implementation in PBT enhances the perception of clinical benefit expected by protecting normal anatomy from unnecessary irradiation.*

precision of PBT compares favorably with photon therapy and, guided by beam homogeneity in the delivery and imaging systems for precision control (4D and quasi-real-time control), its results in clinical practice will be equivalent and reproducible (**Figure 1**).

The value of a treatment is defined as the outcomes obtained divided by the cost, measured over the entire cycle of care [15]. The clinical potential of proton cancer therapy requires sophisticated and realistic assessment of integral cost of care estimations including "costicity" (the cost of toxicity and general health-related supportive care). A collaborative effort between clinicians, patients, and policy makers is needed to design clinical trials with meaningful patient engagement. In particular, patients may help to identify and refine approaches that will lead to improved enrollment and retention in clinical trials as evidence generators sources. One crucial element in arriving at meaningful conclusions from such analyses is the need to account for the costs of managing not only acute RT toxicity but also long-term morbidities that can occur years to decades after RT is completed.

In 2016, Mishra et al. reviewed the context of developing evidence in cancer proton therapy [16]. PBT clinical trials identified from clinicaltrials.gov and the World Health Organization International Clinical Trials Platform Registry showed a total of 122 active PBT clinical trials, with target enrollment of >42,000 patients worldwide. Ninety-six trials (79%) were interventional and 21% were observational studies. The most common PBT clinical trials focus on gastrointestinal tract tumors (21%), tumors of the central nervous system (15%), and prostate cancer (12%). Five active studies (lung, esophagus, head and neck, prostate, breast) randomize patients between protons and photons, and 3 between protons and carbon ion therapy.

Pediatric cancer patients referred to proton therapy centers do benefit from expert dedicated highly specialized care both in terms of normal tissue protection to radiation exposure during treatment delivery and from early access to medical integral care and radiotherapy process (5 weeks median starting time) [19]. A critical milestone to facilitate long-term clinical outcomes research in the modern era has been achieved. The Pediatric Proton Consortium Registry (PPCR) has reported a total of 1854 patients enrolled from October 2012 until September 2017. The cohort is 55% male, 70% Caucasian, and comprised of 79% United States residents. Central nervous system (CNS) tumors were the most frequent group of diseases (61%). The most common non-CNS tumors diagnoses were: rhabdomyosarcoma (n = 191), Ewing sarcoma (n = 105), Hodgkin lymphoma (n = 66), and

*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update*

Radiotherapy confers survival advantages to patients with glioblastoma, medulloblastoma, germ cell, ependymoma and other intracranial neoplasms. This costeffective and accessible treatment modality has proven efficacy in the adjuvant and definitive setting, as a first-line treatment or after prior lines of therapy. Neuroradiation oncology has witnessed a burgeoning of new techniques, technologies and strategies that will better optimize the therapeutic ratio. Proton beam therapy (PBT) offers the potential to minimize late-onset toxicities while preserving disease-related outcomes. Multidisciplinary efforts explore synergies between the effects of radiotherapy and novel systemic therapies to tailor the delivery by

PBT has emerged as a novel means to reduce toxicity and potentially further improve tumor control in head and neck cancer patients. The unique physical properties of charged particles allow a steep dose gradient with a reduced integral dose delivered to the patient in a proportion that can meaningfully reduce dose-

For the National Comprehensive Cancer Network guidelines, proton therapy is a standard of care for base of skull tumors and is an optimized option for periorbital tumors. The use of proton therapy is expanding for other cancer sites. Novel forms of proton therapy such as IMPT, and technical improvements in dose modeling, patient setup, image guidance and radiobiology, will help further enhance the benefits of proton therapy. The present cost of delivering PBT is approximately 2–3 times higher than for delivering IMRT photons in the head and neck (H&N) cancer model of health care. However, the cost difference is reduced when costs are considered over the entire cycle of care. Predictive models using comorbidity scales could defined a subpopulation of patients for whom proton therapy is likely to reduce side effects and subsequent use of health care resources (**Table 3**) [52].

The call for designing and conducting "smart" proton therapy trials for lung cancer patients requires establishing clinical evidence and patient selection criteria to make proton therapy a truly personalized form of treatment. Comparative trials could focus on endpoints such as cardiac toxicity, low-dose radiation bath, and lymphopenia. The enhancement of dosimetric and biological advantages of PBT to

improve clinical outcomes requires further developments in image-guided

neuroblastoma (n = 55) (**Table 1**) [20].

*DOI: http://dx.doi.org/10.5772/intechopen.94937*

**3.2 Central nervous system**

molecular profile (**Table 2**) [41].

**3.3 Head and neck cancer**

related toxicity.

**3.4 Lung cancer**

**85**

The medical vision in 2020 and ahead, confirms that PBT clinical trial portfolio expands rapidly. Results of PBT studies, generated with synchrotron technology, need additional evaluation in terms of comparative effectiveness, as well as incremental effectiveness and health value offered by PBT in comparison with conventional radiation modalities among other topics of clinical relevance.

Aside from future technological improvements, PBT has already been well received in the international medical community, and is now available in more than 57 centers worldwide [17].

As in other precision RT techniques, phase III randomized clinical trials (RCTs) are not the best research setting, as they have intrinsic limitations in design and data analysis that prevent the positive findings of randomized trials investigating pharmaceuticals agents to be extrapolated to phase III studies with medical technologies. New availability of pencil-beam scanning and the consideration of new biological rationales such as avoidance of bone marrow and circulating blood radiation exposure, may be especially relevant to patients due to the central role of the immune system in cancer therapy.

#### **3. Evolutive and consolidated clinical outcomes**

Clinical results based on novel treatments need both time to mature, and a method of comparison that can define the best indications in the context of currently available accurate precise RT. Mature results from some studies recommend PBT for extreme indications in radioresistant, indolent yet highly infiltrative and extensive cancer lesions, and in patients requiring re-irradiation due to symptomatic oligo-recurrence.

The following is a summary of the clinical results of a selective review of the latest, most influential, clinical studies analyzing synchrotron-based PBT institutional outcomes. The data available generally relates to established and developmental indications, together with some comparative analysis with other RT technologies. The information was obtained from a specific literature search and systematic reviews spanning 2010–2020.

#### **3.1 Pediatric tumors**

In 2020 PBT is the radiation therapy technology of election for pediatric oncology patients. The evolution towards this practice status has been fast. A survey conducted between July 2017 and June 2018 in all proton centers treating pediatric patients in 2016 worldwide identified a total of 54 centers operating in 11 countries (Particle Therapy Co-Operative Group, PTCOG website). Among the 40 participating centers (74%), a total of 1860 patients were treated in 2016 (North America: 1205, Europe: 432, Asia: 223.

More than 30 pediatric tumor types were identified, mainly treated with curative intent. About half of the patients were treated with pencil beam scanning [18]. *Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update DOI: http://dx.doi.org/10.5772/intechopen.94937*

Pediatric cancer patients referred to proton therapy centers do benefit from expert dedicated highly specialized care both in terms of normal tissue protection to radiation exposure during treatment delivery and from early access to medical integral care and radiotherapy process (5 weeks median starting time) [19].

A critical milestone to facilitate long-term clinical outcomes research in the modern era has been achieved. The Pediatric Proton Consortium Registry (PPCR) has reported a total of 1854 patients enrolled from October 2012 until September 2017. The cohort is 55% male, 70% Caucasian, and comprised of 79% United States residents. Central nervous system (CNS) tumors were the most frequent group of diseases (61%). The most common non-CNS tumors diagnoses were: rhabdomyosarcoma (n = 191), Ewing sarcoma (n = 105), Hodgkin lymphoma (n = 66), and neuroblastoma (n = 55) (**Table 1**) [20].

#### **3.2 Central nervous system**

Radiotherapy confers survival advantages to patients with glioblastoma, medulloblastoma, germ cell, ependymoma and other intracranial neoplasms. This costeffective and accessible treatment modality has proven efficacy in the adjuvant and definitive setting, as a first-line treatment or after prior lines of therapy. Neuroradiation oncology has witnessed a burgeoning of new techniques, technologies and strategies that will better optimize the therapeutic ratio. Proton beam therapy (PBT) offers the potential to minimize late-onset toxicities while preserving disease-related outcomes. Multidisciplinary efforts explore synergies between the effects of radiotherapy and novel systemic therapies to tailor the delivery by molecular profile (**Table 2**) [41].

#### **3.3 Head and neck cancer**

PBT has emerged as a novel means to reduce toxicity and potentially further improve tumor control in head and neck cancer patients. The unique physical properties of charged particles allow a steep dose gradient with a reduced integral dose delivered to the patient in a proportion that can meaningfully reduce doserelated toxicity.

For the National Comprehensive Cancer Network guidelines, proton therapy is a standard of care for base of skull tumors and is an optimized option for periorbital tumors. The use of proton therapy is expanding for other cancer sites. Novel forms of proton therapy such as IMPT, and technical improvements in dose modeling, patient setup, image guidance and radiobiology, will help further enhance the benefits of proton therapy. The present cost of delivering PBT is approximately 2–3 times higher than for delivering IMRT photons in the head and neck (H&N) cancer model of health care. However, the cost difference is reduced when costs are considered over the entire cycle of care. Predictive models using comorbidity scales could defined a subpopulation of patients for whom proton therapy is likely to reduce side effects and subsequent use of health care resources (**Table 3**) [52].

#### **3.4 Lung cancer**

The call for designing and conducting "smart" proton therapy trials for lung cancer patients requires establishing clinical evidence and patient selection criteria to make proton therapy a truly personalized form of treatment. Comparative trials could focus on endpoints such as cardiac toxicity, low-dose radiation bath, and lymphopenia. The enhancement of dosimetric and biological advantages of PBT to improve clinical outcomes requires further developments in image-guided


**Authors**

**87**

 **Year N°**

**Stage histology**

**Multidisciplinar**

**Dose/N° fractions**

 **Proton**

**Observations**

**technique**

IQ slopes did not differ between

groups (P = .509

**patients**

medulloblastoma/

ependymoma

(17), other (15)

Taddei,

2018 9

Medulloblastoma

Estimate reductions in projected

CSI 23.4 Gy-RBE in

PB vs.

Ratio SMN incidence PB CSI to

Photon

photon CSI: 0.56 (95% CI, 0.37 to

0.75)

*DOI: http://dx.doi.org/10.5772/intechopen.94937*

Ratio SMN mortality PB CSI to

photon CSI: 0.64 (95% CI, 0.45 to

0.82)

1.8 Gy-RBE fractions

lifetime SMN incidence and mortality if treated with proton CSI

vs. photon CSI

[28]

Peeler, [29] 2016 34

Gunther

2015 72

IMRT: 21 PBRT: 26

infratentorial

infratentorial

Ependymoma:

[30]

Sato, [31]

Adesina,

2019 83

 Low grade glioma: Brainstem (19),

cerebral (13), optic (29), other (16).

> Zhang [33] 2014 17

Medulloblastoma

Surgery +

chemotherapy

CSI 23.4 or 23.4 Gy

PB

Proton superior outcomes (<

predicted risks of 2nd cancer and

cardiac mortality than photon).

(RBE) to the age specific

target volume at 1.8 Gy/

fraction

hemispheres

 (6), thalamus

Surgery

(IMRT 32, PBT 51)

chemotherapy

Median, range (Gy):

PB

Post-RT IMRT: HR 2.15, 95% CI 1.06–4.38,

p = 0.04). RT dose

(RBE) > rates of PsP (HR 2.61, 95%

CI 1.20–5.68, p = 0.016)

>50.4Gy

enlargement

 rates PBT vs.

> IMRT: 50.4 (45–59.4)

PBT: 50.4 (45–54)

pathway/hypothalamus

[32]

 2017 79

Ependymoma

 (54

infratentorial)

after RT

(IMRT 38, PRT 41)

Postoperative

 RT

chemotherapy

Median, range (cGy):

PBT and

3-year PFS rates were 60% and 82%

IMRT

with IMRT and PRT, respectively

(P = .031)

IMRT: 5400 (5040–

5940)

PB: 5580

(5040–5940)

Ependymoma

infratentorial

 24)

(supratentorial

 10,

After surgery

54–59.4 Gy

PB

Image changes dependence increasing LET and dose. TD50

decreased with increasing LET = increase in biological dose

effectiveness

 on

*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update*

To determine if areas of normal tissue damage were associated with

increased biological dose

effectiveness.

Postoperative

before RT

chemotherapy

 after RT

 RT

chemotherapy

Median, range(Gy):

PB and

PBRT was associated with more

IMRT

frequent imaging

P < .024).

changes(OR:

 3.89,

IMRT 54.0 (50.4–59.4)

PB 59.4 (53.0–59.4)

 (4), germ cell tumor

 PNET (34),


#### *Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update DOI: http://dx.doi.org/10.5772/intechopen.94937*


**Authors**

**89**

Tamura,

2017 26

 A. Brain B. Chest C. Abdomen

D. Whole

> **Table 1.**

*Clinical experiences* *malignant neoplasms;*

*intensity modulated*

 *with synchrotron*

 *LET: linear energy transfer; TD50; dose at which 50% of patients would experience toxicity; PsP:* 

*radiotherapy;*

 *IMPT: intensity modulated*

 *proton therapy; CSI craniospinal*

*irradiation).*

 *PBT in pediatric tumors (AT/RT: atypical teratoid rhabdoid tumors; OS: overall survival; PFS:* 

CNS(medulloblastoma)

[40]

 **Year N°**

**Stage histology**

**Multidisciplinar**

Surgery

Comparison

lifetime attributable

radiation-induced

secondary cancer (LAR)

 risk of

 PBT to IMXT in

chemotherapy

**A:** **B:** 25.2–60 Gy. /1.8–

2.5Gy

**C:** 25.2–72.6 Gy/ 1.8–

3.3 Gy. **D:** 18–23.4 Gy/ 1.8 Gy *progression-free*

*Pseudoprogression;*

 *EFS: event-free survival; PB: passive beam; IMRT:*

*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update*

 *survival; LC: Local control; SMN: secondary*

30.6–57.6 Gy/ 1.8 Gy.

PB

In pts. undergone PBT LAR was

lower than IMXT estimated LAR useful marker of secondary

cancer induced by

radiotherapy

*DOI: http://dx.doi.org/10.5772/intechopen.94937*

**Dose/N° fractions**

 **Proton**

**Observations**

**technique**

**patients**


**Table 1.** *Clinical experiences with synchrotron PBT in pediatric tumors (AT/RT: atypical teratoid rhabdoid tumors; OS: overall survival; PFS: progression-free survival; LC: Local control;malignant neoplasms; LET: linear energy transfer; TD50; dose at which 50% of patients would experience toxicity; PsP: Pseudoprogression; EFS: event-free survival; PB: passiveintensity modulated radiotherapy; IMPT: intensity modulated proton therapy; CSI craniospinal irradiation).*

#### *Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update DOI: http://dx.doi.org/10.5772/intechopen.94937*

 *SMN: secondary*

 *beam; IMRT:*


**Authors**

**91**

Brown [49] 2013 40

Zhang [50] 2012 1

Bielamowicz

2018 95

PBT n = 41

Medulloblastoma

MRF surgery + CSI

Photons vs. PBI

hypothiroidism

23.4 RBE

PB

mFT PBT 3y 19%

mFT photons 9y 46.3%

Hypothiroidism:

standard CSI

36–39 RBE in HR

pts.

