Clinical Trials in Proton Therapy

*Proton Therapy - Current Status and Future Directions*

[28] Jagsi R, DeLaney TF, Donelan K, Tarbell NJ. Real-time rationing of scarce resources: the Northeast Proton Therapy Center experience. Journal of Clinical Oncology. 2004;22(11):2246-2250. DOI:10.1200/JCO.2004.10.083.

[29] Penn Medicine. Roberts Proton Therapy Center. [Internet]. 2020. Available from: https://www.

pennmedicine.org/cancer/navigatingcancer-care/programs-and-centers/ roberts-proton-therapy-center.

[30] DeLaney TF. Clinical proton radiation therapy research at the Francis H. Burr Proton Therapy Center. Technology in Cancer Research & Treatment. 2007;6(4 Suppl):61-66. DOI:

10.1177/15330346070060S410.

[32] Darafsheh A, Hao Y, Zwart T, Wagner M, Catanzano D, Williamson JF, Knutson N, Sun B, Mutic S, Zhao T. Feasibility of proton FLASH irradiation using a synchrocyclotron for preclinical studies. Medical Physics. 2020;47(9): 4348-4355. DOI:10.1002/mp.14253.

[33] Furlow B. Dosimetric promise versus cost: critics question proton

therapy. Lancet. Oncology. 2013;14(9):805-806. DOI:10.1016/

s1470-2045(13)70314-0.

[31] Bradley J, Bottani B, Klein E. Proton therapy. An update on the S. Lee Kling Proton Therapy Center at Barnes-Jewish Hospital and Washington University. Missouri Medicine. 2015;112(5):355-357.

{Accessed 2020-09-09].

**22**

**25**

**Chapter 3**

Registry

**Abstract**

research interests.

**1. Introduction**

Multi-Institutional Data Collection

*Nicholas J. DeNunzio, Miranda P. Lawell and Torunn I. Yock*

Care of patients with proton therapy has increased in the past decade. It is important to report on outcomes and disease specific utilization of particle therapy. In this chapter, we review our experience in developing a registry for pediatric patients treated with radiation to assess outcomes and provide a platform for shared

**Keywords:** Pediatric cancer, radiation therapy, particle therapy, proton registry

Pediatric cancers comprise a simultaneously rare but highly varied cadre of diseases. They account for less than 1% of all new cancer diagnoses made in the United States each year with nearly 17,000 projected in 2020 for patients under 20 years of age [1]. These can be classified as liquid tumors (leukemias and lymphomas) and solid tumors originating in central nervous system (CNS) and non-CNS sites. While many patients undergo radiotherapy (RT) as part of standard disease management, a significant portion of treatment paradigms does not include RT outright or requires RT to the entire body (e.g. total body irradiation in conditioning for stem cell transplants in patients with leukemia), thereby obviating the need for highly technical delivery methods such as proton radiotherapy (PRT). The number of patients available for study, therefore, is substantially less such that studying treatment outcomes is challenging and limits the ability of any one radiation center

Survival and toxicity outcomes associated with PRT, as with photon radiotherapy (XRT), can be obtained through inquiries ranging in quality from singleinstitution retrospective studies to prospective randomized phase three clinical trials. However, in the pediatric population, randomized trials are not feasible given lack of equipoise among parents of patients and caregivers between proton- and photon-based radiation. In addition, low disease prevalence, varied disease management options, and varied anatomic sites can result in limited data availability. Consequently, collaboration among institutions is needed to obtain a critical mass of data that enables meaningful outcomes research. Children's Oncology Group (COG) and the International Society of Pediatric Oncology (SIOP) are cooperative

to amass clinical data and generate timely empirical results.

and Analysis via the Pediatric

Proton/Photon Consortium

#### **Chapter 3**

## Multi-Institutional Data Collection and Analysis via the Pediatric Proton/Photon Consortium Registry

*Nicholas J. DeNunzio, Miranda P. Lawell and Torunn I. Yock*

#### **Abstract**

Care of patients with proton therapy has increased in the past decade. It is important to report on outcomes and disease specific utilization of particle therapy. In this chapter, we review our experience in developing a registry for pediatric patients treated with radiation to assess outcomes and provide a platform for shared research interests.

**Keywords:** Pediatric cancer, radiation therapy, particle therapy, proton registry

#### **1. Introduction**

Pediatric cancers comprise a simultaneously rare but highly varied cadre of diseases. They account for less than 1% of all new cancer diagnoses made in the United States each year with nearly 17,000 projected in 2020 for patients under 20 years of age [1]. These can be classified as liquid tumors (leukemias and lymphomas) and solid tumors originating in central nervous system (CNS) and non-CNS sites. While many patients undergo radiotherapy (RT) as part of standard disease management, a significant portion of treatment paradigms does not include RT outright or requires RT to the entire body (e.g. total body irradiation in conditioning for stem cell transplants in patients with leukemia), thereby obviating the need for highly technical delivery methods such as proton radiotherapy (PRT). The number of patients available for study, therefore, is substantially less such that studying treatment outcomes is challenging and limits the ability of any one radiation center to amass clinical data and generate timely empirical results.

Survival and toxicity outcomes associated with PRT, as with photon radiotherapy (XRT), can be obtained through inquiries ranging in quality from singleinstitution retrospective studies to prospective randomized phase three clinical trials. However, in the pediatric population, randomized trials are not feasible given lack of equipoise among parents of patients and caregivers between proton- and photon-based radiation. In addition, low disease prevalence, varied disease management options, and varied anatomic sites can result in limited data availability. Consequently, collaboration among institutions is needed to obtain a critical mass of data that enables meaningful outcomes research. Children's Oncology Group (COG) and the International Society of Pediatric Oncology (SIOP) are cooperative

groups that work together to try to answer critical treatment-related questions on the more common pediatric malignancies. However, access to cooperative group data for ad hoc studies is limited, even among cooperative group members. Furthermore, these groups are focused on primary disease-specific endpoints and typically do not prioritize the collection of data on health outcomes and morbidity that can affect health-related quality of life. Importantly, COG has a registry called Project:EveryChild that attempts to capture limited information and biological specimens on all patients with a pediatric malignancy or benign tumor. However, the only information collected on RT is whether a patient was treated with it but no information on dose, site, timing of radiotherapy, or other factors that can play a role in disease control and other health outcomes [2].

To address these challenges, the Pediatric Proton/Photon Consortium Registry (PPCR) was initiated in 2010 [3–5], first focusing exclusively on studying clinical outcomes after PRT. Herein we describe the PPCR's administrative structure and processes, collected data (including patient demographics), and our vision for how the PPCR may further evolve.

#### **2. PPCR overview**

The PPCR is a consented registry established by and centrally coordinated through a team at Massachusetts General Hospital (MGH). Nineteen institutions are currently contributing data while 11 are in the process of joining [6]. Pediatric patients treated with radiation prior to 22 years of age are offered enrollment and all treatment exposures and baseline patient health and tumor characteristics are collected. The registry also tracks survival and treatment-related toxicity for all and patient-reported quality-of-life (PedsQL) data on a voluntary basis at 14 institutions. The PPCR enrolled its first participant in October, 2012 and was initially designed to collect data on the pediatric proton cohort. Then in 2018, after input from the National Cancer Institute (NCI) and various stakeholders, patients treated with any radiation modality became eligible to enroll. The PPCR was jointly funded by the NCI/MGH Federal Share of Proton Income research fund until 2019 and is now funded predominantly through MGH research funds and philanthropic donations.

#### **2.1 Site acquisition**

All radiation centers that treat pediatric patients are welcome to join, although current laws hinder some centers from joining among those based outside the United States, Canada, and Australia. Once clinicians at an institution express interest in participating, they are provided the current protocol, informed consent form, financial disclosure form, signature and delegation of responsibilities logs, and investigator agreement. The interested investigator(s) will then begin the regulatory proceedings needed to open the study at their institution. Unlike involvement in other registries and cooperative groups, there is no central cost to join though institutions are responsible for supporting the staff needed to complete study-related tasks.

#### **2.2 Team composition**

The coordinating team at MGH consists of five individuals: principal investigator (PI), project manager, biostatistician, and two clinical research coordinators (CRC). The coordinating team is responsible for central registry oversight and

**27**

*Multi-Institutional Data Collection and Analysis via the Pediatric Proton/Photon Consortium…*

reporting, patient registration, database management, monitoring, and quality assurance. Individual site team composition is dependent on available resources and ranges from a single physician up to a staff of eight. Notably, limited institutional

Each site uses its own Institutional Review Board (IRB) and abides by its own institutional regulations. The site's protocol and consent forms are approved by the coordinating team at MGH. Eight centers use the Western Institutional Review Board, Inc., in lieu of a local IRB. To streamline ongoing review and protocol changes, the coordinating team compiles study changes into a single annual amend-

All children and young adults (<22 years of age) who receive radiation at one of our participating institutions are eligible and invited to enroll. For this minimalrisk study, informed consent may be obtained by any member of the study team (e.g. CRC, research nurse, advanced practice provider, physician/PI) and must be obtained prior to completing any study-related procedures. Most patients are enrolled at some point during their primary treatment, although prior radiation treatment does not exclude them from being eligible. PedsQL study consent is sought in the first week of treatment to facilitate timely completion of the baseline survey. All patients are centrally registered at the coordinating center and assigned a study identification number (SIDN). The registry's goal is to capture all pediatric patients treated with RT. However, some patients decline to enroll, which can introduce bias in the collected data. To mitigate this effect, basic, non-identifying demographic information is gathered on patients who decline to participate, including their reason for doing so. This facilitates identifying barriers to registry enrollment and meaningful disparities between participants and patients who do not consent. Participants remain on study until death, withdrawal of consent, or

Clinical data and patient-reported outcomes are collected and managed using the REDCap platform available through the National Institutes of Health [7–9]. This is a no-cost, web-based software platform for collecting and managing data and administering online surveys. Each study site is assigned its own data access group

Participants are entered into the database using their assigned SIDN. Data are collected at the following time points, each with its own specifications: baseline (pre-RT), during treatment, and follow-up. A total of 1,604 data variables provide information on demographics, diagnosis and associated genetic factors, imaging dates and results, all cancer-related treatments, survival outcomes, and all treatment-related toxicities. Question formats allow for quantitative and qualitative responses and include drop-down boxes, radio buttons, check-boxes (multiple selections), text with validation (dates, numbers), and text without validation. Branching logic streamlines data input by displaying relevant data variables based on prior selections. Radiation plans (inclusive of planning scan, contours, and dose files) and pertinent diagnostic imaging (e.g. magnetic resonance imaging) are collected and managed using MIM Software Inc.'s MIMcloud (Cleveland, OH; [10]), which is a

resources is the most commonly reported barrier to participation.

*DOI: http://dx.doi.org/10.5772/intechopen.95960*

ment submission that is implemented study-wide.

**2.3 Regulatory structure**

**2.4 Consent and enrollment**

study termination.

**2.5 Data infrastructure and collection**

and can only see records entered by users within this group.

*Multi-Institutional Data Collection and Analysis via the Pediatric Proton/Photon Consortium… DOI: http://dx.doi.org/10.5772/intechopen.95960*

reporting, patient registration, database management, monitoring, and quality assurance. Individual site team composition is dependent on available resources and ranges from a single physician up to a staff of eight. Notably, limited institutional resources is the most commonly reported barrier to participation.

#### **2.3 Regulatory structure**

*Proton Therapy - Current Status and Future Directions*

role in disease control and other health outcomes [2].

the PPCR may further evolve.

**2. PPCR overview**

donations.

**2.1 Site acquisition**

plete study-related tasks.

**2.2 Team composition**

groups that work together to try to answer critical treatment-related questions on the more common pediatric malignancies. However, access to cooperative group data for ad hoc studies is limited, even among cooperative group members. Furthermore, these groups are focused on primary disease-specific endpoints and typically do not prioritize the collection of data on health outcomes and morbidity that can affect health-related quality of life. Importantly, COG has a registry called Project:EveryChild that attempts to capture limited information and biological specimens on all patients with a pediatric malignancy or benign tumor. However, the only information collected on RT is whether a patient was treated with it but no information on dose, site, timing of radiotherapy, or other factors that can play a

To address these challenges, the Pediatric Proton/Photon Consortium Registry (PPCR) was initiated in 2010 [3–5], first focusing exclusively on studying clinical outcomes after PRT. Herein we describe the PPCR's administrative structure and processes, collected data (including patient demographics), and our vision for how

The PPCR is a consented registry established by and centrally coordinated through a team at Massachusetts General Hospital (MGH). Nineteen institutions are currently contributing data while 11 are in the process of joining [6]. Pediatric patients treated with radiation prior to 22 years of age are offered enrollment and all treatment exposures and baseline patient health and tumor characteristics are collected. The registry also tracks survival and treatment-related toxicity for all and patient-reported quality-of-life (PedsQL) data on a voluntary basis at 14 institutions. The PPCR enrolled its first participant in October, 2012 and was initially designed to collect data on the pediatric proton cohort. Then in 2018, after input from the National Cancer Institute (NCI) and various stakeholders, patients treated with any radiation modality became eligible to enroll. The PPCR was jointly funded by the NCI/MGH Federal Share of Proton Income research fund until 2019 and is now funded predominantly through MGH research funds and philanthropic

All radiation centers that treat pediatric patients are welcome to join, although

The coordinating team at MGH consists of five individuals: principal investigator (PI), project manager, biostatistician, and two clinical research coordinators (CRC). The coordinating team is responsible for central registry oversight and

current laws hinder some centers from joining among those based outside the United States, Canada, and Australia. Once clinicians at an institution express interest in participating, they are provided the current protocol, informed consent form, financial disclosure form, signature and delegation of responsibilities logs, and investigator agreement. The interested investigator(s) will then begin the regulatory proceedings needed to open the study at their institution. Unlike involvement in other registries and cooperative groups, there is no central cost to join though institutions are responsible for supporting the staff needed to com-

**26**

Each site uses its own Institutional Review Board (IRB) and abides by its own institutional regulations. The site's protocol and consent forms are approved by the coordinating team at MGH. Eight centers use the Western Institutional Review Board, Inc., in lieu of a local IRB. To streamline ongoing review and protocol changes, the coordinating team compiles study changes into a single annual amendment submission that is implemented study-wide.

#### **2.4 Consent and enrollment**

All children and young adults (<22 years of age) who receive radiation at one of our participating institutions are eligible and invited to enroll. For this minimalrisk study, informed consent may be obtained by any member of the study team (e.g. CRC, research nurse, advanced practice provider, physician/PI) and must be obtained prior to completing any study-related procedures. Most patients are enrolled at some point during their primary treatment, although prior radiation treatment does not exclude them from being eligible. PedsQL study consent is sought in the first week of treatment to facilitate timely completion of the baseline survey. All patients are centrally registered at the coordinating center and assigned a study identification number (SIDN). The registry's goal is to capture all pediatric patients treated with RT. However, some patients decline to enroll, which can introduce bias in the collected data. To mitigate this effect, basic, non-identifying demographic information is gathered on patients who decline to participate, including their reason for doing so. This facilitates identifying barriers to registry enrollment and meaningful disparities between participants and patients who do not consent. Participants remain on study until death, withdrawal of consent, or study termination.

#### **2.5 Data infrastructure and collection**

Clinical data and patient-reported outcomes are collected and managed using the REDCap platform available through the National Institutes of Health [7–9]. This is a no-cost, web-based software platform for collecting and managing data and administering online surveys. Each study site is assigned its own data access group and can only see records entered by users within this group.

Participants are entered into the database using their assigned SIDN. Data are collected at the following time points, each with its own specifications: baseline (pre-RT), during treatment, and follow-up. A total of 1,604 data variables provide information on demographics, diagnosis and associated genetic factors, imaging dates and results, all cancer-related treatments, survival outcomes, and all treatment-related toxicities. Question formats allow for quantitative and qualitative responses and include drop-down boxes, radio buttons, check-boxes (multiple selections), text with validation (dates, numbers), and text without validation. Branching logic streamlines data input by displaying relevant data variables based on prior selections. Radiation plans (inclusive of planning scan, contours, and dose files) and pertinent diagnostic imaging (e.g. magnetic resonance imaging) are collected and managed using MIM Software Inc.'s MIMcloud (Cleveland, OH; [10]), which is a

secure internet-based file transfer service. Files that are uploaded to MIMcloud are anonymized by SIDN and then stored on a centrally housed server that is maintained by the coordinating center.

PedsQL Core Module surveys, added in September, 2015 as a voluntary component of the PPCR, collect data on physical, emotional, social, and cognitive functioning [11, 12]. Surveys are administered to patients at the beginning and end of treatment, and annually thereafter. For patients under five years of age, surveys are completed by the parent only. For patients aged 5–18 years, both the parent and child complete the surveys. For patients over the age of 18, no parental survey is given. REDCap's survey functionality allows participants to complete the survey electronically as well as receive a secure link by email or text to access follow-up surveys. This REDCap function directly deposits the patient's responses into the database, thereby obviating the need for manual data entry.

Each site has permission through the consent process to contact their site's participants, families, and home physicians to request outside medical records and update the database. This is critical as proton therapy centers are quaternary referral centers and the majority of patients return to their home institution for continued oncologic care, which makes longitudinal follow up more difficult [13].

#### **2.6 Data safety and monitoring**

All data entered into REDCap are monitored for timeliness of submission, completeness, and adherence to protocol requirements. Ongoing monitoring procedures include: (1) review of all participant consents and study eligibility at registration; (2) database review for discrepancies and potential errors; (3) remote or on-site monitoring; (4) monthly reports that identify missing data that are vital to the integrity and completeness of the dataset and are subject to a higher standard of data monitoring.

#### **2.7 Data usage**

All institutions have unfettered access to their own data and can use their data for operational planning, quality purposes, or research purposes. Data can be extracted manually or via REDCap's built-in reporting features. For use of multi-center data, investigators may submit a "Request for Data" (RFD) through a REDCap questionnaire. RFDs are then reviewed by the PPCR coordinating center and each site PI. Each PI can decide whether to include their site's data in the requested project. Data are available for investigator-initiated research and for investigators wishing to partner with the PPCR to answer questions in pediatric oncology.

#### **3. Data and patient characteristics**

This collaborative effort aims to expedite investigations into and understanding of pediatric patient survival, treatment toxicity, and impacts on quality of life after RT by pooling data from multiple institutions and making them available for study to participating investigators. Data are qualitative and quantitative in nature, inclusive of patient demographics, dosimetric statistics of the radiation target and healthy tissues, and neoadjuvant and/or adjuvant treatments that are administered as part of standard comprehensive cancer care. In addition, dose distribution data are curated, which are critical in providing a higher level of granularity in dosimetric studies.

To date, the PPCR has enrolled more than 3,200 patients, with a steady annual accrual of about 450 patients in recent years. Notably, the COVID pandemic has

**29**

α

β

**Table 1.**

*Multi-Institutional Data Collection and Analysis via the Pediatric Proton/Photon Consortium…*

slowed accrual in 2020 due to the various institutional responses that put non-COVID research on hold to focus attention on the health crisis. Patients have a median age of ten years and are mostly residents of the United States (76%), male (57%), White/ Caucasian (71%), and non-Hispanic/Latino (71%) (**Table 1**, **Figures 1**, **2**). RT has been delivered using protons in 99% of participants, reflecting that the bulk of institutions that joined were proton centers prior to 2018 when enrollment criteria

**Age at RT (years)** 9.74 (<1–27.7)

Male 1860 (57.1%) Female 1400 (42.9%)

Black or African American 242 (7.4%) Arabic/Middle Eastern 35 (1.1%) Asian 171 (5.2%) White/Caucasian 2329 (71.4%) Native American/Alaska Native 16 (0.5%) Native Hawaiian or Other Pacific Islander 11 (0.3%) Unknown/Not Specified 425 (13.0%) Other 29 (0.9%) Missing 42 (1.3%)

Hispanic or Latino 353 (10.8%) Not Hispanic or Latino 2305 (70.7%) Unknown or Not Reported 602 (18.5%)

United States 2461 (75.5%) Non-United States 542 (16.6%) Not Reported 257 (7.9%)

CNS 1929 (59.2%) Non-CNS 1299 (39.8%) Missing 32 (1.0%)

Protons 3238 (99.3%) Photons 188 (5.8%) Electrons 7 (0.2%)

**Total (n = 3260)**

*DOI: http://dx.doi.org/10.5772/intechopen.95960*

**Characteristics**

**Sex**

**Race** <sup>α</sup>

**Ethnicity**

**Tumor Site**

**Radiation Modality**<sup>α</sup>

*Characteristics of PPCR participants.*

*Totals sum >100% due to multiple selections per patient.*

*Due to IRB restrictions, patient residency is not reported for some patients.*

**United States Residency**<sup>β</sup>

#### *Multi-Institutional Data Collection and Analysis via the Pediatric Proton/Photon Consortium… DOI: http://dx.doi.org/10.5772/intechopen.95960*

slowed accrual in 2020 due to the various institutional responses that put non-COVID research on hold to focus attention on the health crisis. Patients have a median age of ten years and are mostly residents of the United States (76%), male (57%), White/ Caucasian (71%), and non-Hispanic/Latino (71%) (**Table 1**, **Figures 1**, **2**). RT has been delivered using protons in 99% of participants, reflecting that the bulk of institutions that joined were proton centers prior to 2018 when enrollment criteria


β *Due to IRB restrictions, patient residency is not reported for some patients.*

#### **Table 1.**

*Characteristics of PPCR participants.*

*Proton Therapy - Current Status and Future Directions*

database, thereby obviating the need for manual data entry.

by the coordinating center.

**2.6 Data safety and monitoring**

of data monitoring.

