**Prostate Seed Brachytherapy – Methods to Improve Implant Characteristics**

Bruce Libby, Matthew D. Orton, Haidy Lee, Mark E. Smolkin, Stanley H. Benedict and Bernard F. Schneider *University of Virginia Health System, Charlottesville, Virginia, USA* 

#### **1. Introduction**

Prostate cancer is diagnosed in over 230,000 men each year in the United States (Jemel, et al, 2006), and with the use of screening prostate specific antigen (PSA) the majority is diagnosed with locally confined prostate cancer. Many of these patients are good candidates for prostate brachytherapy. With the development of transperineal implantation using trans-rectal ultrasound guidance the number of patients undergoing permanent radioactive seed implants for prostate cancer has increased significantly over the past ten years. (Cooperberg, et al, 2004).

A variety of techniques have been used to deliver transperineal prostate brachytherapy, using Pd-103, I-125 and, more recently, Cs -131(Sommerkamp, et al 1988, Reed, et al, 2007, Spadlinger, et al, 2006, Meigooni, et al, 2004, Yue, et al, 2005). These sources are typically implanted as individual seeds, or as seeds that are stranded together or held together using plastic linking devices (Sommerkamp, et al 1988, Reed, et al, 2007, Spadlinger, et al, 2006). Stranded or linked seeds have the advantage that they are less likely to migrate from their implant position than individually implanted seeds (Sommerkamp, et al 1988, Reed, et al, 2007, Spadlinger, et al, 2006). Additionally, implants can be either performed via pre-plans, in which a planning ultrasound is performed before the surgery, or with intra-operative planning (Matzkin, et al, 2003).

While a linear brachytherapy source in the form of a coiled 103Pd wire was developed, it never became available clinically (Meigooni, et al, 2004). The possibility of using a continuous linear source led to the consideration of continuously linked seeds in an implant rather than the normal use of seeds separated by spacers. The elimination of spacers would allow the same number of seeds to be implanted into the prostate with fewer needles. The number of needles used in prostate seed implants has been shown to be correlated with acute urinary morbidity after seed implantation. (Eapen, et al, 2004, Ohashi, et al, 2006, Bucci, et al, 2002, Lee, et al, 2000, Buskirk, et al, 2004, Bottomley, et al, 2007, Keyer, et al, 2009, Thomas, et al, 2008). Also, the use of fewer needles should cause less trauma to the base of the penis, which may help preserve erectile function (Macdonald, et al, 2005, Steggerda, et al, 2010).

Prostate Seed Brachytherapy – Methods to Improve Implant Characteristics 137

Forty-eight patients (**+S**) were implanted using linked seeds with a single spacer between each seed, except at the apex of the gland where 2 seeds were frequently placed without a spacer between them. Another 53 patients (**-S**) had implants in which all seeds were linked without spacers between them. Other than use of spacers, both groups of patients were

Using the Variseed TM 7.0 software (Varian, Palo Alto, CA), dose-volume histograms were compiled for each patient and were used to determine the prostate V800, V400, V350, V300, V250, V200, V150, V100, V90 and V80, prostate D100, D90 and D80, and urethral D90, D30,

The automatic seed finder was utilized to locate the Pd-103 seeds in the CT data sets, which were subsequently reviewed by the physician to assure that location of the seeds was correctly identified and that the number of seeds identified matched the number that was implanted. The post implant prostatic D90 is defined as the dose covering 90% of the prostate volume. The V100 is defined as the volume of the prostate that receives 100% of prescribed dose. The post implant dosimetric analysis was performed according to the American Brachytherapy Society's guidelines for permanent prostate brachytherapy (Nag,

**Statistical Methods**: The dosimetric variables, as well as the average number of needles and seeds used for each group, were statistically compared using Student's t-tests to determine if there were significant differences between the two types of implants. Demographic and clinical factors including prostate volume, patient age, clinical stage, pre-implant PSA, and Gleason score were evaluated using Student's t-tests or chi-square tests of association to determine whether the two cohorts were similar. All statistical analyses were performed using SAS® Version 9.1 (Cary, NC, USA). All tests were performed using a Type I error rate

The clinical characteristics of our study cohorts are presented in Table 1. Statistical analysis showed no significant differences between age, mean pre-implant PSA, Gleason's score or pre-implant prostate volume. The prostate volumes were similar for the two groups (39.3

Comparison between the two cohorts (Table 1) showed that an average of 100.8 seeds and 23.1 needles were used for implants without spacers, while an average of 94 seeds and 31.5 needles were required when implanting with spacers. This difference in numbers of needles used was statistically significant (p<0.001), but there was no statistically significant

Detailed dosimetric analysis results are found in Table 2. The mean prostatic D90 for the **+S** cohort was 99.2 Gy, slightly higher than the 95.5 Gy calculated for the **-S** cohort, but this

**3.1 Demographics, disease and treatment characteristics** 

difference in the number of seeds in the two types of implants (p=0.16).

and D10 using a point source approximation (Pd-103 M200 Corrected [NIST 99]).

planned and implanted in the same manner.

et al, 2000).

of 0.05.

cm3 for **+S** and 36.7 cm3 for **-S**).

**3.2 Number of needles and seeds** 

**3.3 Dosimetric parameters and outcomes** 

In eliminating spacers between seeds and reducing the number of needles used for implantation, it is important that implant quality is not adversely affected. In this study a comparison of post-implant dosimetry in patients treated with conventional linked seed implants with spacers (**+S**) to those treated with a novel technique using linked seed implants without spacers between the sources (**-S**) is performed, as well as a comparison of the numbers of needles used for each technique.

#### **2. Strategy to provide monotherapy palladium-103 implants**

The day 0 post implant dosimetry of 101 consecutive patients who received monotherapy Palladium-103 implants was retrospectively reviewed. To avoid selection bias the dosimetric data from the final 48 **+S,** and the first 53 **-S** patients implanted at our institution were analyzed. Prior to this study the implant team had performed more than 800 permanent seed prostate implants. The ultrasound images taken at the time of the implant in the operating room were transferred to the Variseed TM 7.0 software (Varian, Palo Alto, CA). The radiation oncologist then developed a treatment plan to deliver a minimum dose of 125 Gy to the prostate with a margin of approximately 5 mm anteriorly and laterally, with a smaller posterior margin. All patients were implanted using Bard® BrachyStar® seed implant needles containing Theragenics® TheraSeed® palladium-103 sources with an average activity of 2.08 (Range 1.78-2.31) linked with 0.5 mm seed-to-seed SourceLink™ links or 5 mm SourceLink™ spacer links, for the **-S** and **+S** cohorts respectively, assembled using a SourceLink™ loader. A photograph of the linked seeds without the use of spacers is shown in Figure 1, along with a schematic diagram of the linked seeds. All patients had a CT scan for post-implant dosimetry within 3 hours following the implant. A Foley catheter was in place during the implant procedure, and for the post-implant CT scan. A single radiation oncologist planned, treated, and performed post-implant contouring of the prostate.

Fig. 1. Photograph (a) and schematic diagram (b) of a strand of linked seeds.

In eliminating spacers between seeds and reducing the number of needles used for implantation, it is important that implant quality is not adversely affected. In this study a comparison of post-implant dosimetry in patients treated with conventional linked seed implants with spacers (**+S**) to those treated with a novel technique using linked seed implants without spacers between the sources (**-S**) is performed, as well as a comparison of

The day 0 post implant dosimetry of 101 consecutive patients who received monotherapy Palladium-103 implants was retrospectively reviewed. To avoid selection bias the dosimetric data from the final 48 **+S,** and the first 53 **-S** patients implanted at our institution were analyzed. Prior to this study the implant team had performed more than 800 permanent seed prostate implants. The ultrasound images taken at the time of the implant in the operating room were transferred to the Variseed TM 7.0 software (Varian, Palo Alto, CA). The radiation oncologist then developed a treatment plan to deliver a minimum dose of 125 Gy to the prostate with a margin of approximately 5 mm anteriorly and laterally, with a smaller posterior margin. All patients were implanted using Bard® BrachyStar® seed implant needles containing Theragenics® TheraSeed® palladium-103 sources with an average activity of 2.08 (Range 1.78-2.31) linked with 0.5 mm seed-to-seed SourceLink™ links or 5 mm SourceLink™ spacer links, for the **-S** and **+S** cohorts respectively, assembled using a SourceLink™ loader. A photograph of the linked seeds without the use of spacers is shown in Figure 1, along with a schematic diagram of the linked seeds. All patients had a CT scan for post-implant dosimetry within 3 hours following the implant. A Foley catheter was in place during the implant procedure, and for the post-implant CT scan. A single radiation oncologist planned, treated,

the numbers of needles used for each technique.

and performed post-implant contouring of the prostate.