[51]

**Table 2.** *Clinical experiences*

 *in CNS tumors treated with synchrotron*

 *technology* 

*(2012–2019).*

 *OARs: organs at risk; RBE:* 

*radiobiological*

 *equivalence;*

 *CNS: central nervous system; ChT:* 

*Chemotherapy).*

*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update*

Medulloblastoma

Risk of second cancer: 3-field

6MV photon vs. 4-field PBT

 **Year N°**

**Stage histology**

**Multidisciplinar**

**Dose/N°**

**Proton**

**Observations**

**technique**

**fractions**

CSI 30.6 RBE

PB

 PBT pts. lost significantly

less Esophagitis

 57% vs. 5%

nausea/vomiting,

 less cytopenia.

 less weight than photon pts.,

+

Boost 54 RBE CSI 23.4 RBE

 PB

 Lifetime risk second cancer 7.7 vs. 92%. Proton therapy

confers lower predicted risk of second cancer for the

pediatric photon therapy.

medulloblastoma

 patient compared with

*DOI: http://dx.doi.org/10.5772/intechopen.94937*

**patients**

Medulloblastoma

 in adults

 Surgery. EP: Acute toxicity

n = 19 PBT; n = 21 photon CSI


**Table 2.** *Clinical experiences in CNS tumors treated with synchrotron technology (2012–2019). OARs: organs at risk; RBE: radiobiological equivalence; CNS: central nervous system; ChT: Chemotherapy).*

#### *Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update DOI: http://dx.doi.org/10.5772/intechopen.94937*


**Authors**

**93**

Ludmir

2018 14

H&N alveolar rhabdomyosarcoma

children

57% localized

43% N+

SCC 40 pts.

Reirradiation

66 RBE/30

25% IMPT

mFT: 13.6 m

fx

75% PB

1-y: LC 68.4%

OS 83.8%

*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update*

PFS 60% DMFS 75% 30% toxicity G3.

58% upfront surgery

73% ChT

Non-SCC 20 pts.

Phan [62] 2016 60

**Table 3.** *Clinical experiences*

 *in head and neck cancer treated with synchrotron*

 *technology* 

*(2014–2019).*

 *(mFT: median follow up time).*

 in

Systemic ChT

50.4 RBE/

PB

 mFT: 4.3 y 5-y: OS 45%

DFS 25%

*DOI: http://dx.doi.org/10.5772/intechopen.94937*

71% relapsed

25 fx.

[61]

 **Year N° patients**

 **Stage histology**

**Multidisciplinar**

**Dose/N°**

**Proton**

**Observations**

**fractions**

**technique**

LC: 84% Tumor size >5 cm, delayed RT after ChT and ICE increased

risk.


 **3.** *Clinical experiences in head and neck*

 *cancer treated with synchrotron*

 *technology* 

*(2014–2019).*

 *(mFT: median follow up time).*

*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update DOI: http://dx.doi.org/10.5772/intechopen.94937*

hypofractionated intensity modulated proton therapy (IMPT) and combinations of hypofractionated proton therapy with immunotherapy [63].

For early-stage non-small cell lung cancer (NSCLC), the optimal clinical context for proton beam therapy (PBT) is challenging due to the increasing evidence demonstrating high rates of local control and good tolerance of stereotactic ablative body radiation (SABR). The potential advantage may be significant in treating larger tumors, multiple tumors, or central tumors. Most of the published studies are based on passive scattering PBT. Dosimetric benefits are likely to increase whith pencil beam scanning/intensity-modulated proton therapy (IMPT) [64]. A prospective longitudinal observational study of 82 patients with unresectable primary or recurrent NSCLC treated with 3-dimensional conformal radiation therapy (3DCRT), IMRT, or proton therapy included patient-reported symptom burden, assessed weekly for up to 12 weeks with the validated MD Anderson Symptom Inventory. Despite the fact that the proton group received significantly higher target radiation doses (P < 0.001), patients receiving proton therapy reported significantly less severe symptoms than did patients receiving IMRT or 3DCRT [63]. (**Table 4**).

#### **3.5 Esophageal cancer**

Radiation therapy (RT) has become an important component in the curative management of esophageal cancer (EC). Since most of the ECs seen in the Western hemisphere (i.e., Europe and the United States) are located in the mid- to distalesophageal locations, heart and lungs invariably receive significant radiation doses. Proton beam therapy (PBT) provides the ability to further reduce normal tissue exposure because of its lack of exit dose, which is expected to provide clinically meaningful benefit for at least some EC patients [90].

Investigators at MD Anderson Cancer Center have reported a phase IIb randomized trial comparing PBT and IMRT for patients with EC (NCT01512589). The primary endpoints are progression-free survival and total toxicity burden, which is a composite endpoint including serious adverse events and postoperative complications. Among the 145 patients randomized, total toxicity burden was 2.3 times higher for photon IMRT and the postoperative complications (50% of patients were operated) was 7.6 times higher in photon IMRT cohort. The 3-year overall survival was similar in both groups (44%) [91]. Results from prospective clinical trials will greatly improve our knowledge regarding the role and benefits expected from proton therapy for EC. (**Table 5**).

#### **3.6 Hepatocellular cancer**

Proton beam therapy has the unique dosimetric performance, particularly valuable for the treatment of hepatocellular carcinoma (HCC). Clinical data is available in a limited number of patients, especially from Japan. In a systematic review from 1983 to June 2016 to identify clinical studies on charged particle therapy for HCC, a total of 13 cohorts from 11 papers. The reported actuarial local control rates ranged from 71 to 95% at 3 years, and the overall survival rates ranged from 25–42% at 5 years. Late severe radiation morbidities were uncommon, and a total of 18 patients with grade ≥ 3 late adverse events were reported among the 787 patients included in the analysis.

The American Society for Radiation Oncology (ASTRO) issued a Model Policy on PBT in 2014 and PBT for HCC is covered by medical insurance in the United States. The Japanese Clinical Study Group of Particle Therapy (JCPT), the Japanese Society for Radiation Oncology (JASTRO), the Japanese Radiation Oncology Study

**Authors**

**95**

Lin [65] Welsh [66] 2013 260

Matney [67] 2013 20

Nguyen [68] 2015 134

Niedzielski

2017 134

 NSCLC stage III.

 IMRT(85 pts) vs. PSPT(49 pts)

60–70 Gy/30–35 fx PB

Esophageal

 toxicity (clinical and image)

[69]

Ohnishi [70] 2019 669

 NSCLS stage I

Efficacy and safety PBT

74–113 Gy

 PB

 3-y OS 79,5%.

>100 GyE improved outcomes

38% T1a; 31% T1b; 29%

T2a.

Elhammali

2019 51

 Advanced inoperable

Concurrent

 Cht

67.3 Gy

IMPT

 3-y LC 78%.

mOS 33 G3 toxicity 18%

months,DFS

 12 months.

NSCLC

[71]

Nakajima

2018 55

 Stage I NSCLC

Image-guided

 fiducials (71%)

66 Gy/10fx

PB

 3-y OS 87%; 74% DFS; 96% LC

No G3 toxicities.

72 Gy/ 22 fx

50 Gy/4 fx

 PB

 3-y OS 27%

LC 90%

IA 33 pts.

IB 22 pts

[72]

Nantavithya

2018 19

 Inoperable stage

SBRT vs. SBPT

> NSCLC with HR

features.

[73]

 NSCLC II-III inoperable

 Concurrent 21 stage II

113 stage III

 CT

60–70 Gy/30–35 fx PB

 NSCLC IIB-III

 Primary NSCLC

 SBRT photon vs. SBRT proton

dosimetric comparison

Randomized

4D-3D dose variables

 IMRT vs. PSPT.

60–70 Gy/ 30–35

PB

 -Target coverage maintained

2/11 pts. less susceptible

PSPT

4.7 y follow-up -mOS stage II: 40 months

Stage III: 30 months.

*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update*

OS, DFS, LC no difference by stage.

 No significant difference in esophageal toxicity

found between proton and

therapy for the study cohort, based on imaging

biomarker or CTCAE grade

photon-based

 radiation

 up to 17 mm in both.

*DOI: http://dx.doi.org/10.5772/intechopen.94937*

 to respiratory motion

fx

 2016 11

 II-III NSCLC

4D versus 3D Robust

Optimization

 66 RBE/33 fx

50 Gy/4 fx

 PB

 SBRT protons: Same coverage, significant reduction

dose in chest wall and lung.

 PB

 4D robust comparable

 targets.

optimization

 improved dosimetry in

 **Year N°**

**Stage histology**

**Multidisciplinar**

**Dose/N° fractions**

 **Proton**

**Observations**

**technique**

**patients**


*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update DOI: http://dx.doi.org/10.5772/intechopen.94937*


**Authors**

**97**

Shusharina

2018 83

 Inoperable II-III stage.

Compare lung injury IMRT vs. PBT

revealed by

uptake

18F-FDG

post-treatment

74 RBE/ 37fx

 PB

 The slope of linear

did not differ significantly

modalities

18F-FDG-uptake

 between the two

 – dose response

> Oligo-mtx NSCLC

[81]

Jeter [82] Chang [83] 2017 64

NSCLC


> Chang [84] 2017 35

Chao [85] Giaddui [86] 2016 52

Wang [87]

McAvoy

2014 99

Reirradiation

intrathoracic

NSCLC

 recurrent

 for

Concurrent

 ChT

[88]

 2016 82

 Locally advanced

NSCLC.

 Inoperable stage II-IIIB Compliance

 criteria RTOG 1308: Phase

70 RBE/35fx

 PB

 RTOG 1308 dosimetric compliance

feasible and achievable

III

26 IMRT vs. 26 PBT

3DCRT (22) vs.

Patient-reported

 symptom burden

IMRT(34)vs.

 PBT(26)

Higher radiation

PB

 Patients reported significantly (pain, fatigue, lack of appetite, sleep and

drowsiness).

 less severe symptoms

> target dose used

PBT

60 EQD2

IMPT

 Toxicity ≥ G3 7% esophageal and 10% pulmonary. Median LC,DMFS, and OS times were 11.43 months,

11.43 months, and 14.71,

respectively.

Reirradiation

70 Gy median

inital dose.

 dose.

 2017 52

 IIIA 51%.

Re-irradiation

66 Gy

PB

 42% ≥ G3 toxicity. The 1-year rates of overall and

survival were 59% and 58%,

progression-free

respectively.

 criteria are

30–74 RBE

67% concurrent ChT

Recurrent NSCLC

 Early stage (IA-II).

Phase I-II prospective

escalated PBT

 inoperable dose-

87 RBE/35fx

 PB

 -Median follow up: 83 months.

5-y OS 28%

LC 54% Pneumonitis

Heart G2 5,7%; Chest wall 2,9%.

 G2 11%; G3 3%

12 T1N0 23 T2–3 N0

Unresectable

 stage III

Phase II study

Concurrent

 ChT

 2018 15

 Stage II-III NSCLC

 Phase I study.

Integrated escalation IMRT (6) vs. IMPT (9).

simultaneous

 boost for dose-

72 Gy IMRT

IMPT

 Grade ≥ 3 patients treated to 78 Gy(CGE) IMPT SIB

pneumonitis

 developed in 2 of the 6

*DOI: http://dx.doi.org/10.5772/intechopen.94937*

78 RBE IMPT

74 RBE/37fx

 PB

 mOS 26 months 5y PFS 22%; LRR 28%

Late G3 12%

3% bronchial stricture.

*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update*

pneumonitis

 G2 16%

 **Year N°**

**Stage histology**

**Multidisciplinar**

**Dose/N° fractions**

 **Proton**

**Observations**

**technique**

**patients**


*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update DOI: http://dx.doi.org/10.5772/intechopen.94937*


**Table 4.** **Authors**

**99**

Ono [92] Fang [93]

Xi [94] Shiraishi

2017 272

 IIA-IVA

III 59%

94% lower third

94% adenoca.

Prayongrat

2017 19

 IIB + III 80%

CRT (4 surgery)

50,4 Gy/28 fx IMPT single

field

84% complete response. 4% surgery.

*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update*

G3 esophagitis

1-y OS 100%

Mean heart dose 7.5 Gy

 Significant lower radiation exposure, MHD (chambers and

coronary arteries).

 (3 pts)

13

63% Distal third

[96]

Shiraishi

2017 727

 I-IVA

477 IMRT

50,4 Gy/28 fx IMPT 13

> 250 PB

DVH Surgery 50%

37% 3D

50,4 Gy/28 fx 3 institutions

(1/3 PB)

LOS: 3D 13.2d

IMRT 11.6 d

PB 9.3 d Pulmonary+cardiac+wound

complications

ΔWET inspirations

44% IMRT

19% PB Postop hospital. Stay LOS

> Yu [99]

 2016 11

Echeverria

2012 100

 I-IV

Pneumonitis

Re-staging PET-CT FDG 100%

 CTCAEv4

> III 51%

82% Distal third

[100]

 100% Distal and

4D robust CT calculations

Dosimetric

IMPT

 Changes of water equivalent thickness

and espiration

Linear higher dose response slope.

dose–response

 on FDG PET-CT.

Symptomatic

 pts. had

comparison

50,4 Gy/28 fx PB

GEJ

morbidity+outcome

 lenght in

comparisons//Cardiac

 dose//

III 60%

89% Distal third

[97]

Lin [98]

 2017 580

 I-IV III 63%

[95]

 2017 343

 I-III

CRT definitive

IMRT vs. PBT

Neoadyuvant

IMRT vs. PBT

lymphopenia

 CRT

III 65%

 2017 448

 IA-IVA

IMRT vs. PBT

Lymphopenia

III 56%

 2019 202

 100 patients

90 inoperable patients.