**2.7 Data usage**

secure internet-based file transfer service. Files that are uploaded to MIMcloud are anonymized by SIDN and then stored on a centrally housed server that is maintained

PedsQL Core Module surveys, added in September, 2015 as a voluntary component of the PPCR, collect data on physical, emotional, social, and cognitive functioning [11, 12]. Surveys are administered to patients at the beginning and end of treatment, and annually thereafter. For patients under five years of age, surveys are completed by the parent only. For patients aged 5–18 years, both the parent and child complete the surveys. For patients over the age of 18, no parental survey is given. REDCap's survey functionality allows participants to complete the survey electronically as well as receive a secure link by email or text to access follow-up surveys. This REDCap function directly deposits the patient's responses into the

Each site has permission through the consent process to contact their site's participants, families, and home physicians to request outside medical records and update the database. This is critical as proton therapy centers are quaternary referral centers and the majority of patients return to their home institution for continued

All data entered into REDCap are monitored for timeliness of submission, completeness, and adherence to protocol requirements. Ongoing monitoring procedures include: (1) review of all participant consents and study eligibility at registration; (2) database review for discrepancies and potential errors; (3) remote or on-site monitoring; (4) monthly reports that identify missing data that are vital to the integrity and completeness of the dataset and are subject to a higher standard

All institutions have unfettered access to their own data and can use their data for operational planning, quality purposes, or research purposes. Data can be extracted manually or via REDCap's built-in reporting features. For use of multi-center data, investigators may submit a "Request for Data" (RFD) through a REDCap questionnaire. RFDs are then reviewed by the PPCR coordinating center and each site PI. Each PI can decide whether to include their site's data in the requested project. Data are available for investigator-initiated research and for investigators wishing to

This collaborative effort aims to expedite investigations into and understanding of pediatric patient survival, treatment toxicity, and impacts on quality of life after RT by pooling data from multiple institutions and making them available for study to participating investigators. Data are qualitative and quantitative in nature, inclusive of patient demographics, dosimetric statistics of the radiation target and healthy tissues, and neoadjuvant and/or adjuvant treatments that are administered as part of standard comprehensive cancer care. In addition, dose distribution data are curated, which are critical in providing a higher level of granularity in dosimetric studies. To date, the PPCR has enrolled more than 3,200 patients, with a steady annual accrual of about 450 patients in recent years. Notably, the COVID pandemic has

oncologic care, which makes longitudinal follow up more difficult [13].

partner with the PPCR to answer questions in pediatric oncology.

**3. Data and patient characteristics**

**28**

**Figure 1.** *Participant residency by state in the United States.*

**Figure 2.** *Participant residency by country.*

became agnostic of radiation modality. Nearly 60% of the tumors treated in this cohort originated in the CNS (**Table 1**, **Figure 3**), which is the most common site of solid tumors in the pediatric population.

Since its inception, the PPCR's structure and scope have developed and expanded to adapt to the ongoing treatment landscape to address this unmet need within pediatric radiation medicine. For instance, in 2018 patients treated with XRT were made eligible for enrollment [14]. Incorporation of these data will facilitate photon/proton comparison studies that are critical for better understanding the strengths and weaknesses of PRT. This is especially true for developing dose constraints for organs at risk as these may not be identical across RT modalities. Such is the case for the brainstem, whose PRT dose limit was reduced on the most recent COG ependymoma protocol (ACNS0831). While the topic is controversial, there is some concern that there may be an increased risk of brainstem injury with PRT compared to XRT using a typical relative biological effectiveness dose conversion of 1.1 for PRT [15–18].

**31**

*Multi-Institutional Data Collection and Analysis via the Pediatric Proton/Photon Consortium…*

The PPCR has established a centralized, collaborative, and adaptive framework for data acquisition in pediatric patients receiving RT, with respect to treatment parameters and quality of life. This registry resource is now robustly able to better evaluate differences in practice patterns, dosimetric changes, and the clinical impacts of the treatments we deliver. The platform we have created is now being leveraged by the Epidemiology branch of the NCI to allow for large-scale cohort research. Furthermore, the PPCR study staff are also participating in the larger effort of the Childhood Cancer Data Initiative [19] recently started to accelerate the speed of research with the ultimate goal of improving cancer treatment and out-

*Histogram showing the ten most-represented histologies in the PPCR. CNS tumors are shown in blue and non-*

Looking forward, we aim to continue to expand the network of participating institutions not only domestically, but also internationally - first into Canada and Australia and then into other countries that allow sharing of de-identified data. This will not only serve to continue to amass data for rare tumors for which singleinstitution studies are simply not feasible, but will also yield insights into variations in practice patterns and which treatment regimens are the most effective and safest. In addition, the dynamic nature of the registry facilitates incorporation of data from other treatment modalities (e.g. FLASH radiotherapy, other particle therapies, etc.), much like how photon-based treatment data have been incorporated recently. This will further expand our understanding of how to best manage pediatric malignancies by adapting data acquisition to ongoing technologic developments and changes in practice patterns. We encourage all to use this resource to improve cancer care and outcomes for pediatric cancer patients undergoing treatment as

*DOI: http://dx.doi.org/10.5772/intechopen.95960*

**4. Future objectives**

*CNS tumors are shown in red.*

**Figure 3.**

comes for pediatric patients.

well as those who have completed therapy.

*Multi-Institutional Data Collection and Analysis via the Pediatric Proton/Photon Consortium… DOI: http://dx.doi.org/10.5772/intechopen.95960*

**Figure 3.**

*Proton Therapy - Current Status and Future Directions*

became agnostic of radiation modality. Nearly 60% of the tumors treated in this cohort originated in the CNS (**Table 1**, **Figure 3**), which is the most common site of

Since its inception, the PPCR's structure and scope have developed and expanded to adapt to the ongoing treatment landscape to address this unmet need within pediatric radiation medicine. For instance, in 2018 patients treated with XRT were made eligible for enrollment [14]. Incorporation of these data will facilitate photon/proton comparison studies that are critical for better understanding the strengths and weaknesses of PRT. This is especially true for developing dose constraints for organs at risk as these may not be identical across RT modalities. Such is the case for the brainstem, whose PRT dose limit was reduced on the most recent COG ependymoma protocol (ACNS0831). While the topic is controversial, there is some concern that there may be an increased risk of brainstem injury with PRT compared to XRT using a typical relative biological effectiveness dose conversion of 1.1 for PRT [15–18].

solid tumors in the pediatric population.

*Participant residency by state in the United States.*

**30**

**Figure 1.**

**Figure 2.**

*Participant residency by country.*

*Histogram showing the ten most-represented histologies in the PPCR. CNS tumors are shown in blue and non-CNS tumors are shown in red.*

#### **4. Future objectives**

The PPCR has established a centralized, collaborative, and adaptive framework for data acquisition in pediatric patients receiving RT, with respect to treatment parameters and quality of life. This registry resource is now robustly able to better evaluate differences in practice patterns, dosimetric changes, and the clinical impacts of the treatments we deliver. The platform we have created is now being leveraged by the Epidemiology branch of the NCI to allow for large-scale cohort research. Furthermore, the PPCR study staff are also participating in the larger effort of the Childhood Cancer Data Initiative [19] recently started to accelerate the speed of research with the ultimate goal of improving cancer treatment and outcomes for pediatric patients.

Looking forward, we aim to continue to expand the network of participating institutions not only domestically, but also internationally - first into Canada and Australia and then into other countries that allow sharing of de-identified data. This will not only serve to continue to amass data for rare tumors for which singleinstitution studies are simply not feasible, but will also yield insights into variations in practice patterns and which treatment regimens are the most effective and safest. In addition, the dynamic nature of the registry facilitates incorporation of data from other treatment modalities (e.g. FLASH radiotherapy, other particle therapies, etc.), much like how photon-based treatment data have been incorporated recently. This will further expand our understanding of how to best manage pediatric malignancies by adapting data acquisition to ongoing technologic developments and changes in practice patterns. We encourage all to use this resource to improve cancer care and outcomes for pediatric cancer patients undergoing treatment as well as those who have completed therapy.

*Proton Therapy - Current Status and Future Directions*

#### **Author details**

Nicholas J. DeNunzio, Miranda P. Lawell and Torunn I. Yock\* Harvard Medical School, Massachusetts General Hospital, Boston, USA

\*Address all correspondence to: tyock@mgh.harvard.edu

© 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.

**33**

*Multi-Institutional Data Collection and Analysis via the Pediatric Proton/Photon Consortium…*

Consortium Registry. 2020. Available from: www.pediatricradiationregistry.

[7] National Institutes of Health and Vanderbilt University. REDCap. Available from: https://projectredcap.

[8] Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. Journal of Biomedical Informatics. 2009;42(2):377-381. DOI:10.1016/j.jbi.2008.08.010.

[9] Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O'Neal L, McLeod L, Delacqua G, Delacqua F, Kirby J, Duda SN; REDCap Consortium. The REDCap consortium: Building an international community of software platform partners. Journal of Biomedical Informatics. 2019;95:103208. DOI:10.1016/j.

jbi.2019.103208.

2020-09-09].

cncr.10428.

[10] MIM Software Inc. MIM Software. 2020. Available from: www.mimsoftware.com. [Accessed:

[11] Varni JW, Burwinkle TM, Katz ER, Meeske K, Dickinson P. The PedsQL in pediatric cancer: Reliability and validity of the Pediatric Quality of Life Inventory Generic Core Scales, Multidimensional Fatigue Scale, and Cancer Module*.* Cancer. 2002;94(7):2090-2106. DOI:10.1002/

[12] Varni JW, Burwinkle TM, Seid M, Skarr D. The PedsQL 4.0 as a pediatric population health measure: feasibility, reliability, and validity*.* Ambulatory Pediatrics. 2003;3(6):329-341. DOI:10.1367/1539-4409(2003) 003<0329:tpaapp>2.0.co;2.

org.[Accessed: 2020-09-09].

org. [Accessed: 2020-09-09].

*DOI: http://dx.doi.org/10.5772/intechopen.95960*

[1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA: Cancer Journal for Clinicians. 2020;70(1):7-30.

[2] Children's Oncology Group. Project:EveryChild. [Internet]. 2020. Available from: http://www. projecteverychild.org/. [Accessed:

[3] Kasper HB, Raeke L, Indelicato DJ, Symecko H, Hartsell W, Mahajan A, Hill-Kayser C, Perkins SM, Chang AL, Childs S, Buchsbaum JC, Laurie F, Khan AJ, Giraud C, Yeap BY, Yock TI. The Pediatric Proton Consortium Registry: A multi-institutional collaboration in U.S. proton centers*.* International Journal of Particle Therapy. 2014;1(2):323-333. DOI:

DOI:10.3322/caac.21590.

10.14338/IJPT.13-00006.1.

[4] Yock T, Indelicato DJ,

Perkins S, Hill-Kayser C,

pbc.25314.

fonc.2018.00165.

Hartsell W, Symecko H, Kasper H,

Mahajan A, Chang AL, Childs S, Laurie F, Buchsbaum J, Roeke L, Neville C, Ladro M, Yeap BY.

Preliminary results from the pediatric proton consortium registry (PPCR): A collaboration of US proton centers to accelerate proton therapy research. Pediatric Blood & Cancer. 2014;61(52):O-234. DOI:10.1002/

[5] Hess CB, Indelicato DJ, Paulino AC,

[6] Massachusetts General Hospital for Children. Pediatric Proton/Photon

Hartsell WF, Hill-Kayser CE, Perkins SM, Mahajan A, Laack NN, Ermoian RP, Chang AL, Wolden SL, Mangona VS, Kwok Y, Breneman JC, Perentesis JP, Gallotto SL, Weyman EA, Bajaj BVM, Lawell MP, Yeap BY, Yock TI. An update from the Pediatric Proton Consortium Registry*.* Frontiers in Oncology. 2018;8:165. DOI:10.3389/

**References**

2020-09-09].

*Multi-Institutional Data Collection and Analysis via the Pediatric Proton/Photon Consortium… DOI: http://dx.doi.org/10.5772/intechopen.95960*

#### **References**

*Proton Therapy - Current Status and Future Directions*

**32**

**Author details**

Nicholas J. DeNunzio, Miranda P. Lawell and Torunn I. Yock\*

\*Address all correspondence to: tyock@mgh.harvard.edu

provided the original work is properly cited.

Harvard Medical School, Massachusetts General Hospital, Boston, 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, [1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA: Cancer Journal for Clinicians. 2020;70(1):7-30. DOI:10.3322/caac.21590.

[2] Children's Oncology Group. Project:EveryChild. [Internet]. 2020. Available from: http://www. projecteverychild.org/. [Accessed: 2020-09-09].

[3] Kasper HB, Raeke L, Indelicato DJ, Symecko H, Hartsell W, Mahajan A, Hill-Kayser C, Perkins SM, Chang AL, Childs S, Buchsbaum JC, Laurie F, Khan AJ, Giraud C, Yeap BY, Yock TI. The Pediatric Proton Consortium Registry: A multi-institutional collaboration in U.S. proton centers*.* International Journal of Particle Therapy. 2014;1(2):323-333. DOI: 10.14338/IJPT.13-00006.1.

[4] Yock T, Indelicato DJ, Hartsell W, Symecko H, Kasper H, Perkins S, Hill-Kayser C, Mahajan A, Chang AL, Childs S, Laurie F, Buchsbaum J, Roeke L, Neville C, Ladro M, Yeap BY. Preliminary results from the pediatric proton consortium registry (PPCR): A collaboration of US proton centers to accelerate proton therapy research. Pediatric Blood & Cancer. 2014;61(52):O-234. DOI:10.1002/ pbc.25314.

[5] Hess CB, Indelicato DJ, Paulino AC, Hartsell WF, Hill-Kayser CE, Perkins SM, Mahajan A, Laack NN, Ermoian RP, Chang AL, Wolden SL, Mangona VS, Kwok Y, Breneman JC, Perentesis JP, Gallotto SL, Weyman EA, Bajaj BVM, Lawell MP, Yeap BY, Yock TI. An update from the Pediatric Proton Consortium Registry*.* Frontiers in Oncology. 2018;8:165. DOI:10.3389/ fonc.2018.00165.

[6] Massachusetts General Hospital for Children. Pediatric Proton/Photon Consortium Registry. 2020. Available from: www.pediatricradiationregistry. org.[Accessed: 2020-09-09].

[7] National Institutes of Health and Vanderbilt University. REDCap. Available from: https://projectredcap. org. [Accessed: 2020-09-09].

[8] Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. Journal of Biomedical Informatics. 2009;42(2):377-381. DOI:10.1016/j.jbi.2008.08.010.

[9] Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O'Neal L, McLeod L, Delacqua G, Delacqua F, Kirby J, Duda SN; REDCap Consortium. The REDCap consortium: Building an international community of software platform partners. Journal of Biomedical Informatics. 2019;95:103208. DOI:10.1016/j. jbi.2019.103208.

[10] MIM Software Inc. MIM Software. 2020. Available from: www.mimsoftware.com. [Accessed: 2020-09-09].

[11] Varni JW, Burwinkle TM, Katz ER, Meeske K, Dickinson P. The PedsQL in pediatric cancer: Reliability and validity of the Pediatric Quality of Life Inventory Generic Core Scales, Multidimensional Fatigue Scale, and Cancer Module*.* Cancer. 2002;94(7):2090-2106. DOI:10.1002/ cncr.10428.

[12] Varni JW, Burwinkle TM, Seid M, Skarr D. The PedsQL 4.0 as a pediatric population health measure: feasibility, reliability, and validity*.* Ambulatory Pediatrics. 2003;3(6):329-341. DOI:10.1367/1539-4409(2003) 003<0329:tpaapp>2.0.co;2.

[13] Lawell MP, Bajaj BVM, Gallotto SL, Hess CB, Patteson BE, Nartowicz JA, Giblin MJ, Kleinerman RA, Berrington de Gonzalez A, Ebb DH, Tarbell NJ, MacDonald SM, Weyman EA, Yock TI. Increased distance from a treating proton center is associated with diminished ability to follow patients enrolled on a multicenter radiation oncology registry. Radiotherapy and Oncology. 2019;134:25-29. DOI: 10.1016/j.radonc.2019.01.007.

[14] Lawell MP, Indelicato DJ, Paulino AC, Hartsell W, Laack NN, Ermoian RP, Perentesis JP, Vatner R, Perkins S, Mangona VS, Hill-Kayser CE, Wolden SL, Kwok Y, Chang JH, Wilkinson JB, MacEwan I, Chang AL, Eaton BR, Ladra MM, Gallotto SL, Weyman EA, Bajaj BVM, Baliga S, Yeap BY, Berrington de Gonzalez A, Yock TI. An open invitation to join the Pediatric Proton/ Photon Consortium Registry to standardize data collection in pediatric radiation oncology. British Journal of Radiology. 2020;93(1107):20190673. DOI:10.1259/bjr.20190673.

[15] Indelicato DJ, Flampouri S, Rotondo RL, Bradley JA, Morris CG, Aldana PR, Sandler E, Mendenhall NP. Incidence and dosimetric parameters of pediatric brainstem toxicity following proton therapy. Acta Oncologica. 2014;53(10):1298-1304. DOI:10.3109/02 84186X.2014.957414.

[16] McGovern SL, Okcu MF, Munsell MF, Kumbalasseriyil N, Grosshans DR, McAleer MF, Chintagumpala M, Khatua S, Mahajan A. Outcomes and acute toxicities of proton therapy for pediatric atypical teratoid/ rhabdoid tumor of the central nervous system. International Journal of Radiation Oncology • Biology • Physics. 2014;90(5):1143-1152. DOI:10.1016/j. ijrobp.2014.08.354.

[17] Gentile MS, Yeap BY, Paganetti H, Goebel CP, Gaudet DE, Gallotto SL, Weyman EA, Morgan ML,

MacDonald SM, Giantsoudi D, Adams J, Tarbell NJ, Kooy H, Yock TI. Brainstem injury in pediatric patients with posterior fossa tumors treated with proton beam therapy and associated dosimetric factors*.* International Journal of Radiation Oncology • Biology • Physics. 2018;100(3):719-729. DOI:10.1016/j.ijrobp.2017.11.026.

[18] Haas-Kogan D, Indelicato D, Paganetti H, Esiashvili N, Mahajan A, Yock T, Flampouri S, MacDonald S, Fouladi M, Stephen K, Kalapurakal J, Terezakis S, Kooy H, Grosshans D, Makrigiorgos M, Mishra K, Poussaint TY, Cohen K, Fitzgerald T, Gondi V, Liu A, Michalski J, Mirkovic D, Mohan R, Perkins S, Wong K, Vikram B, Buchsbaum J, Kun L. National Cancer Institute workshop on proton therapy for children: Considerations regarding brainstem injury. International Journal of Radiation Oncology • Biology • Physics. 2018;101(1):152-168. DOI:10.1016/j.ijrobp.2018.01.013.

[19] National Cancer Institute. Childhood Cancer Data Initiative. 2020. Available from: https://www. cancer.gov/research/areas/childhood/ childhood-cancer-data-initiative. [Accessed: 2020-09-09].

**35**

**Chapter 4**

**Abstract**

**1. Introduction**

Clinical Trials

*Paige A. Taylor*

Credentialing Proton Centers for

This chapter will provide an overview of quality assurance processes to credential proton therapy centers for clinical trial participation. There are a number of credentialing audit steps, including independent output verification, anthropomorphic phantom audits, image guidance credentialing, knowledge assessments, and on-site dosimetry review. The purpose of these credentialing steps is to ensure consistency across proton centers participating in clinical trials, and well as comparability with photon centers for randomized trials. This uniformity ensures high quality data for measuring patient outcomes, which are pivotal at a

**Keywords:** proton therapy, quality assurance, credentialing, Imaging and Radiation

Clinical trials are designed to give us confidence in a course of care. For cancer treatment, clinical trials have played a crucial role in the advancement of treatment for a variety of disease sites over the last century. As discussed in the chapter on clinical trials, there are a number of active protocols seeking to better understand the role of proton therapy within modern radiotherapy. Clinical trials have varied points of emphasis and radiation therapy may be an important aspect of the trial but not the trial endpoint. Phase II and III trials often require many participants to reach a statistically significant conclusion. With limited numbers of patients of various disease sites seen at an individual institution, it is common for proton therapy trials to be conducted among multiple institutions. When a trial includes multiple institutions, variability in treatment practices increases. One way to minimize differences across participating centers is to require QA of the trial treatment. QA helps minimize deviations within trials, and can improve clinical outcomes such as overall and progression-free survival [1–4]. This is particularly important for many proton therapy clinical trials, as insurance companies want to see quantification of

In 2007, the NCI formed an ad-hoc panel of proton experts to outline guidelines

for the use of proton therapy in clinical trials. The original guidelines included

Oncology Core, phantoms, dosimeters, image guidance, benchmarks, audits

time when proton therapy is being assessed for superior outcomes.

**1.1 Importance of clinical trial quality assurance (QA)**

superior outcomes before agreeing to cover the cost of therapy.

**1.2 National Cancer Institute (NCI) proton guidelines**

#### **Chapter 4**

*Proton Therapy - Current Status and Future Directions*

MacDonald SM, Giantsoudi D, Adams J, Tarbell NJ, Kooy H, Yock TI. Brainstem injury in pediatric patients with posterior fossa tumors treated with proton beam therapy and associated dosimetric factors*.* International Journal of Radiation Oncology • Biology • Physics. 2018;100(3):719-729. DOI:10.1016/j.ijrobp.2017.11.026.

[18] Haas-Kogan D, Indelicato D, Paganetti H, Esiashvili N, Mahajan A, Yock T, Flampouri S, MacDonald S, Fouladi M, Stephen K, Kalapurakal J, Terezakis S, Kooy H, Grosshans D, Makrigiorgos M, Mishra K, Poussaint TY, Cohen K, Fitzgerald T, Gondi V, Liu A, Michalski J, Mirkovic D, Mohan R, Perkins S, Wong K, Vikram B, Buchsbaum J,

Kun L. National Cancer Institute workshop on proton therapy for children: Considerations regarding brainstem injury. International Journal of Radiation Oncology • Biology • Physics. 2018;101(1):152-168. DOI:10.1016/j.ijrobp.2018.01.013.