Fig. 1. Photograph (a) and schematic diagram (b) of a strand of linked seeds.

**2. Strategy to provide monotherapy palladium-103 implants** 

Forty-eight patients (**+S**) were implanted using linked seeds with a single spacer between each seed, except at the apex of the gland where 2 seeds were frequently placed without a spacer between them. Another 53 patients (**-S**) had implants in which all seeds were linked without spacers between them. Other than use of spacers, both groups of patients were planned and implanted in the same manner.

Using the Variseed TM 7.0 software (Varian, Palo Alto, CA), dose-volume histograms were compiled for each patient and were used to determine the prostate V800, V400, V350, V300, V250, V200, V150, V100, V90 and V80, prostate D100, D90 and D80, and urethral D90, D30, and D10 using a point source approximation (Pd-103 M200 Corrected [NIST 99]).

The automatic seed finder was utilized to locate the Pd-103 seeds in the CT data sets, which were subsequently reviewed by the physician to assure that location of the seeds was correctly identified and that the number of seeds identified matched the number that was implanted. The post implant prostatic D90 is defined as the dose covering 90% of the prostate volume. The V100 is defined as the volume of the prostate that receives 100% of prescribed dose. The post implant dosimetric analysis was performed according to the American Brachytherapy Society's guidelines for permanent prostate brachytherapy (Nag, et al, 2000).

**Statistical Methods**: The dosimetric variables, as well as the average number of needles and seeds used for each group, were statistically compared using Student's t-tests to determine if there were significant differences between the two types of implants. Demographic and clinical factors including prostate volume, patient age, clinical stage, pre-implant PSA, and Gleason score were evaluated using Student's t-tests or chi-square tests of association to determine whether the two cohorts were similar. All statistical analyses were performed using SAS® Version 9.1 (Cary, NC, USA). All tests were performed using a Type I error rate of 0.05.

#### **3.1 Demographics, disease and treatment characteristics**

The clinical characteristics of our study cohorts are presented in Table 1. Statistical analysis showed no significant differences between age, mean pre-implant PSA, Gleason's score or pre-implant prostate volume. The prostate volumes were similar for the two groups (39.3 cm3 for **+S** and 36.7 cm3 for **-S**).

#### **3.2 Number of needles and seeds**

Comparison between the two cohorts (Table 1) showed that an average of 100.8 seeds and 23.1 needles were used for implants without spacers, while an average of 94 seeds and 31.5 needles were required when implanting with spacers. This difference in numbers of needles used was statistically significant (p<0.001), but there was no statistically significant difference in the number of seeds in the two types of implants (p=0.16).

#### **3.3 Dosimetric parameters and outcomes**

Detailed dosimetric analysis results are found in Table 2. The mean prostatic D90 for the **+S** cohort was 99.2 Gy, slightly higher than the 95.5 Gy calculated for the **-S** cohort, but this

Prostate Seed Brachytherapy – Methods to Improve Implant Characteristics 139

Fig. 2. Mean Prostate dose for the implants performed with (+S) and without (-S) spacers.

Fig. 3. Mean urethral dose for the implants performed with (+S) and without (-S) spacers.

between the two cohorts, as shown in Figure 4.

The mean V150, V200,V250, V300, V350, V400 and V800 were also calculated and compared


difference was not statistically significant (p=0.22). The prostate D80 and D100 values were also not significantly different between the two cohorts (Figure 2).

\*+S: Patients receiving implantation with spacers. † -S: Patients receiving implantation with linked seed implants without spacers between the sources. ‡PSA = Prostate Specific Antigen.

Table 1. Demographic and Clinical Cohort Comparison


\*+S = Patients receiving implantation with spacers between the linked sources.

† -S = Patients receiving implantation with linked seed implants without spacers

Table 2. Summary of Dosimetric Analysis

The urethral D90 was significantly higher (p=0.038) in the group without spacers (51.5 Gy) compared to the group with spacers (41.5 Gy) shown in Figure 3.

The mean V100 for the **-S** cohort was 85.8% compared to a mean V100 of 88.1% for the **+S** cohort (p= 0.19). Also there were no statistically significant differences in the mean V80 and V90 for each of the cohorts.

difference was not statistically significant (p=0.22). The prostate D80 and D100 values were

Mean Age (years) 66.2 63.5 0.068 Mean Preimplant PSA‡ (ng/ml) 6.3 6.0 0.93 Mean Combined Gleason Score 6.2 6.2 0.88

Mean Prostate Volume (cm3) 39.3 36.7 0.31 Mean Urethral Volume (cm3) 1.4 1.4 0.97 Mean Number of Needles 31.5 23.1 <0.001 Mean number of Seeds 94 100.8 0.16 Mean number of seeds per needle 3.0 4.4 <0.001 \*+S: Patients receiving implantation with spacers. † -S: Patients receiving implantation with linked seed

implants without spacers between the sources. ‡PSA = Prostate Specific Antigen.

\*+S = Patients receiving implantation with spacers between the linked sources. † -S = Patients receiving implantation with linked seed implants without spacers

compared to the group with spacers (41.5 Gy) shown in Figure 3.

Table 2. Summary of Dosimetric Analysis

V90 for each of the cohorts.

Table 1. Demographic and Clinical Cohort Comparison

Variable +S\* -S† p-Value

38 (79.2) 9 (18.8) 0 (0) 1 (2.1)

Dosimetric Variable **+S**\* **-S**† **p-Value**

Prostate, Mean V800(%) 2.4 2.0 0.029 Prostate, Mean V400(%) 7.1 6.1 0.005 Prostate, Mean V200(%) 30.6 27.4 0.058 Prostate, Mean V150(%) 56.3 52.0 0.077 Prostate, Mean V100(%) 88.1 85.8 0.19 Prostate, Mean V90(%) 92.2 90.8 0.28 Prostate, Mean D100 (Gy) 44.2 45.4 0.63 Prostate, Mean D90 (Gy) 99.2 95.5 0.22 Prostate, Mean D80 (Gy) 116.8 112.3 0.15 Urethra, Mean V100(%) 41.5 51.5 0.038 Urethra, Mean V100(%) 121.4 119.7 0.70 Urethra, Mean V100(%) 139.8 137.6 0.70

The urethral D90 was significantly higher (p=0.038) in the group without spacers (51.5 Gy)

The mean V100 for the **-S** cohort was 85.8% compared to a mean V100 of 88.1% for the **+S** cohort (p= 0.19). Also there were no statistically significant differences in the mean V80 and

45 (84.9) 7 (13.2) 0(0) 1 (1.9)

0.45

also not significantly different between the two cohorts (Figure 2).

T-stage, number (%)

T1c T2a T2b T2c

Fig. 2. Mean Prostate dose for the implants performed with (+S) and without (-S) spacers.

Fig. 3. Mean urethral dose for the implants performed with (+S) and without (-S) spacers.

The mean V150, V200,V250, V300, V350, V400 and V800 were also calculated and compared between the two cohorts, as shown in Figure 4.