> stage III/IV

 **Year N°**

**Stage histology**

**Multidisciplinar**

**Dose/N°**

**Proton**

**Observations**

**technique**

**fractions**

87,2 median

4 PB centers

 5y OS 56,3%

5Y LC 64,4% Significant less

lymphopenia

 in lower esophagus

BED

50.4 Gy/28 fx PB

≤50,4 Gy/28 fx

Only 7 IMPT

PBT significant better

OS,PFS,DMFS,LRFFS

*DOI: http://dx.doi.org/10.5772/intechopen.94937*

(5,3%)

87%

50,4 Gy/28 fx PB

G4

lymphopenia

 40% vs. 17% during nCRT

**patients**

*Clinical experiences in lung cancer treated with synchrotron technology (2011–2019).*


#### *Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update DOI: http://dx.doi.org/10.5772/intechopen.94937*


**Table 5.**

*Clinical experiences in esophageal cancer treated with synchrotron technology (2012–2019).* Group (JROSG) and other groups are conducting multi-institutional prospective clinical trials in order to obtain approval for national health insurance for HCC and other cancers. The NCCN guidelines recommend that PBT may be appropriate in specific situations. In the Japanese guidelines, can be considered for HCCs that are difficult to treat with other local therapies, such as those with portal vein or inferior vena cava tumor thrombus and large lesions. The Korean Liver Cancer Study Group also mentioned the efficacy of PBT in their guidelines [104]. Guidelines from expert hepatologists evaluating the of data available for HCC patients will influence on the pattern of clinical practice considering the option of PBT as upfront therapy in the

*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update*

In adult lymphoma survivors, radiation treatment with increase excess of radiation dose to organs at risk (OARs) does increase the risk for side effects, especially late toxicities. Minimizing radiation to organs at risk (OARs) in adult patients with Hodgkin and non-Hodgkin lymphomas involving the mediastinum is the decisive

Proton therapy reduces the unnecessary radiation to the OARs and reduces toxicities, especially the risks for cardiac morbidity and second cancers. In modern guidelines for adult lymphoma patients, the benefit from proton therapy and the advantages and disadvantages of proton treatment are considered. The dosimetric advantage of reducing the unnecessary dose to lung, breast, heart, spinal cord, vessels, vertebrae, thyroid and other structures in certain lymphoma involvements can be significant and highly desirable for patients that will be extreme long-term survivors at risk for severe chronic conditions and second malignancies [112]

PBT for prostate cancer patients has been a continuously growing option due to its promising characteristics of high precision dose distribution in the target and a sharp distal fall-off. Considering the large number of proton beam facilities in Japan, the further increase of patients undergoing this treatment will be related to the policies of the Japanese National Health Insurance (NHI) together with the development of medical equipment and technology. A review conducted review to identify and discuss research studies of proton beam therapy for prostate cancer in Japan (up to June 2018) included 23 articles (14 observational, focused on the adverse effects), and 7 interventional on treatment planning, equipment parts, as well as target positioning. Favorable clinical results of PBT were consistent and future research should focus on longer follow-up clinical data. PBT is a suitable

At present, as particle beam therapy for prostate cancer is covered by the Japanese national health insurance system (since April 2018), and the number of facilities practicing particle beam therapy has increased recently, the number of prostate cancer patients treated with particle beam therapy in Japan is expected to

PBT has been explored in a variety of cancer sites, histological subtypes and disease stages, including localized breast cancer, seminoma, pancreatic cancer,

**3.9 Miscellaneous neoplasms and oncological clinical conditions**

oligo-recurrences and other cancer conditions. (**Table 9**).

decision-making process (**Table 6**) [105].

*DOI: http://dx.doi.org/10.5772/intechopen.94937*

factor to select the treatment modality.

treatment option for localized prostate cancer [116].

increase drastically [117]. (**Table 8**).

**3.7 Lymphoma**

(**Table 7**).

**3.8 Prostate**

**101**

*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update DOI: http://dx.doi.org/10.5772/intechopen.94937*

Group (JROSG) and other groups are conducting multi-institutional prospective clinical trials in order to obtain approval for national health insurance for HCC and other cancers. The NCCN guidelines recommend that PBT may be appropriate in specific situations. In the Japanese guidelines, can be considered for HCCs that are difficult to treat with other local therapies, such as those with portal vein or inferior vena cava tumor thrombus and large lesions. The Korean Liver Cancer Study Group also mentioned the efficacy of PBT in their guidelines [104]. Guidelines from expert hepatologists evaluating the of data available for HCC patients will influence on the pattern of clinical practice considering the option of PBT as upfront therapy in the decision-making process (**Table 6**) [105].

#### **3.7 Lymphoma**

In adult lymphoma survivors, radiation treatment with increase excess of radiation dose to organs at risk (OARs) does increase the risk for side effects, especially late toxicities. Minimizing radiation to organs at risk (OARs) in adult patients with Hodgkin and non-Hodgkin lymphomas involving the mediastinum is the decisive factor to select the treatment modality.

Proton therapy reduces the unnecessary radiation to the OARs and reduces toxicities, especially the risks for cardiac morbidity and second cancers. In modern guidelines for adult lymphoma patients, the benefit from proton therapy and the advantages and disadvantages of proton treatment are considered. The dosimetric advantage of reducing the unnecessary dose to lung, breast, heart, spinal cord, vessels, vertebrae, thyroid and other structures in certain lymphoma involvements can be significant and highly desirable for patients that will be extreme long-term survivors at risk for severe chronic conditions and second malignancies [112] (**Table 7**).

#### **3.8 Prostate**

PBT for prostate cancer patients has been a continuously growing option due to its promising characteristics of high precision dose distribution in the target and a sharp distal fall-off. Considering the large number of proton beam facilities in Japan, the further increase of patients undergoing this treatment will be related to the policies of the Japanese National Health Insurance (NHI) together with the development of medical equipment and technology. A review conducted review to identify and discuss research studies of proton beam therapy for prostate cancer in Japan (up to June 2018) included 23 articles (14 observational, focused on the adverse effects), and 7 interventional on treatment planning, equipment parts, as well as target positioning. Favorable clinical results of PBT were consistent and future research should focus on longer follow-up clinical data. PBT is a suitable treatment option for localized prostate cancer [116].

At present, as particle beam therapy for prostate cancer is covered by the Japanese national health insurance system (since April 2018), and the number of facilities practicing particle beam therapy has increased recently, the number of prostate cancer patients treated with particle beam therapy in Japan is expected to increase drastically [117]. (**Table 8**).

#### **3.9 Miscellaneous neoplasms and oncological clinical conditions**

PBT has been explored in a variety of cancer sites, histological subtypes and disease stages, including localized breast cancer, seminoma, pancreatic cancer, oligo-recurrences and other cancer conditions. (**Table 9**).


 **6.** *Clinical experiences in liver cancer treated with synchrotron technology (2016–2019); RILD: radiation induced liver disease; mOS: median overall survival.*

A special challenge for defining PBT health value are geriatric cancer patients. Aging and chronic comorbidity is a medical reality in the present and future of oncology practice. It is projected that 1 of 5 Americans will be aged ≥65 years in 2050 and that 60% of cancers will occur in this group. As PBT resources are limited, centers have designed decision-making systems for prioritization. Elderly cancer patients are as fragile as pediatric oncology patients in terms of "normal" tissues protection importance, their tissues are not that "normal" at all but link to comorbid and biological senescence. A small pilot survey of international academic radiation oncologists with particular experience in geriatric care recommended a preference for irradiation with PBT, due to the age condition and cancer stage. Although this finding may sound provocative, it shows that, while currently inclined toward pediatrics, many practitioners see strong indications in the elderly population. The Eurocare showed that the age-standardized death rate for cancer was ≥12 times higher among elderly persons than among younger persons, in part, because treatments most commonly associated with cancer cure are less commonly given to elderly patients. The use of PBT will, through reducing morbidity, make the delivery of curative therapy more possible, merits a serious thought. Older patients are more likely to be admitted for cancer treatment as a result of an emergency or at an advanced stage. These factors may be associated with increased costs. The societal cost of delayed or inadequate treatment will require formal measurement against the cost of these advanced radiation technologies. PT should now be regarded as a relevant method to limit the short- and long-term toxicity of irradiation and reduce

**Multidisciplinar Dose/N°**

Consolidation ChT


Dosimetric comparison IMRT vs. 3DCRT vs. IMPT

*Clinical experiences in malignant lymphoma treated with synchrotron technology (2016–2017).*

**fractions**

21 RBE pediatric 30.6 RBE adults

30.6 RBE/17 fx

30.6 RBE/17 fx

**Proton technique** **Observations**

No G3 radiation toxicities

PB 3-y DFS 92%

PB DIBH with PBT significantly reduced life of year lost compared to IMRT in FB

> significantly reduced lung and cardiac doses.

IMPT IMPT

While research protocols no longer exclude patients based solely on age, many currently do so because of these patients' comorbidities. It is time to consider the inclusion of comprehensively assessed elderly men and women in clinical trials of PBT. It is among these patients that some of the greatest benefits may yet be revealed. Until specific trials report their findings, a proactive guidance for the

the need for costly supportive care.

**103**

**Authors Year N°**

Ricardi [113]

Rechner [114]

Zeng [115]

**Table 7.**

**patients**

*DOI: http://dx.doi.org/10.5772/intechopen.94937*

2017 138 I-II 73%

2017 22 Early-stage HL: Mediastinal

2016 10 Early-stage HL: Mediastinal

**Stage histology**

III-IV 27% Mediastinal involvement 96% Bulky 57%. No-relapse; Norefractory

*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update*


*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update DOI: http://dx.doi.org/10.5772/intechopen.94937*

**Table 7.**

*Clinical experiences in malignant lymphoma treated with synchrotron technology (2016–2017).*

A special challenge for defining PBT health value are geriatric cancer patients. Aging and chronic comorbidity is a medical reality in the present and future of oncology practice. It is projected that 1 of 5 Americans will be aged ≥65 years in 2050 and that 60% of cancers will occur in this group. As PBT resources are limited, centers have designed decision-making systems for prioritization. Elderly cancer patients are as fragile as pediatric oncology patients in terms of "normal" tissues protection importance, their tissues are not that "normal" at all but link to comorbid and biological senescence. A small pilot survey of international academic radiation oncologists with particular experience in geriatric care recommended a preference for irradiation with PBT, due to the age condition and cancer stage. Although this finding may sound provocative, it shows that, while currently inclined toward pediatrics, many practitioners see strong indications in the elderly population.

The Eurocare showed that the age-standardized death rate for cancer was ≥12 times higher among elderly persons than among younger persons, in part, because treatments most commonly associated with cancer cure are less commonly given to elderly patients. The use of PBT will, through reducing morbidity, make the delivery of curative therapy more possible, merits a serious thought. Older patients are more likely to be admitted for cancer treatment as a result of an emergency or at an advanced stage. These factors may be associated with increased costs. The societal cost of delayed or inadequate treatment will require formal measurement against the cost of these advanced radiation technologies. PT should now be regarded as a relevant method to limit the short- and long-term toxicity of irradiation and reduce the need for costly supportive care.

While research protocols no longer exclude patients based solely on age, many currently do so because of these patients' comorbidities. It is time to consider the inclusion of comprehensively assessed elderly men and women in clinical trials of PBT. It is among these patients that some of the greatest benefits may yet be revealed. Until specific trials report their findings, a proactive guidance for the


 **8.** *Clinicalexperiences inprostatecancer*

**Authors**

**105**

Guttmann

2017 23

secondary soft tissue sarcoma

Reirradiation

 for recurrent and

Reirradation.

68.4 RBE/

PB 78%.

 mFT 36 months

mOS 44 m 3-y LF 41%

Extremity-spared

 amputation

 70%.

30–35 fx.

1°: Acute toxicities.

[125]

Hashimoto

2016 10

 Cervix

WPRT: 3DCRT vs. IMRT

50.4 RBE/

IMPT

 IMPT spared the small intestine, colon, bilateral femoral heads,

skin and pelvic bone to a greater extent than the other

*DOI: http://dx.doi.org/10.5772/intechopen.94937*

modalities.

25 fx

vs. PBT

Locally advanced (IIB/IIIA)

[126]

Haque

2015 1

radiation

Seminoma.Initial

 stage IA. Salvage

IMRT vs. PBT

30 RBE/15

PB

 Complete response with no

month follow-up.

radiation-related

 side effects at the 3-

fx

[127]

Pan [128]

 2015 7

IMRT n = 3

IMPT = 4

Demizu

2017 96

 Skull base n = 68

Surgery performed in 68

pts

Cervical spine n = 8

Lumbar spine = 5

Sacral spine = 15

Smith

2019 51

Reconstructed

 +

 nodes

Post-mastectomy

50 Gy/25 fx

IMPT

 Low rates of acute toxicity.

More Max dermatitis G1 63%.

complications

 with

hypofractionation.

inmediate

reconstruction

(73%)

40 Gy/15 fx

(27%)

Post-mastectomy

50 Gy/25 fx

IMPT

 Skin

radiodermitis

 G3 in 1 patient.

> inmediate

reconstruction

(73%)

 *technology* 

*(2015–2017);*

 *LC: Local Control.*

[130]

Mutter

2016 12

 I-III

[131]

**Table 9.** *Clinical experiences*

 *in* 

*miscellaneous*

 *neoplasms and cancer conditions treated with synchrotron*

[129]

Mesothelioma

Pleurectomy

 n = 6

 60RBE/

IMPT

 Dosimetric

 benefit shown in OARs. Lower mean doses to the

contralateral

with increased

was required for nodal disease.

 lung, heart, esophagus, liver, and ipsilateral kidney,

contralateral

 lung sparing when mediastinal

 boost

*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update*

25fx

Integrated

boost

<70Gy

PB

 5-y OS 75%

PFS 50%

LC 71%

RBE

(50pts)

>70 Gy

RBE

(46pts)

 **year N°**

**Stage histology**

**Multidisciplinar**

 **Dose/N°**

**Proton**

**Observations**

**fractions**

**technique**

**patients**

 *treated with synchrotron*

 *technology* 

*(2013–2018);*

 *GU:* 

*genitourologic;*

 *GI:* 

*gastrointestinal;*

 *QoL: Quality of life; ADT: androgen deprivation.*


*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update DOI: http://dx.doi.org/10.5772/intechopen.94937*

> **Table9.**

 *Clinical experiences in miscellaneous neoplasms and cancer conditions treated with synchrotron technology (2015–2017); LC: Local Control.*

allocation of geriatric patients to PBT in the non-study situation is needed urgently [132].

### **4. Clinica Universidad de Navarra Proton Unit: early clinical experience**

In March 2020, after a 28 months installation period, the first cancer patient was treated. This is the first synchrotron equipment for PBT operating in Europe (**Figure 2**) and the third 360° gantry available for clinical use worldwide. (**Figure 3**). It is important to emphasize that the initiation of clinical activities was coincident with COVID pandemic, in one of the cities in the world (Madrid, Spain) with the more devastating epidemiologic and medical compromise. Under the strict institutional protective policy, none of the professionals involved in PBT

> intra-hospital process have had a positive test for COVID infection (up to the moment of writing the present manuscript October 2020), but several patients (11%) under treatment were detected to be infected along the treatment period

<30 20 36.3% >30 35 63.6%

Female 29 52.7% Male 26 47.3%

Yes 19 34.5% No 36 65.4%

Positive 6 11%

Brain 17 30.9% Skull base 4 7.3% Head & Neck 7 12.7% Thorax 5 9% Spine 8 14.5% Upper abdomen 2 3.6%

Median (range) 42 (3–86)

**#** %

55 100

*Distribution of exclusive synchrotron technology for PBT in the world. Institutions with active 360° gantry*

*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update*

*DOI: http://dx.doi.org/10.5772/intechopen.94937*

(**Table 10**).

N° patients

Age, years

Gender

Reirradiation

COVID-19

TUMOR Site

**107**

**Patient characteristics**

*equipment available.*

**Figure 3.**

#### **Figure 2.**

*Characteristics of the Proton Beam Therapy Unit structure at the Cancer Center Universidad de Navarra, CCUN (Madrid Campus, Spain).*

*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update DOI: http://dx.doi.org/10.5772/intechopen.94937*

#### **Figure 3.**

*Distribution of exclusive synchrotron technology for PBT in the world. Institutions with active 360° gantry equipment available.*

intra-hospital process have had a positive test for COVID infection (up to the moment of writing the present manuscript October 2020), but several patients (11%) under treatment were detected to be infected along the treatment period (**Table 10**).