[19] National Cancer Institute. Childhood Cancer Data Initiative. 2020. Available from: https://www. cancer.gov/research/areas/childhood/ childhood-cancer-data-initiative.

[Accessed: 2020-09-09].

[13] Lawell MP, Bajaj BVM, Gallotto SL, Hess CB, Patteson BE, Nartowicz JA, Giblin MJ, Kleinerman RA, Berrington de Gonzalez A, Ebb DH, Tarbell NJ, MacDonald SM, Weyman EA, Yock TI. Increased distance from a treating proton center is associated with diminished ability to follow patients enrolled on a multicenter radiation oncology registry. Radiotherapy and Oncology. 2019;134:25-29. DOI: 10.1016/j.radonc.2019.01.007.

[14] Lawell MP, Indelicato DJ, Paulino AC, Hartsell W, Laack NN, Ermoian RP, Perentesis JP, Vatner R, Perkins S, Mangona VS, Hill-Kayser CE, Wolden SL, Kwok Y, Chang JH, Wilkinson JB, MacEwan I, Chang AL, Eaton BR, Ladra MM, Gallotto SL, Weyman EA, Bajaj BVM, Baliga S, Yeap BY, Berrington

de Gonzalez A, Yock TI. An open invitation to join the Pediatric Proton/ Photon Consortium Registry to

DOI:10.1259/bjr.20190673.

84186X.2014.957414.

ijrobp.2014.08.354.

Weyman EA, Morgan ML,

[16] McGovern SL, Okcu MF, Munsell MF, Kumbalasseriyil N, Grosshans DR, McAleer MF,

Chintagumpala M, Khatua S, Mahajan A. Outcomes and acute toxicities of proton therapy for pediatric atypical teratoid/ rhabdoid tumor of the central nervous system. International Journal of

Radiation Oncology • Biology • Physics. 2014;90(5):1143-1152. DOI:10.1016/j.

[17] Gentile MS, Yeap BY, Paganetti H, Goebel CP, Gaudet DE, Gallotto SL,

[15] Indelicato DJ, Flampouri S, Rotondo RL, Bradley JA, Morris CG, Aldana PR, Sandler E, Mendenhall NP. Incidence and dosimetric parameters of pediatric brainstem toxicity following proton therapy. Acta Oncologica. 2014;53(10):1298-1304. DOI:10.3109/02

standardize data collection in pediatric radiation oncology. British Journal of Radiology. 2020;93(1107):20190673.

**34**

## Credentialing Proton Centers for Clinical Trials

*Paige A. Taylor*

#### **Abstract**

This chapter will provide an overview of quality assurance processes to credential proton therapy centers for clinical trial participation. There are a number of credentialing audit steps, including independent output verification, anthropomorphic phantom audits, image guidance credentialing, knowledge assessments, and on-site dosimetry review. The purpose of these credentialing steps is to ensure consistency across proton centers participating in clinical trials, and well as comparability with photon centers for randomized trials. This uniformity ensures high quality data for measuring patient outcomes, which are pivotal at a time when proton therapy is being assessed for superior outcomes.

**Keywords:** proton therapy, quality assurance, credentialing, Imaging and Radiation Oncology Core, phantoms, dosimeters, image guidance, benchmarks, audits

#### **1. Introduction**

#### **1.1 Importance of clinical trial quality assurance (QA)**

Clinical trials are designed to give us confidence in a course of care. For cancer treatment, clinical trials have played a crucial role in the advancement of treatment for a variety of disease sites over the last century. As discussed in the chapter on clinical trials, there are a number of active protocols seeking to better understand the role of proton therapy within modern radiotherapy. Clinical trials have varied points of emphasis and radiation therapy may be an important aspect of the trial but not the trial endpoint. Phase II and III trials often require many participants to reach a statistically significant conclusion. With limited numbers of patients of various disease sites seen at an individual institution, it is common for proton therapy trials to be conducted among multiple institutions. When a trial includes multiple institutions, variability in treatment practices increases. One way to minimize differences across participating centers is to require QA of the trial treatment. QA helps minimize deviations within trials, and can improve clinical outcomes such as overall and progression-free survival [1–4]. This is particularly important for many proton therapy clinical trials, as insurance companies want to see quantification of superior outcomes before agreeing to cover the cost of therapy.

#### **1.2 National Cancer Institute (NCI) proton guidelines**

In 2007, the NCI formed an ad-hoc panel of proton experts to outline guidelines for the use of proton therapy in clinical trials. The original guidelines included

recommendations about beam calibration protocol, relative biological effectiveness (RBE), target volumes, and clinical trial audits. The guidelines have been updated several times since then, most recently in 2019, to include requirements for modulated pencil beam scanning delivery, robust optimization, advanced treatment planning algorithms, and recommendations about clinical trial credentialing [5].

#### **2. General proton approval**

#### **2.1 Output checks**

Regular remote output checks are part of clinical trial QA around the world [6]. In the United States (US), output checks are required on an annual basis for all proton beams used in the NCI's National Clinical Trial Network (NCTN) protocols. The purpose of these QA audits is to verify the output of a uniform field. Typically institutions use their reference calibration (International Atomic Energy Agency Technical Report Series 398) field for this purpose. Use of the same field year after year can catch drifts in output or dramatic changes that may be caused by an error in calibration.

#### **2.2 On-site audit**

In addition to the remote output check, all proton therapy centers in the US receive an on-site dosimetry audit as part of the baseline approval process for clinical trial participation. With relatively few proton centers in the US (as compared to photon clinics), many personnel are coming to work at new proton facilities without prior experience with proton therapy. On-site audits are perhaps the most crucial component of proton approval, as they allow a deep dive into the dosimetry and clinical operations of a facility, and check for practice consistency across these new facilities.

The on-sites audit consists of a number of dosimetric measurements, including beam calibration, calibration equipment intercomparison, depth dose profiles, lateral beam profiles of reference and patient fields, imaging vs. radiation isocenter coincidence, and Hounsfield Unit (HU) – Relative Linear Stopping Power (RLSP) calibration. On-site audits allow for greater dosimetric accuracy and complexity than remote audits. Recommendations are made to the institution about how they can improve their clinical practice and make it more consistent with other proton centers on multi-institutional trials. The most common recommendation relates to the HU-RLSP conversion curve that institutions use to predict proton range within a patient [7, 8]. The curve is sensitive to errors at low densities (e.g. lung tissue) and variability is observed across institutions at both low and high densities. Accuracy of this calibration is critical to accurate proton beam modeling and by minimizing deviations in the calibration, treatment delivery deviations can also be mitigated.

The on-site audit also includes a review of clinical practices, covering topics like CT simulation and re-simulation over the course of treatment, patient immobilization, treatment planning and robustness evaluation, and image guidance. The goal is to ensure consistency across institutions, in an effort to minimize deviations on trials. For example, if an institution is not performing any kind of rectal sparing technique for prostate treatment, a recommendation might be made to investigate and adopt a technique in order to follow standard clinical practices. The machine QA practices are also reviewed to ensure compliance with recommended standards [9–12]. The proton QA standards are relatively new, so the review of QA practices provides useful feedback on ways to implement different tests, benefits and drawbacks of different equipment, and failure modes within the system.

**37**

institutions.

trial participation [18].

*Credentialing Proton Centers for Clinical Trials DOI: http://dx.doi.org/10.5772/intechopen.95958*

**3. Protocol-specific credentialing**

Anthropomorphic phantoms are one of the most robust options for remote audits of a radiotherapy modality. They encompass an end-to-end test of simulation, treatment planning, setup, and delivery of radiation. Proton therapy presents some unique challenges for phantom tests. The plastics typically used for QA of photon beams are not necessarily "tissue-equivalent" in a proton beam, thus appropriate phantom materials need to be tested to ensure they fall on a clinical proton

The phantoms currently available for proton credentialing test a variety of different clinical requirements: conformality (brain, head and neck (H&N), spine), organs at risk (OAR) avoidance (H&N, prostate), motion management (liver, lung), heterogeneities (lung, spine), and multiple targets (liver) [13, 14]. Proton anthropomorphic phantom credentialing has already led to improvements in accuracy of treatment dose calculations for clinical trials. The lung phantom credentialing for the Radiation Therapy Oncology Group's (RTOG) randomized proton vs. photon trial for non-small cell lung cancer (NSCLC) (RTOG 1308) found gross overestimates of dose when using an analytic algorithm for dose calculations in low-density heterogeneities [15]. The NCI has updated their proton therapy guidelines to require Monte Carlo or advanced algorithms for future trials with low

Image guidance is a crucial component of proton therapy because the beam range is dependent on the density of the material in its path. If you plan a field in soft tissue and then a bone is in the beam path at the time of treatment, you could entirely miss your target. Alternatively, if high density tissue is in the beam path at the time of planning but not at the time of treatment delivery, you risk delivering full dose to the tissue distal to the target. Most proton centers began by using orthogonal kV image guidance, but many now have in-room volumetric imaging

There are many components of image guidance that are important to verify: image quality, geometric accuracy, imaging dose, imaging system communication, and safety [9–11]. Some of these components, like imaging dose and image-guided radiotherapy (IGRT) safety checks, are left to the institution's physics team to test. Other elements are verified through clinical trial credentialing. Many protocols require IGRT credentialing for both photon and proton therapy if "reduced margins" (typically less than 5 mm) are used. The IGRT credentialing requires submission of actual patient IGRT data for central review, as well as completion of a questionnaire outlining IGRT practices. The images are reviewed for registration to reference treatment planning data as well as consistency from day-to-day. The goal of this credentialing is to ensure consistency of IGRT processes and quality across

Of course, there could be accurate in-room images, but if the proton beam is not coincident with the IGRT isocenter, the accuracy of the beam delivery is negatively impacted. For this reason, the coincidence of the IGRT and proton beam isocenters is verified for proton therapy centers participating in clinical trials. This is done with a Winston-Lutz type test as part of the baseline approval process for clinical

capabilities with CT or cone-beam CT (CBCT) [16, 17].

**3.1 Anthropomorphic phantoms**

HU-RLSP curve [8].

density heterogeneities [5].

**3.2 Image guidance**

#### **3. Protocol-specific credentialing**

#### **3.1 Anthropomorphic phantoms**

*Proton Therapy - Current Status and Future Directions*

**2. General proton approval**

**2.1 Output checks**

**2.2 On-site audit**

recommendations about beam calibration protocol, relative biological effectiveness (RBE), target volumes, and clinical trial audits. The guidelines have been updated several times since then, most recently in 2019, to include requirements for modulated pencil beam scanning delivery, robust optimization, advanced treatment planning algorithms, and recommendations about clinical trial credentialing [5].

Regular remote output checks are part of clinical trial QA around the world [6]. In the United States (US), output checks are required on an annual basis for all proton beams used in the NCI's National Clinical Trial Network (NCTN) protocols. The purpose of these QA audits is to verify the output of a uniform field. Typically institutions use their reference calibration (International Atomic Energy Agency Technical Report Series 398) field for this purpose. Use of the same field year after year can catch drifts

In addition to the remote output check, all proton therapy centers in the US receive an on-site dosimetry audit as part of the baseline approval process for clinical trial participation. With relatively few proton centers in the US (as compared to photon clinics), many personnel are coming to work at new proton facilities without prior experience with proton therapy. On-site audits are perhaps the most crucial component of proton approval, as they allow a deep dive into the dosimetry and clinical operations of a facility, and check for practice consistency across these new facilities. The on-sites audit consists of a number of dosimetric measurements, including beam calibration, calibration equipment intercomparison, depth dose profiles, lateral beam profiles of reference and patient fields, imaging vs. radiation isocenter coincidence, and Hounsfield Unit (HU) – Relative Linear Stopping Power (RLSP) calibration. On-site audits allow for greater dosimetric accuracy and complexity than remote audits. Recommendations are made to the institution about how they can improve their clinical practice and make it more consistent with other proton centers on multi-institutional trials. The most common recommendation relates to the HU-RLSP conversion curve that institutions use to predict proton range within a patient [7, 8]. The curve is sensitive to errors at low densities (e.g. lung tissue) and variability is observed across institutions at both low and high densities. Accuracy of this calibration is critical to accurate proton beam modeling and by minimizing deviations in the calibration, treatment delivery deviations can also be mitigated. The on-site audit also includes a review of clinical practices, covering topics like CT simulation and re-simulation over the course of treatment, patient immobilization, treatment planning and robustness evaluation, and image guidance. The goal is to ensure consistency across institutions, in an effort to minimize deviations on trials. For example, if an institution is not performing any kind of rectal sparing technique for prostate treatment, a recommendation might be made to investigate and adopt a technique in order to follow standard clinical practices. The machine QA practices are also reviewed to ensure compliance with recommended standards [9–12]. The proton QA standards are relatively new, so the review of QA practices provides useful feedback on ways to implement different tests, benefits and drawbacks of different equipment, and failure modes within the system.

in output or dramatic changes that may be caused by an error in calibration.

**36**

Anthropomorphic phantoms are one of the most robust options for remote audits of a radiotherapy modality. They encompass an end-to-end test of simulation, treatment planning, setup, and delivery of radiation. Proton therapy presents some unique challenges for phantom tests. The plastics typically used for QA of photon beams are not necessarily "tissue-equivalent" in a proton beam, thus appropriate phantom materials need to be tested to ensure they fall on a clinical proton HU-RLSP curve [8].

The phantoms currently available for proton credentialing test a variety of different clinical requirements: conformality (brain, head and neck (H&N), spine), organs at risk (OAR) avoidance (H&N, prostate), motion management (liver, lung), heterogeneities (lung, spine), and multiple targets (liver) [13, 14]. Proton anthropomorphic phantom credentialing has already led to improvements in accuracy of treatment dose calculations for clinical trials. The lung phantom credentialing for the Radiation Therapy Oncology Group's (RTOG) randomized proton vs. photon trial for non-small cell lung cancer (NSCLC) (RTOG 1308) found gross overestimates of dose when using an analytic algorithm for dose calculations in low-density heterogeneities [15]. The NCI has updated their proton therapy guidelines to require Monte Carlo or advanced algorithms for future trials with low density heterogeneities [5].

#### **3.2 Image guidance**

Image guidance is a crucial component of proton therapy because the beam range is dependent on the density of the material in its path. If you plan a field in soft tissue and then a bone is in the beam path at the time of treatment, you could entirely miss your target. Alternatively, if high density tissue is in the beam path at the time of planning but not at the time of treatment delivery, you risk delivering full dose to the tissue distal to the target. Most proton centers began by using orthogonal kV image guidance, but many now have in-room volumetric imaging capabilities with CT or cone-beam CT (CBCT) [16, 17].

There are many components of image guidance that are important to verify: image quality, geometric accuracy, imaging dose, imaging system communication, and safety [9–11]. Some of these components, like imaging dose and image-guided radiotherapy (IGRT) safety checks, are left to the institution's physics team to test. Other elements are verified through clinical trial credentialing. Many protocols require IGRT credentialing for both photon and proton therapy if "reduced margins" (typically less than 5 mm) are used. The IGRT credentialing requires submission of actual patient IGRT data for central review, as well as completion of a questionnaire outlining IGRT practices. The images are reviewed for registration to reference treatment planning data as well as consistency from day-to-day. The goal of this credentialing is to ensure consistency of IGRT processes and quality across institutions.

Of course, there could be accurate in-room images, but if the proton beam is not coincident with the IGRT isocenter, the accuracy of the beam delivery is negatively impacted. For this reason, the coincidence of the IGRT and proton beam isocenters is verified for proton therapy centers participating in clinical trials. This is done with a Winston-Lutz type test as part of the baseline approval process for clinical trial participation [18].

#### **3.3 Motion management**

Motion management is of particular importance in proton therapy due to the sensitivity of the beam range to changes in tissue density [19, 20]. Several anthropomorphic phantoms (liver, lung) assess the end-to-end process of motion management, but there are some clinical trials that also require a motion management questionnaire. This questionnaire assesses the standard clinical practices for assessing and accommodating target motion, such as the upper limit for motion magnitude, simulation practices, respiratory management system, and patient setup requirements. Many of these aspects are also reviewed during the on-site audit, so a separate motion management questionnaire for a specific clinical trial may not be necessary.

#### **3.4 Knowledge assessments**

A knowledge assessment asks questions about a clinical trial to ensure that participants have carefully reviewed the protocol and understand its requirements. Knowledge assessments are used for credentialing in a handful of NCTN clinical trials. Knowledge assessments can be useful for randomized proton vs. photon trials because there are intricacies of treating with two modalities, such as accounting for RBE, different definitions of target structures, and partnerships among multiple institutions. Unfortunately the knowledge assessment only captures the knowledge of a few personnel at a specific point in time, so it does not ensure that everyone involved over the course of the trial has carefully read the protocol. For this reason, most new NCTN proton clinical trials do not require knowledge assessments.

#### **3.5 Benchmark cases**

Benchmark cases have commonly been used for clinical trial credentialing [21, 22]. The objective is to have a standard sample case that all participants plan on. The reviewer can then assess quality of contours, beam arrangement, and target coverage. Often an independent dose recalculation is also performed to assess the accuracy of the institutions' treatment plan dose calculations. Benchmarks can be a great way to identify variability across centers and offer a platform to provide feedback to participants for improving their practices.

In addition to planning benchmark cases, there is also an image-fusion benchmark case that is used for some central nervous system (CNS) trials. The benchmark reviews an institution's fusion of CT and MR images. For proton therapy, this benchmark can be particularly useful. Proton therapy cannot be planned directly on MR images because the HU values from CT are required for beam range calculations, and the proton range is sensitive to anatomical changes, so proper fusion of MR and CT images is important for treatment delivery accuracy.

There are two challenges with benchmarks; one general and one proton-specific. There have been a few instances where a clinical trial required a benchmark and hundreds of institutions completed the benchmark, but then when it came to patient enrollment, only a small fraction of those initial institutions enrolled patients on-protocol. Reviewing benchmarks is time-intensive for the QA office and at times this method of up-front verification does not yield commensurate reward. For proton therapy specifically, the NCTN QA group does not yet have an independent dose calculation that can be used for all proton therapy centers, so benchmarks can only be used as a qualitative assessment rather than a quantitative one. For these reasons, clinical trial QA is shifting away from standard benchmark cases.

**39**

*Credentialing Proton Centers for Clinical Trials DOI: http://dx.doi.org/10.5772/intechopen.95958*

throughout the protocol.

**4. Conclusion**

**Conflict of interest**

consistency as the trial moves forward.

**3.6 Pre-treatment, on-treatment and post-treatment review**

potential sources of range uncertainty are also evaluated.

In lieu of benchmark cases, many clinical trials are shifting toward pre-treatment

or on-treatment review of actual patients enrolled in the trials. A pre-treatment review is the submission of the actual treatment plan for a patient intended to be treated on protocol. The plan is rapidly reviewed by clinical trial staff or volunteers and feedback is provided to the participating institution before the start of that patient's treatment. Most commonly, the contours, target dose coverage, and dose to critical structures are reviewed. For proton therapy, the beam arrangement and

The advantage of pre-treatment review is that it can reduce the number of protocol deviations. If an institution receives feedback about ways to improve one patient's treatment, this benefits the individual patient and can also benefit subsequent patients treated at the same institution. The biggest drawback of pre-treatment review is the time-sensitivity of the plan review. Typically the turnaround for such reviews is three business days, but sometimes this is done more quickly. This requires that there is always personnel available to review cases, and does not allow for the reviewer to batch reviews at a time convenient to them. To balance the demands of pre-treatment review, some protocols will require pre-treatment review for the first few (e.g. five) patients from an individual institution. Other trials might place a quantitative criterion for when to require pre-treatment review; one trial requires pre-treatment review if the high dose goal for the target is not met. This is a good compromise to allow early feedback to shape an institution's practices

On-treatment reviews, performed while the patient is being treated, can allow similar timely feedback as pre-treatment reviews. They are less time-sensitive, but can have a similar positive down-stream impact on subsequent patients treated by the same institution. Another benefit of the pre- and on-treatment reviews is they give the reviewers a chance to see common issues across multiple institutions, which can be addressed during investigator discussions during the trial and help ensure

Post-treatment reviews are typically performed for all plans, regardless of whether pre- or on-treatment reviews were performed. They assess many of the same criteria, as well as protocol compliance for duration of treatment time.

Independent peer review is an important component in clinical trials with radiation therapy, particularly in the emerging field of proton therapy. The credentialing efforts required by the NCI are a paradigm for other proton clinical trials. With the future of proton therapy relying on results of many clinical trials, it is important to get the basics right. Through standard checks of consistency and comparability, we

ensure high quality trial data for strong statistical analysis of outcomes.

The author declares no conflict of interest.

*Proton Therapy - Current Status and Future Directions*

Motion management is of particular importance in proton therapy due to the sensitivity of the beam range to changes in tissue density [19, 20]. Several anthropomorphic phantoms (liver, lung) assess the end-to-end process of motion management, but there are some clinical trials that also require a motion management questionnaire. This questionnaire assesses the standard clinical practices for assessing and accommodating target motion, such as the upper limit for motion magnitude, simulation practices, respiratory management system, and patient setup requirements. Many of these aspects are also reviewed during the on-site audit, so a separate motion management questionnaire for a specific clinical trial

A knowledge assessment asks questions about a clinical trial to ensure that participants have carefully reviewed the protocol and understand its requirements. Knowledge assessments are used for credentialing in a handful of NCTN clinical trials. Knowledge assessments can be useful for randomized proton vs. photon trials because there are intricacies of treating with two modalities, such as accounting for RBE, different definitions of target structures, and partnerships among multiple institutions. Unfortunately the knowledge assessment only captures the knowledge of a few personnel at a specific point in time, so it does not ensure that everyone involved over the course of the trial has carefully read the protocol. For this reason, most new NCTN proton clinical trials do not require knowledge assessments.