Prostate Seed Brachytherapy – Methods to Improve Implant Characteristics 141

0 10 20 30 40 50 60 70 80 90 **Prostate Volume (cc)**

Fig. 5. Total Implanted activity as a function of prostate volume for the two arms of the

Our data show a significant decrease in the volume of prostate tissue receiving greater that 100% of the prescribed dose (V250-V800) in the **-S** patients. This result was not expected. One of the main concerns about using continuous sources is the creation of "hot spots". However, our data show that this is not the case. All of the mean V values calculated for the

The elimination of spacers between seeds allowed a significant decrease in the total number of needles used during prostate implants. This may prove to be clinically significant since needle trauma likely plays a role in post implant morbidity. Acute urinary toxicity is the predominant side effect of prostate brachytherapy and acute urinary retention (AUR) is a well recognized and described early toxicity (Mallick, et al, 2003). Most obstructive symptoms occur quickly after the implant procedure before the dose deposited by the sources to the surrounding tissue can reach a significant level (Bucci, et al, 2009). This suggests that prostatic trauma from the procedure is the predominant factor in obstructive urinary symptoms. Studies have been conducted to try to identify factors that predict post

+S -S

0

**-S** cohort were less than those of the **+S** cohort.

study

implant AUR.

50

100

150

200

250

**Total Implanted Activity (U)**

300

350

400

450

Fig. 4. Mean Prostate V150-800 for the implants performed with (+S) and without (-S) spacers.

The mean V150 and V200 for the **+S** were 56.3% and 30.6% of the prostatic volume respectively compared to 52.0% and 27.4% of the prostatic volume respectively for the **-S** group. While the differences in the V150 and V200 are surprisingly higher for the **+S** as compared to the **-S** cohort these differences failed to be statistically significant but were trending (p=0.077 and p=0.058 respectively). This trend of higher V values for the **+S** cohort as compared to the **-S** group continued. The **+S** mean V250, V300,V350, V400 and V800 are 17.9%, 12% , 9.1%, 7.1% and 2.4% of the total prostatic volume respectively and are elevated compared to these same values for the **-S** cohort which are, 15.8%, 10.5%, 7.8%, 6.1% and 2% of the total prostatic volume respectively (Figure 3). Statistical analysis demonstrated that for each of these measurements that the percentage of volume of the prostate receiving 2.5-8 times the prescribed dose was significantly higher for the **+S** cohort. A plot of total implanted activity as a function of prostate volume for both the +S and –S cohorts is shown in Figure 5. This plot shows that the total implanted activity is the same for implants using spacers or not, which confirms the dosimetric data.

#### **4. Review of implants**

The development of the RadioCoilTM linear 103Pd source prompted studying the use of Pd-103 seeds linked in a continuous linear fashion, in order to decrease the number of implant needles and possibly decrease toxicity. This study was not intended to assess toxicity, but rather to compare post-implant dosimetry for patients receiving implants using conventional spacers with those whose implants used seeds continuously linked without spacers. Interestingly there are few dosimetric differences between the two groups.

Fig. 4. Mean Prostate V150-800 for the implants performed with (+S) and without (-S)

spacers or not, which confirms the dosimetric data.

**4. Review of implants** 

The mean V150 and V200 for the **+S** were 56.3% and 30.6% of the prostatic volume respectively compared to 52.0% and 27.4% of the prostatic volume respectively for the **-S** group. While the differences in the V150 and V200 are surprisingly higher for the **+S** as compared to the **-S** cohort these differences failed to be statistically significant but were trending (p=0.077 and p=0.058 respectively). This trend of higher V values for the **+S** cohort as compared to the **-S** group continued. The **+S** mean V250, V300,V350, V400 and V800 are 17.9%, 12% , 9.1%, 7.1% and 2.4% of the total prostatic volume respectively and are elevated compared to these same values for the **-S** cohort which are, 15.8%, 10.5%, 7.8%, 6.1% and 2% of the total prostatic volume respectively (Figure 3). Statistical analysis demonstrated that for each of these measurements that the percentage of volume of the prostate receiving 2.5-8 times the prescribed dose was significantly higher for the **+S** cohort. A plot of total implanted activity as a function of prostate volume for both the +S and –S cohorts is shown in Figure 5. This plot shows that the total implanted activity is the same for implants using

The development of the RadioCoilTM linear 103Pd source prompted studying the use of Pd-103 seeds linked in a continuous linear fashion, in order to decrease the number of implant needles and possibly decrease toxicity. This study was not intended to assess toxicity, but rather to compare post-implant dosimetry for patients receiving implants using conventional spacers with those whose implants used seeds continuously linked without

spacers. Interestingly there are few dosimetric differences between the two groups.

spacers.

Fig. 5. Total Implanted activity as a function of prostate volume for the two arms of the study

Our data show a significant decrease in the volume of prostate tissue receiving greater that 100% of the prescribed dose (V250-V800) in the **-S** patients. This result was not expected. One of the main concerns about using continuous sources is the creation of "hot spots". However, our data show that this is not the case. All of the mean V values calculated for the **-S** cohort were less than those of the **+S** cohort.

The elimination of spacers between seeds allowed a significant decrease in the total number of needles used during prostate implants. This may prove to be clinically significant since needle trauma likely plays a role in post implant morbidity. Acute urinary toxicity is the predominant side effect of prostate brachytherapy and acute urinary retention (AUR) is a well recognized and described early toxicity (Mallick, et al, 2003). Most obstructive symptoms occur quickly after the implant procedure before the dose deposited by the sources to the surrounding tissue can reach a significant level (Bucci, et al, 2009). This suggests that prostatic trauma from the procedure is the predominant factor in obstructive urinary symptoms. Studies have been conducted to try to identify factors that predict post implant AUR.

Prostate Seed Brachytherapy – Methods to Improve Implant Characteristics 143

Cooperberg M, Lubeck D, Meng M, et al. The changing face of low risk prostate cancer:

Eapen L, Kayser C, Deshaies Y, et al. Correlating the degree of needle trauma during

Lee N, Wuu C, Brody R, et al. Factors predicting for postimplantation urinary retention

Macdonald AG, Keyes M, Kruk A, et al. Predictive factors for erectile dysfunction in men

Mallick S, Azzouzi R, Cormier L, et al. Urinary morbidity after 125I brachytherapy of the

Matzkin, H, Kaver, I, Stenger, A, et al, Iodine-125 Brachytherapy for localized prostate

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Reed DR, Wallner KE, Merrick GS, et al. A prospective randomized comparison of

Sommerkamp H, Ruppercht M, Wannenmacher M. Seed loss in interstitial radiotherapy of prostatic carcinoma with I-125. *Int J Radiat Oncol Biol Phys* 1988;14:389-392. Spadingler I, Hilts M, Keyes M, et al. Prostate brachytherapy postimplant dosimetry: a

Steggerda, M, van der Poel, H, and Moonen, L, Minimizing the number of implant needles

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Jemal A, Siegel R, Ward E, et al. Cancer statistics. *2006 CA Cancer J Clin* 2006;56:106-130. Keyes, M, Miller, S, Moravan, V, et al. Predictive Factors for Acute and Late Urinary Toxicity

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Toxicity in Patients with no Urinary Symptons Before Permanent Prostate

There have been many studies reporting on AUR rates after prostate brachytherapy, with the number of needles used, the number of seeds implanted, hormonal manipulation, preimplant prostate volume, the level of post-implant prostatic edema, and diabetes all linked to increased AUR rates(Ohashi, et al 2006, Bucci, et al, 2002, Lee, et al 2000, Buskirk, et al, 2004, Bottomley, et al, 2007, Keyer, et al, 2009, Thomas, et al 2008, Macdonald, et al, 2005). While there are no large randomized controlled trials, many of the references cited provide evidence that prostate gland trauma caused by needle insertion during brachytherapy implant plays some role in the development of post-operative AUR. Therefore, decreasing the number of needles required to perform quality implants could play a role in decreasing post implant AUR. It remains to be seen if reduced AUR is seen in patients undergoing **-S** compared to **+S**. It is important to note that decreasing the number of needles used for prostate implantation can predispose to unwanted hot or cold regions if the needle position is not placed correctly. Thus, this technique should only be undertaken by experienced brachytherapy teams.

The use of a retrospective, rather than a randomized, method to study possible dosimetric differences between the +S and –S arms of the study could have led to errors associated with all non-randomized trials. The use of Day 30, rather than or in addition to Day 0 CT scans, may have shown either differences in the data not present in the Day 0 or allowed the tracking of the dosimetric parameters as a function of time.