#### *Proton Therapy - Current Status and Future Directions*


potentially improving local control and survival while at the same time reducing toxicity, carcinogenesis and improving quality of life. Synchrotron technology matches these benefits with proven reproducibility of its dosimetric properties and

*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update*

Despite the high potential of PBT, the clinical evidence supporting the broad use of protons is still under consolidation. The clinical data generated in institutions with synchrotron technology is abundant and of high scientific quality in terms of bibliometric records. An update has been summarized in the present publication. Clinical scientists operating with synchrotron proton beams are remarkably active in generating knowledge on topics such as cost effectiveness, the implementation of randomized trials and the collection of outcomes data in multi-institutional

Some fundamental issues to understand clinical outcomes are unsolved. This includes the equivalence of passive beams versus pencil beam radiation delivery and

From 2012 to 2017, both ASTRO's Emerging Technology Committee report and ASTRO Model Policy document on proton beam therapy consider its recommendation reasonable in instances where sparing the surrounding normal tissue cannot be adequately achieved with photon-based radiotherapy and is of added clinical benefit to the patient. Based on the medical necessity requirements or the generation of clinical evidence in IRB-approved clinical trials or in multi-institutional patient registries adhering to Medicare requirements, PBT is expanding widely in clinical

For a practicing oncologist evaluating treatment plans has uncertainties about the radiobiological equivalences (RBE) and other dosimetric elements that are taken into current models, which means that, the dose displayed on a commercial treatment plan is likely to be less accurate. These features are not intuitive for oncologists and allied cancer specialties clinicians and need further refinement in the assessment of dosimetric displays. It means the dose effects may extend past the isodose lines shown on paper, not considering certain uncertainties and this effect

Synchrotron technology is a component of the integral health care of a patient requiring radiotherapy and all the elements involved in the medical process need to be optimized to achieve an improved quality and safety standards in proton cancer

*"Authors express their recognition to all the health professionals involved in the initial efforts to start and consolidate the proton therapy program at Clinica Universidad de*

beyond the target will always be in non-target normal tissues [134].

the relative biological effectiveness (RBE) of protons which is simplistically assumed to have a constant value of 1.1. In reality, the RBE is variable and a complex function of the energy of protons, dose per fraction, tissue and cell type,

clinical observations.

*DOI: http://dx.doi.org/10.5772/intechopen.94937*

registries.

end point, etc.

practice [133].

therapy [135].

**Acknowledgements**

*Navarra in Spain".*

**Conflict of interest**

**109**

The authors declare no conflict of interest.

#### **Table 10.**

*Early clinical demographic data in patients treated in the Clinica Universidad de Navarra synchrotron PBT system: 6 months period (March–October 2020).*

#### **5. Conclusions**

In principle, PBT offers a substantial clinical advantage over conventional photon therapy. This is because of the unique dose-deposition characteristics of protons, which can be exploited to achieve significant reductions in normal tissue doses proximal and distal to the target volume. These may allow escalation of tumor doses and greater sparing of normal tissues from unnecessary irradiation exposure, thus

#### *Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update DOI: http://dx.doi.org/10.5772/intechopen.94937*

potentially improving local control and survival while at the same time reducing toxicity, carcinogenesis and improving quality of life. Synchrotron technology matches these benefits with proven reproducibility of its dosimetric properties and clinical observations.

Despite the high potential of PBT, the clinical evidence supporting the broad use of protons is still under consolidation. The clinical data generated in institutions with synchrotron technology is abundant and of high scientific quality in terms of bibliometric records. An update has been summarized in the present publication. Clinical scientists operating with synchrotron proton beams are remarkably active in generating knowledge on topics such as cost effectiveness, the implementation of randomized trials and the collection of outcomes data in multi-institutional registries.

Some fundamental issues to understand clinical outcomes are unsolved. This includes the equivalence of passive beams versus pencil beam radiation delivery and the relative biological effectiveness (RBE) of protons which is simplistically assumed to have a constant value of 1.1. In reality, the RBE is variable and a complex function of the energy of protons, dose per fraction, tissue and cell type, end point, etc.

From 2012 to 2017, both ASTRO's Emerging Technology Committee report and ASTRO Model Policy document on proton beam therapy consider its recommendation reasonable in instances where sparing the surrounding normal tissue cannot be adequately achieved with photon-based radiotherapy and is of added clinical benefit to the patient. Based on the medical necessity requirements or the generation of clinical evidence in IRB-approved clinical trials or in multi-institutional patient registries adhering to Medicare requirements, PBT is expanding widely in clinical practice [133].

For a practicing oncologist evaluating treatment plans has uncertainties about the radiobiological equivalences (RBE) and other dosimetric elements that are taken into current models, which means that, the dose displayed on a commercial treatment plan is likely to be less accurate. These features are not intuitive for oncologists and allied cancer specialties clinicians and need further refinement in the assessment of dosimetric displays. It means the dose effects may extend past the isodose lines shown on paper, not considering certain uncertainties and this effect beyond the target will always be in non-target normal tissues [134].

Synchrotron technology is a component of the integral health care of a patient requiring radiotherapy and all the elements involved in the medical process need to be optimized to achieve an improved quality and safety standards in proton cancer therapy [135].

#### **Acknowledgements**

*"Authors express their recognition to all the health professionals involved in the initial efforts to start and consolidate the proton therapy program at Clinica Universidad de Navarra in Spain".*

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Author details**

Felipe Angel Calvo Manuel<sup>1</sup> \*, Elena Panizo3 , Santiago M. Martin1 , Javier Serrano<sup>1</sup> , Mauricio Cambeiro<sup>1</sup> , Diego Azcona<sup>2</sup> , Daniel Zucca<sup>2</sup> , Borja Aguilar<sup>2</sup> , Alvaro Lassaletta<sup>3</sup> and Javier Aristu<sup>1</sup>

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1 Department of Radiation Oncology, Clinica Universidad de Navarra Cancer Center, Madrid-Pamplona, Spain

2 Department of Medical Physics, Clinica Universidad de Navarra Cancer Center, Madrid-Pamplona, Spain

3 Department of Pediatric Oncology, Clinica Universidad de Navarra Cancer Center, Madrid-Pamplona, Spain

\*Address all correspondence to: fcalvom@unav.es

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update DOI: http://dx.doi.org/10.5772/intechopen.94937*

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[102] Zhang X, Zhao K le, Guerrero TM, et al. Four-Dimensional Computed Tomography-Based Treatment Planning for Intensity-Modulated Radiation Therapy and Proton Therapy for Distal Esophageal Cancer. *Int J Radiat Oncol Biol Phys*. 2008;72(1):278–287. doi: 10.1016/j.ijrobp.2008.05.014

[103] Lin SH, Hobbs BP, Verma V, et al. Randomized phase IIB trial of proton beam therapy versus intensitymodulated radiation therapy for locally advanced esophageal cancer. J Clin Oncol. 2020;38(14):1569–1578. doi: 10.1200/JCO.19.02503

[104] Igaki H, Mizumoto M, Okumura T, Hasegawa K, Kokudo N, Sakurai H. A systematic review of publications on charged particle therapy for hepatocellular carcinoma. Int J Clin Oncol. 2018; 23(3):423–433. Doi: 10.1007/s10147-017-1190-2

[105] Chuong MD, Kaiser A, Khan F, et al. Consensus report from the Miami liver proton therapy conference. Front Oncol. 2019; 9(MAY):1–6. doi:10.3389/ fonc.2019.00457

mediastinal lymphomas: The international lymphoma radiation oncology group guidelines. Blood. 2018; 132(16):1635–1646. Doi: 10.1182/blood-

[113] Ricardi U, Dabaja B, Hodgson DC. Proton therapy in mediastinal Hodgkin lymphoma: moving from dosimetric prediction to clinical evidence. *Ann Oncol Off J Eur Soc Med Oncol*. 2017;28 (9):2049–2050. doi:10.1093/annonc/

*DOI: http://dx.doi.org/10.5772/intechopen.94937*

*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update*

[119] Pan HY, Jiang J, Hoffman KE, et al. Comparative toxicities and cost of intensity-modulated radiotherapy, proton radiation, and stereotactic body radiotherapy among younger men with prostate cancer. *J Clin Oncol*. 2018;36

(18):1823–1830. doi:10.1200/

[120] Iwata H, Ishikawa H, Takagi M, et al. Long-term outcomes of proton therapy for prostate cancer in Japan: a multi-institutional survey of the Japanese Radiation Oncology Study Group. *Cancer Med*. 2018;7(3):677–689.

[121] Nakajima K, Iwata H, Ogino H, et al. Acute toxicity of image-guided hypofractionated proton therapy for localized prostate cancer. *Int J Clin Oncol*. 2018;23(2):353–360. doi:10.1007/

[122] Takagi M, Demizu Y, Terashima K, et al. Long-term outcomes in patients treated with proton therapy for localized prostate cancer. *Cancer Med*. 2017;6(10):2234–2243. doi:10.1002/

[123] Rana S, Cheng CY, Zhao L, et al. Dosimetric and radiobiological impact of intensity modulated proton therapy and RapidArc planning for high-risk prostate cancer with seminal vesicles. *J Med Radiat Sci*. 2017;64(1):18–24. doi:

[124] Pugh TJ, Munsell MF, Choi S, et al.

Carmona R, et al. A prospective study of proton reirradiation for recurrent and secondary soft tissue sarcoma. *Radiother Oncol*. 2017;124(2):271–276. doi:10.1016/

Quality of life and toxicity from passively scattered and spot-scanning proton beam therapy for localized prostate cancer. *Int J Radiat Oncol Biol Phys*. 2013;87(5):946–953. doi:10.1016/j.

[125] Guttmann DM, Frick MA,

JCO.2017.75.5371

doi:10.1002/cam4.1350

s10147-017-1209-8

cam4.1159

10.1002/jmrs.175

ijrobp.2013.08.032

j.radonc.2017.06.024

[114] Rechner LA, Maraldo MV, Vogelius IR, et al. Life years lost attributable to late effects after radiotherapy for early stage Hodgkin lymphoma: The impact of proton therapy and/or deep inspiration breath hold. *Radiother Oncol*. 2017;125(1):41– 47. doi:10.1016/j.radonc.2017.07.033

[115] Zeng C, Plastaras JP, James P, et al. Proton pencil beam scanning for mediastinal lymphoma: treatment planning and robustness assessment. *Acta Oncol (Madr)*. 2016;55(9–10):1132–

[117] Takemoto S, Shibamoto Y, Sugie C, et al. Long-term results of intensitymodulated radiotherapy with three dose-fractionation regimens for localized prostate cancer. J Radiat Res. 2019; 60(2):221–227. doi:10.1093/jrr/

[118] Deville C, Jain A, Hwang WT, et al. Initial report of the genitourinary and gastrointestinal toxicity of postprostatectomy proton therapy for prostate cancer patients undergoing adjuvant or salvage radiotherapy. *Acta Oncol (Madr)*. 2018;57(11):1506–1514. doi:10.1080/0284186X.2018.1487583

1138. doi:10.1080/ 0284186X.2016.1191665

rry089

**119**

[116] Hoshina RM, Matsuura T, Umegaki K, Shimizu S. A Literature Review of Proton Beam Therapy for Prostate Cancer in Japan. J Clin Med. 2019; 8(1):48. Doi:10.3390/jcm8010048

2018-03-837633

mdx356

[106] Takahashi H, Mori K, Sekino Y, et al. Angiographic findings in patients with hepatocellular carcinoma previously treated using proton beam therapy. *J Oncol*. 2019;2019:4–11. doi: 10.1155/2019/3580379

[107] Chadha AS, Gunther JR, Hsieh CE, et al. Proton beam therapy outcomes for localized unresectable hepatocellular carcinoma. *Radiother Oncol*. 2019;133: 54–61. doi:10.1016/j.radonc.2018.10.041

[108] Hsieh CE, Venkatesulu BP, Lee CH, et al. Predictors of Radiation-Induced Liver Disease in Eastern and Western Patients With Hepatocellular Carcinoma Undergoing Proton Beam Therapy. *Int J Radiat Oncol Biol Phys*. 2019;105(1):73– 86. doi:10.1016/j.ijrobp.2019.02.032

[109] Sanford NN, Pursley J, Noe B, et al. Protons versus Photons for Unresectable Hepatocellular Carcinoma: Liver Decompensation and Overall Survival. *Int J Radiat Oncol Biol Phys*. 2019;105(1): 64–72. doi:10.1016/j.ijrobp.2019.01.076

[110] Hong TS, Wo JY, Yeap BY, et al. Multi-institutional phase II study of high-dose hypofractionated proton beam therapy in patients with localized, unresectable hepatocellular carcinoma and intrahepatic cholangiocarcinoma. *J Clin Oncol*. 2016;34(5):460–468. doi: 10.1200/JCO.2015.64.2710

[111] Grassberger C, Hong TS, Hato T, et al. Differential Association Between Circulating Lymphocyte Populations With Outcome After Radiation Therapy in Subtypes of Liver Cancer. *Int J Radiat Oncol Biol Phys*. 2018;101(5):1222–1225. doi:10.1016/j.ijrobp.2018.04.026

[112] Dabaja BS, Hoppe BS, Plastaras JP, et al. Proton therapy for adults with

*Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update DOI: http://dx.doi.org/10.5772/intechopen.94937*

mediastinal lymphomas: The international lymphoma radiation oncology group guidelines. Blood. 2018; 132(16):1635–1646. Doi: 10.1182/blood-2018-03-837633

[113] Ricardi U, Dabaja B, Hodgson DC. Proton therapy in mediastinal Hodgkin lymphoma: moving from dosimetric prediction to clinical evidence. *Ann Oncol Off J Eur Soc Med Oncol*. 2017;28 (9):2049–2050. doi:10.1093/annonc/ mdx356

[114] Rechner LA, Maraldo MV, Vogelius IR, et al. Life years lost attributable to late effects after radiotherapy for early stage Hodgkin lymphoma: The impact of proton therapy and/or deep inspiration breath hold. *Radiother Oncol*. 2017;125(1):41– 47. doi:10.1016/j.radonc.2017.07.033

[115] Zeng C, Plastaras JP, James P, et al. Proton pencil beam scanning for mediastinal lymphoma: treatment planning and robustness assessment. *Acta Oncol (Madr)*. 2016;55(9–10):1132– 1138. doi:10.1080/ 0284186X.2016.1191665

[116] Hoshina RM, Matsuura T, Umegaki K, Shimizu S. A Literature Review of Proton Beam Therapy for Prostate Cancer in Japan. J Clin Med. 2019; 8(1):48. Doi:10.3390/jcm8010048

[117] Takemoto S, Shibamoto Y, Sugie C, et al. Long-term results of intensitymodulated radiotherapy with three dose-fractionation regimens for localized prostate cancer. J Radiat Res. 2019; 60(2):221–227. doi:10.1093/jrr/ rry089

[118] Deville C, Jain A, Hwang WT, et al. Initial report of the genitourinary and gastrointestinal toxicity of postprostatectomy proton therapy for prostate cancer patients undergoing adjuvant or salvage radiotherapy. *Acta Oncol (Madr)*. 2018;57(11):1506–1514. doi:10.1080/0284186X.2018.1487583