Benchmark cases have commonly been used for clinical trial credentialing [21, 22]. The objective is to have a standard sample case that all participants plan on. The reviewer can then assess quality of contours, beam arrangement, and target coverage. Often an independent dose recalculation is also performed to assess the accuracy of the institutions' treatment plan dose calculations. Benchmarks can be a great way to identify variability across centers and offer a platform to provide

In addition to planning benchmark cases, there is also an image-fusion benchmark case that is used for some central nervous system (CNS) trials. The benchmark reviews an institution's fusion of CT and MR images. For proton therapy, this benchmark can be particularly useful. Proton therapy cannot be planned directly on MR images because the HU values from CT are required for beam range calculations, and the proton range is sensitive to anatomical changes, so proper fusion of

There are two challenges with benchmarks; one general and one proton-specific.

There have been a few instances where a clinical trial required a benchmark and hundreds of institutions completed the benchmark, but then when it came to patient enrollment, only a small fraction of those initial institutions enrolled patients on-protocol. Reviewing benchmarks is time-intensive for the QA office and at times this method of up-front verification does not yield commensurate reward. For proton therapy specifically, the NCTN QA group does not yet have an independent dose calculation that can be used for all proton therapy centers, so benchmarks can only be used as a qualitative assessment rather than a quantitative one. For these

reasons, clinical trial QA is shifting away from standard benchmark cases.

feedback to participants for improving their practices.

MR and CT images is important for treatment delivery accuracy.

**3.3 Motion management**

may not be necessary.

**3.5 Benchmark cases**

**3.4 Knowledge assessments**

**38**

#### **3.6 Pre-treatment, on-treatment and post-treatment review**

In lieu of benchmark cases, many clinical trials are shifting toward pre-treatment or on-treatment review of actual patients enrolled in the trials. A pre-treatment review is the submission of the actual treatment plan for a patient intended to be treated on protocol. The plan is rapidly reviewed by clinical trial staff or volunteers and feedback is provided to the participating institution before the start of that patient's treatment. Most commonly, the contours, target dose coverage, and dose to critical structures are reviewed. For proton therapy, the beam arrangement and potential sources of range uncertainty are also evaluated.

The advantage of pre-treatment review is that it can reduce the number of protocol deviations. If an institution receives feedback about ways to improve one patient's treatment, this benefits the individual patient and can also benefit subsequent patients treated at the same institution. The biggest drawback of pre-treatment review is the time-sensitivity of the plan review. Typically the turnaround for such reviews is three business days, but sometimes this is done more quickly. This requires that there is always personnel available to review cases, and does not allow for the reviewer to batch reviews at a time convenient to them. To balance the demands of pre-treatment review, some protocols will require pre-treatment review for the first few (e.g. five) patients from an individual institution. Other trials might place a quantitative criterion for when to require pre-treatment review; one trial requires pre-treatment review if the high dose goal for the target is not met. This is a good compromise to allow early feedback to shape an institution's practices throughout the protocol.

On-treatment reviews, performed while the patient is being treated, can allow similar timely feedback as pre-treatment reviews. They are less time-sensitive, but can have a similar positive down-stream impact on subsequent patients treated by the same institution. Another benefit of the pre- and on-treatment reviews is they give the reviewers a chance to see common issues across multiple institutions, which can be addressed during investigator discussions during the trial and help ensure consistency as the trial moves forward.

Post-treatment reviews are typically performed for all plans, regardless of whether pre- or on-treatment reviews were performed. They assess many of the same criteria, as well as protocol compliance for duration of treatment time.

#### **4. Conclusion**

Independent peer review is an important component in clinical trials with radiation therapy, particularly in the emerging field of proton therapy. The credentialing efforts required by the NCI are a paradigm for other proton clinical trials. With the future of proton therapy relying on results of many clinical trials, it is important to get the basics right. Through standard checks of consistency and comparability, we ensure high quality trial data for strong statistical analysis of outcomes.

#### **Conflict of interest**

The author declares no conflict of interest.

*Proton Therapy - Current Status and Future Directions*

#### **Author details**

Paige A. Taylor University of Texas MD Anderson Cancer Center, Houston, TX, USA

\*Address all correspondence to: pataylor@mdanderson.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.

**41**

*Credentialing Proton Centers for Clinical Trials DOI: http://dx.doi.org/10.5772/intechopen.95958*

> Hurkmans C, Alvarez P, Alves A, Bokulic T, Followill D, Kazantsev P, Lowenstein J, Molineu A, Palmer J, Smith SA, Taylor P, Wesolowska P, Williams I. Remote beam output audits: a global assessment of results out of tolerance. Physics and Imaging in Radiation Oncology. 2018;7:39-44. DOI:10.1016/j.phro.2018.08.005.

[7] Moyers MF. Comparison of x ray computed tomography number to proton relative linear stopping power conversion functions using a standard phantom. Medical Physics. 2014;41(6):061705.

[8] Grant RL, Summers PA, Neihart JL, Blatnica AP, Sahoo N, Gillin MT, Followill DS, Ibbott GS. Relative stopping power measurements to aid in the design of anthropomorphic phantoms for proton radiotherapy. Journal of Applied Clinical Medical Physics. 2014;15(2):4523. DOI:10.1120/

[9] Arjomandy B, Taylor P, Ainsley C, Safai S, Sahoo N, Pankuch M, Farr JB, Yong Park S, Klein E, Flanz J, Yorke ED, Followill D, Kase Y. AAPM task group 224: Comprehensive proton therapy machine quality assurance. Medical Physics. 2019;46(8):e678-e705.

DOI:10.1118/1.4870956.

jacmp.v15i2.4523.

DOI:10.1002/mp.13622.

[10] Bissonnette JP, Balter PA, Dong L, Langen KM, Lovelock DM, Miften M, Moseley DJ, Pouliot J, Sonke JJ, Yoo S. Quality assurance for image-guided radiation therapy utilizing CT-based technologies: a report of the AAPM TG-179. Medical Physics. 2012;39(4):1946-1963. DOI:10.1118/1.3690466.

[11] Klein EE, Hanley J, Bayouth J, Yin FF, Simon W, Dresser S, Serago C, Aguirre F, Ma L, Arjomandy B, Liu C, Sandin C, Holmes T; Task Group 142, American Association of Physicists in

[1] Peters LJ, O'Sullivan B, Giralt J, Fitzgerald TJ, Trotti A, Bernier J, Bourhis J, Yuen K, Fisher R, Rischin D. Critical impact of radiotherapy protocol compliance and quality in the treatment of advanced head and neck cancer: results from TROG 02.02. Journal of Clinical Oncology. 2010;28(18):2996- 3001. DOI:10.1200/JCO.2009.27.4498.

[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):246-60. DOI:10.1016/j.

[3] Weber DC, Tomsej M, Melidis C, Hurkmans CW. QA makes a clinical trial stronger: evidence-based medicine in radiation therapy. Radiotherapy and Oncology. 2012;105(1): 4-8. DOI:10.1016/j.radonc.2012.08.008.

[4] Abrams RA, Winter KA, Regine WF,

Safran H, Hoffman JP, Lustig R, Konski AA, Benson AB, Macdonald JS,

Rich TA, Willett CG. Failure to adhere to protocol specified radiation therapy guidelines was associated with decreased survival in RTOG 9704--a phase III trial of adjuvant chemotherapy and chemoradiotherapy for patients with resected adenocarcinoma of the pancreas. International Journal of Radiation Oncology • Biology • Physics. 2012;82(2):809-816. DOI:10.1016/j.

[5] NCI. Guidelines for the Use of Hadron Radiation Therapy in NCI-Sponsored Cooperative Group Clinical Trials [Internet]. 2019. Available from :http://irochouston.mdanderson.org/ RPC/home\_page/Proton\_guidelines.

htm. [Accessed 2020-09-28].

[6] Kry SF, Peterson CB, Howell RM, Izewska J, Lye J, Clark CH, Nakamura M,

ijrobp.2010.11.039.

ijrobp.2013.03.036.

**References**

*Credentialing Proton Centers for Clinical Trials DOI: http://dx.doi.org/10.5772/intechopen.95958*

#### **References**

*Proton Therapy - Current Status and Future Directions*

**40**

**Author details**

Paige A. Taylor

University of Texas MD Anderson Cancer Center, Houston, TX, 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,

\*Address all correspondence to: pataylor@mdanderson.org

provided the original work is properly cited.

[1] Peters LJ, O'Sullivan B, Giralt J, Fitzgerald TJ, Trotti A, Bernier J, Bourhis J, Yuen K, Fisher R, Rischin D. Critical impact of radiotherapy protocol compliance and quality in the treatment of advanced head and neck cancer: results from TROG 02.02. Journal of Clinical Oncology. 2010;28(18):2996- 3001. DOI:10.1200/JCO.2009.27.4498.

[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):246-60. DOI:10.1016/j. ijrobp.2013.03.036.

[3] Weber DC, Tomsej M, Melidis C, Hurkmans CW. QA makes a clinical trial stronger: evidence-based medicine in radiation therapy. Radiotherapy and Oncology. 2012;105(1): 4-8. DOI:10.1016/j.radonc.2012.08.008.

[4] Abrams RA, Winter KA, Regine WF, Safran H, Hoffman JP, Lustig R, Konski AA, Benson AB, Macdonald JS, Rich TA, Willett CG. Failure to adhere to protocol specified radiation therapy guidelines was associated with decreased survival in RTOG 9704--a phase III trial of adjuvant chemotherapy and chemoradiotherapy for patients with resected adenocarcinoma of the pancreas. International Journal of Radiation Oncology • Biology • Physics. 2012;82(2):809-816. DOI:10.1016/j. ijrobp.2010.11.039.

[5] NCI. Guidelines for the Use of Hadron Radiation Therapy in NCI-Sponsored Cooperative Group Clinical Trials [Internet]. 2019. Available from :http://irochouston.mdanderson.org/ RPC/home\_page/Proton\_guidelines. htm. [Accessed 2020-09-28].

[6] Kry SF, Peterson CB, Howell RM, Izewska J, Lye J, Clark CH, Nakamura M, Hurkmans C, Alvarez P, Alves A, Bokulic T, Followill D, Kazantsev P, Lowenstein J, Molineu A, Palmer J, Smith SA, Taylor P, Wesolowska P, Williams I. Remote beam output audits: a global assessment of results out of tolerance. Physics and Imaging in Radiation Oncology. 2018;7:39-44. DOI:10.1016/j.phro.2018.08.005.

[7] Moyers MF. Comparison of x ray computed tomography number to proton relative linear stopping power conversion functions using a standard phantom. Medical Physics. 2014;41(6):061705. DOI:10.1118/1.4870956.

[8] Grant RL, Summers PA, Neihart JL, Blatnica AP, Sahoo N, Gillin MT, Followill DS, Ibbott GS. Relative stopping power measurements to aid in the design of anthropomorphic phantoms for proton radiotherapy. Journal of Applied Clinical Medical Physics. 2014;15(2):4523. DOI:10.1120/ jacmp.v15i2.4523.

[9] Arjomandy B, Taylor P, Ainsley C, Safai S, Sahoo N, Pankuch M, Farr JB, Yong Park S, Klein E, Flanz J, Yorke ED, Followill D, Kase Y. AAPM task group 224: Comprehensive proton therapy machine quality assurance. Medical Physics. 2019;46(8):e678-e705. DOI:10.1002/mp.13622.

[10] Bissonnette JP, Balter PA, Dong L, Langen KM, Lovelock DM, Miften M, Moseley DJ, Pouliot J, Sonke JJ, Yoo S. Quality assurance for image-guided radiation therapy utilizing CT-based technologies: a report of the AAPM TG-179. Medical Physics. 2012;39(4):1946-1963. DOI:10.1118/1.3690466.

[11] Klein EE, Hanley J, Bayouth J, Yin FF, Simon W, Dresser S, Serago C, Aguirre F, Ma L, Arjomandy B, Liu C, Sandin C, Holmes T; Task Group 142, American Association of Physicists in

Medicine. Task Group 142 report: quality assurance of medical accelerators. Medical Physics. 2009;36(9):4197-4212. DOI:10.1118/1.3190392.

[12] Fontenot JD, Alkhatib H, Garrett JA, Jensen AR, McCullough SP, Olch AJ, Parker BC, Yang CC, Fairobent LA; AAMP Staff. AAPM Medical Physics Practice Guideline 2.a: Commissioning and quality assurance of X-ray-based image-guided radiotherapy systems. Journal of Applied Clinical Medical Physics. 2014;15(1):4528. DOI:10.1120/ jacmp.v15i1.4528.

[13] Taylor PA, Kry SF, Alvarez P, Keith T, Lujano C, Hernandez N, Followill DS. Results from the Imaging and Radiation Oncology Core Houston's anthropomorphic phantoms used for proton therapy clinical trial credentialing. International Journal of Radiation Oncology • Biology • Physics. 2016;95(1):242-248. DOI:10.1016/j. ijrobp.2016.01.061.

[14] Branco D, Taylor P, Zhang X, Li H, Guindani M, Followill D. An anthropomorphic head and neck quality assurance phantom for credentialing of intensity-modulated proton therapy. International Journal of Particle Therapy. 2018;4(3):40-47. DOI:10.14338/IJPT-17-00005.1.

[15] Taylor PA, Kry SF, Followill DS. Pencil beam algorithms are unsuitable for proton dose calculations in lung. International Journal of Radiation Oncology • Biology • Physics. 2017;99(3):750-756. DOI:10.1016/j. ijrobp.2017.06.003.

[16] Oliver JA, Zeidan O, Meeks SL, Shah AP, Pukala J, Kelly P, Ramakrishna NR, Willoughby TR. Commissioning an in-room mobile CT for adaptive proton therapy with a compact proton system. Journal of Applied Clinical Medical Physics. 2018;19(3):149- 158. DOI:10.1002/acm2.12319.

[17] Hua C, Yao W, Kidani T, Tomida K, Ozawa S, Nishimura T, Fujisawa T, Shinagawa R, Merchant TE. A robotic C-arm cone beam CT system for image-guided proton therapy: design and performance. British Journal of Radiology. 2017;90(1079):20170266. DOI:10.1259/bjr.20170266.

[18] Kry SF, Jones J, Childress NL. Implementation and evaluation of an end-to-end IGRT test. Journal of Applied Clinical Medical Physics. 2012;13(5):3939. DOI:10.1120/jacmp. v13i5.3939.

[19] De Ruysscher D, Sterpin E, Haustermans K, Depuydt T. Tumour movement in proton therapy: Solutions and remaining questions: A review. Cancers (Basel). 2015;7(3):1143-1153. DOI:10.3390/cancers7030829.

[20] Chang JY, Zhang X, Knopf A, Li H, Mori S, Dong L, Lu HM, Liu W, Badiyan SN, Both S, Meijers A, Lin L, Flampouri S, Li Z, Umegaki K, Simone CB 2nd, Zhu XR. Consensus guidelines for implementing pencilbeam scanning proton therapy for thoracic malignancies on behalf of the PTCOG Thoracic and Lymphoma Subcommittee. International Journal of Radiation Oncology • Biology • Physics. 2017;99(1): 41-50. DOI:10.1016/j. ijrobp.2017.05.014.

[21] Ibbott GS, Haworth A, Followill DS. Quality assurance for clinical trials. Frontiers in Oncology-Radiation Oncology. 2013;3:311. DOI:10.3389/ fonc.2013.00311.

[22] Olch AJ, Kline RW, Ibbott GS, Anderson JR, Deye J, FitzGerald TJ, Followill D, Gillin MT, Huq S, Palta JR, Purdy JA, Urie MM. AAPM Report No. 86 - Quality Assurance for Clinical Trials: A Primer for Physicists. 2004. Available from: https://www.aapm.org/ pubs/reports/rpt\_86.PDF. [Accessed: 2020-08-22].

**43**

**Chapter 5**

**Abstract**

**1. Introduction**

**1.1 Clinical trial importance**

*1.1.1 Safety and efficacy*

Therapy

*Paige A. Taylor*

Clinical Trials Evaluating Proton

Although proton therapy was developed almost 80 years ago, widespread clinical implementation has been limited until the past decade. With the growing use of proton therapy, there is a desire to prove the equivalence or superiority of proton therapy across a number of cancer disease sites. Dozens of clinical trials have been developed to accomplish this within individual institutions, among a few centers, and across national and international networks such as the National Cancer Institute's National Clinical Trial Network. The protocols include proton therapy imbedded in trials with photon therapy as well as randomized photon vs. proton trials. This chapter provides an overview of the design of such trials as well as some

**Keywords:** proton therapy, clinical trials, protocols, randomized, phase II, phase III,

Clinical trials are an important step to ensuring the safety and efficacy of medical treatment. For radiation therapy, clinical trials have allowed us to look at important questions like dose escalation, fractionation, and new radiotherapy technologies. Much like the use of instensity-modulated radiation therapy (IMRT) was critically reviewed in the early 2000s, proton therapy has come under careful scrutiny over the past decade. Many radiation therapy departments commissioned proton therapy centers and began to integrate protons into their clinical practice.

Most people who work in radiation therapy have seen the striking treatment plan comparisons between proton therapy and traditional photon therapy for a pediatric craniospinal case, noting the marked reduction in dose to organs at risk and normal tissue outside of the target region [1]. These in-silico studies are even more exciting given the potential reduction in secondary cancer for pediatric patients. The potential benefits in these studies come with corresponding risk; if the beam modeling or treatment delivery positioning is not accurate, there is a risk of high overdose to normal tissue or severe underdose of the target. For this reason, the National Cancer Institute (NCI), the American Society for Radiation Oncology (ASTRO), and other

of the challenges facing protocols with proton therapy.

National Cancer Institute, National Clinical Trial Network

#### **Chapter 5**

*Proton Therapy - Current Status and Future Directions*

[17] Hua C, Yao W, Kidani T, Tomida K, Ozawa S, Nishimura T, Fujisawa T, Shinagawa R, Merchant TE. A robotic C-arm cone beam CT system for image-guided proton therapy: design and performance. British Journal of Radiology. 2017;90(1079):20170266.

DOI:10.1259/bjr.20170266.

v13i5.3939.

[18] Kry SF, Jones J, Childress NL. Implementation and evaluation of an end-to-end IGRT test. Journal of Applied Clinical Medical Physics. 2012;13(5):3939. DOI:10.1120/jacmp.

[19] De Ruysscher D, Sterpin E, Haustermans K, Depuydt T. Tumour movement in proton therapy: Solutions and remaining questions: A review. Cancers (Basel). 2015;7(3):1143-1153.

DOI:10.3390/cancers7030829.

ijrobp.2017.05.014.

fonc.2013.00311.

2020-08-22].

[20] Chang JY, Zhang X, Knopf A, Li H, Mori S, Dong L, Lu HM, Liu W, Badiyan SN, Both S, Meijers A, Lin L, Flampouri S, Li Z, Umegaki K, Simone CB 2nd, Zhu XR. Consensus guidelines for implementing pencilbeam scanning proton therapy for thoracic malignancies on behalf of the PTCOG Thoracic and Lymphoma Subcommittee. International Journal of Radiation Oncology • Biology • Physics. 2017;99(1): 41-50. DOI:10.1016/j.

[21] Ibbott GS, Haworth A, Followill DS. Quality assurance for clinical trials. Frontiers in Oncology-Radiation Oncology. 2013;3:311. DOI:10.3389/

[22] Olch AJ, Kline RW, Ibbott GS, Anderson JR, Deye J, FitzGerald TJ, Followill D, Gillin MT, Huq S, Palta JR, Purdy JA, Urie MM. AAPM Report No. 86 - Quality Assurance for Clinical Trials: A Primer for Physicists. 2004. Available from: https://www.aapm.org/ pubs/reports/rpt\_86.PDF. [Accessed:

Medicine. Task Group 142 report: quality assurance of medical accelerators. Medical Physics. 2009;36(9):4197-4212.

[12] Fontenot JD, Alkhatib H, Garrett JA, Jensen AR, McCullough SP, Olch AJ, Parker BC, Yang CC, Fairobent LA; AAMP Staff. AAPM Medical Physics Practice Guideline 2.a: Commissioning and quality assurance of X-ray-based image-guided radiotherapy systems. Journal of Applied Clinical Medical Physics. 2014;15(1):4528. DOI:10.1120/

DOI:10.1118/1.3190392.

jacmp.v15i1.4528.

ijrobp.2016.01.061.

ijrobp.2017.06.003.

[13] Taylor PA, Kry SF, Alvarez P, Keith T, Lujano C, Hernandez N, Followill DS. Results from the

[14] Branco D, Taylor P, Zhang X, Li H, Guindani M, Followill D. An anthropomorphic head and neck quality assurance phantom for credentialing of intensity-modulated proton therapy. International Journal of Particle Therapy. 2018;4(3):40-47. DOI:10.14338/IJPT-17-00005.1.

[15] Taylor PA, Kry SF, Followill DS. Pencil beam algorithms are unsuitable for proton dose calculations in lung. International Journal of Radiation Oncology • Biology • Physics. 2017;99(3):750-756. DOI:10.1016/j.

[16] Oliver JA, Zeidan O, Meeks SL,

Ramakrishna NR, Willoughby TR. Commissioning an in-room mobile CT for adaptive proton therapy with a compact proton system. Journal of Applied Clinical Medical Physics. 2018;19(3):149-

Shah AP, Pukala J, Kelly P,

158. DOI:10.1002/acm2.12319.

Imaging and Radiation Oncology Core Houston's anthropomorphic phantoms used for proton therapy clinical trial credentialing. International Journal of Radiation Oncology • Biology • Physics. 2016;95(1):242-248. DOI:10.1016/j.