#### **5. Conclusion**

This study was designed as an analysis of prostate seed implants comparing the dosimetric characteristics of implants performed both with **(+S**) or without **(-S**) the use of spacers between the seeds**.** The results presented in this study show that **+S** and **-S** implants were dosimetrically similar, with a significant reduction in the number of needles required for the treatments without the use spacers **(-S**). Analysis of the total implanted activity as a function of prostate volume are essentially identical between the two arms of the study, which helps to clarify the similarity in dosimetric characteristics of the **–S** and **+S** implants. Studies have shown that the number of needles used for brachytherapy correlates to AUR; therefore, we expect a decreased rate of AUR with this technique. It remains to be evaluated what significance implants with **-S** has on urinary quality of life.

#### **6. References**


There have been many studies reporting on AUR rates after prostate brachytherapy, with the number of needles used, the number of seeds implanted, hormonal manipulation, preimplant prostate volume, the level of post-implant prostatic edema, and diabetes all linked to increased AUR rates(Ohashi, et al 2006, Bucci, et al, 2002, Lee, et al 2000, Buskirk, et al, 2004, Bottomley, et al, 2007, Keyer, et al, 2009, Thomas, et al 2008, Macdonald, et al, 2005). While there are no large randomized controlled trials, many of the references cited provide evidence that prostate gland trauma caused by needle insertion during brachytherapy implant plays some role in the development of post-operative AUR. Therefore, decreasing the number of needles required to perform quality implants could play a role in decreasing post implant AUR. It remains to be seen if reduced AUR is seen in patients undergoing **-S** compared to **+S**. It is important to note that decreasing the number of needles used for prostate implantation can predispose to unwanted hot or cold regions if the needle position is not placed correctly. Thus, this technique should only be undertaken by experienced

The use of a retrospective, rather than a randomized, method to study possible dosimetric differences between the +S and –S arms of the study could have led to errors associated with all non-randomized trials. The use of Day 30, rather than or in addition to Day 0 CT scans, may have shown either differences in the data not present in the Day 0 or allowed the

This study was designed as an analysis of prostate seed implants comparing the dosimetric characteristics of implants performed both with **(+S**) or without **(-S**) the use of spacers between the seeds**.** The results presented in this study show that **+S** and **-S** implants were dosimetrically similar, with a significant reduction in the number of needles required for the treatments without the use spacers **(-S**). Analysis of the total implanted activity as a function of prostate volume are essentially identical between the two arms of the study, which helps to clarify the similarity in dosimetric characteristics of the **–S** and **+S** implants. Studies have shown that the number of needles used for brachytherapy correlates to AUR; therefore, we expect a decreased rate of AUR with this technique. It remains to be evaluated what significance implants with **-S** has on urinary

Bottomley D, Ash D, Al-Qaisieh B, et al. Side effects of permanent I125 prostate seed implants in 667 patients treated in Leeds. *Radiotherapy and Oncology* 2007;82:46-49. Bucci J, Morris JW, Keyes M, et al. Predictive factors of urinary retention following prostate

Buskirk SJ, Pinkstaff DM, Petrou SP, et al. Acute urinary retention after transperineal template- guided prostate biopsy. *Int J Radiat Oncol Biol Phys* 2004;59:1360-1366.

brachytherapy. *Int J Radiat Oncol Biol Phys* 2002;53:91-98.

tracking of the dosimetric parameters as a function of time.

brachytherapy teams.

**5. Conclusion** 

quality of life.

**6. References** 


**Intra-Operative Radiotherapy** 

*3Istituto Regina Elena, Medical Physics Department,* 

Surgery is in many cases the most effective therapy to eradicate tumors in the human body. It is applied effectively in cases of tumors with low production of metastasis. However since the early decades of the last century a large fraction of recurrence after the operation have been observed. The number of cases with the onset of recurrence greatly decreases when the region which underwent surgical resection is treated with radiotherapy. External beam radiation therapy with photons is currently the most widely used. The conformal techniques and the intensity modulated radiotherapy reduce but do not completely eliminate damage to healthy tissues traversed by the radiation. In cases where the tumor is located very close to radiosensitive normal tissues or in cases of cancer for which fractioned treatments are ineffective, external beam radiation becomes difficult to apply. The technique of intraoperative radiotherapy (IORT) is effective in such cases as it allows direct visualization of the region to be irradiated after the removal of the lesion and it allows healthy tissue to be protected. The IORT technique consists in the delivering of a single high dose of radiation to

In the early years of application of IORT, beams of low energy photons (Comas & Prio, 1907; Beck, 1909) were used. The penetrating ability, however, produced damage to underlying tissues traversed by the radiation. This approach was then abandoned until beams of

Fig. 1 shows the trends of the absorbed dose in water as a function of depth normalized to the value of maximum dose. Two beams generated by a Varian Clinac 2100 DH were used: A 6-MV photon beam and an electron beam of energy 6 MeV. It can be observed that the release of the maximum dose occurs at depths very similar for both electrons and photons. However, while the dose of electrons is released in a few cm from the entry point, the dose of photons is released at greater depths. The electrons are the most suitable particles to give the required dose of radiation directly to the tissues displayed during surgery, thus

electrons instead of photons were used in Japan (Abe & Takahashi, 1981; Abe, 1989).

the target volume, by shielding the healthy tissue, during the operation.

protecting the underlying healthy tissues.

**1. Introduction** 

 **with Electron Beam** 

*Italy* 

Ernesto Lamanna1, Alessandro Gallo1, Filippo Russo1,Rosa Brancaccio2, Antonella Soriani3 and Lidia Strigari3 *1Magna Graecia University, Medicine Faculty, 2Bologna University, Physics Department,* 

Yue N, Heron DE, Komanduri K, et al. Prescription dose in permanent (131)Cs seed prostate implants. *Medical Physics* 2005;32:2496-2502. **9** 

## **Intra-Operative Radiotherapy with Electron Beam**

Ernesto Lamanna1, Alessandro Gallo1, Filippo Russo1,Rosa Brancaccio2, Antonella Soriani3 and Lidia Strigari3 *1Magna Graecia University, Medicine Faculty, 2Bologna University, Physics Department, 3Istituto Regina Elena, Medical Physics Department, Italy* 

#### **1. Introduction**

144 Modern Practices in Radiation Therapy

Yue N, Heron DE, Komanduri K, et al. Prescription dose in permanent (131)Cs seed prostate

Surgery is in many cases the most effective therapy to eradicate tumors in the human body. It is applied effectively in cases of tumors with low production of metastasis. However since the early decades of the last century a large fraction of recurrence after the operation have been observed. The number of cases with the onset of recurrence greatly decreases when the region which underwent surgical resection is treated with radiotherapy. External beam radiation therapy with photons is currently the most widely used. The conformal techniques and the intensity modulated radiotherapy reduce but do not completely eliminate damage to healthy tissues traversed by the radiation. In cases where the tumor is located very close to radiosensitive normal tissues or in cases of cancer for which fractioned treatments are ineffective, external beam radiation becomes difficult to apply. The technique of intraoperative radiotherapy (IORT) is effective in such cases as it allows direct visualization of the region to be irradiated after the removal of the lesion and it allows healthy tissue to be protected. The IORT technique consists in the delivering of a single high dose of radiation to the target volume, by shielding the healthy tissue, during the operation.

In the early years of application of IORT, beams of low energy photons (Comas & Prio, 1907; Beck, 1909) were used. The penetrating ability, however, produced damage to underlying tissues traversed by the radiation. This approach was then abandoned until beams of electrons instead of photons were used in Japan (Abe & Takahashi, 1981; Abe, 1989).

Fig. 1 shows the trends of the absorbed dose in water as a function of depth normalized to the value of maximum dose. Two beams generated by a Varian Clinac 2100 DH were used: A 6-MV photon beam and an electron beam of energy 6 MeV. It can be observed that the release of the maximum dose occurs at depths very similar for both electrons and photons. However, while the dose of electrons is released in a few cm from the entry point, the dose of photons is released at greater depths. The electrons are the most suitable particles to give the required dose of radiation directly to the tissues displayed during surgery, thus protecting the underlying healthy tissues.