[119] Pan HY, Jiang J, Hoffman KE, et al. Comparative toxicities and cost of intensity-modulated radiotherapy, proton radiation, and stereotactic body radiotherapy among younger men with prostate cancer. *J Clin Oncol*. 2018;36 (18):1823–1830. doi:10.1200/ JCO.2017.75.5371

[120] Iwata H, Ishikawa H, Takagi M, et al. Long-term outcomes of proton therapy for prostate cancer in Japan: a multi-institutional survey of the Japanese Radiation Oncology Study Group. *Cancer Med*. 2018;7(3):677–689. doi:10.1002/cam4.1350

[121] Nakajima K, Iwata H, Ogino H, et al. Acute toxicity of image-guided hypofractionated proton therapy for localized prostate cancer. *Int J Clin Oncol*. 2018;23(2):353–360. doi:10.1007/ s10147-017-1209-8

[122] Takagi M, Demizu Y, Terashima K, et al. Long-term outcomes in patients treated with proton therapy for localized prostate cancer. *Cancer Med*. 2017;6(10):2234–2243. doi:10.1002/ cam4.1159

[123] Rana S, Cheng CY, Zhao L, et al. Dosimetric and radiobiological impact of intensity modulated proton therapy and RapidArc planning for high-risk prostate cancer with seminal vesicles. *J Med Radiat Sci*. 2017;64(1):18–24. doi: 10.1002/jmrs.175

[124] Pugh TJ, Munsell MF, Choi S, et al. Quality of life and toxicity from passively scattered and spot-scanning proton beam therapy for localized prostate cancer. *Int J Radiat Oncol Biol Phys*. 2013;87(5):946–953. doi:10.1016/j. ijrobp.2013.08.032

[125] Guttmann DM, Frick MA, Carmona R, et al. A prospective study of proton reirradiation for recurrent and secondary soft tissue sarcoma. *Radiother Oncol*. 2017;124(2):271–276. doi:10.1016/ j.radonc.2017.06.024

[126] Hashimoto S, Shibamoto Y, Iwata H, et al. Whole-pelvic radiotherapy with spot-scanning proton beams for uterine cervical cancer: A planning study. *J Radiat Res*. 2016;57(5): 524–532. doi:10.1093/jrr/rrw052

[127] Haque W, Wages C, Zhu XR, et al. Proton therapy for seminoma: Case report describing the technique, efficacy, and advantages of protonbased therapy for seminoma. *Pract Radiat Oncol*. 2015;5(2):135–140. doi: 10.1016/j.prro.2014.07.006

[128] Pan HY, Jiang S, Sutton J, et al. Early experience with intensity modulated proton therapy for lungintact mesothelioma: A case series. *Pract Radiat Oncol*. 2015;5(4):e345-e353. doi: 10.1016/j.prro.2014.11.005

[129] Demizu Y, Mizumoto M, Onoe T, et al. Proton beam therapy for bone sarcomas of the skull base and spine: A retrospective nationwide multicenter study in Japan. *Cancer Sci*. 2017;108(5): 972–977. doi:10.1111/cas.13192

[130] Smith NL, Jethwa KR, Viehman JK, et al. Post-mastectomy intensity modulated proton therapy after immediate breast reconstruction: Initial report of reconstruction outcomes and predictors of complications. *Radiother Oncol*. 2019;140:76–83. doi:10.1016/j. radonc.2019.05.022

[131] Mutter RW, Remmes NB, Kahila MM, et al. Initial clinical experience of postmastectomy intensity modulated proton therapy in patients with breast expanders with metallic ports. *Pract Radiat Oncol*. 2017;7(4): e243-e252. doi:10.1016/j. prro.2016.12.002

[132] Thariat J, Sio T, Blanchard P, et al. Using Proton Beam Therapy in the Elderly Population: A Snapshot of Current Perception and Practice. Int J Radiat Oncol Biol Phys. 2017; 98(4):840– 842. doi: 10.1016/j.ijrobp.2017.01.007

[133] Mohan R, Grosshans D. Proton therapy – Present and future. Adv Drug Deliv Rev. 2017; 109:26–44. doi:10.1016/ j.addr.2016.11.006

[134] Woodward WA, Amos RA. Proton Radiation Biology Considerations for Radiation Oncologists. Int J Radiat Oncol Biol Phys. 2016; 95(1):59–61. doi: 10.1016/j.ijrobp.2015.10.022.

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**121**

**Chapter 9**

**Abstract**

**1. Introduction**

The Future of Proton Therapy

*Thomas J. FitzGerald, Linda Ding, Christopher Riberdy,* 

*Jack Bailey, Michael Anderegg, Ameer Elaimy, James Shen,* 

*Kevin O'Connor, Carla Bradford, I-Lin Kuo, Yankhua Fan,* 

*Fenghong Liu, Suhong Yu, Harry Bushe, Jonathan Saleeby,* 

Proton therapy is increasing in utilization worldwide at a rapid rate. With process improvements in costs, footprints, and continued advances in the delivery of care, including intensity modulation and image guidance, proton therapy may evolve into standard treatment with photon radiation therapy. This chapter reviews process improvements in proton therapy and the application in modern care.

In this chapter, issues associated with the current practice and future of proton therapy are presented including the costs of operation and financial risks involved with developing a program. With process improvements in costs, footprints, and continued advances in the delivery of care, including intensity modulation and image guidance, proton therapy may evolve into standard treatment with photon radiation therapy. In this chapter, process improvements in proton therapy and the

**2. The influence of process improvements in proton delivery systems**

Historically, proton therapy has always been perceived as an advantage for radiation oncology. With the first generation of proton therapy units, the advantage of sparing normal tissue with precision manipulation of the Bragg peak limiting exit dose to normal tissue structures has been viewed as an opportunity to escalate dose to tumor targets less amenable to photon therapy and limit dose to normal tissues in all body areas. Successful application of proton therapy for patient care has been acknowledged as self-evident in areas where sparing of normal tissue was of considerable importance. These situations include critical body locations where exit dose would be a distinct disadvantage. Lesions at the skull base treated with curative

**Keywords:** proton therapy, particle therapy, radiotherapy reimbursement

*Paul Rava, Shirin Sioshansi, M. Giulia Cicchetti,* 

*Janaki Moni, Eric Ko, Allison Sacher, Daniel Han* 

*and Maryann Bishop-Jodoin*

application in modern care are reviewed.

### **Chapter 9**

## The Future of Proton Therapy

*Thomas J. FitzGerald, Linda Ding, Christopher Riberdy, Jack Bailey, Michael Anderegg, Ameer Elaimy, James Shen, Kevin O'Connor, Carla Bradford, I-Lin Kuo, Yankhua Fan, Fenghong Liu, Suhong Yu, Harry Bushe, Jonathan Saleeby, Paul Rava, Shirin Sioshansi, M. Giulia Cicchetti, Janaki Moni, Eric Ko, Allison Sacher, Daniel Han and Maryann Bishop-Jodoin*

#### **Abstract**

Proton therapy is increasing in utilization worldwide at a rapid rate. With process improvements in costs, footprints, and continued advances in the delivery of care, including intensity modulation and image guidance, proton therapy may evolve into standard treatment with photon radiation therapy. This chapter reviews process improvements in proton therapy and the application in modern care.

**Keywords:** proton therapy, particle therapy, radiotherapy reimbursement

### **1. Introduction**

In this chapter, issues associated with the current practice and future of proton therapy are presented including the costs of operation and financial risks involved with developing a program. With process improvements in costs, footprints, and continued advances in the delivery of care, including intensity modulation and image guidance, proton therapy may evolve into standard treatment with photon radiation therapy. In this chapter, process improvements in proton therapy and the application in modern care are reviewed.

#### **2. The influence of process improvements in proton delivery systems**

Historically, proton therapy has always been perceived as an advantage for radiation oncology. With the first generation of proton therapy units, the advantage of sparing normal tissue with precision manipulation of the Bragg peak limiting exit dose to normal tissue structures has been viewed as an opportunity to escalate dose to tumor targets less amenable to photon therapy and limit dose to normal tissues in all body areas. Successful application of proton therapy for patient care has been acknowledged as self-evident in areas where sparing of normal tissue was of considerable importance. These situations include critical body locations where exit dose would be a distinct disadvantage. Lesions at the skull base treated with curative

intent and pediatric malignancies where limiting exit and integral dose would be a distinct advantage for amelioration of long-term effects on normal tissue, are some examples.

Up until the past decade, there were a limited number of proton facilities world wide and access to proton therapy was challenging and elusive. Footprints were extremely large and maintenance costs were significant. The planning for proton care required unique personnel. Devices to alter the Bragg peak had to be constructed for each proton field based on a rigorous process further complicated by the lack of volumetric three- and four-dimensional image anatomy to mill devices for the appropriate treatment. The team of physicists, dosimetrists, and therapists were often not aligned with other department efforts as the processes involved with proton therapy care required unique radiation therapy planning tools and different manners of therapy execution disparate from those applied to photon care. Proton therapy delivery, accordingly, could not function at an enterprise level and remained an eclectic subset of patient care units limited by access and availability. Accordingly, only a few institutions worldwide were able to provide proton care treatment delivery. Early generation units were difficult to maintain as they required unique engineering skills for daily therapy. Vehicles were not available to image validate daily therapy and, often due to the complexity of geometries, only a limited number of therapy fields could be treated in a single day further limiting the ability of proton therapy to function at a level commensurate with photon management.

Photon therapy delivery processes moved forward more quickly due to the nimble application of x-ray therapy tools and the ability to add diagnostic quality image guidance and extended collimation to linear accelerators for intensity modulation with and without modulated arc therapy. The footprint for linear accelerators was small by relative comparison and many corporate strategies aligned to integrate advanced technology imaging and therapeutic process improvements into them. As accelerators become more computer controlled, their down time became less associated with mechanical failure and more associated with computer driven issues. Cerrobend blocks were replaced by multi-leaf collimators which provided enhanced shaping of the beam both at the beam edge and in a dynamic manner within the field itself. Dynamic motion of the multi-leafs permitted alteration in beam intensity creating "beamlets" of radiation which could be aligned to the inverse topography of the target and normal tissue. Fluence profiles for photon therapy could be modulated and daily treatment reproducibility could be optimized and validated with portal dosimeters and adaptive therapy design.

Volume modulated arc therapy for photons has compressed treatment time with dynamic and simultaneous harmonization of gantry motion coupled with multileaf motion. This influenced and simplified motion management for radiosurgery and daily traditional therapy applications by significantly decreasing the time required for daily therapy. As a positive consequence, the risk of patient movement and motion of the target away from the intended target of therapy was limited, providing more security that the targets were correctly treated enhancing the quality of daily care. In many series, the quality of care has direct impact on patient outcome, therefore improved quality has the potential of maximizing tumor control and titration of the therapy effect on normal tissue function [1, 2]. Successful improvements in the application of photon care have moved the field forward at a rapid pace and vendors are evaluating the applicability of these improvements to proton care.

In contrast, proton care remained challenged by the footprint and strategy behind therapy application. The mechanics of particle delivery improved with the development of pencil beam application systems as these systems were more facile to apply care than passive scatter systems. Nevertheless, despite the

**123**

**Figure 1.**

*The Future of Proton Therapy*

an enterprise level [3–7].

*DOI: http://dx.doi.org/10.5772/intechopen.97935*

facilitating the integration of business models [8–15].

limitations in application strategy, the ability of limiting exit dose and improving the geometry of the application of radiation therapy for patient care remained alive in the minds of many radiation oncologists, physics application specialists, and cyclotron engineers; and, by the early part of the 21st Century, the ideas supporting proton delivery became increasingly realistic and able to function at

Initially, proton systems placed emphasis on traditional models of care which had multiple therapy gantries including research gantries aligned with a single central source to generate particles. The facilities cost hundreds of millions of dollars to construct and maintain, therefore considerable commitment and investment were required by all involved to insure a successful outcome for institutions and patients. The enthusiasm was generated by clinical altruism and institutional visibility. Institutions and facilities used multiple business models to achieve the objectives for design, construction, and implementation of care. Often the models were built on partnerships between otherwise competing institutions to manage costs. Institutions would also partner with business venture firms to share cost and profit. Multiple cottage industries grew from these partnerships. Disease areas of high patient volume were targeted for application to support the fiscal infrastructure of the program. Informatics tools permitted off-site management and planning,

The most important change occurred with miniaturization of proton design coupled with the integration of tools that have made photon care nimble and precise. The production of single gantry systems that could be directly integrated into department function has become a working model for the future of particle care (**Figure 1**). These systems offered a much smaller footprint at a significant cost reduction, thus making proton care achievable for institutions who otherwise could not consider particle therapy. This has evolved into a powerful tool and has permitted particle therapy to mature in many parts of the world. Proton care is no longer an eclectic sub-specialty of radiation therapy but a dynamic growing component of radiation therapy maturing at a rapid rate in parallel to photon care. There have been many challenges in reaching this point and more challenges lie ahead.

*Single gantry radiation therapy system. Copyright. Creative commons attribution license (CC BY) [16].*

#### *The Future of Proton Therapy DOI: http://dx.doi.org/10.5772/intechopen.97935*

*Proton Therapy - Current Status and Future Directions*

examples.

management.

intent and pediatric malignancies where limiting exit and integral dose would be a distinct advantage for amelioration of long-term effects on normal tissue, are some

Photon therapy delivery processes moved forward more quickly due to the nimble application of x-ray therapy tools and the ability to add diagnostic quality image guidance and extended collimation to linear accelerators for intensity modulation with and without modulated arc therapy. The footprint for linear accelerators was small by relative comparison and many corporate strategies aligned to integrate advanced technology imaging and therapeutic process improvements into them. As accelerators become more computer controlled, their down time became less associated with mechanical failure and more associated with computer driven issues. Cerrobend blocks were replaced by multi-leaf collimators which provided enhanced shaping of the beam both at the beam edge and in a dynamic manner within the field itself. Dynamic motion of the multi-leafs permitted alteration in beam intensity creating "beamlets" of radiation which could be aligned to the inverse topography of the target and normal tissue. Fluence profiles for photon therapy could be modulated and daily treatment reproducibility could be optimized and validated

Volume modulated arc therapy for photons has compressed treatment time with dynamic and simultaneous harmonization of gantry motion coupled with multileaf motion. This influenced and simplified motion management for radiosurgery and daily traditional therapy applications by significantly decreasing the time required for daily therapy. As a positive consequence, the risk of patient movement and motion of the target away from the intended target of therapy was limited, providing more security that the targets were correctly treated enhancing the quality of daily care. In many series, the quality of care has direct impact on patient outcome, therefore improved quality has the potential of maximizing tumor control and titration of the therapy effect on normal tissue function [1, 2]. Successful improvements in the application of photon care have moved the field forward at a rapid pace and vendors are evaluating the applicability of these improvements to proton care. In contrast, proton care remained challenged by the footprint and strategy behind therapy application. The mechanics of particle delivery improved with the development of pencil beam application systems as these systems were more facile to apply care than passive scatter systems. Nevertheless, despite the

with portal dosimeters and adaptive therapy design.