**42**

## Clinical Trials Evaluating Proton Therapy

*Paige A. Taylor*

#### **Abstract**

Although proton therapy was developed almost 80 years ago, widespread clinical implementation has been limited until the past decade. With the growing use of proton therapy, there is a desire to prove the equivalence or superiority of proton therapy across a number of cancer disease sites. Dozens of clinical trials have been developed to accomplish this within individual institutions, among a few centers, and across national and international networks such as the National Cancer Institute's National Clinical Trial Network. The protocols include proton therapy imbedded in trials with photon therapy as well as randomized photon vs. proton trials. This chapter provides an overview of the design of such trials as well as some of the challenges facing protocols with proton therapy.

**Keywords:** proton therapy, clinical trials, protocols, randomized, phase II, phase III, National Cancer Institute, National Clinical Trial Network

#### **1. Introduction**

#### **1.1 Clinical trial importance**

Clinical trials are an important step to ensuring the safety and efficacy of medical treatment. For radiation therapy, clinical trials have allowed us to look at important questions like dose escalation, fractionation, and new radiotherapy technologies. Much like the use of instensity-modulated radiation therapy (IMRT) was critically reviewed in the early 2000s, proton therapy has come under careful scrutiny over the past decade. Many radiation therapy departments commissioned proton therapy centers and began to integrate protons into their clinical practice.

#### *1.1.1 Safety and efficacy*

Most people who work in radiation therapy have seen the striking treatment plan comparisons between proton therapy and traditional photon therapy for a pediatric craniospinal case, noting the marked reduction in dose to organs at risk and normal tissue outside of the target region [1]. These in-silico studies are even more exciting given the potential reduction in secondary cancer for pediatric patients. The potential benefits in these studies come with corresponding risk; if the beam modeling or treatment delivery positioning is not accurate, there is a risk of high overdose to normal tissue or severe underdose of the target. For this reason, the National Cancer Institute (NCI), the American Society for Radiation Oncology (ASTRO), and other

groups have encouraged methodical, careful study of the clinical benefits of proton therapy through clinical trials [2].

The potential benefits of proton therapy are also complicated by the higher biological effectiveness of protons as compared with photons. The current clinical practice in the US is to use a relative biological effectiveness (RBE) of 1.1 for protons, but studies have shown that the true biological response is more complicated and variable [3]. While the higher RBE of protons is a potential benefit for killing tumor cells, there is potential increased biological risk to critical organs proximate to the target. Clinical trials with proton therapy can allow us to look at both sides of the coin by analyzing the correlation between RBE and clinical outcomes.

#### *1.1.2 Evidence for insurance*

Insurance companies have played a role in driving the development of randomized proton vs. photon clinical trials as well. Due to the higher up-front cost of proton therapy for many disease sites, insurance companies have asked for data showing marked improvement in survival outcomes for patients treated with proton therapy in order to cover treatment costs. As discussed later in the chapter, this presents a bit of a catch-22 in clinical trial accrual, as insurers are waiting for trial data to approve coverage, but trial data is nearly impossible to collect without insurance coverage for patients enrolled on-study.

#### **1.2 Clinical trial landscape in the US**

#### *1.2.1 Clinical trial groups*

The largest clinical trial system that supports proton therapy protocols in the US is the National Clinical Trial Network (NCTN), funded by the NCI. The NCTN is made up of four adult and one pediatric clinical trial groups, as well as a partnership with the Canadian Cancer Trials Group. Most of the proton therapy studies run through the NCTN are large-scale, multi-institutional Phase II and Phase III trials. These trials either randomize patients to proton or photon therapy to compare treatment outcomes or imbed proton therapy as a possible treatment modality in a study designed to answer a different clinical question. The NCI has also funded proton clinical trials outside of the NCTN [4–7]. These are often run by a single proton center "sponsor" in partnership with other proton facilities and funded through NCI grants.

Outside of the NCI, there are several other groups that help sponsor clinical trials for proton therapy. The National Association for Proton Therapy (NAPT) is a nonprofit group that helps facilitate proton therapy research collaborations. Most of the operational proton therapy centers in the US are members of NAPT. The Patient-Centered Outcomes Research Institute (PCORI) provides funding for clinical trials comparing proton vs. photon therapy for prostate and breast treatment. The NCI also has a Childhood Cancer Data Initiative (CCDI) that collects standard patient data, including proton therapy data, in a central repository for data sharing and analysis within the research community.

Outside of the US, several groups in Europe and Asia have proton therapy protocols open or in development. The Japan Clinical Oncology Group (JCOG) is funded by Japan's National Cancer Center Research and Development Fund and conducts studies with proton therapy [8]. The European Organization for Research and Treatment of Cancer (EORTC) operates clinical trials within Europe and currently has two protocols with proton therapy embedded [9]. The European Society for Radiotherapy (ESTRO) recently established the European Particle

**45**

*Clinical Trials Evaluating Proton Therapy DOI: http://dx.doi.org/10.5772/intechopen.95957*

**2. Randomized proton vs. photon trials**

and long-term toxicities and associated medical costs.

Oncology/RTOG 1308 have low dose and high dose arms.

**2.1 Challenges of randomized proton vs. photon trials**

vs. photon trials face a number of unique challenges.

already be creating double plans for insurance purposes.

*2.1.1 Treatment planning*

collection for the assessment of biomarkers.

in the future.

Therapy Network (EPTN), which conducts a number of prospective studies looking at proton (and carbon) therapy, and works in concert with the EORTC [10, 11]. Global collaborations on clinical trials have been limited so far. The US has the largest catalog of proton therapy clinical trials and has sought participation of international proton centers, but the many steps to opening the protocols (NCTN membership, state department clearance, baseline approval quality assurance) have slowed down collaboration. The clinical trial groups are working on streamlining these processes to allow for expanded international partnerships

In order to move past in-silico studies that promise superior dosimetry with proton therapy, clinical evidence is needed. One of the best ways to get these data are through randomized clinical trials. For proton therapy trials, randomization is generally structured with two arms: proton vs. photon. In order to get enough patients for statistical significance, these trials require a lot of patients (usually hundreds) and are typically run as multi-institutional studies. These large randomized studies may be designed to show superiority of proton therapy or to demonstrate non-inferiority [12]. Most NCTN randomized proton vs. photon trials have a primary endpoint of assessing overall survival. Secondary endpoints include progression-free survival, local control, toxicities, cognitive outcomes, symptoms burden, quality of life, cost effectiveness, and cost–benefit economics. While proton therapy generally has a higher up-front cost, it is hypothesized that proton therapy may be more cost-effective for some disease sites due to reduction in acute

Typically NCTN clinical trial data is only assessed for objectives explicitly listed in the protocol and analysis outside the original scope is only permitted after the trial has been closed several years. For this reason, somewhat indefinite exploratory objectives are written into the protocol to allow for analyses that may not be understood at the time of protocol development. For randomized proton vs. photon trials within the NCTN, exploratory objectives include biospecimen and imaging data

Most randomized proton vs. photon studies randomize 1:1, though some protocols have randomize 2:1 in favor of proton therapy. The two arms typically have the same radiobiological dose prescription, though some studies like NRG

Clinical trials can be challenging for a number of reasons - increased personnel effort to coordinate patient enrollment and data submission, increased operational costs, low patient interest, and low physician engagement – but randomized proton

One unique aspect of proton vs. photon trials is that it is common to create treatment plans for patients using both modalities to ensure that both can meet the planning dose constraints required by the protocol [13]. This may require increased time on the part of the participating institutions, though many proton centers may

#### *Clinical Trials Evaluating Proton Therapy DOI: http://dx.doi.org/10.5772/intechopen.95957*

*Proton Therapy - Current Status and Future Directions*

insurance coverage for patients enrolled on-study.

**1.2 Clinical trial landscape in the US**

and analysis within the research community.

*1.2.1 Clinical trial groups*

NCI grants.

therapy through clinical trials [2].

*1.1.2 Evidence for insurance*

groups have encouraged methodical, careful study of the clinical benefits of proton

The potential benefits of proton therapy are also complicated by the higher biological effectiveness of protons as compared with photons. The current clinical practice in the US is to use a relative biological effectiveness (RBE) of 1.1 for protons, but studies have shown that the true biological response is more complicated and variable [3]. While the higher RBE of protons is a potential benefit for killing tumor cells, there is potential increased biological risk to critical organs proximate to the target. Clinical trials with proton therapy can allow us to look at both sides of

Insurance companies have played a role in driving the development of randomized proton vs. photon clinical trials as well. Due to the higher up-front cost of proton therapy for many disease sites, insurance companies have asked for data showing marked improvement in survival outcomes for patients treated with proton therapy in order to cover treatment costs. As discussed later in the chapter, this presents a bit of a catch-22 in clinical trial accrual, as insurers are waiting for trial data to approve coverage, but trial data is nearly impossible to collect without

The largest clinical trial system that supports proton therapy protocols in the US is the National Clinical Trial Network (NCTN), funded by the NCI. The NCTN is made up of four adult and one pediatric clinical trial groups, as well as a partnership with the Canadian Cancer Trials Group. Most of the proton therapy studies run through the NCTN are large-scale, multi-institutional Phase II and Phase III trials. These trials either randomize patients to proton or photon therapy to compare treatment outcomes or imbed proton therapy as a possible treatment modality in a study designed to answer a different clinical question. The NCI has also funded proton clinical trials outside of the NCTN [4–7]. These are often run by a single proton center "sponsor" in partnership with other proton facilities and funded through

Outside of the NCI, there are several other groups that help sponsor clinical trials for proton therapy. The National Association for Proton Therapy (NAPT) is a nonprofit group that helps facilitate proton therapy research collaborations. Most of the operational proton therapy centers in the US are members of NAPT. The Patient-Centered Outcomes Research Institute (PCORI) provides funding for clinical trials comparing proton vs. photon therapy for prostate and breast treatment. The NCI also has a Childhood Cancer Data Initiative (CCDI) that collects standard patient data, including proton therapy data, in a central repository for data sharing

Outside of the US, several groups in Europe and Asia have proton therapy protocols open or in development. The Japan Clinical Oncology Group (JCOG) is funded by Japan's National Cancer Center Research and Development Fund and conducts studies with proton therapy [8]. The European Organization for Research and Treatment of Cancer (EORTC) operates clinical trials within Europe and currently has two protocols with proton therapy embedded [9]. The European Society for Radiotherapy (ESTRO) recently established the European Particle

the coin by analyzing the correlation between RBE and clinical outcomes.

**44**

Therapy Network (EPTN), which conducts a number of prospective studies looking at proton (and carbon) therapy, and works in concert with the EORTC [10, 11]. Global collaborations on clinical trials have been limited so far. The US has the largest catalog of proton therapy clinical trials and has sought participation of international proton centers, but the many steps to opening the protocols (NCTN membership, state department clearance, baseline approval quality assurance) have slowed down collaboration. The clinical trial groups are working on streamlining these processes to allow for expanded international partnerships in the future.

#### **2. Randomized proton vs. photon trials**

In order to move past in-silico studies that promise superior dosimetry with proton therapy, clinical evidence is needed. One of the best ways to get these data are through randomized clinical trials. For proton therapy trials, randomization is generally structured with two arms: proton vs. photon. In order to get enough patients for statistical significance, these trials require a lot of patients (usually hundreds) and are typically run as multi-institutional studies. These large randomized studies may be designed to show superiority of proton therapy or to demonstrate non-inferiority [12]. Most NCTN randomized proton vs. photon trials have a primary endpoint of assessing overall survival. Secondary endpoints include progression-free survival, local control, toxicities, cognitive outcomes, symptoms burden, quality of life, cost effectiveness, and cost–benefit economics. While proton therapy generally has a higher up-front cost, it is hypothesized that proton therapy may be more cost-effective for some disease sites due to reduction in acute and long-term toxicities and associated medical costs.

Typically NCTN clinical trial data is only assessed for objectives explicitly listed in the protocol and analysis outside the original scope is only permitted after the trial has been closed several years. For this reason, somewhat indefinite exploratory objectives are written into the protocol to allow for analyses that may not be understood at the time of protocol development. For randomized proton vs. photon trials within the NCTN, exploratory objectives include biospecimen and imaging data collection for the assessment of biomarkers.

Most randomized proton vs. photon studies randomize 1:1, though some protocols have randomize 2:1 in favor of proton therapy. The two arms typically have the same radiobiological dose prescription, though some studies like NRG Oncology/RTOG 1308 have low dose and high dose arms.

#### **2.1 Challenges of randomized proton vs. photon trials**

Clinical trials can be challenging for a number of reasons - increased personnel effort to coordinate patient enrollment and data submission, increased operational costs, low patient interest, and low physician engagement – but randomized proton vs. photon trials face a number of unique challenges.

#### *2.1.1 Treatment planning*

One unique aspect of proton vs. photon trials is that it is common to create treatment plans for patients using both modalities to ensure that both can meet the planning dose constraints required by the protocol [13]. This may require increased time on the part of the participating institutions, though many proton centers may already be creating double plans for insurance purposes.

Treatment planning itself is different between proton therapy and photon therapy. The planning target volume (PTV) that is commonly used for photon plans is generally not used in the same way for proton therapy. Instead of uniform expansion from clinical target volume (CTV) to the PTV, proton treatment plans may have one pre-defined lateral margin, and a different margin in the direction of the beam range that depends on the maximum beam energy [14, 15]. In this way, the proton "PTV" is beam-specific. This presents a challenge for clinical trial data analysis, as most protocols are written with historical photon PTV constraints. Future protocols should be designed with this in mind.

Furthermore, proton therapy treatment planning has started to shift away from the standard lateral and range margins in favor of robust optimization of the CTV [16, 17]. There are many different ways to report dose when using robust optimization (e.g. voxel-wise worst-case approach, scenario-wise worst-case approach, delivered dose variance) [18]. Clinical trials should soon consider how robustly optimized treatment planning data will be collected to ensure appropriate data comparison between the proton and photon arm. This highlights the crucial role that physicists and data (i.e. Digital Imaging and Communications in Medicine (DICOM)) experts play in the development of clinical trials.

In addition to the nuances of physical dose, randomized proton vs. photon trials need to consider the implications of radiobiology. The NCTN currently uses an RBE of 1.1, but many proton centers are starting to consider variable RBE in their treatment planning practices [19, 20]. If variable RBE treatment planning becomes standard, clinical trials will need to incorporate it into treatment planning constraints, and determine what patient data needs to be collected to appropriately compare different treatment plans.

#### *2.1.2 Patient preference*

One challenge with randomized clinical trials comparing proton therapy with photon therapy is patient preference. This manifests when a patient is randomized to one arm but has a strong desire to be treated on the other arm, and thus goes off protocol. Patients randomized to the photon arm may decide they want proton therapy instead due to an impression gathered through independent online research or a preference for the "latest and greatest" technology. Conversely, some patients randomized to the proton arm may go off protocol to receive photon therapy due to mistrust of a new, "unproven" technology.

#### *2.1.3 Insurance denial*

Another challenge of proton trial accrual is insurance denial for proton therapy [21]. This is particularly challenging in the case of randomized proton vs. photon trials because it can make it harder to reach accrual goals on the proton arm of the protocol. Insurance denials of proton therapy can also skew the patient demographics of the proton arm. For example, Medicare is significantly more likely to cover proton therapy than private insurers, which can skew the age of the proton cohort toward older participants [22]. This older patient cohort might have comorbidities or other characteristics that make it challenging to compare outcomes data between the two arms. Lastly, the process of appealing insurance denials can lead to delays in the start of radiation treatment [23]. Clinical trial patients may already wait slightly longer for treatment to start due to clinical trial requirements such as pre-treatment reviews of the treatment plan. These delays might result in a patient going off trial to pursue treatment sooner.

**47**

*Clinical Trials Evaluating Proton Therapy DOI: http://dx.doi.org/10.5772/intechopen.95957*

protocols [26].

abroad [27].

**3.1 Pediatric trials**

**3. Imbedded proton trials**

One way to counteract the deleterious effect of proton insurance denial on randomization is to use a 2:1 randomization in favor of proton therapy. This gives the trial more opportunities to accrue proton patients, even if insurance challenges persist. But most proton centers choose to challenge insurance denials, and the best way to combat insurance denial is through support networks and sharing of resources. The NAPT offers a guide for patients on steps to deal with insurance denial, many of which are applicable to clinical teams as well [24]. Many proton centers have dedicated personnel to manage insurance appeals. For the NCTN, proton insurance denials are a frequent topic at operations management and proton working group meetings. These forums allow physicians to share successful techniques to overcome insurance barriers. Physicians have banded together to publish pleas for insurance companies to change the insurance approval process for proton therapy [25]. Some proton therapy centers have negotiated with insurance companies to reimburse proton therapy at the cost of IMRT, picking up the rest of the costs themselves [25]. The NCI has also advocated on behalf of proton therapy centers in the context of clinical trial insurance reimbursement for randomized NCTN

*2.1.4 Logistics of partnerships with proton centers in other cities, countries*

Due to the limited number of proton therapy centers, many randomized proton vs. photon trials encourage partnerships between one proton center and any number of photon clinics. There are many considerations when establishing a partnership between two institutions, such as who gets "credit" for the clinical trial accrual, how clinical trial reimbursement is allocated between the institutions, which personnel have rights to upload patient data to the appropriate portals, etc. There is a possibility that a photon clinic might partner with a proton center in another country. In this case, the logistics of travel reimbursement (if provided) should be addressed, as well as clinical trial membership and state approval if the trial is run through the NCTN. This type of partnership may become increasingly common as clinical trials for carbon therapy are being developed, with most carbon centers located in Europe and Eastern Asia. A few concepts have been proposed that randomize IMRT treatment to centers in the US, and carbon therapy to centers

In addition to randomized proton vs. photon clinical trials, there are a number of trials that imbed proton therapy as one of several allowed treatment modalities. This practice was most common this past decade in pediatric trials, such as those conducted by the Children's Oncology Group (COG), but has been applied to adult trials as well. While the superiority of proton therapy outcomes might not be the primary endpoint of these studies, the hope is that with enough data, secondary analyses can be performed to look at proton patient cohorts compared to others.

To date, the standard method of including proton therapy in pediatric clinical trials has been to imbed protons in the protocols. The strategy recognizes the challenges of accrual to disease-specific radiation therapy protocols in pediatric patients

and permits parallel treatment strategies for both photon and proton care to

#### *Clinical Trials Evaluating Proton Therapy DOI: http://dx.doi.org/10.5772/intechopen.95957*

*Proton Therapy - Current Status and Future Directions*

Future protocols should be designed with this in mind.

(DICOM)) experts play in the development of clinical trials.

compare different treatment plans.

mistrust of a new, "unproven" technology.

*2.1.2 Patient preference*

*2.1.3 Insurance denial*

to pursue treatment sooner.

Treatment planning itself is different between proton therapy and photon therapy. The planning target volume (PTV) that is commonly used for photon plans is generally not used in the same way for proton therapy. Instead of uniform expansion from clinical target volume (CTV) to the PTV, proton treatment plans may have one pre-defined lateral margin, and a different margin in the direction of the beam range that depends on the maximum beam energy [14, 15]. In this way, the proton "PTV" is beam-specific. This presents a challenge for clinical trial data analysis, as most protocols are written with historical photon PTV constraints.

Furthermore, proton therapy treatment planning has started to shift away from the standard lateral and range margins in favor of robust optimization of the CTV [16, 17]. There are many different ways to report dose when using robust optimization (e.g. voxel-wise worst-case approach, scenario-wise worst-case approach, delivered dose variance) [18]. Clinical trials should soon consider how robustly optimized treatment planning data will be collected to ensure appropriate data comparison between the proton and photon arm. This highlights the crucial role that physicists and data (i.e. Digital Imaging and Communications in Medicine

In addition to the nuances of physical dose, randomized proton vs. photon trials need to consider the implications of radiobiology. The NCTN currently uses an RBE of 1.1, but many proton centers are starting to consider variable RBE in their treatment planning practices [19, 20]. If variable RBE treatment planning becomes standard, clinical trials will need to incorporate it into treatment planning constraints, and determine what patient data needs to be collected to appropriately

One challenge with randomized clinical trials comparing proton therapy with photon therapy is patient preference. This manifests when a patient is randomized to one arm but has a strong desire to be treated on the other arm, and thus goes off protocol. Patients randomized to the photon arm may decide they want proton therapy instead due to an impression gathered through independent online research or a preference for the "latest and greatest" technology. Conversely, some patients randomized to the proton arm may go off protocol to receive photon therapy due to

Another challenge of proton trial accrual is insurance denial for proton therapy [21]. This is particularly challenging in the case of randomized proton vs. photon trials because it can make it harder to reach accrual goals on the proton arm of the protocol. Insurance denials of proton therapy can also skew the patient demographics of the proton arm. For example, Medicare is significantly more likely to cover proton therapy than private insurers, which can skew the age of the proton cohort toward older participants [22]. This older patient cohort might have comorbidities or other characteristics that make it challenging to compare outcomes data between the two arms. Lastly, the process of appealing insurance denials can lead to delays in the start of radiation treatment [23]. Clinical trial patients may already wait slightly longer for treatment to start due to clinical trial requirements such as pre-treatment reviews of the treatment plan. These delays might result in a patient going off trial

**46**

One way to counteract the deleterious effect of proton insurance denial on randomization is to use a 2:1 randomization in favor of proton therapy. This gives the trial more opportunities to accrue proton patients, even if insurance challenges persist. But most proton centers choose to challenge insurance denials, and the best way to combat insurance denial is through support networks and sharing of resources. The NAPT offers a guide for patients on steps to deal with insurance denial, many of which are applicable to clinical teams as well [24]. Many proton centers have dedicated personnel to manage insurance appeals. For the NCTN, proton insurance denials are a frequent topic at operations management and proton working group meetings. These forums allow physicians to share successful techniques to overcome insurance barriers. Physicians have banded together to publish pleas for insurance companies to change the insurance approval process for proton therapy [25]. Some proton therapy centers have negotiated with insurance companies to reimburse proton therapy at the cost of IMRT, picking up the rest of the costs themselves [25]. The NCI has also advocated on behalf of proton therapy centers in the context of clinical trial insurance reimbursement for randomized NCTN protocols [26].