Intra-Operative Radiotherapy with Electron Beam 147

from the operating theatre to the accelerator room for treatment. In some cases, the entire

In the last ten years there has been an increasing interest in the IORT technique due to the development of mobile accelerators which produce only electron beams. This type of machine can be introduced directly into the operating room without any other special fixed shielding systems. Several types of mobile accelerator are now available on the market (Mobetron, Novac7, Liac®). These mobile machines have solved logistical and radioprotection problems which are related to their use in conventional operating theatres. These machines have allowed a widespread use of this approach. In the following paragraphs, we will describe the most important features of the three mobile accelerators

The Mobetron® (Mobetron is a registered trademark of IntraOp Medical, Inc.), has been

The Mobetron is a lightweight X-band linear accelerator mounted on a C-arm gantry. The gantry is attached to a stand that contains the accelerator cooling system and a transportation system. A mobile modulator rack, a lightweight operator control console, and connecting cables complete the Mobetron system. The Mobetron may be adjusted for two configurations: accelerator horizontal with a low center of gravity for transportation and storage; and accelerator vertical for treatment. In transport configuration, the Mobetron is compact; its dimensions are such that it may fit on to many elevators. The unit can be removed from the operating theatre for maintenance and annual calibrations. The control system contains the dosimetry readout parameters, accelerator controls, machine interlock

At 12 MeV, R50 value (i.e. the value of the depth in water at which the dose is 50% of its

While conventional medical linear accelerators operate in the S band (10 cm wavelength, 3 GHz frequency), the Mobetron operates in the X band (3 cm wavelength, 10 GHz frequency) and this allows transportability and positioning flexibility. In fact, the diameter of the

The gantry is in the configuration of a C-arm, but with some additional flexibility of movement. The gantry may be rotated ±45° downward in the transverse plane. In addition, the gantry may be tilted ±30° in the radial plane. Also, the gantry may be moved in and out, and from side to side in the horizontal plane, ±5 cm. The gantry tilt and horizontal movements are unique features not found in conventional accelerators used for intraoperative radiotherapy. The axis of rotation is 99 cm above the floor and the nominal electron source to treatment surface distance (SSD) is 50 cm (i.e to the end of the treatment applicators). Gantry rotation and tilt movements are controlled by the hand held pendant and are variable from 0 to 1° per second. Horizontal movements are controlled in a similar manner and vary from 0 to 2 mm per second. The gantry design includes an integral

surgical procedure was performed in a modified accelerator treatment room.

designed and configured for intraoperative radiotherapy.

status, and a color video output of the treatment viewing system.

accelerator structures is therefore reduced by a factor of three.

The Mobetron produces electron beams of nominal energies 4, 6, 9, and 12 MeV.

mentioned previously.

maximal value) is 47.7 mm.

**2.1 Mobetron** 

Fig. 1. Per cent Depth Dose (PDD) as a function of depth in water. The photon behaviour is compared to the electron delivered dose. In a few cm the electron dose is absorbed while a greater depth is needed to absorb the photon dose.

The results obtained with electrons have contributed to the diffusion of IORT in the world and to the development of dedicated mobile accelerators to be used in operating rooms. The three compact Linac (linear accelerator), Mobetron (IntraOp Medical Inc., 2011), NOVAC7 (Ronsivalle et al., 2001), LIAC (Soriani et al., 2010), were the most used in the first decade of 2000. These machines generate electron beams of variable energy range 3-12 MeV. The ability of high dose rate (up to 20 Gy/min) allows the delivering of the required dose in a few minutes. The experience accumulated over the past ten years for the research of more versatile systems has produced new proposals on the market (NRT, 2011).

In the next section we will describe such systems. Two were completely designed and built in Italy.

A detailed description of the technique and a presentation of results according to disease-site may be found in the recent textbook "Intraoperative Irradiation" (Gunderson et al., 2011).

However, two aspects of IORT technique with dedicated accelerators have not yet been fully defined. The first is the difficulty of making a treatment plan similar to that prepared for treatment with external beam. The second is the difficulty of using dosimeters recommended by the standard protocols for radiotherapy, due to the high dose per pulse (3-12 cGy/pulse).

In the following paragraphs we present some results and methods intended to overcome these difficulties and provide a good basis for future developments.

#### **2. Dedicated LINAC**

Until some years ago, it was not possible to perform intraoperative radiotherapy with electrons in a conventional operating theatre. In fact, the accelerators were located within a bunker of radiotherapy departments and patients had to be transferred under anesthesia from the operating theatre to the accelerator room for treatment. In some cases, the entire surgical procedure was performed in a modified accelerator treatment room.

In the last ten years there has been an increasing interest in the IORT technique due to the development of mobile accelerators which produce only electron beams. This type of machine can be introduced directly into the operating room without any other special fixed shielding systems. Several types of mobile accelerator are now available on the market (Mobetron, Novac7, Liac®). These mobile machines have solved logistical and radioprotection problems which are related to their use in conventional operating theatres. These machines have allowed a widespread use of this approach. In the following paragraphs, we will describe the most important features of the three mobile accelerators mentioned previously.

#### **2.1 Mobetron**

146 Modern Practices in Radiation Therapy

Fig. 1. Per cent Depth Dose (PDD) as a function of depth in water. The photon behaviour is compared to the electron delivered dose. In a few cm the electron dose is absorbed while a

The results obtained with electrons have contributed to the diffusion of IORT in the world and to the development of dedicated mobile accelerators to be used in operating rooms. The three compact Linac (linear accelerator), Mobetron (IntraOp Medical Inc., 2011), NOVAC7 (Ronsivalle et al., 2001), LIAC (Soriani et al., 2010), were the most used in the first decade of 2000. These machines generate electron beams of variable energy range 3-12 MeV. The ability of high dose rate (up to 20 Gy/min) allows the delivering of the required dose in a few minutes. The experience accumulated over the past ten years for the research of more

In the next section we will describe such systems. Two were completely designed and built

A detailed description of the technique and a presentation of results according to disease-site may be found in the recent textbook "Intraoperative Irradiation" (Gunderson et al., 2011).

However, two aspects of IORT technique with dedicated accelerators have not yet been fully defined. The first is the difficulty of making a treatment plan similar to that prepared for treatment with external beam. The second is the difficulty of using dosimeters recommended by the standard protocols for radiotherapy, due to the high dose per pulse (3-12 cGy/pulse). In the following paragraphs we present some results and methods intended to overcome

Until some years ago, it was not possible to perform intraoperative radiotherapy with electrons in a conventional operating theatre. In fact, the accelerators were located within a bunker of radiotherapy departments and patients had to be transferred under anesthesia

versatile systems has produced new proposals on the market (NRT, 2011).

these difficulties and provide a good basis for future developments.

greater depth is needed to absorb the photon dose.

in Italy.

**2. Dedicated LINAC** 

The Mobetron® (Mobetron is a registered trademark of IntraOp Medical, Inc.), has been designed and configured for intraoperative radiotherapy.

The Mobetron is a lightweight X-band linear accelerator mounted on a C-arm gantry. The gantry is attached to a stand that contains the accelerator cooling system and a transportation system. A mobile modulator rack, a lightweight operator control console, and connecting cables complete the Mobetron system. The Mobetron may be adjusted for two configurations: accelerator horizontal with a low center of gravity for transportation and storage; and accelerator vertical for treatment. In transport configuration, the Mobetron is compact; its dimensions are such that it may fit on to many elevators. The unit can be removed from the operating theatre for maintenance and annual calibrations. The control system contains the dosimetry readout parameters, accelerator controls, machine interlock status, and a color video output of the treatment viewing system.

The Mobetron produces electron beams of nominal energies 4, 6, 9, and 12 MeV.

At 12 MeV, R50 value (i.e. the value of the depth in water at which the dose is 50% of its maximal value) is 47.7 mm.

While conventional medical linear accelerators operate in the S band (10 cm wavelength, 3 GHz frequency), the Mobetron operates in the X band (3 cm wavelength, 10 GHz frequency) and this allows transportability and positioning flexibility. In fact, the diameter of the accelerator structures is therefore reduced by a factor of three.