Up until the past decade, there were a limited number of proton facilities world wide and access to proton therapy was challenging and elusive. Footprints were extremely large and maintenance costs were significant. The planning for proton care required unique personnel. Devices to alter the Bragg peak had to be constructed for each proton field based on a rigorous process further complicated by the lack of volumetric three- and four-dimensional image anatomy to mill devices for the appropriate treatment. The team of physicists, dosimetrists, and therapists were often not aligned with other department efforts as the processes involved with proton therapy care required unique radiation therapy planning tools and different manners of therapy execution disparate from those applied to photon care. Proton therapy delivery, accordingly, could not function at an enterprise level and remained an eclectic subset of patient care units limited by access and availability. Accordingly, only a few institutions worldwide were able to provide proton care treatment delivery. Early generation units were difficult to maintain as they required unique engineering skills for daily therapy. Vehicles were not available to image validate daily therapy and, often due to the complexity of geometries, only a limited number of therapy fields could be treated in a single day further limiting the ability of proton therapy to function at a level commensurate with photon

**122**

limitations in application strategy, the ability of limiting exit dose and improving the geometry of the application of radiation therapy for patient care remained alive in the minds of many radiation oncologists, physics application specialists, and cyclotron engineers; and, by the early part of the 21st Century, the ideas supporting proton delivery became increasingly realistic and able to function at an enterprise level [3–7].

Initially, proton systems placed emphasis on traditional models of care which had multiple therapy gantries including research gantries aligned with a single central source to generate particles. The facilities cost hundreds of millions of dollars to construct and maintain, therefore considerable commitment and investment were required by all involved to insure a successful outcome for institutions and patients. The enthusiasm was generated by clinical altruism and institutional visibility. Institutions and facilities used multiple business models to achieve the objectives for design, construction, and implementation of care. Often the models were built on partnerships between otherwise competing institutions to manage costs. Institutions would also partner with business venture firms to share cost and profit. Multiple cottage industries grew from these partnerships. Disease areas of high patient volume were targeted for application to support the fiscal infrastructure of the program. Informatics tools permitted off-site management and planning, facilitating the integration of business models [8–15].

The most important change occurred with miniaturization of proton design coupled with the integration of tools that have made photon care nimble and precise. The production of single gantry systems that could be directly integrated into department function has become a working model for the future of particle care (**Figure 1**). These systems offered a much smaller footprint at a significant cost reduction, thus making proton care achievable for institutions who otherwise could not consider particle therapy. This has evolved into a powerful tool and has permitted particle therapy to mature in many parts of the world. Proton care is no longer an eclectic sub-specialty of radiation therapy but a dynamic growing component of radiation therapy maturing at a rapid rate in parallel to photon care. There have been many challenges in reaching this point and more challenges lie ahead.

Nevertheless, proton care now has a solid footprint in clinical radiation therapy and will continue to grow moving forward [17–24].

#### **3. Financial considerations**

Proton therapy systems require a strong financial commitment from institutions and financial partners. Investments of \$200 million and higher were required to build centers with multiple gantries. Investors and institutions needed security to insure their investment would merit the expense required for construction, operation, and maintenance. Business models were designed anticipating predictable high-volume radiation therapy. Many of these models were based on the treatment of prostate cancer anticipating a paradigm shift away from surgery and photonbased therapy strategies. This was an attractive model as dose distribution to normal tissues including bladder and rectum appeared superior and would accordingly be supported by insurers and third-party support systems.

Many payors, however, chose not to support proton therapy for prostate care due in part to the successful application of advancements in using photons. The ability to alter fluence profiles over the entire radiation therapy treatment field coupled with the ability to document positioning with kilovoltage (kV) fiducial tracking and volumetric computer tomography created a significant paradigm shift in the treatment of prostate cancer. Multiple photon-based trials demonstrated both outstanding local control and minimal treatment sequelae with photon based image-guided intensity-modulated radiation therapy (IMRT) and, as such, it was challenging to demonstrate clinical improvement with the use of protons despite unambiguous improvements in dose distribution to normal tissue with proton care. Because a statistically significant improvement in normal tissue outcome could not be demonstrated between photon and proton therapy, many payors decided not to support the cost of proton therapy for prostate cancer. A typical comparable American Medical Accounting and Consulting (AMAC) reimbursement for a cancer patient treated with proton therapy versus intensity modulated photon therapy results in a greater than \$16 thousand increase per patient revenue for proton therapy, hence the reason for pause in approval and requirement of clinical improvement outcome data to re-visit the discussion.

For most radiation therapy departments, the three largest disease treatment groups are breast cancer, thoracic/lung cancer, and genitourinary (GU)/prostate cancer. In many departments with standard surgical sub-specialty care institutional colleagues, these disease groups in aggregate, comprise 25–35% of the patient population on treatment. Therefore, to justify proton care with multiple gantry platforms, a common therapy disease site would help secure the fiscal security required for investment. Business models were often driven by predictions for prostate cancer management and when reimbursement models changed, and prostate cancer therapy was no longer supported by insurance carriers, many proton centers faced fiscal uncertainty. There were centers in the United States that entered bankruptcy and one center closed because of fiscal challenges maintaining the facility. The future of multiple gantry centers became less certain. Institutions in large metropolitan areas with an integrated prominent bandwidth for a referral network remained successful, however it became less certain that proton care could successfully enter geographic regions of more limited population centers in medical markets with competition. For proton centers to survive the new era of fiscal compromise where reimbursement may not be commensurate with investment and cost, proton application would need to become more cost effective and demonstrate clinical advantage in multiple disease groups.

**125**

*The Future of Proton Therapy*

*DOI: http://dx.doi.org/10.5772/intechopen.97935*

proton development moving forward [25, 26].

among the physics and therapy staff [25, 26].

**4. Adjustments in proton footprint for future care**

Significant progress has been made in the development of proton delivery systems and cost has evolved to become achievable with effort for institutions who could otherwise not consider particle therapy. The technology has made considerable progress over the past two decades and will continue to improve. The footprint will become smaller and more compressed. This will increase the likelihood that proton facilities can be located in closer approximation to traditional photon facilities and conceivably be placed in photon vaults, saving cost of construction. Current single gantry optimal building strategies build out from facilities with a general cost of \$6 million for construction costs. Being able to build and install particle therapy into traditional departments and photon vaults will save cost and serve to bring particle therapy to the staff creating synergy for all department full time employees (FTE). Photon care today has extraordinary image guidance and intensity modulation with tools for optical tracking and patient care has never been better. This has created nimble treatment that can be validated and treated in a few minutes. The goal for proton care moving forward is to integrate to advantages of photon care into the proton footprint. This would include tools for image guidance, beam precision, and optical tracking as well as create synergy and integration

Approximately 12 years ago, single gantry proton units came to market and the paradigm of care changed. The units had a more attractive cost at a fraction of multi-gantry facilities with a smaller footprint for construction and maintenance. Although the initial units had challenges with image guidance and nimble platforms for treatment execution, over the past decade process improvements in these areas have made the execution of proton treatment the near equivalent of photon therapy. Coupled with the advantage of dose distribution, institutions have been able to revisit their cancer center specific strategic plans and incorporate proton units into their capital equipment plans for the next generation of radiation oncology. Companies manufacturing proton single gantry cyclotrons may or may not be aligned with the production of photon linear accelerators. Those aligned may have a long-term advantage in their ability to integrate photon and proton planning into a single overarching system and more easily transfer patient care between units on an as needed basis. Nevertheless, it is a unique time in the history of radiation therapy as proton care has now moved to enterprise function with multiple proton facilities throughout the United States and the world. Many institutions are planning for proton construction in the near future. The investment must be planned with a strategy for growth. Although the cost is significantly less than previous multiple gantry systems, cost remains significantly higher than photon therapy and the advantages must balance the investment for financial security. Although in selected circumstances proton care is reimbursed by insurance carriers at a higher level per treatment, it is not clear and in fact unlikely the reimbursement models will remain at current levels. Proposals over the past several years have suggested movement to a single model of reimbursement agnostic of therapy approach, implying that proton and photon case reimbursement including the use of advanced technologies would be identical. Although these models for reimbursement have not yet been implemented, institutions planning on developing proton care must remain cognizant that reimbursement models will likely change in the near future and a strategy for both growth and cost containment must be incorporated into the business plan for

#### *The Future of Proton Therapy DOI: http://dx.doi.org/10.5772/intechopen.97935*

*Proton Therapy - Current Status and Future Directions*

will continue to grow moving forward [17–24].

supported by insurers and third-party support systems.

**3. Financial considerations**

data to re-visit the discussion.

clinical advantage in multiple disease groups.

Nevertheless, proton care now has a solid footprint in clinical radiation therapy and

Proton therapy systems require a strong financial commitment from institutions and financial partners. Investments of \$200 million and higher were required to build centers with multiple gantries. Investors and institutions needed security to insure their investment would merit the expense required for construction, operation, and maintenance. Business models were designed anticipating predictable high-volume radiation therapy. Many of these models were based on the treatment of prostate cancer anticipating a paradigm shift away from surgery and photonbased therapy strategies. This was an attractive model as dose distribution to normal tissues including bladder and rectum appeared superior and would accordingly be

Many payors, however, chose not to support proton therapy for prostate care due in part to the successful application of advancements in using photons. The ability to alter fluence profiles over the entire radiation therapy treatment field coupled with the ability to document positioning with kilovoltage (kV) fiducial tracking and volumetric computer tomography created a significant paradigm shift in the treatment of prostate cancer. Multiple photon-based trials demonstrated both outstanding local control and minimal treatment sequelae with photon based image-guided intensity-modulated radiation therapy (IMRT) and, as such, it was challenging to demonstrate clinical improvement with the use of protons despite unambiguous improvements in dose distribution to normal tissue with proton care. Because a statistically significant improvement in normal tissue outcome could not be demonstrated between photon and proton therapy, many payors decided not to support the cost of proton therapy for prostate cancer. A typical comparable American Medical Accounting and Consulting (AMAC) reimbursement for a cancer patient treated with proton therapy versus intensity modulated photon therapy results in a greater than \$16 thousand increase per patient revenue for proton therapy, hence the reason for pause in approval and requirement of clinical improvement outcome

For most radiation therapy departments, the three largest disease treatment groups are breast cancer, thoracic/lung cancer, and genitourinary (GU)/prostate cancer. In many departments with standard surgical sub-specialty care institutional colleagues, these disease groups in aggregate, comprise 25–35% of the patient population on treatment. Therefore, to justify proton care with multiple gantry platforms, a common therapy disease site would help secure the fiscal security required for investment. Business models were often driven by predictions for prostate cancer management and when reimbursement models changed, and prostate cancer therapy was no longer supported by insurance carriers, many proton centers faced fiscal uncertainty. There were centers in the United States that entered bankruptcy and one center closed because of fiscal challenges maintaining the facility. The future of multiple gantry centers became less certain. Institutions in large metropolitan areas with an integrated prominent bandwidth for a referral network remained successful, however it became less certain that proton care could successfully enter geographic regions of more limited population centers in medical markets with competition. For proton centers to survive the new era of fiscal compromise where reimbursement may not be commensurate with investment and cost, proton application would need to become more cost effective and demonstrate

**124**

Approximately 12 years ago, single gantry proton units came to market and the paradigm of care changed. The units had a more attractive cost at a fraction of multi-gantry facilities with a smaller footprint for construction and maintenance. Although the initial units had challenges with image guidance and nimble platforms for treatment execution, over the past decade process improvements in these areas have made the execution of proton treatment the near equivalent of photon therapy. Coupled with the advantage of dose distribution, institutions have been able to revisit their cancer center specific strategic plans and incorporate proton units into their capital equipment plans for the next generation of radiation oncology. Companies manufacturing proton single gantry cyclotrons may or may not be aligned with the production of photon linear accelerators. Those aligned may have a long-term advantage in their ability to integrate photon and proton planning into a single overarching system and more easily transfer patient care between units on an as needed basis. Nevertheless, it is a unique time in the history of radiation therapy as proton care has now moved to enterprise function with multiple proton facilities throughout the United States and the world. Many institutions are planning for proton construction in the near future. The investment must be planned with a strategy for growth. Although the cost is significantly less than previous multiple gantry systems, cost remains significantly higher than photon therapy and the advantages must balance the investment for financial security. Although in selected circumstances proton care is reimbursed by insurance carriers at a higher level per treatment, it is not clear and in fact unlikely the reimbursement models will remain at current levels. Proposals over the past several years have suggested movement to a single model of reimbursement agnostic of therapy approach, implying that proton and photon case reimbursement including the use of advanced technologies would be identical. Although these models for reimbursement have not yet been implemented, institutions planning on developing proton care must remain cognizant that reimbursement models will likely change in the near future and a strategy for both growth and cost containment must be incorporated into the business plan for proton development moving forward [25, 26].

#### **4. Adjustments in proton footprint for future care**

Significant progress has been made in the development of proton delivery systems and cost has evolved to become achievable with effort for institutions who could otherwise not consider particle therapy. The technology has made considerable progress over the past two decades and will continue to improve. The footprint will become smaller and more compressed. This will increase the likelihood that proton facilities can be located in closer approximation to traditional photon facilities and conceivably be placed in photon vaults, saving cost of construction. Current single gantry optimal building strategies build out from facilities with a general cost of \$6 million for construction costs. Being able to build and install particle therapy into traditional departments and photon vaults will save cost and serve to bring particle therapy to the staff creating synergy for all department full time employees (FTE). Photon care today has extraordinary image guidance and intensity modulation with tools for optical tracking and patient care has never been better. This has created nimble treatment that can be validated and treated in a few minutes. The goal for proton care moving forward is to integrate to advantages of photon care into the proton footprint. This would include tools for image guidance, beam precision, and optical tracking as well as create synergy and integration among the physics and therapy staff [25, 26].

This idea has begun to mature. Image guidance has played an important role in providing security in daily patient setup well beyond what could be achieved with kV imaging. The addition of both diagnostic kV imaging and cone beam computer tomography has brought a new era to radiation treatments and has permitted radiation oncologists to titrate target volumes due to the confidence in daily set up. Proton centers are beginning to integrate imaging strategies into daily care including ring-based geometries to secure volumetric set up for treatment. Many centers now use multi-leaf collimators to provide intensity modulation including strategies to apply small volume radiosurgery with proton therapy. Flash therapy is being applied with electrons, photons, and now protons. The more particle care can synergize with the advances in photon care, proton care can be easily integrated into the work flow of department management.

Artificial intelligence will play an increasing role in the daily practice of radiation oncology. Even early iterations of artificial intelligence have provided both consistent normal tissue contouring and enhancement of planning function for dosimetry and physics planning staff. This saves time and effort permitting planning staff to focus more on the important planning tasks at hand and could serve to introduce particle planning strategies to all planning staff. An appropriate economy of scale for staff could be created so not to segregate staff into separate divisions as contouring of normal tissue and tumor targets is therapy agnostic. The ultimate therapy approach can be applied for photon/proton per assessment of benefit to the patient including insurance requirements. Department functions can become more transparent between staff as artificial intelligence matures and ultimately resides in a single planning system that manufacturers that participate in developing both photon and proton treatment units. Staff can become familiar with the tools of therapy as the processes of plan development and therapy execution become more parallel and aligned [27].