#### *2.1.4 Logistics of partnerships with proton centers in other cities, countries*

Due to the limited number of proton therapy centers, many randomized proton vs. photon trials encourage partnerships between one proton center and any number of photon clinics. There are many considerations when establishing a partnership between two institutions, such as who gets "credit" for the clinical trial accrual, how clinical trial reimbursement is allocated between the institutions, which personnel have rights to upload patient data to the appropriate portals, etc. There is a possibility that a photon clinic might partner with a proton center in another country. In this case, the logistics of travel reimbursement (if provided) should be addressed, as well as clinical trial membership and state approval if the trial is run through the NCTN. This type of partnership may become increasingly common as clinical trials for carbon therapy are being developed, with most carbon centers located in Europe and Eastern Asia. A few concepts have been proposed that randomize IMRT treatment to centers in the US, and carbon therapy to centers abroad [27].

#### **3. Imbedded proton trials**

In addition to randomized proton vs. photon clinical trials, there are a number of trials that imbed proton therapy as one of several allowed treatment modalities. This practice was most common this past decade in pediatric trials, such as those conducted by the Children's Oncology Group (COG), but has been applied to adult trials as well. While the superiority of proton therapy outcomes might not be the primary endpoint of these studies, the hope is that with enough data, secondary analyses can be performed to look at proton patient cohorts compared to others.

#### **3.1 Pediatric trials**

To date, the standard method of including proton therapy in pediatric clinical trials has been to imbed protons in the protocols. The strategy recognizes the challenges of accrual to disease-specific radiation therapy protocols in pediatric patients and permits parallel treatment strategies for both photon and proton care to

successfully manage the study. Approximately 50% of pediatric malignancies are in the leukemia domain, therefore protocols requiring radiation therapy are directed to tumors of the central nervous system, sarcoma, renal, orbit including retinoblastoma, and lymphoma. Therapy volumes and target dose are uniform between proton and photon care with guidelines imbedded in the study to insure synergistic care for tumor control acknowledging subtle differences in planning target volumes and dose distribution to normal tissue. Both proton and photon patients need to meet the identical dose to tumor and normal tissue. Dose to normal tissue in most situations is more easily achieved with proton therapy. In pediatric studies, outcome analysis including imaging are part of the longitudinal aspect of protocol management, therefore colleagues in the COG and the Imaging and Radiation Oncology Core (IROC) can evaluate normal tissue endpoints with outcome imaging validation to review comparison plans in retrospect to acquire important outcome analysis for secondary study endpoints between proton and photon care.

One challenge pediatric trials have faced is the apparent racial disparities between who receives proton therapy, with non-Hispanic white pediatric patients significantly more likely to be treated with protons than black patients [28]. This presents a challenge to proportional racial representation in clinical trial data.

#### **3.2 Adult trials**

In the US, adult clinical trial groups have imbedded proton therapy in dozens of clinical trials. At times, proton therapy has been added through clinical trial amendments with the hope of boosting accrual to protocols struggling to accrue patients. For a number of reasons (small number of proton centers, insurance denials, competing proton-specific trials), this has not proven to be the silver bullet, however, and generally it's not recommended to add proton therapy as an allowable modality solely to improve trial accrual for adult protocols. Despite lower accrual numbers, proton therapy can be a good addition to a trial, adding the possibility of secondary analyses to look at proton therapy outcomes in relation to other treatment modalities.

#### **4. Proton therapy registries**

Outside of prospective clinical trials with proton therapy, there are a number of proton therapy registries. These are generally less structured than Phase II/ Phase III trials and allow for more flexibility in which data are analyzed. The Proton Collaborative Group (PCG) is a registry of nearly six thousand proton patients in the US [29]. The PCG looks at survival outcomes and quality of life, and fosters peer review collaboration across centers for clinical trial development. The Pediatric Proton Consortium Registry (PPCR) is a multi-institutional collaborative registry of demographic and clinical data for pediatric patients treated with proton and photon therapy [30]. The goal of the PPCR is to compare benefits of the two radiotherapy techniques, such as disease outcomes and quality of life. Washington University School of Medicine and Radialogica, LLC have a Proton Therapy Registry for adult and pediatric patients that collects clinical and dosimetric data [31].

#### **5. Conclusions**

Proton therapy has great potential and in some cases, proven clinical benefit. The best way to gather evidence to secure proton therapy as a standard of care for

**49**

**Author details**

Paige A. Taylor

Houston, TX, USA

University of Texas MD Anderson Cancer Center, Department of Radiation Physics,

© 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,

\*Address all correspondence to: pataylor@mdanderson.org

provided the original work is properly cited.

*Clinical Trials Evaluating Proton Therapy DOI: http://dx.doi.org/10.5772/intechopen.95957*

proton therapy treatment outcomes.

The author declares no conflict of interest.

**Conflict of interest**

cancer treatment is through thoughtful, controlled clinical trials. Much work has already been done to this effect, and with so many clinical trials for proton therapy currently accruing, we will soon have data to answer the myriad questions related to *Clinical Trials Evaluating Proton Therapy DOI: http://dx.doi.org/10.5772/intechopen.95957*

cancer treatment is through thoughtful, controlled clinical trials. Much work has already been done to this effect, and with so many clinical trials for proton therapy currently accruing, we will soon have data to answer the myriad questions related to proton therapy treatment outcomes.

### **Conflict of interest**

*Proton Therapy - Current Status and Future Directions*

successfully manage the study. Approximately 50% of pediatric malignancies are in the leukemia domain, therefore protocols requiring radiation therapy are directed to tumors of the central nervous system, sarcoma, renal, orbit including retinoblastoma, and lymphoma. Therapy volumes and target dose are uniform between proton and photon care with guidelines imbedded in the study to insure synergistic care for tumor control acknowledging subtle differences in planning target volumes and dose distribution to normal tissue. Both proton and photon patients need to meet the identical dose to tumor and normal tissue. Dose to normal tissue in most situations is more easily achieved with proton therapy. In pediatric studies, outcome analysis including imaging are part of the longitudinal aspect of protocol management, therefore colleagues in the COG and the Imaging and Radiation Oncology Core (IROC) can evaluate normal tissue endpoints with outcome imaging validation to review comparison plans in retrospect to acquire important outcome analysis

for secondary study endpoints between proton and photon care.

One challenge pediatric trials have faced is the apparent racial disparities between who receives proton therapy, with non-Hispanic white pediatric patients significantly more likely to be treated with protons than black patients [28]. This presents a challenge to proportional racial representation in clinical trial data.

In the US, adult clinical trial groups have imbedded proton therapy in dozens of clinical trials. At times, proton therapy has been added through clinical trial amendments with the hope of boosting accrual to protocols struggling to accrue patients. For a number of reasons (small number of proton centers, insurance denials, competing proton-specific trials), this has not proven to be the silver bullet, however, and generally it's not recommended to add proton therapy as an allowable modality solely to improve trial accrual for adult protocols. Despite lower accrual numbers, proton therapy can be a good addition to a trial, adding the possibility of secondary analyses to look at proton therapy outcomes in relation to

Outside of prospective clinical trials with proton therapy, there are a number of proton therapy registries. These are generally less structured than Phase II/ Phase III trials and allow for more flexibility in which data are analyzed. The Proton Collaborative Group (PCG) is a registry of nearly six thousand proton patients in the US [29]. The PCG looks at survival outcomes and quality of life, and fosters peer review collaboration across centers for clinical trial development. The Pediatric Proton Consortium Registry (PPCR) is a multi-institutional collaborative registry of demographic and clinical data for pediatric patients treated with proton and photon therapy [30]. The goal of the PPCR is to compare benefits of the two radiotherapy techniques, such as disease outcomes and quality of life. Washington University School of Medicine and Radialogica, LLC have a Proton Therapy Registry for adult

Proton therapy has great potential and in some cases, proven clinical benefit. The best way to gather evidence to secure proton therapy as a standard of care for

and pediatric patients that collects clinical and dosimetric data [31].

**48**

**5. Conclusions**

**3.2 Adult trials**

other treatment modalities.

**4. Proton therapy registries**

The author declares no conflict of interest.

### **Author details**

Paige A. Taylor University of Texas MD Anderson Cancer Center, Department of Radiation Physics, Houston, TX, USA

\*Address all correspondence to: pataylor@mdanderson.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.

### **References**

[1] Howell RM, Giebeler A, Koontz-Raisig W, Mahajan A, Etzel CJ, D'Amelio AM Jr, Homann KL, Newhauser WD. Comparison of therapeutic dosimetric data from passively scattered proton and photon craniospinal irradiations for medulloblastoma. Radiation Oncology. 2012;7:116. DOI:10.1186/1748- 717X-7-116. PMID: 22828073.

[2] Allen AM, Pawlicki T, Dong L, Fourkal E, Buyyounouski M, Cengel K, Plastaras J, Bucci MK, Yock TI, Bonilla L, Price R, Harris EE, Konski AA. An evidence based review of proton beam therapy: the report of ASTRO's emerging technology committee. Radiotherapy and Oncology. 2012;103(1):8-11. DOI:10.1016/j. radonc.2012.02.001.

[3] Paganetti H, Niemierko A, Ancukiewicz M, Gerweck LE, Goitein M, Loeffler JS, Suit HD. Relative biological effectiveness (RBE) values for proton beam therapy. International Journal of Radiation Oncology • Biology • Physics. 2002;53(2):407-421. DOI:10.1016/ s0360-3016(02)02754-2.

[4] United States National Library of Medicine (NLM) - National Institutes of Health (NIH). Randomized Trial of Intensity-Modulated Proton Beam Therapy (IMPT) Versus Intensity-Modulated Photon Therapy (IMRT) for the Treatment of Oropharyngeal Cancer of the Head and Neck [Internet]. 2020. Available from: https://clinicaltrials. gov/ct2/show/NCT01893307. [Accessed: 2020-09-03].

[5] United States National Library of Medicine (NLM) - National Institutes of Health (NIH). Vertebral Body Sparing Craniospinal Irradiation for Pediatric Patients with Cancer of the Central Nervous System [Internet]. 2020. Available from: https://clinicaltrials.gov/ ct2/show/NCT04276194. [Accessed: 2020-09-03].

[6] United States National Library of Medicine (NLM) - National Institutes of Health (NIH). A Trial of Increased Dose Intensity Modulated Proton Therapy (IMPT) for High-Grade Meningiomas [Internet]. 2020. Available from: https://clinicaltrials.gov/ct2/show/ NCT02693990. [Accessed: 2020-09-03].

[7] United States National Library of Medicine (NLM) - National Institutes of Health (NIH). Radiation Therapy (Hypofractionated Proton Beam Therapy or IMRT) for the Treatment of Recurrent, Oligometastatic Prostate Cancer Following Primary Localized Treatment [Internet]. 2020. Available from: https://clinicaltrials.gov/ct2/ show/NCT04190446. [Accessed: 2020-09-03].

[8] Nakamura K, Fukuda H, Shibata T, Kaba H, Takashima A, Tomii Y, Murooka A, Toshima H, Abe J, Katayama H, Kunieda F, Kimura A, Kanato K, Mizusawa J, Yamashita N. Current Status and Challenges in Jcog Data Center (DC) And Operations Office (OPS). Annals of Oncology. 2012;23(S11):X169. DOI:10.1093/ annonc/mds570.

[9] European Organisation for Research and Treatment of Cancer (EORTC). Clinical Trials Database [Internet]. 2020. Available from: https://www.eortc.org/clinical-trialsdatabase/#location=25. [Accessed: 2020-09-05].

[10] Weber DC, Langendijk JA, Grau C, Thariat J. Proton therapy and the European Particle Therapy Network: The past, present and future. Cancer radiothérapie: journal de la Société française de radiothérapie oncologique. 2020; (6-7):687-690. DOI:10.1016/j. canrad.2020.05.002.

[11] Weber DC, Grau C, Lim PS, Georg D, Lievens Y. Bringing Europe

**51**

*Clinical Trials Evaluating Proton Therapy DOI: http://dx.doi.org/10.5772/intechopen.95957*

together in building clinical evidence for proton therapy - the EPTN-ESTRO-EORTC endeavor. Acta Oncologica. 2019;58(10):1340-1342. DOI:10.1080/02 [17] Unkelbach J, Paganetti H. Robust proton treatment planning: Physical and biological optimization. Seminars in Radiation Oncology. 2018;28(2):88-96. DOI:10.1016/j.semradonc.2017.11.005.

[18] Yock AD, Mohan R, Flampouri S, Bosch W, Taylor PA, Gladstone D, Kim S, Sohn J, Wallace R, Xiao Y, Buchsbaum J. Robustness analysis for external beam radiation therapy treatment plans: Describing uncertainty scenarios and reporting their dosimetric consequences. Practical Radiation Oncology. 2019;9(4):200-207. DOI:10.1016/j.prro.2018.12.002.

[19] Willers H, Allen A, Grosshans D, McMahon SJ, von Neubeck C, Wiese C, Vikram B. Toward a variable RBE for proton beam therapy. Radiotherapy and Oncology. 2018;128(1):68-75. DOI:10.1016/j.radonc.2018.05.019.

[20] McNamara A L, Willers H,

DOI:10.1259/bjr.20190334.

[21] Bekelman JE, Denicoff A, Buchsbaum J. Randomized trials of proton therapy: Why they are at risk, proposed solutions, and implications for evaluating advanced technologies to diagnose and treat cancer. Journal of Clinical Oncology. 2018;36(24):2461- 2464. DOI:10.1200/JCO.2018.77.7078.

[22] Ning MS, Gomez DR, Shah AK, Kim CR, Palmer MB, Thaker NG, Grosshans DR, Liao Z, Chapman BV, Brooks ED, Tang C, Rosenthal DI, Garden AS, Frank SJ, Gunn GB. The insurance approval process for proton radiation therapy: A significant barrier to patient care. International Journal of Radiation Oncology • Biology • Physics. 2019;104(4):724-733. DOI:10.1016/j.

ijrobp.2018.12.019.

[23] Yu NY, Sio TT, Mohindra P, Regine WF, Miller RC, Mahajan A,

Paganetti H. Modelling variable proton relative biological effectiveness for treatment planning. British Journal of Radiology. 2020;93(1107):20190334.

[12] Frank SJ, Blanchard P, Lee JJ, Sturgis EM, Kies MS, Machtay M, Vikram B, Garden AS, Rosenthal DI, Gunn GB, Fuller CD, Hutcheson K, Lai S, Busse PM, Lee NY, Lin A, Foote RL. Comparing intensitymodulated proton therapy with intensity-modulated photon therapy for oropharyngeal cancer: The journey from clinical trial concept to activation. Seminars in Radiation Oncology. 2018;28(2):108-113. DOI:10.1016/j.

84186X.2019.1624820.

semradonc.2017.12.002.

JCO.2017.74.0720.

s0360-3016(00)01555-8.

meddos.2009.05.004.

[16] Liu W, Zhang X, Li Y,

DOI:10.1118/1.3679340.

[13] Liao Z, Lee JJ, Komaki R,

Gomez DR, O'Reilly MS, Fossella FV, Blumenschein GR Jr, Heymach JV, Vaporciyan AA, Swisher SG, Allen PK, Choi NC, DeLaney TF, Hahn SM, Cox JD, Lu CS, Mohan R. Bayesian adaptive randomization trial of passive scattering proton therapy and intensitymodulated photon radiotherapy for locally advanced non-small-cell lung cancer. Journal of Clinical Oncology. 2018;36(18):1813-1822. DOI:10.1200/

[14] Moyers MF, Miller DW, Bush DA, Slater JD. Methodologies and tools for proton beam design for lung tumors. International Journal of Radiation Oncology • Biology • Physics. 2001;49(5):1429-1438. DOI:10.1016/

[15] Moyers MF, Sardesai M, Sun S, Miller DW. Ion stopping powers and CT numbers. Medical Dosimetry. 2010;35(3):179-194. DOI:10.1016/j.

Mohan R. Robust optimization of intensity modulated proton therapy. Medical Physics. 2012;39(2):1079-1091.

#### *Clinical Trials Evaluating Proton Therapy DOI: http://dx.doi.org/10.5772/intechopen.95957*

together in building clinical evidence for proton therapy - the EPTN-ESTRO-EORTC endeavor. Acta Oncologica. 2019;58(10):1340-1342. DOI:10.1080/02 84186X.2019.1624820.

[12] Frank SJ, Blanchard P, Lee JJ, Sturgis EM, Kies MS, Machtay M, Vikram B, Garden AS, Rosenthal DI, Gunn GB, Fuller CD, Hutcheson K, Lai S, Busse PM, Lee NY, Lin A, Foote RL. Comparing intensitymodulated proton therapy with intensity-modulated photon therapy for oropharyngeal cancer: The journey from clinical trial concept to activation. Seminars in Radiation Oncology. 2018;28(2):108-113. DOI:10.1016/j. semradonc.2017.12.002.

[13] Liao Z, Lee JJ, Komaki R, Gomez DR, O'Reilly MS, Fossella FV, Blumenschein GR Jr, Heymach JV, Vaporciyan AA, Swisher SG, Allen PK, Choi NC, DeLaney TF, Hahn SM, Cox JD, Lu CS, Mohan R. Bayesian adaptive randomization trial of passive scattering proton therapy and intensitymodulated photon radiotherapy for locally advanced non-small-cell lung cancer. Journal of Clinical Oncology. 2018;36(18):1813-1822. DOI:10.1200/ JCO.2017.74.0720.

[14] Moyers MF, Miller DW, Bush DA, Slater JD. Methodologies and tools for proton beam design for lung tumors. International Journal of Radiation Oncology • Biology • Physics. 2001;49(5):1429-1438. DOI:10.1016/ s0360-3016(00)01555-8.

[15] Moyers MF, Sardesai M, Sun S, Miller DW. Ion stopping powers and CT numbers. Medical Dosimetry. 2010;35(3):179-194. DOI:10.1016/j. meddos.2009.05.004.

[16] Liu W, Zhang X, Li Y, Mohan R. Robust optimization of intensity modulated proton therapy. Medical Physics. 2012;39(2):1079-1091. DOI:10.1118/1.3679340.

[17] Unkelbach J, Paganetti H. Robust proton treatment planning: Physical and biological optimization. Seminars in Radiation Oncology. 2018;28(2):88-96. DOI:10.1016/j.semradonc.2017.11.005.

[18] Yock AD, Mohan R, Flampouri S, Bosch W, Taylor PA, Gladstone D, Kim S, Sohn J, Wallace R, Xiao Y, Buchsbaum J. Robustness analysis for external beam radiation therapy treatment plans: Describing uncertainty scenarios and reporting their dosimetric consequences. Practical Radiation Oncology. 2019;9(4):200-207. DOI:10.1016/j.prro.2018.12.002.

[19] Willers H, Allen A, Grosshans D, McMahon SJ, von Neubeck C, Wiese C, Vikram B. Toward a variable RBE for proton beam therapy. Radiotherapy and Oncology. 2018;128(1):68-75. DOI:10.1016/j.radonc.2018.05.019.

[20] McNamara A L, Willers H, Paganetti H. Modelling variable proton relative biological effectiveness for treatment planning. British Journal of Radiology. 2020;93(1107):20190334. DOI:10.1259/bjr.20190334.

[21] Bekelman JE, Denicoff A, Buchsbaum J. Randomized trials of proton therapy: Why they are at risk, proposed solutions, and implications for evaluating advanced technologies to diagnose and treat cancer. Journal of Clinical Oncology. 2018;36(24):2461- 2464. DOI:10.1200/JCO.2018.77.7078.

[22] Ning MS, Gomez DR, Shah AK, Kim CR, Palmer MB, Thaker NG, Grosshans DR, Liao Z, Chapman BV, Brooks ED, Tang C, Rosenthal DI, Garden AS, Frank SJ, Gunn GB. The insurance approval process for proton radiation therapy: A significant barrier to patient care. International Journal of Radiation Oncology • Biology • Physics. 2019;104(4):724-733. DOI:10.1016/j. ijrobp.2018.12.019.

[23] Yu NY, Sio TT, Mohindra P, Regine WF, Miller RC, Mahajan A,

**50**

*Proton Therapy - Current Status and Future Directions*

[6] United States National Library of Medicine (NLM) - National Institutes of Health (NIH). A Trial of Increased Dose Intensity Modulated Proton Therapy (IMPT) for High-Grade Meningiomas [Internet]. 2020. Available from: https://clinicaltrials.gov/ct2/show/ NCT02693990. [Accessed: 2020-09-03].

[7] United States National Library of Medicine (NLM) - National Institutes of Health (NIH). Radiation Therapy (Hypofractionated Proton Beam Therapy or IMRT) for the Treatment of Recurrent, Oligometastatic Prostate Cancer Following Primary Localized Treatment [Internet]. 2020. Available from: https://clinicaltrials.gov/ct2/ show/NCT04190446. [Accessed:

[8] Nakamura K, Fukuda H, Shibata T, Kaba H, Takashima A, Tomii Y, Murooka A, Toshima H, Abe J, Katayama H, Kunieda F, Kimura A, Kanato K, Mizusawa J, Yamashita N. Current Status and Challenges in Jcog Data Center (DC) And Operations Office (OPS). Annals of Oncology. 2012;23(S11):X169. DOI:10.1093/

2020-09-03].

annonc/mds570.

2020-09-05].

canrad.2020.05.002.