The gantry is in the configuration of a C-arm, but with some additional flexibility of movement. The gantry may be rotated ±45° downward in the transverse plane. In addition, the gantry may be tilted ±30° in the radial plane. Also, the gantry may be moved in and out, and from side to side in the horizontal plane, ±5 cm. The gantry tilt and horizontal movements are unique features not found in conventional accelerators used for intraoperative radiotherapy. The axis of rotation is 99 cm above the floor and the nominal electron source to treatment surface distance (SSD) is 50 cm (i.e to the end of the treatment applicators). Gantry rotation and tilt movements are controlled by the hand held pendant and are variable from 0 to 1° per second. Horizontal movements are controlled in a similar manner and vary from 0 to 2 mm per second. The gantry design includes an integral

Intra-Operative Radiotherapy with Electron Beam 149

form of an articulated arm with four rotational joints, allowing movements similar to those of human arms. The base permits the entire structure to move without modifying the head

The beam collimation is performed through poly methyl methacrylate applicators consisting of two separated sections: the upper is fastened to the accelerator's head, with the lower in contact with the patient. These sections are aligned and finally hard-docked together before dose delivery. The applicators set consists of cylindrical tubes with a wall thickness of 5 mm, diameter ranging from 4 to 10 cm, and face angles of 0–45°. The length of the applicators varies according to the diameter: 80 cm for diameters up to 8 cm and 100 cm for those up to 10 cm. Using an applicator of 10 cm diameter and the maximum energy, the depth corresponding to 85% of maximum dose, measured in water, is about 18 mm on the geometrical central axis. When beveled applications are used the dose distribution is

The Novac7 does not employ scattering filters which in conventional machines are the main source of stray radiation, but for this reason it is complicated to modulate accelerator dose rate, which is high compared to conventional accelerators. The total bremmstrahlung photon dose for conventional accelerators is at least 2-3% of the dose at the depth of Rmax, mainly due to head scatter. For Novac7 9MeV nominal energy this value is 0.2% of the dose

The novelty of the Novac7 system (NRT, 2011) concerns the accelerating structure. The accelerating structure consists of a β graded SW 2998 MHz on-axis coupled linac operating in π/2 mode with 11 accelerating cavities and is 50 cm long, powered by a 2.6 MW magnetron: it is a compact accelerating structure in which the beam focusing is automatically achieved without using external magnetic lenses and the losses are kept at

**Model Old Novac7 (Hitesys) New Novac7 (NRT)** 

**Nominal Energy** 3 – 5 – 7 – 9 MeV 4 – 6 – 8 – 10 MeV

Dose rate 9 > e < 21 Gy/min >6 e < 39 Gy/min Field Diameter 4,5,6,7,8,10 3,4,5,6,7,8,10 X-ray contamination < 0.2 % < 0.2 % Power dissipation <1kW <1kW

The single cavity shapes were optimized in order to maximize the efficiency and to reduce the dark currents, which could be a serious problem for the operation of the system at very low currents. In particular the beam hole diameter was reduced from 8 to 6 mm and the cavity nose shape was modified. The shunt impedance was increased of 15%: in this way adding only four cavities to the Novac7 structure it is possible to increase the maximum

Beam current 1.5 mA 1.5 mA Frequency of emission 5 Hz 9 Hz Scattering foil No No

orientation.

value at Rmax.

asymmetric and with high gradients of dose.

low energy so getting a negligible diffused X radiation.

Table 1. Novac system evolution

energy with the same power.

The main characteristics are reported in Table 1.

beamstop to intercept photon contamination generated in the accelerator, collimation system, and the patient. The gantry with accelerator, cooling system, beamstop, and transportation system has a mass of 1250 Kg. Mobetron transportation is accomplished by using a modified pallet jack, located at the rear of the gantry stand. Wheels attached to the front of the gantry support legs and wheels integral to the pallet jack provide a stable support for transportation.

The Mobetron uses two X-band linear accelerators in tandem. One-third of the radio frequency power is injected into the first accelerator, producing electron energy of 4 MeV. The remaining two-thirds of the power may be absorbed in a water load and/or injected into the second accelerator guide. Adjusting the phase to change the amount of power that enters the second guide, as opposed to the water load, varies the energy. As the power in the second guide is changed, the phase of the microwaves in the second guide is simultaneously adjusted to maintain optimal resonance in the accelerator structure. This allows energy control between 4 and 12 MeV without using a bending magnet, which corresponds to a therapeutic range of 4 cm. The injector system, together with a prebuncher and beam alignment system, control the electrons to occupy a very narrow energy spectrum, reducing radiation leakage. Since the bending magnet is a major source of radiation leakage in conventional accelerator designs, this design feature also contributes to a significant reduction of photon leakage.

Applicator sizes ranged from 3 to 10 cm diameter for flat applicators, and 3 to 6 cm diameter for 30° beveled applicators. The Mobetron uses a soft-docking system in which the treatment applicator is connected to a special rigid clamp system attached to the surgical bed and the gantry is optically guided to the docking position above the applicator. During irradiation, the docking is interlocked for both alignments of the treatment head with the applicator and for treatment distance.

The dose-rate ranges from 2.5 to 10 Gy/min at SSD of 50 cm with an applicator of 10 cm diameter.

As the unit is designed to operate only in the electron mode, beam currents are low, producing less inherent radiation leakage. Together with the compact beamstop opposite the electron beam, the overall design allows the system to be used in rooms with no additional shielding.

#### **2.2 Novac**

The first model, named Novac7 (Hitesys SpA (LT) Italy 1997), is a dedicated accelerator with four nominal electron energy levels: 3,5,7,9 MeV. At 9 MeV, R50 value is 31 mm. This value is related to the mean energy of electrons, about 7.2 MeV, on the surface of the water equivalent phantom.

The most important Novac7 dosimetric characteristic is the very high dose-per-pulse, ranging from 2.5 to 12 cGy/pulse, values up to 100 times greater than the doses per pulse produced by a conventional accelerator.

Novac7 has both a mobile and a fixed unit. The mobile unit is a stand structure on a motorized base, which supports the accelerator and modulator. The stand structure has the

beamstop to intercept photon contamination generated in the accelerator, collimation system, and the patient. The gantry with accelerator, cooling system, beamstop, and transportation system has a mass of 1250 Kg. Mobetron transportation is accomplished by using a modified pallet jack, located at the rear of the gantry stand. Wheels attached to the front of the gantry support legs and wheels integral to the pallet jack provide a stable

The Mobetron uses two X-band linear accelerators in tandem. One-third of the radio frequency power is injected into the first accelerator, producing electron energy of 4 MeV. The remaining two-thirds of the power may be absorbed in a water load and/or injected into the second accelerator guide. Adjusting the phase to change the amount of power that enters the second guide, as opposed to the water load, varies the energy. As the power in the second guide is changed, the phase of the microwaves in the second guide is simultaneously adjusted to maintain optimal resonance in the accelerator structure. This allows energy control between 4 and 12 MeV without using a bending magnet, which corresponds to a therapeutic range of 4 cm. The injector system, together with a prebuncher and beam alignment system, control the electrons to occupy a very narrow energy spectrum, reducing radiation leakage. Since the bending magnet is a major source of radiation leakage in conventional accelerator designs, this design feature also contributes to a significant

Applicator sizes ranged from 3 to 10 cm diameter for flat applicators, and 3 to 6 cm diameter for 30° beveled applicators. The Mobetron uses a soft-docking system in which the treatment applicator is connected to a special rigid clamp system attached to the surgical bed and the gantry is optically guided to the docking position above the applicator. During irradiation, the docking is interlocked for both alignments of the treatment head with the

The dose-rate ranges from 2.5 to 10 Gy/min at SSD of 50 cm with an applicator of 10 cm

As the unit is designed to operate only in the electron mode, beam currents are low, producing less inherent radiation leakage. Together with the compact beamstop opposite the electron beam, the overall design allows the system to be used in rooms with no

The first model, named Novac7 (Hitesys SpA (LT) Italy 1997), is a dedicated accelerator with four nominal electron energy levels: 3,5,7,9 MeV. At 9 MeV, R50 value is 31 mm. This value is related to the mean energy of electrons, about 7.2 MeV, on the surface of the water

The most important Novac7 dosimetric characteristic is the very high dose-per-pulse, ranging from 2.5 to 12 cGy/pulse, values up to 100 times greater than the doses per pulse

Novac7 has both a mobile and a fixed unit. The mobile unit is a stand structure on a motorized base, which supports the accelerator and modulator. The stand structure has the

support for transportation.

reduction of photon leakage.

diameter.