#### **5. Strategy for the future**

Historical models of radiation oncology departments offering photon and proton care had FTE including physicists and therapists that were skilled in their specific area with little overlap in function, therefore there were redundancies and no economy of scale for the FTE. This was due to the disparate nature of treatment planning and treatment delivery creating silos in the department without hybrid function. Even engineering skills and requirements were disparate and FTE functioned in independent areas with minimal overlap in work flow, resulting in increased cost and challenging to function with backfill staff support between the teams. The process of care and the planning of care were and currently remain different requiring separate computer operation systems further separating work flow. The infrastructure required for proton care was unique and planning for care required separate modeling systems. This was necessary by default and hybrid strategies to provide an economy of scale for individual FTE could not be developed because the employee skill set could not co-exist in a hybrid model. Even today, many proton manufacturers do not participate in developing photon patient care. As reimbursement models change and become agnostic to radiation therapy technique, there will be more effort to move this strategy into a different pathway as reimbursement for proton care will become more aligned with photon care. It will be necessary for departments to provide hybrid strategies as reimbursement becomes photon/particle transparent and internal economies of scale for patient care will need to be enhanced [25–38].

**127**

*The Future of Proton Therapy*

*DOI: http://dx.doi.org/10.5772/intechopen.97935*

the capacity for motion management.

tracking, intensity modulation, and image guidance.

To accomplish these important objectives, proton care of the future will need to become more cost aligned with current costs of photon care. Cost for photon care has increased over the past decade as process improvements in intensity modulation, image guidance, and optical tracking have become commonplace in a department. Computer operations require cost including upgrades and institutions need to be prepared to undergo constant process improvements and support these improvements for cost. Cost of vault construction and modern linear accelerators can now exceed \$5 million for photon care as the cost includes tools for optical

The current cost of vault construction and build out for single gantry cyclotron function is now in the minimal range of \$30 million with \$6 million dedicated to vault construction as a build out from the primary facility and \$24 million for the equipment. It is likely that adding many of the current areas of flexibility now used with routine for photon care including optical tracking, intensity modulation, and image guidance will increase cost for the next iterative application of proton care. Proton care will need to continue to work on cost and the current belief is cost will decrease with volume-based adjustments. Specifically, once proton units become more numerous and populated worldwide, cost may decrease over time as expenses can be modified based on the redundancy of production. This will require further miniaturization of the proton footprint in a manner similar to the photon footprint including the computer operations. Couch function for proton care will likewise need to adjust to the flexibility of protons including further improvements in the precision of proton care delivery. This has begun with the introduction of multileaf collimation. Photon multi-leaf collimation has provided field size adjustment with significant precision and efforts to apply this technology will further support proton care in ultra-small targets identical to photons. The stereotactic body radiosurgery tools have been well developed for photons. Given the improved radiation therapy dose distribution for protons, applying radiosurgery techniques for protons in the similar manner used for photon care will improve patient outcome including

Continued miniaturization and re-modeling of existing technology for the generation of protons will continue to decrease cost with smaller footprints and more limited shielding. This will continue to make proton care more affordable. One of the smallest footprints is generated by a high-energy superconducting synchrocyclotron which eliminates the need for complex magnet-guided beamlines. This also serves to optimize power consumption further reducing cost of maintenance. Designs facilitating upgrades of hardware are important to limit future costs. Technologies including dielectric wall accelerator units and proton plasma acceleration may pivot the strategy for the infrastructure for these units and promote further change in cost and footprint. Of equal importance, protons are now being used to treat malignancies of all cell types and tissues of origin. Independent of cell type and body site of disease, dose distribution is simply better with protons and the improvements can be applied across all epithelial and liquid disease sites. The challenge has uniformly been in proof of principle. Although dose to normal tissue can be titrated with protons in nearly all body areas, demonstrating with statistical significance the benefit of dose reduction is not a simple or straightforward task as scoring a null event for significance requires large cohorts of patients with decades of follow up. This creates a challenge to score tissues of limited self-renewal capacity such as heart and lung for late effects. While many feel the advantage or proton dosimetry is self-evident, it remains to be proven to payers that the improvements provide the efficacy to balance the cost. Both areas require process improvements as we are obliged to provide effective and safe care

#### *The Future of Proton Therapy DOI: http://dx.doi.org/10.5772/intechopen.97935*

*Proton Therapy - Current Status and Future Directions*

the work flow of department management.

parallel and aligned [27].

**5. Strategy for the future**

care will need to be enhanced [25–38].

This idea has begun to mature. Image guidance has played an important role in providing security in daily patient setup well beyond what could be achieved with kV imaging. The addition of both diagnostic kV imaging and cone beam computer tomography has brought a new era to radiation treatments and has permitted radiation oncologists to titrate target volumes due to the confidence in daily set up. Proton centers are beginning to integrate imaging strategies into daily care including ring-based geometries to secure volumetric set up for treatment. Many centers now use multi-leaf collimators to provide intensity modulation including strategies to apply small volume radiosurgery with proton therapy. Flash therapy is being applied with electrons, photons, and now protons. The more particle care can synergize with the advances in photon care, proton care can be easily integrated into

Artificial intelligence will play an increasing role in the daily practice of radiation oncology. Even early iterations of artificial intelligence have provided both consistent normal tissue contouring and enhancement of planning function for dosimetry and physics planning staff. This saves time and effort permitting planning staff to focus more on the important planning tasks at hand and could serve to introduce particle planning strategies to all planning staff. An appropriate economy of scale for staff could be created so not to segregate staff into separate divisions as contouring of normal tissue and tumor targets is therapy agnostic. The ultimate therapy approach can be applied for photon/proton per assessment of benefit to the patient including insurance requirements. Department functions can become more transparent between staff as artificial intelligence matures and ultimately resides in a single planning system that manufacturers that participate in developing both photon and proton treatment units. Staff can become familiar with the tools of therapy as the processes of plan development and therapy execution become more

Historical models of radiation oncology departments offering photon and proton care had FTE including physicists and therapists that were skilled in their specific area with little overlap in function, therefore there were redundancies and no economy of scale for the FTE. This was due to the disparate nature of treatment planning and treatment delivery creating silos in the department without hybrid function. Even engineering skills and requirements were disparate and FTE functioned in independent areas with minimal overlap in work flow, resulting in increased cost and challenging to function with backfill staff support between the teams. The process of care and the planning of care were and currently remain different requiring separate computer operation systems further separating work flow. The infrastructure required for proton care was unique and planning for care required separate modeling systems. This was necessary by default and hybrid strategies to provide an economy of scale for individual FTE could not be developed because the employee skill set could not co-exist in a hybrid model. Even today, many proton manufacturers do not participate in developing photon patient care. As reimbursement models change and become agnostic to radiation therapy technique, there will be more effort to move this strategy into a different pathway as reimbursement for proton care will become more aligned with photon care. It will be necessary for departments to provide hybrid strategies as reimbursement becomes photon/particle transparent and internal economies of scale for patient

**126**

To accomplish these important objectives, proton care of the future will need to become more cost aligned with current costs of photon care. Cost for photon care has increased over the past decade as process improvements in intensity modulation, image guidance, and optical tracking have become commonplace in a department. Computer operations require cost including upgrades and institutions need to be prepared to undergo constant process improvements and support these improvements for cost. Cost of vault construction and modern linear accelerators can now exceed \$5 million for photon care as the cost includes tools for optical tracking, intensity modulation, and image guidance.

The current cost of vault construction and build out for single gantry cyclotron function is now in the minimal range of \$30 million with \$6 million dedicated to vault construction as a build out from the primary facility and \$24 million for the equipment. It is likely that adding many of the current areas of flexibility now used with routine for photon care including optical tracking, intensity modulation, and image guidance will increase cost for the next iterative application of proton care. Proton care will need to continue to work on cost and the current belief is cost will decrease with volume-based adjustments. Specifically, once proton units become more numerous and populated worldwide, cost may decrease over time as expenses can be modified based on the redundancy of production. This will require further miniaturization of the proton footprint in a manner similar to the photon footprint including the computer operations. Couch function for proton care will likewise need to adjust to the flexibility of protons including further improvements in the precision of proton care delivery. This has begun with the introduction of multileaf collimation. Photon multi-leaf collimation has provided field size adjustment with significant precision and efforts to apply this technology will further support proton care in ultra-small targets identical to photons. The stereotactic body radiosurgery tools have been well developed for photons. Given the improved radiation therapy dose distribution for protons, applying radiosurgery techniques for protons in the similar manner used for photon care will improve patient outcome including the capacity for motion management.

Continued miniaturization and re-modeling of existing technology for the generation of protons will continue to decrease cost with smaller footprints and more limited shielding. This will continue to make proton care more affordable. One of the smallest footprints is generated by a high-energy superconducting synchrocyclotron which eliminates the need for complex magnet-guided beamlines. This also serves to optimize power consumption further reducing cost of maintenance. Designs facilitating upgrades of hardware are important to limit future costs. Technologies including dielectric wall accelerator units and proton plasma acceleration may pivot the strategy for the infrastructure for these units and promote further change in cost and footprint. Of equal importance, protons are now being used to treat malignancies of all cell types and tissues of origin. Independent of cell type and body site of disease, dose distribution is simply better with protons and the improvements can be applied across all epithelial and liquid disease sites. The challenge has uniformly been in proof of principle. Although dose to normal tissue can be titrated with protons in nearly all body areas, demonstrating with statistical significance the benefit of dose reduction is not a simple or straightforward task as scoring a null event for significance requires large cohorts of patients with decades of follow up. This creates a challenge to score tissues of limited self-renewal capacity such as heart and lung for late effects. While many feel the advantage or proton dosimetry is self-evident, it remains to be proven to payers that the improvements provide the efficacy to balance the cost. Both areas require process improvements as we are obliged to provide effective and safe care

with proton manufacturers remaining responsible for cost reduction to promote its application at an enterprise level [28–38].

#### **6. Summary**

Since its inception, proton care has been an important component of radiation therapy. Because of the challenges of size and infrastructure, centers of operation were few and application of proton care remained eclectic as photon therapy matured at a rapid rate with significant process improvements for treatment delivery and validation. Proton centers became more numerous during the past two decades in the United States and with the development of single gantry systems, smaller units became commercially available at a more affordable cost that could be reached by health care institutions and private oncology systems. The number of centers has significantly increased over the past decade and protons are now used with more routine in multiple disease sites worldwide. In selected clinical protocols, twenty-five percent of pediatric patients treated with radiation therapy are treated with protons. Proton dosimetry has provided decrease dose to normal tissue in all disease sites with therapeutic advantages in all body areas. At one level, if cost can be contained and hybrid workflow strategies can be developed, one can envision proton care as an equal partner to photon care for the next generation of radiation oncologists [34, 35].

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Author details**

Thomas J. FitzGerald1 \*, Linda Ding1 , Christopher Riberdy1 , Jack Bailey1 , Michael Anderegg2 , Ameer Elaimy1 , James Shen1 , Kevin O'Connor1 , Carla Bradford1 , I-Lin Kuo1 , Yankhua Fan1 , Fenghong Liu1 , Suhong Yu1 , Harry Bushe1 , Jonathan Saleeby1 , Paul Rava1 , Shirin Sioshansi1 , M. Giulia Cicchetti1 , Janaki Moni1 , Eric Ko1 , Allison Sacher1 , Daniel Han1 and Maryann Bishop-Jodoin1

1 Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, MA, USA

2 Cancer Center, University of Massachusetts Medical School, Worcester, MA, USA

\*Address all correspondence to: tj.fitzgerald@umassmemorial.org

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**129**

pbc21530.

*The Future of Proton Therapy*

**References**

*DOI: http://dx.doi.org/10.5772/intechopen.97935*

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[8] Zap! You're not dead. The Economist.

[9] Whalen D, Langreth R. The \$150 Million Zapper: Does every Cancer Patient Really Need Proton Beam

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[12] Smith A. Vision 20/20: Proton therapy. Medical Physics. 2009; 36(2):556-568. DOI:10.1118/

[13] Chao HH, Berman AT, Simone CB 2nd, Ciunci C, Gabriel P, Lin H, Both S,

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[2] Fairchild A, Straube W, Laurie F, Followill D. Does quality of radiation therapy predict outcomes of multicenter cooperative group trials? A literature review. International Journal of Radiation Oncology Biology Physics. 2013;87(2) 246-260. DOI:10.1016/j.

[3] St Clair WH, Adams JA, Bues M, Fullerton BC, La Shell S, Kooy HM, Loeffler JS, Tarbell NJ. Advantage of protons compared to conventional X-ray/IMRT in treatment of a pediatric

patient with medulloblastoma. International Journal of Radiation

[4] Merchant TE, Hua CH, Shukla H, Ying X, Nill S, Oelfke U. Proton versus photon radiotherapy for common brain tumors; comparison of characteristics and their relationship to cognitive function. Pediatric Blood & Cancer. 2008;51(1):110-117. DOI:10.1002/

[5] Yuan TZ, Zhan ZJ, Qian CN. New frontiers in proton therapy: Applications in cancers. Cancer Communications.

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[6] Slater JM, Slater JD, Kang JI, Namihas IC, Jabola BR, Brown K, Grove R, Watt C, Bush DA.

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ijrobp.2013.03.036.

### **References**

*Proton Therapy - Current Status and Future Directions*

its application at an enterprise level [28–38].

with proton manufacturers remaining responsible for cost reduction to promote

Since its inception, proton care has been an important component of radiation therapy. Because of the challenges of size and infrastructure, centers of operation were few and application of proton care remained eclectic as photon therapy matured at a rapid rate with significant process improvements for treatment delivery and validation. Proton centers became more numerous during the past two decades in the United States and with the development of single gantry systems, smaller units became commercially available at a more affordable cost that could be reached by health care institutions and private oncology systems. The number of centers has significantly increased over the past decade and protons are now used with more routine in multiple disease sites worldwide. In selected clinical protocols, twenty-five percent of pediatric patients treated with radiation therapy are treated with protons. Proton dosimetry has provided decrease dose to normal tissue in all disease sites with therapeutic advantages in all body areas. At one level, if cost can be contained and hybrid workflow strategies can be developed, one can envision proton care as an equal partner to photon care for the next generation of radiation

**128**

**Author details**

oncologists [34, 35].

**Conflict of interest**

**6. Summary**

Thomas J. FitzGerald1

Michael Anderegg2

Worcester, MA, USA

Carla Bradford1

Harry Bushe1

Janaki Moni1

\*, Linda Ding1

, Allison Sacher1

\*Address all correspondence to: tj.fitzgerald@umassmemorial.org

, Yankhua Fan1

, Paul Rava1

, Ameer Elaimy1

The authors declare no conflict of interest.

, I-Lin Kuo1

provided the original work is properly cited.

, Eric Ko1

, Jonathan Saleeby1

, Christopher Riberdy1

, Daniel Han1

, Fenghong Liu1

, Shirin Sioshansi1

, James Shen1

1 Department of Radiation Oncology, University of Massachusetts Medical School,

2 Cancer Center, University of Massachusetts Medical School, Worcester, MA, USA

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, Jack Bailey1

, Suhong Yu1

,

and Maryann Bishop-Jodoin1

, Kevin O'Connor1

,

,

, M. Giulia Cicchetti1

,

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clinical\_indications\_paper\_ hodgkin\_va.pdf.