[9] European Organisation for Research and Treatment of Cancer (EORTC). Clinical Trials Database [Internet]. 2020. Available from: https://www.eortc.org/clinical-trialsdatabase/#location=25. [Accessed:

[10] Weber DC, Langendijk JA, Grau C, Thariat J. Proton therapy and the European Particle Therapy Network: The past, present and future. Cancer radiothérapie: journal de la Société française de radiothérapie oncologique. 2020; (6-7):687-690. DOI:10.1016/j.

[11] Weber DC, Grau C, Lim PS, Georg D, Lievens Y. Bringing Europe

[1] Howell RM, Giebeler A, Koontz-Raisig W, Mahajan A, Etzel CJ, D'Amelio AM Jr, Homann KL, Newhauser WD. Comparison of therapeutic dosimetric data from passively scattered proton and photon craniospinal irradiations for medulloblastoma. Radiation Oncology.

**References**

2012;7:116. DOI:10.1186/1748- 717X-7-116. PMID: 22828073.

[2] Allen AM, Pawlicki T, Dong L, Fourkal E, Buyyounouski M, Cengel K, Plastaras J, Bucci MK, Yock TI, Bonilla L, Price R, Harris EE, Konski AA. An evidence based review of proton beam therapy: the report of ASTRO's emerging technology committee. Radiotherapy and Oncology.

2012;103(1):8-11. DOI:10.1016/j.

[3] Paganetti H, Niemierko A,

s0360-3016(02)02754-2.

2020-09-03].

2020-09-03].

Ancukiewicz M, Gerweck LE, Goitein M, Loeffler JS, Suit HD. Relative biological effectiveness (RBE) values for proton beam therapy. International Journal of Radiation Oncology • Biology • Physics. 2002;53(2):407-421. DOI:10.1016/

[4] United States National Library of Medicine (NLM) - National Institutes of Health (NIH). Randomized Trial of Intensity-Modulated Proton Beam Therapy (IMPT) Versus Intensity-Modulated Photon Therapy (IMRT) for the Treatment of Oropharyngeal Cancer of the Head and Neck [Internet]. 2020. Available from: https://clinicaltrials. gov/ct2/show/NCT01893307. [Accessed:

[5] United States National Library of Medicine (NLM) - National Institutes of Health (NIH). Vertebral Body Sparing Craniospinal Irradiation for Pediatric Patients with Cancer of the Central Nervous System [Internet]. 2020. Available from: https://clinicaltrials.gov/ ct2/show/NCT04276194. [Accessed:

radonc.2012.02.001.

Keole SR. The insurance approval process for proton beam therapy must change: Prior authorization is crippling access to appropriate health care. International Journal of Radiation Oncology • Biology • Physics. 2019;104(4):737-739. DOI:10.1016/j. ijrobp.2019.04.007.

[24] The National Association for Proton Therapy (NAPT). Patient Insurance Strategies. [Internet]. 2020. Available from: https://www.proton-therapy.org/ patient-resources/insurance/. [Accessed 2020-09-02].

[25] Gupta A, Khan AJ, Goyal S, Millevoi R, Elsebai N, Jabbour SK, Yue NJ, Haffty BG, Parikh RR. Insurance approval for proton beam therapy and its impact on delays in treatment. International Journal of Radiation Oncology • Biology • Physics. 2019;104(4):714-723. DOI: 10.1016/j. ijrobp.2018.12.021.

[26] Vikram B, Denicoff A. NRG Insurer Letter D.o.H.H. Services. Editor. 2020: Available from: www.ctsu.org. [Accessed: 2020-08-26].

[27] United States National Library of Medicine (NLM) - National Institute of Health {NIH). Trial of Carbon Ion Versus Photon Radiotherapy for Locally Advanced, Unresectable Pancreatic Cancer (CIPHER) [Internet]. 2020. Available from: https://clinicaltrials. gov/ct2/show/NCT03536182. [Accessed 2020-09-02].

[28] Bitterman DS, Bona K, Laurie F, Kao PC, Terezakis SA, London WB, Haas-Kogan DA. Race disparities in proton radiotherapy use for cancer treatment in patients enrolled in Children's Oncology Group trials. JAMA Oncology. 2020;6(9):1465-1468. DOI:10.1001/jamaoncol.2020.2259.

[29] Proton Collaborative Group (PCG). Proton Collaborative Group [Internet]. 2020. Available from:

https://pcgresearch.org/. [Accessed: 2020-09-27].

[30] Hess CB, Indelicato DJ, Paulino AC, Hartsell WF, Hill-Kayser CE, Perkins SM, Mahajan A, Laack NN, Ermoian RP, Chang AL, Wolden SL, Mangona VS, Kwok Y, Breneman JC, Perentesis JP, Gallotto SL, Weyman EA, Bajaj BVM, Lawell MP, Yeap BY, Yock TI. An update from the Pediatric Proton Consortium Registry. Frontiers in Oncology. 2018;8:165. DOI:10.3389/fonc.2018.00165.

[31] Multi-Site Proton Therapy Registry [Internet]. 2020. Available from: https:// protonregistry.wustl.edu/. [Accessed: 2020-09-27].

**53**

**Chapter 6**

**Abstract**

**1. Introduction**

and Neck Cancer

*Nagarjuna Burela*

Adaptive Proton Therapy in Head

Anatomic and dosimetric changes occur in head and neck cancer during fractionated proton radiotherapy, and the actual dose received by patient is considerably different from original plan. Adaptive radiotherapy aims to modify treatment according to changes that occur during proton therapy. Intensity modulated proton therapy for head and neck cancer (HNC) patients benefitted by adaptation to correct the dose perturbations caused by weight loss, tumor volume changes, setup and range uncertainties. The following sections have elaborated the rationale of adaptation in HNC, proton physics in HNC, studies comparing non-adaptive and adaptive intensity modulated proton therapy (IMPT) plans,

**Keywords:** adaptative radiotherapy, proton, intensity modulated, head and neck

Intensity Modulated Radiation Therapy (IMRT) with photons has become standard treatment for locally advanced head and neck cancer (HNC) because of its high conformality and better sparing of critical structures [1–3]. However proton therapy using spot scanning (Intensity Modulated Proton Therapy-IMPT) has shown superior dose distribution compared to IMRT in head and neck cancer patients [4–8]. The physical characteristics of proton i.e., its ability of sharp distal fall of inside tissue made substantial advantages over photon therapy. The unnecessary radiation to organ at risks (OARs) and nearby healthy tissues was significantly reduced with proton when compared with photons. The advantages of proton therapy (over photon) in head and neck malignancies have already documented in literature [9, 10]. Protons significantly reduce the risk of xerostomia, dysgeusia,

During radiation treatment of Head and neck cancer, changes in anatomy occur like shrinkage of tumor and normal tissues, which is in response to radiation and combined chemotherapy. So plan adaptation is desirable to optimally treat these patients undergoing anatomical modifications and weight loss. These little alterations during proton therapy lead to huge dosimetric changes (like high dose to normal structures and low dose to target volume) because of sharp dose fall off between target volume (TV) and OAR, thus leading to increased complications and marginal failure. The influence of anatomical changes for proton therapy is more pronounced due to range uncertainties. To counteract these limitations, the best

reasons for adaptation and how to mitigate these changes.

cancer, anatomic changes, dosimetric changes, uncertainties

dysphagia, tube feeding dependence and hypothyroidism.

#### **Chapter 6**

*Proton Therapy - Current Status and Future Directions*

https://pcgresearch.org/. [Accessed:

[31] Multi-Site Proton Therapy Registry [Internet]. 2020. Available from: https:// protonregistry.wustl.edu/. [Accessed:

[30] Hess CB, Indelicato DJ, Paulino AC, Hartsell WF, Hill-Kayser CE, Perkins SM, Mahajan A, Laack NN, Ermoian RP, Chang AL, Wolden SL, Mangona VS, Kwok Y, Breneman JC, Perentesis JP, Gallotto SL, Weyman EA, Bajaj BVM, Lawell MP, Yeap BY, Yock TI. An update from the Pediatric Proton Consortium Registry. Frontiers in Oncology. 2018;8:165. DOI:10.3389/fonc.2018.00165.

2020-09-27].

2020-09-27].

Keole SR. The insurance approval process for proton beam therapy must change: Prior authorization is crippling access to appropriate health care. International Journal of Radiation Oncology • Biology • Physics. 2019;104(4):737-739. DOI:10.1016/j.

[24] The National Association for Proton Therapy (NAPT). Patient Insurance Strategies. [Internet]. 2020. Available from: https://www.proton-therapy.org/ patient-resources/insurance/. [Accessed

[26] Vikram B, Denicoff A. NRG Insurer

[27] United States National Library of Medicine (NLM) - National Institute of Health {NIH). Trial of Carbon Ion Versus Photon Radiotherapy for Locally Advanced, Unresectable Pancreatic Cancer (CIPHER) [Internet]. 2020. Available from: https://clinicaltrials. gov/ct2/show/NCT03536182. [Accessed

[28] Bitterman DS, Bona K, Laurie F, Kao PC, Terezakis SA, London WB, Haas-Kogan DA. Race disparities in proton radiotherapy use for cancer treatment in patients enrolled in Children's Oncology Group trials. JAMA Oncology. 2020;6(9):1465-1468. DOI:10.1001/jamaoncol.2020.2259.

[29] Proton Collaborative Group (PCG). Proton Collaborative Group [Internet]. 2020. Available from:

Letter D.o.H.H. Services. Editor. 2020: Available from: www.ctsu.org.

[Accessed: 2020-08-26].

2020-09-02].

[25] Gupta A, Khan AJ, Goyal S, Millevoi R, Elsebai N, Jabbour SK, Yue NJ, Haffty BG, Parikh RR. Insurance approval for proton beam therapy and its impact on delays in treatment. International Journal of Radiation Oncology • Biology • Physics. 2019;104(4):714-723. DOI: 10.1016/j.

ijrobp.2019.04.007.

2020-09-02].

ijrobp.2018.12.021.

**52**

## Adaptive Proton Therapy in Head and Neck Cancer

*Nagarjuna Burela*

#### **Abstract**

Anatomic and dosimetric changes occur in head and neck cancer during fractionated proton radiotherapy, and the actual dose received by patient is considerably different from original plan. Adaptive radiotherapy aims to modify treatment according to changes that occur during proton therapy. Intensity modulated proton therapy for head and neck cancer (HNC) patients benefitted by adaptation to correct the dose perturbations caused by weight loss, tumor volume changes, setup and range uncertainties. The following sections have elaborated the rationale of adaptation in HNC, proton physics in HNC, studies comparing non-adaptive and adaptive intensity modulated proton therapy (IMPT) plans, reasons for adaptation and how to mitigate these changes.

**Keywords:** adaptative radiotherapy, proton, intensity modulated, head and neck cancer, anatomic changes, dosimetric changes, uncertainties

#### **1. Introduction**

Intensity Modulated Radiation Therapy (IMRT) with photons has become standard treatment for locally advanced head and neck cancer (HNC) because of its high conformality and better sparing of critical structures [1–3]. However proton therapy using spot scanning (Intensity Modulated Proton Therapy-IMPT) has shown superior dose distribution compared to IMRT in head and neck cancer patients [4–8]. The physical characteristics of proton i.e., its ability of sharp distal fall of inside tissue made substantial advantages over photon therapy. The unnecessary radiation to organ at risks (OARs) and nearby healthy tissues was significantly reduced with proton when compared with photons. The advantages of proton therapy (over photon) in head and neck malignancies have already documented in literature [9, 10]. Protons significantly reduce the risk of xerostomia, dysgeusia, dysphagia, tube feeding dependence and hypothyroidism.

During radiation treatment of Head and neck cancer, changes in anatomy occur like shrinkage of tumor and normal tissues, which is in response to radiation and combined chemotherapy. So plan adaptation is desirable to optimally treat these patients undergoing anatomical modifications and weight loss. These little alterations during proton therapy lead to huge dosimetric changes (like high dose to normal structures and low dose to target volume) because of sharp dose fall off between target volume (TV) and OAR, thus leading to increased complications and marginal failure. The influence of anatomical changes for proton therapy is more pronounced due to range uncertainties. To counteract these limitations, the best

possible strategy is Adaptive Radiotherapy (ART) of proton, i.e., repeat imaging and repeat planning to adapt to actual patient anatomy.

#### **2. Physics: HNC**

The anatomy of head and neck is complex and tumor is surrounded by many critical structures or organ at risk (OAR) like parotid, spinal cord, constrictors, thyroid etc.

The physical properties of protons are very useful for the treatment of these cancers. The physical properties of photon Vs proton are depicted in **Table 1**. Protons travel a well-defined distance, losing energy at an increasing rate before stopping, forming the characteristic Bragg peak. The distal penumbra is limited and is well adapted to the treatment of head and neck cancer. Besides this, a therapeutic beam can be produced by (a) Passive Scattering Proton Therapy (PSPT), i.e., where narrow monoenergetic beam pass through a range modulation wheel and scattering it laterally to cover the tumor volume, (b) Pencil Beam Scanning (PBS), i.e., scanning the narrow (pencil) beams magnetically by energy layers. To create homogenous depth dose, the Spread Out Bragg Peak (SOBP) is created by summing of all pristine Bragg peaks.

Passive Scattering PT is not well adapted to the complex anatomies of head and neck cancer compared to pencil beam scanning. In PSPT, the dose distribution is conformed laterally with an aperture, and range uncertainties are minimized through range compensator smearing. In large volume tumors, field junctions are used, known as beam patching. While beam patching is sensitive to set-up uncertainties. However, in Pencil Beam Scanning (PBS), the beam is scanned magnetically which facilitates intensity modulation and allowing to treat tumor surrounded by complex anatomies.

In PBS, there are two different optimization techniques:

i.Single-field optimization (SFO) and

ii.Multi-field optimization (MFO/IMPT).

In the SFO approach, each beam is optimized independently to achieve a uniform dose to the target. SFO is quite robust to changes. With IMPT, the optimization


**55**

**Table 2.**

*Adaptive Proton Therapy in Head and Neck Cancer DOI: http://dx.doi.org/10.5772/intechopen.94530*

setup and range uncertainties during optimization.

of uncertainties.

**3. Dosimetric studies**

path.

in **Table 2**.

Prescribed dose (GyE)

IMPT plan Non-

adaptive

Timing of replanning

I/L parotid (Dmean, Gy)

C/L parotid (Dmean, Gy)

Glottic larynx (Dmean, Gy)

process simultaneously optimizes the intensities of the spots from all of the beams, thereby irradiating the tumor heterogeneously with each beam but providing a uniform dose to it. IMPT is therefore more relevant for the complex head and neck anatomy and OAR constraints. IMPT is clearly less robust than SFO in the presence

The advantage in IMPT, we can use multiple field arrangements for better curvilinear dose distributions around critical structures and this is less easily achieved with single field optimization. The critical structures are better spared in MFO/ IMPT than SFO. The MFO plan can be made more robust by taking into account

In photons, adaptive planning is done mainly because of change in size of tumor

Multiple studies have shown that proton therapy in head and neck malignancies produce similar or better target coverage and conformity than IMRT. Minor variations in change in anatomy would result in significant change in dose distribution in proton therapy. Very few studies have quantified the degree of dose variations during treatment for patients undergoing IMPT. The three studies are summarized

**Parameter Simone et al., 2011 [11] J Gora et al., 2015 [12] Wu et al., 2017 [13]** Number n = 10 n = 6 n = 10

Adaptive Non-

*IMPT-intensity modulated proton therapy, BS-brain stem, SC-spinal cord, I/L-ipsilateral, C/L-contralateral.*

*Studies showing dosimetric results and comparison between non-adaptive and adaptive IMPT plans.*

hypopharynx

70 70, 63, 56 70

Adaptive Non-

adaptive

parotid)

parotid)

After 36 Gy (week 4) Week 4 Week 4

adaptive

32.9 29.8 — — 7.64 (Rt

19.5 18.3 20.7 20.8 8.73 (Lt

35.3 31 39.4 45.9 — —

BS (Dmax, Gy) 31.3 29 24.7 21.1 10.15 9.8 SC (Dmax, Gy) 30.5 28.4 25.3 20.8 10.95 10.58

oropharynx

Adaptive

7.26 (Rt parotid)

8.75(Lt parotid)

Location oropharynx oropharynx,

and relative shift in critical structures. While in protons, the sharp dose fall off and air-borne interface (different stopping power) makes proton very sensitive to variations in treatment depths. Proton therapy is more susceptible to tissue density heterogeneities as proton range is density dependent. In the proton beam path if bone is present the beam is pulled back, while beam is pushed forward if air is in the

#### **Table 1.**

*Physics: photon vs proton.*

*Adaptive Proton Therapy in Head and Neck Cancer DOI: http://dx.doi.org/10.5772/intechopen.94530*

process simultaneously optimizes the intensities of the spots from all of the beams, thereby irradiating the tumor heterogeneously with each beam but providing a uniform dose to it. IMPT is therefore more relevant for the complex head and neck anatomy and OAR constraints. IMPT is clearly less robust than SFO in the presence of uncertainties.

The advantage in IMPT, we can use multiple field arrangements for better curvilinear dose distributions around critical structures and this is less easily achieved with single field optimization. The critical structures are better spared in MFO/ IMPT than SFO. The MFO plan can be made more robust by taking into account setup and range uncertainties during optimization.

#### **3. Dosimetric studies**

*Proton Therapy - Current Status and Future Directions*

summing of all pristine Bragg peaks.

by complex anatomies.

**2. Physics: HNC**

thyroid etc.

and repeat planning to adapt to actual patient anatomy.

possible strategy is Adaptive Radiotherapy (ART) of proton, i.e., repeat imaging

The anatomy of head and neck is complex and tumor is surrounded by many critical structures or organ at risk (OAR) like parotid, spinal cord, constrictors,

The physical properties of protons are very useful for the treatment of these cancers. The physical properties of photon Vs proton are depicted in **Table 1**. Protons travel a well-defined distance, losing energy at an increasing rate before stopping, forming the characteristic Bragg peak. The distal penumbra is limited and is well adapted to the treatment of head and neck cancer. Besides this, a therapeutic beam can be produced by (a) Passive Scattering Proton Therapy (PSPT), i.e., where narrow monoenergetic beam pass through a range modulation wheel and scattering it laterally to cover the tumor volume, (b) Pencil Beam Scanning (PBS), i.e., scanning the narrow (pencil) beams magnetically by energy layers. To create homogenous depth dose, the Spread Out Bragg Peak (SOBP) is created by

Passive Scattering PT is not well adapted to the complex anatomies of head and neck cancer compared to pencil beam scanning. In PSPT, the dose distribution is conformed laterally with an aperture, and range uncertainties are minimized through range compensator smearing. In large volume tumors, field junctions are used, known as beam patching. While beam patching is sensitive to set-up uncertainties. However, in Pencil Beam Scanning (PBS), the beam is scanned magnetically which facilitates intensity modulation and allowing to treat tumor surrounded

In the SFO approach, each beam is optimized independently to achieve a uniform dose to the target. SFO is quite robust to changes. With IMPT, the optimization

At beam entrance i. Maximum dose in beam path i. No maximum dose, Flat

Around target No distal fall off Distal fall off seen (proton stop) After target Exit dose seen No exit dose (no dose behind

Laterally Lateral penumbra is stable relative to depth Lateral penumbra increase with

Everywhere Electron contamination Neutron contamination

entrance dose

target)

depth

ii. No skin sparing effect

In PBS, there are two different optimization techniques:

**Variable Photon Proton**

after certain depth)

ii. Skin sparing effect present (build up dose

i.Single-field optimization (SFO) and

ii.Multi-field optimization (MFO/IMPT).

**54**

**Table 1.**

*Physics: photon vs proton.*

In photons, adaptive planning is done mainly because of change in size of tumor and relative shift in critical structures. While in protons, the sharp dose fall off and air-borne interface (different stopping power) makes proton very sensitive to variations in treatment depths. Proton therapy is more susceptible to tissue density heterogeneities as proton range is density dependent. In the proton beam path if bone is present the beam is pulled back, while beam is pushed forward if air is in the path.

Multiple studies have shown that proton therapy in head and neck malignancies produce similar or better target coverage and conformity than IMRT. Minor variations in change in anatomy would result in significant change in dose distribution in proton therapy. Very few studies have quantified the degree of dose variations during treatment for patients undergoing IMPT. The three studies are summarized in **Table 2**.


#### **Table 2.**

*Studies showing dosimetric results and comparison between non-adaptive and adaptive IMPT plans.*

### **4. Reasons for adaptation**

#### i.Target deformation:

In patients of head and neck cancer treated with photons, various studies shown that the reduction in target volume ranges from 5 to 13% during treatment [14–16]. In Gunn et al. [17], out of 50 patients of oropharyngeal cancers treated with IMPT, in view of weight loss and tumor volume changes 19 patients (38%) had adaptive replanning.

ii.Anatomical and OAR deformation

The potential anatomical changes are weight loss, decrease in size of surgical flap, reduction in swelling, parotid gland shrinkage etc. [16, 18, 19]. **Figure 1** depicts the reasons of replanning.

#### **Figure 1.**

*Reasons for adaptation: (A) anatomical change – weight loss, (B) target deformation – nodal response, and (C) beam path change.*

**57**

*Adaptive Proton Therapy in Head and Neck Cancer DOI: http://dx.doi.org/10.5772/intechopen.94530*

iii.Beam path change

**Figure 2.**

therapy [20–22].

stem [24].

iv.Uncertainties

a.Range calculation in TPS

As proton range is density dependent, it is more susceptible than photons. The nasal cavity and paranasal sinuses region contains variable amount of complicated structures such as bone, mucosa, tumor tissue, collected fluid, and air, which can alter the different proton beam ranges. Variations in air and fluid content in the nasal cavity and paranasal sinuses during the course of radiotherapy could affect the proton dose distribution. Clearing or opacification of sinuses may result in shift of the high dose deposition, potentially lead to change in dose to the targets and critical structures (**Figure 2**). Late toxicities such as brain injury, cerebrospinal fluid leakage, and vision loss have been reported for patients with head and neck cancer patients treated with proton or carbon

*The variation in filling of maxillary sinus affecting dose distribution during treatment.*

In a study by Fukumitsu et al., twenty patients of nasal and paranasal sinuses

i.Inaccuracies arising from CT (HU to stopping power conversion, CT reconstruction, HU uncertainty like metal artifacts, partial volume effect)

b.Discrepancies between planned and delivered dose – like geometric changes

received proton therapy and in 18 out of 20 cases, the air content in the cavities increased. This resulted an increase in dose to brainstem above 60Gy in 3 patients and increase in dose above 50Gy in 10 patients [23]. Susharina et al. also demonstrated that change in aeration in vicinity of target lead to decreased

dose to target (5%) and increased dose to optic structures and brain

The main factors leading to range uncertainty are

ii.Inaccuracies arising from dose algorithm

(setup and motion) and density heterogeneities.