**2.2 Novac** 

additional shielding.

equivalent phantom.

applicator and for treatment distance.

produced by a conventional accelerator.

form of an articulated arm with four rotational joints, allowing movements similar to those of human arms. The base permits the entire structure to move without modifying the head orientation.

The beam collimation is performed through poly methyl methacrylate applicators consisting of two separated sections: the upper is fastened to the accelerator's head, with the lower in contact with the patient. These sections are aligned and finally hard-docked together before dose delivery. The applicators set consists of cylindrical tubes with a wall thickness of 5 mm, diameter ranging from 4 to 10 cm, and face angles of 0–45°. The length of the applicators varies according to the diameter: 80 cm for diameters up to 8 cm and 100 cm for those up to 10 cm. Using an applicator of 10 cm diameter and the maximum energy, the depth corresponding to 85% of maximum dose, measured in water, is about 18 mm on the geometrical central axis. When beveled applications are used the dose distribution is asymmetric and with high gradients of dose.

The Novac7 does not employ scattering filters which in conventional machines are the main source of stray radiation, but for this reason it is complicated to modulate accelerator dose rate, which is high compared to conventional accelerators. The total bremmstrahlung photon dose for conventional accelerators is at least 2-3% of the dose at the depth of Rmax, mainly due to head scatter. For Novac7 9MeV nominal energy this value is 0.2% of the dose value at Rmax.

The novelty of the Novac7 system (NRT, 2011) concerns the accelerating structure. The accelerating structure consists of a β graded SW 2998 MHz on-axis coupled linac operating in π/2 mode with 11 accelerating cavities and is 50 cm long, powered by a 2.6 MW magnetron: it is a compact accelerating structure in which the beam focusing is automatically achieved without using external magnetic lenses and the losses are kept at low energy so getting a negligible diffused X radiation.


Table 1. Novac system evolution

The single cavity shapes were optimized in order to maximize the efficiency and to reduce the dark currents, which could be a serious problem for the operation of the system at very low currents. In particular the beam hole diameter was reduced from 8 to 6 mm and the cavity nose shape was modified. The shunt impedance was increased of 15%: in this way adding only four cavities to the Novac7 structure it is possible to increase the maximum energy with the same power.

The main characteristics are reported in Table 1.

Intra-Operative Radiotherapy with Electron Beam 151

The 12 MeV LINAC is 92.5 cm long (19 accelerating cavities) and its total weight, including electron gun and ionic vacuum pumps, is less than 30 kg. Radiofrequency power is supplied

The particular design of the LIAC 12 MeV accelerator head guarantees a minimal head leakage radiation, much lower than target scatter radiation. The accelerating waveguide has no external solenoid for electron beam radial focusing, but electrostatic focusing is used instead. This radial focusing system decreases the tail of electron beam distribution hitting the copper waveguide, reducing bremsstrahlung radiation, and focalizes the electrons along the beam line. It was manufactured in accordance with Italian regulations of

Furthermore there is no bending magnet and the metallic elements which the electron beam crosses along its path are a titanium window, 55 μm thick, an aluminum scattering foil, 820 μm thick and four ionization chamber electrodes, in total 20 μm thick. The total head leakage is less than the scatter radiation by a factor 10. The choice of using an aluminum scattering foil (820 μm) for the 12 MeV instead of a brass one (75 μm), as in the previous model (10 MeV), was made after an experimental study where the optimization parameters had the following characteristics: limited applicator length (for manageability reasons), beam flatness (within ± 5% evaluated at 80% of the dose profile), a controlled environmental

It is worth noting that by reducing the applicator diameter (from 100 mm to 40 mm) the dose per pulse increases correspondingly. This type of collimation together with the absence of a bending magnet and the planning choice of light material make this equipment workable in operating rooms, keeping the stray radiation at a low level. Pulse Repetition Frequency (PRF) can be varied from 1 to 60 Hz. The PRF is set by the manufacturer according to the various e-beam energies to keep the dose rate around 10 Gy/min with an applicator diameter of 100 mm. However, up to 30 Gy/min higher or lower dose rates are readily obtained. A newly designed system has been used to guarantee the LIAC output reliability. The current injected by the electron gun can be adjusted (± 5% maximum) by an automatic dose control board (ADCB) to keep constant the read-out of the two monitor chambers so that the ratio cGy/MU is kept reliably constant. Radiofrequency power is supplied by E2V magnetron MG6090. Electron energy is set by varying the radiofrequency power from 1.2 up to 3 MW. The new machine setup provides four clinical energy points: 6;

The PMMA applicators are 60 cm long and 0.5 cm thick and fully gas sterilizable; various diameters (from 30 to 100 mm typically) and bevel angles are available. The distance from

This passive beam shaping technique allows good uniformity and flatness of the radiation field and a very low x-ray contamination. Furthermore, the electron beam interaction with the PMMA applicator generates low energy electrons which deposit the dose in the region very close to the surface: this fact explains the higher value of the skin dose with respect to (External Beam Radiation Therapy) EBRT linac. Surface dose is greater than 85% with 4 MeV e-beam and reaches about 94% with 12 MeV e-beam. The main characteristics are reported

the scattering foil to the end of the applicator or SSD is 713 mm.

by an E2V magnetron MG6090.

x-ray radiation and a low neutron contamination.

radioprotection.

8; 10 and 12 MeV.

in Table 2.

#### **2.3 Liac**

Liac® 10 MeV (SORDINA SpA Italy) is an intraoperative radiotherapy system, which produces electrons with energies of 4, 6, 8 and 10 MeV with a dose rate between 5 and 20Gy/min and a pulse frequency between 5 and 20 Hz.

At 10 MeV, R50 value (i.e. the value of the depth in water at which the dose is 50% of its maximal value) is 38 mm.

The Liac® system consists of a mobile radiant unit and a operator control rack, connected by a 10 meter cable, which during the irradiation supplies the radiant unit with electrical power and transmits the treatment parameters. During the IORT session the Liac® is not connected to the local electrical system but is fed by the UPS (Uninterruptable Power Supply) hosted in the control rack. The weight of the Liac® radiant unit is less than 400Kg, so that there are no installation problems in any surgical suite; a battery system lets this unit move independently in the operative block. An innovative robotic system allows the LIAC to be extremely mobile and strongly simplifies hard-docking procedures. The LIAC head has three degrees of freedom: it can be moved up and down for a maximum excursion of 100 cm, it has a roll angle of ± 60° and a pitch angle between + 30° and – 15°.

The standing wave S-band linear accelerating structure, specifically designed for Liac , is 850 mm long and consists of 17 autofocusing cavities; it is supplied with a 3.1MW Magnetron, with 2.5 μs pulse length and produces an electron beam of 12 MeV maximum energy. The pulse repetition can vary from 1 up to 20 p.p.s (pulse per second).

The output beam has a 3 mm diameter and is collimated by a sterilizable cylindrical perspex applicator 60 cm long, different diameters and terminal beveled angles. The dose homogeneity on the surface to be treated is generally guaranteed by a 100 μm brass foil scattering filter inserted in front of the titanium window. This technique allows the optimization of the accelerator performances keeping the level of stray radiation below the required limits. A new type of dosimetric system has been implemented to monitor the beam. It is based on a properly designed resonant cavity. The signal, proportional to the absorbed dose, is picked up from the cavity, acquired and displayed in real time on the control rack, with a good signal-noise ratio. This dosimeter is not affected by saturation phenomena and temperature, pressure and humidity are independent.

Due to the need to minimize the length of the Perspex applicator, a scattering foil, made of brass (50- 150 µm thickness), was introduced in the beam to produce a homogenous profile. This technique allows the optimization of the accelerator performances, keeping the level of stray radiation below the required limits.

Sordina's 10 MeV model has been on the market since 2001 and, to meet customer demands, a new Liac® model able to accelerate electrons up to 12 MeV was developed in the last few years.