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[26] Contreras J, Zhao T, Perkins S, Sun B, Goddu S, Mutic S, Bottani B, Endicott S, Michalski J, Robinson C, Tsien C, Huang J, Fischer-Valuck BW, Hallahan D, Klein E, Bradley J. The world's direct single room proton therapy facility: Two-year experience. Practical Radiation Oncology. 2017;7(1):e71-e76. DOI: 10.1016/j. prro.2016.07.003.

**131**

*The Future of Proton Therapy*

*DOI: http://dx.doi.org/10.5772/intechopen.97935*

2017;99(3):667-676. DOI: 10.1016/j.

[32] Hirano Y, Onozawa M, Hojo H, Motegi A, Zenda S, Hotta K, Moriya S, Tachibana H, Nakamura N, Kojima T, Akimoto T. Dosimetric comparison between proton beam therapy and photon radiation therapy for locally advanced esophageal squamous cell carcinoma. Radiation Oncology. 2018;13(1):23. DOI:10.1186/

[33] Warren S, Hurt CN, Crosby T, Partridge M, Hawkins MA. Potential of proton therapy to reduce hematologic toxicity for esophageal cancer. International Journal of Radiation

2017;99(3):729-737. DOI:10.1016/j.

[34] Chang J, Zhang X, Wang X Kang Y, Riley B, Bilton S, Mohan R, Komaki R, Cox JD. Significant reduction in normal tissue dose by proton radiotherapy compared with three dimensional conformal or intensity modulated radiation therapy for stage 1 or stage 3 non-small cell lung cancer. International Journal of Radiation Oncology Biology Physics. 2006;65(4):1087-1096. DOI:

[35] Apinorasethkul O, Kirk M, Teo K, Swisher-McClure S, Lukens JN, Lin A. Pencil beam scanning proton therapy vs rotational arc radiation therapy: A treatment planning comparison for post-operative oropharyngeal cancer. Medical Dosimetry. 2017;42(1):7-11. DOI:10.1016/j.meddos 2016.09.004.

[36] Blanchard P, Garden AS, Gunn GB,

Hernandez M, Crutison J, Lee JJ, Ye R,

Rosenthal DI, Morrison WH,

Fuller CD, Mohamed AS, Hutcheson KA, Holliday EB, Thaker NG, Sturgis EM, Kies MS, Zhu XR, Mohan R, Frank SJ. Intensity modulated proton therapy (IMPT) versus intensity modulated photon

Oncology Biology Physics.

ijrobp.2017.o7.025.

j.ijrobp.2006.01.052.

ijrobp.2017.06.2050.

s13014-018-0966-5.

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[27] Huynh E, Hosny A, Guthier C, Bitterman DS, Petit SF, Haas-Kogan DA,

Kann B, Aerts HJWL, Mak RH. Artificial intelligence in radiation oncology. Nature Reviews. Clinical Oncology. 2020;17(12):771-781. DOI:

10.1038/s41571-020-0417-8.

DOI:10.1001/jama.2012.460.

[29] Baumann BC, Mitra N, Harton JG, Xiao Y, Wojcieszynski AP, Gabriel PE, Zhong H, Geng H, Doucette A, Wei J, O'Dwyer PJ, Bekelman JE, Metz JM. Comparative effectiveness of proton vs photon therapy as part of concurrent chemoradiotherapy for locally advanced cancer. Journal of the American Medical Association- Oncology. 2020;6(2):237- 246. DOI:10.1001/jamaoncol.2019.4889.

[30] Romesser PB, Cahlon O, Scher E, Zhou Y, Berry SL, Rybkin A, Sine KM, Tang S, Sherman EJ, Wong R, Lee NY. Proton beam radiation therapy results in significantly reduced toxicity compared to intensity modulated radiation therapy for head and neck tumors that require ipsilateral radiation. Radiotherapy and Oncology. 2016;118(2):286-292. DOI:

10.1016/j.radonc.2015.12.008.

[31] Xi M, Xu C, Liao Z, Chang JY, Gomez DR, Jeter M, Cox JD, Komaki R, Mehran R, Blum MA, Hofstetter WL, Maru DM, Bhutani MS, Lee JH, Weston B, Ajani JA, Lin SH.

Comparative outcomes after definitive chemoradiotherapy using proton beam therapy versus intensity modulated radiation therapy for esophageal cancer: a retrospective, single institutional analysis. International Journal of Radiation Oncology Biology Physics.

#### *The Future of Proton Therapy DOI: http://dx.doi.org/10.5772/intechopen.97935*

*Proton Therapy - Current Status and Future Directions*

clinical\_indications\_paper\_

[21] IBA. Treating Gastrointestinal Malignancies with Proton Therapy. 2016. Available from: https://ibaworldwide.com/de/node/2172.

[22] Johnson CY. Proton beams vs. radiation 5 year MGH study seeks definitive answers about costly prostate cancer treatment. 2012 Boston Globe. Available from: http://archive.boston. com/lifestyle/health/articles/2012/ 05/14/is\_proton\_beam\_therapy\_a\_ better\_treatment\_for\_prostate\_cancer\_

mass\_general\_trial\_to\_answer\_

British Journal of Cancer.

[23] Levin WP, Kooy H, Loeffler JS, Delaney TF. Proton beam therapy.

2005;93(8):849-854. DOI:10.1038/

[24] Peach K, Wilson P, Jones B.

British Journal of Radiology. 2011;84(1):S4-10. DOI:10.1259/

[25] Forsthoefel MK, Ballew E, Unger KR, Ahn PH, Rudra S, Pang D, Collins SP, Dritschilo A, Harter W, Paudel N, Collins BT, Lischalk JW. Early experience of the first single-room gantry mounted active scanning proton therapy system at an integrated cancer

center. Frontiers in Oncology. 2020;10:861 810: DOI:10.3389/

[26] Contreras J, Zhao T, Perkins S, Sun B, Goddu S, Mutic S, Bottani B, Endicott S, Michalski J, Robinson C, Tsien C, Huang J, Fischer-Valuck BW, Hallahan D, Klein E, Bradley J. The world's direct single room proton therapy facility: Two-year experience.

Practical Radiation Oncology. 2017;7(1):e71-e76. DOI: 10.1016/j.

fonc.2020.00861.

prro.2016.07.003.

Accelerator science in medical physics.

question/.

sj.bjc.6602754.

bjr/16022594.

hodgkin\_va.pdf.

Thoracic Oncology. 2017;12(2):281-292.

DOI:10.1016/j.tho.2016.10.018.

[14] Muralidhar, V, Nguyen P. Maximizing resources in the local treatment of prostate cancer: A summary of cost effectiveness studies. Urologic Oncology. 2017;3 (2) 76-85. DOI:10.1016/j.urolonc.2016.06.003.

[15] Lievens Y, Van den Bogaert W. Proton beam therapy: Too expensive to become true? Radiotherapy and Oncology. 2005;75(2):131-133. DOI:10.1016/jradonc.2005.03.027.

[16] Forsthoefel MK, Ballew E, Unger KR, Ahn PH, Rudra S, Pang D, Collins SP, Dritschilo A, Harter W, Paudel N, Collins BT, Lischalk JW. Early experience of the first single-room gantry mounted active scanning proton therapy system at an integrated cancer

center. Frontiers in Oncology. 2020;10:861. doi: 10.3389/

[18] Tepper J, Blackstock AW. Randomized trials and technology assessment. Annals of Internal Medicine. 2009;151(8) 583-584. DOI:10.7326/0003-4819-151-8-

[19] IBA. Treating Head and Neck Carcinoma with Proton Therapy. 2016. Available from: https://iba-worldwide.

[20] IBA. Treating Hodgkin and Non-Hodgkin Lymphoma with Proton Therapy. 2016. Available from: https://iba-worldwide.com/sites/ protontherapy/files/linkbox\_files/

200910200-00146.

com/es/node/2173.

[17] Owen H, Lomax A, Jolly S. Current and future accelerator technologies for charged particle therapy. Nuclear Instruments & Methods in Physics Research. Section A: Accelerators, Spectrometers, Detectors, and Associated Equipment. 2016;809:96- 104. DOI:10.1016/j.nima.2015.08.038.

fonc.2020.00861.

**130**

[27] Huynh E, Hosny A, Guthier C, Bitterman DS, Petit SF, Haas-Kogan DA, Kann B, Aerts HJWL, Mak RH. Artificial intelligence in radiation oncology. Nature Reviews. Clinical Oncology. 2020;17(12):771-781. DOI: 10.1038/s41571-020-0417-8.

[28] Sheets NC, Goldin GH, Meyer AM, Wu Y, Chang Y, Stürmer T, Holmes JA, Reeve BB, Godley PA, Carpenter WR, Chen RC. Intensity modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer. Journal of the American Medical Association. 2012;307(15):1611-1620. DOI:10.1001/jama.2012.460.

[29] Baumann BC, Mitra N, Harton JG, Xiao Y, Wojcieszynski AP, Gabriel PE, Zhong H, Geng H, Doucette A, Wei J, O'Dwyer PJ, Bekelman JE, Metz JM. Comparative effectiveness of proton vs photon therapy as part of concurrent chemoradiotherapy for locally advanced cancer. Journal of the American Medical Association- Oncology. 2020;6(2):237- 246. DOI:10.1001/jamaoncol.2019.4889.

[30] Romesser PB, Cahlon O, Scher E, Zhou Y, Berry SL, Rybkin A, Sine KM, Tang S, Sherman EJ, Wong R, Lee NY. Proton beam radiation therapy results in significantly reduced toxicity compared to intensity modulated radiation therapy for head and neck tumors that require ipsilateral radiation. Radiotherapy and Oncology. 2016;118(2):286-292. DOI: 10.1016/j.radonc.2015.12.008.

[31] Xi M, Xu C, Liao Z, Chang JY, Gomez DR, Jeter M, Cox JD, Komaki R, Mehran R, Blum MA, Hofstetter WL, Maru DM, Bhutani MS, Lee JH, Weston B, Ajani JA, Lin SH. Comparative outcomes after definitive chemoradiotherapy using proton beam therapy versus intensity modulated radiation therapy for esophageal cancer: a retrospective, single institutional analysis. International Journal of Radiation Oncology Biology Physics.

2017;99(3):667-676. DOI: 10.1016/j. ijrobp.2017.06.2050.

[32] Hirano Y, Onozawa M, Hojo H, Motegi A, Zenda S, Hotta K, Moriya S, Tachibana H, Nakamura N, Kojima T, Akimoto T. Dosimetric comparison between proton beam therapy and photon radiation therapy for locally advanced esophageal squamous cell carcinoma. Radiation Oncology. 2018;13(1):23. DOI:10.1186/ s13014-018-0966-5.

[33] Warren S, Hurt CN, Crosby T, Partridge M, Hawkins MA. Potential of proton therapy to reduce hematologic toxicity for esophageal cancer. International Journal of Radiation Oncology Biology Physics. 2017;99(3):729-737. DOI:10.1016/j. ijrobp.2017.o7.025.

[34] Chang J, Zhang X, Wang X Kang Y, Riley B, Bilton S, Mohan R, Komaki R, Cox JD. Significant reduction in normal tissue dose by proton radiotherapy compared with three dimensional conformal or intensity modulated radiation therapy for stage 1 or stage 3 non-small cell lung cancer. International Journal of Radiation Oncology Biology Physics. 2006;65(4):1087-1096. DOI: j.ijrobp.2006.01.052.

[35] Apinorasethkul O, Kirk M, Teo K, Swisher-McClure S, Lukens JN, Lin A. Pencil beam scanning proton therapy vs rotational arc radiation therapy: A treatment planning comparison for post-operative oropharyngeal cancer. Medical Dosimetry. 2017;42(1):7-11. DOI:10.1016/j.meddos 2016.09.004.

[36] Blanchard P, Garden AS, Gunn GB, Rosenthal DI, Morrison WH, Hernandez M, Crutison J, Lee JJ, Ye R, Fuller CD, Mohamed AS, Hutcheson KA, Holliday EB, Thaker NG, Sturgis EM, Kies MS, Zhu XR, Mohan R, Frank SJ. Intensity modulated proton therapy (IMPT) versus intensity modulated photon

therapy (IMRT) for patients with oropharynx cancer-a case matched analysis. Radiotherapy and Oncology. 2016;120(1):48-55. DOI:10.1016/j. radonc.2016.05.022.

[37] Bekelman JE, Asch DA, Tochner Z, Friedberg J, Vaughn DJ, Rash E, Raksowski K, Hahn SM. Principles and reality of proton therapy treatment allocation. International Journal of Radiation Oncology Biology Physics. 2014;89(3):499-508. DOI:10.1016/j. ijrobp.2014.03.023.

[38] Wong W, Yim YM, Kim A, Cloutier M, Gauthier-Loiselle M, Gagnon-Sanschagrin P, Guerin A. Assessment of costs associated with adverse events in patients with cancer. PLoS One. 2018;13(4):e0196007. DOI:10.1371/journal.pone.0196007.

*Proton Therapy - Current Status and Future Directions*

therapy (IMRT) for patients with oropharynx cancer-a case matched analysis. Radiotherapy and Oncology. 2016;120(1):48-55. DOI:10.1016/j.

[37] Bekelman JE, Asch DA, Tochner Z, Friedberg J, Vaughn DJ, Rash E, Raksowski K, Hahn SM. Principles and reality of proton therapy treatment allocation. International Journal of Radiation Oncology Biology Physics. 2014;89(3):499-508. DOI:10.1016/j.

radonc.2016.05.022.

ijrobp.2014.03.023.

[38] Wong W, Yim YM, Kim A, Cloutier M, Gauthier-Loiselle M, Gagnon-Sanschagrin P, Guerin A. Assessment of costs associated with adverse events in patients with cancer. PLoS One. 2018;13(4):e0196007. DOI:10.1371/journal.pone.0196007.

**132**

### *Edited by Thomas J. FitzGerald and Maryann Bishop-Jodoin*

Over the past twenty-five years, proton therapy has become more prominent worldwide. It is an important component of clinical radiation therapy for both adult and pediatric clinical care. Due to the inherent ability of protons to spare normal tissue, protons will continue to develop and become increasingly important in radiation oncology. As such, *Proton Therapy - Current Status and Future Directions* reviews many aspects of proton care including the application of protons in modern clinical trials. It also reviews problems associated with the migration of proton care worldwide and examines the future direction of proton care. This project was created by colleagues at IntechOpen and was carefully managed by Romina Rovan. It has been a privilege to help coordinate the text and chapters designed to acknowledge the history, footprint, and growing interest of proton care worldwide. Proton management is now embedded in the clinical trials process. In pediatric care, proton delivery is embedded with photons for the management of pediatric malignancies and adult groups have initiated proton-specific clinical trials. A proton registry has been established and outcomes are under evaluation. Due to the inherent ability of protons to spare normal tissue, protons will continue to develop and become increasingly important in radiation oncology.

Published in London, UK © 2021 IntechOpen © FreedomMaster / iStock

Proton Therapy - Current Status and Future Directions

Proton Therapy

Current Status and Future Directions

*Edited by Thomas J. FitzGerald* 

*and Maryann Bishop-Jodoin*