*Adaptive Proton Therapy in Head and Neck Cancer DOI: http://dx.doi.org/10.5772/intechopen.94530*

*Proton Therapy - Current Status and Future Directions*

ii.Anatomical and OAR deformation

In patients of head and neck cancer treated with photons, various studies shown that the reduction in target volume ranges from 5 to 13% during treatment [14–16]. In Gunn et al. [17], out of 50 patients of oropharyngeal cancers treated with IMPT, in view of weight loss and tumor volume changes 19 patients (38%) had adaptive

The potential anatomical changes are weight loss, decrease in size of surgical flap, reduction in swelling, parotid gland shrinkage etc. [16, 18, 19]. **Figure 1** depicts

*Reasons for adaptation: (A) anatomical change – weight loss, (B) target deformation – nodal response, and* 

**4. Reasons for adaptation**

the reasons of replanning.

replanning.

i.Target deformation:

**56**

**Figure 1.**

*(C) beam path change.*

**Figure 2.**

*The variation in filling of maxillary sinus affecting dose distribution during treatment.*

#### iii.Beam path change

As proton range is density dependent, it is more susceptible than photons. The nasal cavity and paranasal sinuses region contains variable amount of complicated structures such as bone, mucosa, tumor tissue, collected fluid, and air, which can alter the different proton beam ranges. Variations in air and fluid content in the nasal cavity and paranasal sinuses during the course of radiotherapy could affect the proton dose distribution. Clearing or opacification of sinuses may result in shift of the high dose deposition, potentially lead to change in dose to the targets and critical structures (**Figure 2**). Late toxicities such as brain injury, cerebrospinal fluid leakage, and vision loss have been reported for patients with head and neck cancer patients treated with proton or carbon therapy [20–22].

In a study by Fukumitsu et al., twenty patients of nasal and paranasal sinuses received proton therapy and in 18 out of 20 cases, the air content in the cavities increased. This resulted an increase in dose to brainstem above 60Gy in 3 patients and increase in dose above 50Gy in 10 patients [23]. Susharina et al. also demonstrated that change in aeration in vicinity of target lead to decreased dose to target (5%) and increased dose to optic structures and brain stem [24].

#### iv.Uncertainties

The main factors leading to range uncertainty are

	- i.Inaccuracies arising from CT (HU to stopping power conversion, CT reconstruction, HU uncertainty like metal artifacts, partial volume effect)
	- ii.Inaccuracies arising from dose algorithm

#### **5. Practical considerations**

The process of adaptive radiotherapy identified by weight loss, mask fitting, changes in patient setup, regularly planned intervals, treatment response assessed by CBCT scans, diagnostic CT or MRI scans (tumor shrinkage), recalculating the dose delivered to targets and OARs.

The other approaches are planning QACT (quality assurance CT) at regular intervals (after every 10 fractions) as reduction in parotid and target volumes occur in early third week resulting in huge dosimetric differences. In the modern proton therapy, image guidance with daily CBCT helps in identifying the anatomical changes and early treatment response.

The IMPT treatment uncertainties can be mitigated by robust optimization. The robust optimization technique is a robust plan generated using CTV as primary target and not requiring geometrically expanded PTV. The robust optimization method takes into account setup and range uncertainty directly during spot weighting. Therefore it does not need extra volume to be irradiated.

There is no consensus on most appropriate timing regimen for adaptation/ replanning during proton therapy.

#### **6. Conclusion**

Proton therapy in head and neck cancer is associated with tissue and target volume changes leading to higher doses to normal tissues (salivary glands/DARS). Adaptation once or twice in middle of treatment will reduce unnecessary doses to parotid, swallowing structures etc., thus improving patient's quality of life by reducing the risk of xerostomia and tube feeding dependence.

#### **Acknowledgements**

I would like to express my sincere gratitude to my teachers and colleagues for their guidance and support. I especially thank my wife for her continuous support in completing the chapter.

**59**

**Author details**

Nagarjuna Burela

Chennai, Tamil Nadu, India

provided the original work is properly cited.

Department of Radiation Oncology, Apollo Proton Cancer Centre,

© 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,

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

*Adaptive Proton Therapy in Head and Neck Cancer DOI: http://dx.doi.org/10.5772/intechopen.94530*

MFO multi field optimization MRI magnetic resonance imaging

PBS pencil beam scanning

SFO single field optimization

OARs organ at risk

SC spinal cord TV target volume

IMPT intensity modulated proton therapy

PSPT passive scanning proton therapy

#### **Conflict of interest**

Nil.

#### **Nomenclature**


*Adaptive Proton Therapy in Head and Neck Cancer DOI: http://dx.doi.org/10.5772/intechopen.94530*

*Proton Therapy - Current Status and Future Directions*

The process of adaptive radiotherapy identified by weight loss, mask fitting, changes in patient setup, regularly planned intervals, treatment response assessed by CBCT scans, diagnostic CT or MRI scans (tumor shrinkage), recalculating the

The other approaches are planning QACT (quality assurance CT) at regular intervals (after every 10 fractions) as reduction in parotid and target volumes occur in early third week resulting in huge dosimetric differences. In the modern proton therapy, image guidance with daily CBCT helps in identifying the anatomical

The IMPT treatment uncertainties can be mitigated by robust optimization. The

robust optimization technique is a robust plan generated using CTV as primary target and not requiring geometrically expanded PTV. The robust optimization method takes into account setup and range uncertainty directly during spot

There is no consensus on most appropriate timing regimen for adaptation/

Proton therapy in head and neck cancer is associated with tissue and target volume changes leading to higher doses to normal tissues (salivary glands/DARS). Adaptation once or twice in middle of treatment will reduce unnecessary doses to parotid, swallowing structures etc., thus improving patient's quality of life by

I would like to express my sincere gratitude to my teachers and colleagues for their guidance and support. I especially thank my wife for her continuous support

weighting. Therefore it does not need extra volume to be irradiated.

reducing the risk of xerostomia and tube feeding dependence.

**5. Practical considerations**

dose delivered to targets and OARs.

changes and early treatment response.

replanning during proton therapy.

**6. Conclusion**

**Acknowledgements**

in completing the chapter.

ART adaptive radiotherapy

CT computed tomography C/L parotid-contralateral parotid

HU Hounsfield Unit HNC head and neck cancer I/L parotid-ipsilateral parotid

CBCT cone beam computed tomography

DARS dysphagia/aspiration at risk structures

IMRT intensity modulated radiation therapy

BS brain stem

**Conflict of interest**

Nil.

**Nomenclature**

**58**


#### **Author details**

Nagarjuna Burela Department of Radiation Oncology, Apollo Proton Cancer Centre, Chennai, Tamil Nadu, India

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

© 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.

### **References**

[1] Gupta T, Hotwani C, Kannan S, Master Z, Rangarajan V, Murthy V, et al. Prospective longitudinal assessment of parotid gland function using dynamic quantitative pertechnate scintigraphy and estimation of dose- response relationship of parotid-sparing radiotherapy in head-neck cancers. Radiat Oncol. 2015;10:67. doi:10.1186/ s13014-015-0371-2.

[2] Studer G, Linsenmeier C, Riesterer O, Najafi Y, Brown M, Yousefi B, et al. Late term tolerance in head neck cancer patients irradiated in the IMRT era. Radiat Oncol. 2013;8:259. doi:10.1186/1748-717X-8-259.

[3] Studer G, Rordorf T, Glanzmann C. Impact of tumor volume and systemic therapy on outcome in patients undergoing IMRT for large volume head neck cancer. Radiat Oncol. 2011;6:120. doi:10.1186/1748-717X-6-120.

[4] Widesott L, Pierelli A, Fiorino C, Dell'oca I, Broggi S, Cattaneo GM, et al. Intensity-modulated proton therapy versus helical tomotherapy in nasopharynx cancer: planning comparison and NTCP evaluation. Int J Radiat Oncol Biol Phys. 2008;72(2):589- 96. doi:10.1016/j.ijrobp.2008.05.065.

[5] Simone 2nd CB, Ly D, Dan TD, Ondos J, Ning H, Belard A, et al. Comparison of intensity-modulated radiotherapy, adaptive radiotherapy, proton radiotherapy, and adaptive proton radiotherapy for treatment of locally advanced head and neck cancer. Radiother Oncol. 2011;101(3):376-82. doi:10.1016/j.radonc.2011.05.028.

[6] van de Water TA, Lomax AJ, Bijl HP, de Jong ME, Schilstra C, Hug EB, et al. Potential benefits of scanned intensity-modulated proton therapy versus advanced photon therapy with regard to sparing of the salivary glands

in oropharyngeal cancer. Int J Radiat Oncol Biol Phys. 2011;79(4):1216-24. doi:10.1016/j.ijrobp.2010.05.012.

[7] van der Laan HP, van de Water TA, van Herpt HE, Christianen ME, Bijl HP, Korevaar EW, et al. The potential of intensity-modulated proton radiotherapy to reduce swallowing dysfunction in the treatment of head and neck cancer: A planning comparative study. Acta Oncol. 2013;52(3): 561-9. doi:10.3109/02841 86X.2012.692885.

[8] Jakobi A, Bandurska-Luque A, Stützer K, Haase R, Löck S, Wack LJ, et al. Identification of Patient Benefit From Proton Therapy for Advanced Head and Neck Cancer Patients Based on Individual and Subgroup Normal Tissue Complication Probability Analysis. Int J Radiat Oncol Biol Phys. 2015;92(5): 1165-74. doi:10.1016/j. ijrobp.2015.04.031.

[9] Steneker M, Lomax A, Schneider U. Intensity modulated photon and proton therapy for the treatment of head and neck tumors. Radiother Oncol. 2006;80:263-7.

[10] Frank SJ, Cox JD, Gillin M, Mohan R, Garden AS, Rosenthal DI, Gunn GB, Weber RS, Kies MS, Lewin JS, Munsell MF, Palmer MB, Sahoo N, Zhang X, Liu W, Zhu XR. Multifield optimization intensity modulated proton therapy for head and neck tumors: a translation to practice. Int J Radiat Oncol Biol Phys. 2014;89:846-53.

[11] Wu RY, Liu AY, Sio, TT, et al. Intensity-Modulated Proton Therapy Adaptive Planning for Patients with Oropharyngeal Cancer. Int J Part Ther. 2017;4:26-34.

**61**

*Adaptive Proton Therapy in Head and Neck Cancer DOI: http://dx.doi.org/10.5772/intechopen.94530*

> with nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2010;77:617-21.

[20] Russo AL, Adams JA, Weyman EA, et al. Long-term outcomes after proton beam therapy for sinonasal squamous cell carcinoma. Int J Radiat Oncol Biol

Phys. 2016;95:368-376. 8.

2009;75:378-384. 9.

[21] Miyawaki D, Murakami M, Demizu Y, et al. Brain injury after proton therapy or carbon ion therapy for head-and-neck cancer and skull base tumors. Int J Radiat Oncol Biol Phys.

[22] Demizu Y, Murakami M,

[23] Fukumitsu N, Ishikawa H, Ohnishi K, et al. Dose distribution result- ing from changes in aeration of nasal cavity or paranasal sinus cancer in the proton therapy. Radiother

[24] Shusharina N, Fullerton B,

of aeration change and beam arrangement on the robustness of proton plans. J Appl Clin Med Phys.2019;20(3):14-21. doi: 10.1002/

Adams JA, Sharp GC, Chan AW. Impact

Oncol.2014;113:72-76.

acm2.12503.

Miyawaki D, et al. Analysis of vision loss caused by radiation-induced optic neuropathy after particle therapy for head-and-neck and skull-base tumors adjacent to optic nerves. Int J Radiat Oncol Biol Phys. 2009;75:1487-1492.

[19] Jensen AD, Nill S, Huber PE, Bendl R, Debus J, Münter MW, et al. A clinical concept for interfractional adaptive radiation therapy in the treatment of head and neck cancer. Int J Radiat Oncol Biol Phys 2012;82:590-6.

Paskeviciute B, et al. ART for head and neck patients: On the difference between VMAT and IMPT. Acta Oncol

[13] Simone CB 2nd, Ly D, Dan TD, et al. Comparison of intensity-modulated radiotherapy, adaptive radiotherapy proton radiotherapy, and adaptive proton radiotherapy for treatment of locally advanced head and neck cancer. Radiother Oncol 2011;101(3):382.

[14] Bhide SA, Davies M, Burke K, McNair HA, Hansen V, Barbachano Y, et al. Weekly volume and dosimetric changes during chemoradiotherapy with intensity-modulated radiation therapy for head and neck cancer: A prospective observational study. Int J Radiat Oncol

[15] Cheng HC, Wu VW, Ngan RK, Tang KW, Chan CC, Wong KH, et al. A prospective study on volumetric and dosimetric changes during intensity-modulated radiotherapy for nasopharyngeal carcinoma patients. Radiother Oncol 2012;104:317-23.

[16] Burela N, Soni TP, Patni N, Natarajan T. Adaptive intensitymodulated radiotherapy in headand-neck cancer: A volumetric and dosimetric study. J Can Res Ther

Int J Radiat Oncol Biol Phys

ijrobp.2016.02.021.

[17] Gunn GB, Blanchard P, Garden AS, Zhu XR, Fuller CD, Mohamed AS, et al. Clinical outcomes and patterns of disease recurrence after intensity modulated proton therapy for oropharyngeal squamous carcinoma.

2016;95:360-7. https://doi.org/10.1016/j.

[18] Wang W, Yang H, Hu W, Shan G, Ding W, Yu C, et al. Clinical study of the necessity of replanning before the 25th fraction during the course of intensitymodulated radiotherapy for patients

2019;15:533-8.

Biol Phys 2010; 76:1360-8.

Epub 2015 Apr 8 : 1-9.

[12] Gora J, Kuess P , Stock M, Andrzejewski P, Kn ä usl B,

*Adaptive Proton Therapy in Head and Neck Cancer DOI: http://dx.doi.org/10.5772/intechopen.94530*

Paskeviciute B, et al. ART for head and neck patients: On the difference between VMAT and IMPT. Acta Oncol Epub 2015 Apr 8 : 1-9.

[13] Simone CB 2nd, Ly D, Dan TD, et al. Comparison of intensity-modulated radiotherapy, adaptive radiotherapy proton radiotherapy, and adaptive proton radiotherapy for treatment of locally advanced head and neck cancer. Radiother Oncol 2011;101(3):382.

[14] Bhide SA, Davies M, Burke K, McNair HA, Hansen V, Barbachano Y, et al. Weekly volume and dosimetric changes during chemoradiotherapy with intensity-modulated radiation therapy for head and neck cancer: A prospective observational study. Int J Radiat Oncol Biol Phys 2010; 76:1360-8.

[15] Cheng HC, Wu VW, Ngan RK, Tang KW, Chan CC, Wong KH, et al. A prospective study on volumetric and dosimetric changes during intensity-modulated radiotherapy for nasopharyngeal carcinoma patients. Radiother Oncol 2012;104:317-23.

[16] Burela N, Soni TP, Patni N, Natarajan T. Adaptive intensitymodulated radiotherapy in headand-neck cancer: A volumetric and dosimetric study. J Can Res Ther 2019;15:533-8.

[17] Gunn GB, Blanchard P, Garden AS, Zhu XR, Fuller CD, Mohamed AS, et al. Clinical outcomes and patterns of disease recurrence after intensity modulated proton therapy for oropharyngeal squamous carcinoma. Int J Radiat Oncol Biol Phys 2016;95:360-7. https://doi.org/10.1016/j. ijrobp.2016.02.021.

[18] Wang W, Yang H, Hu W, Shan G, Ding W, Yu C, et al. Clinical study of the necessity of replanning before the 25th fraction during the course of intensitymodulated radiotherapy for patients

with nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2010;77:617-21.

[19] Jensen AD, Nill S, Huber PE, Bendl R, Debus J, Münter MW, et al. A clinical concept for interfractional adaptive radiation therapy in the treatment of head and neck cancer. Int J Radiat Oncol Biol Phys 2012;82:590-6.

[20] Russo AL, Adams JA, Weyman EA, et al. Long-term outcomes after proton beam therapy for sinonasal squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2016;95:368-376. 8.

[21] Miyawaki D, Murakami M, Demizu Y, et al. Brain injury after proton therapy or carbon ion therapy for head-and-neck cancer and skull base tumors. Int J Radiat Oncol Biol Phys. 2009;75:378-384. 9.

[22] Demizu Y, Murakami M, Miyawaki D, et al. Analysis of vision loss caused by radiation-induced optic neuropathy after particle therapy for head-and-neck and skull-base tumors adjacent to optic nerves. Int J Radiat Oncol Biol Phys. 2009;75:1487-1492.

[23] Fukumitsu N, Ishikawa H, Ohnishi K, et al. Dose distribution result- ing from changes in aeration of nasal cavity or paranasal sinus cancer in the proton therapy. Radiother Oncol.2014;113:72-76.

[24] Shusharina N, Fullerton B, Adams JA, Sharp GC, Chan AW. Impact of aeration change and beam arrangement on the robustness of proton plans. J Appl Clin Med Phys.2019;20(3):14-21. doi: 10.1002/ acm2.12503.

**60**

*Proton Therapy - Current Status and Future Directions*

in oropharyngeal cancer. Int J Radiat Oncol Biol Phys. 2011;79(4):1216-24. doi:10.1016/j.ijrobp.2010.05.012.

[7] van der Laan HP, van de Water TA, van Herpt HE, Christianen ME, Bijl HP, Korevaar EW, et al. The potential of intensity-modulated proton radiotherapy to reduce swallowing dysfunction in the treatment of head and neck cancer: A planning comparative study. Acta Oncol. 2013;52(3): 561-9. doi:10.3109/02841

[8] Jakobi A, Bandurska-Luque A, Stützer K, Haase R, Löck S, Wack LJ, et al. Identification of Patient Benefit From Proton Therapy for Advanced Head and Neck Cancer Patients Based on Individual and Subgroup Normal Tissue Complication Probability Analysis. Int J Radiat Oncol Biol Phys. 2015;92(5): 1165-74. doi:10.1016/j.

[9] Steneker M, Lomax A, Schneider U. Intensity modulated photon and proton therapy for the treatment of head and neck tumors. Radiother Oncol.

[10] Frank SJ, Cox JD, Gillin M, Mohan R, Garden AS, Rosenthal DI, Gunn GB, Weber RS, Kies MS, Lewin JS, Munsell MF, Palmer MB, Sahoo N, Zhang X, Liu W, Zhu XR. Multifield optimization intensity modulated proton therapy for head and neck tumors: a translation to practice. Int J Radiat Oncol Biol Phys. 2014;89:846-53.

[11] Wu RY, Liu AY, Sio, TT, et al. Intensity-Modulated Proton Therapy Adaptive Planning for Patients with Oropharyngeal Cancer. Int J Part Ther.

[12] Gora J, Kuess P , Stock M, Andrzejewski P, Kn ä usl B,

86X.2012.692885.

ijrobp.2015.04.031.

2006;80:263-7.

2017;4:26-34.

[1] Gupta T, Hotwani C, Kannan S, Master Z, Rangarajan V, Murthy V, et al. Prospective longitudinal assessment of parotid gland function using dynamic quantitative pertechnate scintigraphy and estimation of dose- response relationship of parotid-sparing radiotherapy in head-neck cancers. Radiat Oncol. 2015;10:67. doi:10.1186/

[2] Studer G, Linsenmeier C, Riesterer O, Najafi Y, Brown M, Yousefi B, et al. Late term tolerance in head neck cancer

[3] Studer G, Rordorf T, Glanzmann C. Impact of tumor volume and systemic therapy on outcome in patients

undergoing IMRT for large volume head neck cancer. Radiat Oncol. 2011;6:120.

[4] Widesott L, Pierelli A, Fiorino C, Dell'oca I, Broggi S, Cattaneo GM, et al. Intensity-modulated proton therapy versus helical tomotherapy in nasopharynx cancer: planning comparison and NTCP evaluation. Int J Radiat Oncol Biol Phys. 2008;72(2):589- 96. doi:10.1016/j.ijrobp.2008.05.065.

[5] Simone 2nd CB, Ly D, Dan TD, Ondos J, Ning H, Belard A, et al. Comparison of intensity-modulated radiotherapy, adaptive radiotherapy, proton radiotherapy, and adaptive proton radiotherapy for treatment of locally advanced head and neck cancer. Radiother Oncol. 2011;101(3):376-82. doi:10.1016/j.radonc.2011.05.028.

[6] van de Water TA, Lomax AJ, Bijl HP, de Jong ME, Schilstra C, Hug EB, et al. Potential benefits of scanned intensity-modulated proton therapy versus advanced photon therapy with regard to sparing of the salivary glands

patients irradiated in the IMRT era. Radiat Oncol. 2013;8:259. doi:10.1186/1748-717X-8-259.

doi:10.1186/1748-717X-6-120.

s13014-015-0371-2.

**References**

**63**

Section 4

Current Challenges

in Proton Therapy

Section 4