The Liac® 12 MeV accelerating system is a newly designed linac operating in the π/2 mode at 2998 MHz. The electron energy is set by varying the radiofrequency power from 1.2 up to 3 MW. The new machine setup provides four clinical energy points: 6, 8, 10 and 12 MeV. At 12 MeV, R50 value (i.e. the value of the depth in water at which the dose is 50% of its maximal value) is 48 mm.

by an E2V magnetron MG6090.

150 Modern Practices in Radiation Therapy

Liac® 10 MeV (SORDINA SpA Italy) is an intraoperative radiotherapy system, which produces electrons with energies of 4, 6, 8 and 10 MeV with a dose rate between 5 and

At 10 MeV, R50 value (i.e. the value of the depth in water at which the dose is 50% of its

The Liac® system consists of a mobile radiant unit and a operator control rack, connected by a 10 meter cable, which during the irradiation supplies the radiant unit with electrical power and transmits the treatment parameters. During the IORT session the Liac® is not connected to the local electrical system but is fed by the UPS (Uninterruptable Power Supply) hosted in the control rack. The weight of the Liac® radiant unit is less than 400Kg, so that there are no installation problems in any surgical suite; a battery system lets this unit move independently in the operative block. An innovative robotic system allows the LIAC to be extremely mobile and strongly simplifies hard-docking procedures. The LIAC head has three degrees of freedom: it can be moved up and down for a maximum excursion of 100

The standing wave S-band linear accelerating structure, specifically designed for Liac , is 850 mm long and consists of 17 autofocusing cavities; it is supplied with a 3.1MW Magnetron, with 2.5 μs pulse length and produces an electron beam of 12 MeV maximum energy. The

The output beam has a 3 mm diameter and is collimated by a sterilizable cylindrical perspex applicator 60 cm long, different diameters and terminal beveled angles. The dose homogeneity on the surface to be treated is generally guaranteed by a 100 μm brass foil scattering filter inserted in front of the titanium window. This technique allows the optimization of the accelerator performances keeping the level of stray radiation below the required limits. A new type of dosimetric system has been implemented to monitor the beam. It is based on a properly designed resonant cavity. The signal, proportional to the absorbed dose, is picked up from the cavity, acquired and displayed in real time on the control rack, with a good signal-noise ratio. This dosimeter is not affected by saturation

Due to the need to minimize the length of the Perspex applicator, a scattering foil, made of brass (50- 150 µm thickness), was introduced in the beam to produce a homogenous profile. This technique allows the optimization of the accelerator performances, keeping the level of

Sordina's 10 MeV model has been on the market since 2001 and, to meet customer demands, a new Liac® model able to accelerate electrons up to 12 MeV was developed in the last few

The Liac® 12 MeV accelerating system is a newly designed linac operating in the π/2 mode at 2998 MHz. The electron energy is set by varying the radiofrequency power from 1.2 up to 3 MW. The new machine setup provides four clinical energy points: 6, 8, 10 and 12 MeV. At 12 MeV, R50 value (i.e. the value of the depth in water at which the dose is 50% of its

cm, it has a roll angle of ± 60° and a pitch angle between + 30° and – 15°.

pulse repetition can vary from 1 up to 20 p.p.s (pulse per second).

phenomena and temperature, pressure and humidity are independent.

stray radiation below the required limits.

maximal value) is 48 mm.

years.

20Gy/min and a pulse frequency between 5 and 20 Hz.

**2.3 Liac** 

maximal value) is 38 mm.

The 12 MeV LINAC is 92.5 cm long (19 accelerating cavities) and its total weight, including electron gun and ionic vacuum pumps, is less than 30 kg. Radiofrequency power is supplied

The particular design of the LIAC 12 MeV accelerator head guarantees a minimal head leakage radiation, much lower than target scatter radiation. The accelerating waveguide has no external solenoid for electron beam radial focusing, but electrostatic focusing is used instead. This radial focusing system decreases the tail of electron beam distribution hitting the copper waveguide, reducing bremsstrahlung radiation, and focalizes the electrons along the beam line. It was manufactured in accordance with Italian regulations of radioprotection.

Furthermore there is no bending magnet and the metallic elements which the electron beam crosses along its path are a titanium window, 55 μm thick, an aluminum scattering foil, 820 μm thick and four ionization chamber electrodes, in total 20 μm thick. The total head leakage is less than the scatter radiation by a factor 10. The choice of using an aluminum scattering foil (820 μm) for the 12 MeV instead of a brass one (75 μm), as in the previous model (10 MeV), was made after an experimental study where the optimization parameters had the following characteristics: limited applicator length (for manageability reasons), beam flatness (within ± 5% evaluated at 80% of the dose profile), a controlled environmental x-ray radiation and a low neutron contamination.

It is worth noting that by reducing the applicator diameter (from 100 mm to 40 mm) the dose per pulse increases correspondingly. This type of collimation together with the absence of a bending magnet and the planning choice of light material make this equipment workable in operating rooms, keeping the stray radiation at a low level. Pulse Repetition Frequency (PRF) can be varied from 1 to 60 Hz. The PRF is set by the manufacturer according to the various e-beam energies to keep the dose rate around 10 Gy/min with an applicator diameter of 100 mm. However, up to 30 Gy/min higher or lower dose rates are readily obtained. A newly designed system has been used to guarantee the LIAC output reliability. The current injected by the electron gun can be adjusted (± 5% maximum) by an automatic dose control board (ADCB) to keep constant the read-out of the two monitor chambers so that the ratio cGy/MU is kept reliably constant. Radiofrequency power is supplied by E2V magnetron MG6090. Electron energy is set by varying the radiofrequency power from 1.2 up to 3 MW. The new machine setup provides four clinical energy points: 6; 8; 10 and 12 MeV.

The PMMA applicators are 60 cm long and 0.5 cm thick and fully gas sterilizable; various diameters (from 30 to 100 mm typically) and bevel angles are available. The distance from the scattering foil to the end of the applicator or SSD is 713 mm.

This passive beam shaping technique allows good uniformity and flatness of the radiation field and a very low x-ray contamination. Furthermore, the electron beam interaction with the PMMA applicator generates low energy electrons which deposit the dose in the region very close to the surface: this fact explains the higher value of the skin dose with respect to (External Beam Radiation Therapy) EBRT linac. Surface dose is greater than 85% with 4 MeV e-beam and reaches about 94% with 12 MeV e-beam. The main characteristics are reported in Table 2.

Intra-Operative Radiotherapy with Electron Beam 153

length, thickness of glass 0.5 mm) filled with a ferrous sulphate acqueous solution. Dose assessment is performed through optical absorption measurements with a spectrophotometer at a wavelength of 304 nm. The perturbation introduced by the glass walls of the vial should be taken into account. The calibration in terms of dose to water is made using a 60Co gamma ray field in a Primary Standard Laboratory. The stated

An alternative dosimetric system with sensitivity independent from the dose-rate, from the beam energy and from the angle of incidence of the electron beam is the alanine dosimetry. This type of dosimeter consists of a blend of alanine (95% by weight) and polyethylene (5% by weight) pressed into pellets of 4.9 mm in diameter and 2 mm in length (1.2 g/cm3 mass density) (De Angelis et al., 2006). The sample is measured with a spectrometer using the Electron Paramagnetic Resonance (EPR). Typically a set of five alanine pellets is used for each point of dose measurement. Each set is inserted into a quartz tube that is positioned in the microwave cavity for measurement. The alanine dosimeters should be calibrated in terms of dose to water in a 60Co gamma ray field against a Primary Standard Laboratory.

Dose measurements performed using Fricke and alanine dosimeters have shown a good

However, since the ionization chamber is the online absolute dose measurement device accepted as a reference dosimeter in clinical dosimetry, several authors have proposed corrections to take into account the free-electron fraction component which causes the overestimated value. The correction is introduced through the estimation of a saturation

All the approaches are based on three improved theoretical models proposed by Boag (Boag et al., 1996). These authors did not provide particular criteria for choosing any of their three

Italian researches propose two different experimental approaches. Di Martino (Di Martino et al., 2005) suggested a new equation for ksat in high dose-per-pulse beams based on the first Boag's formulas and experimentally derived the free-electron fraction p. The evaluation of some chamber-specific parameters is needed for calculation of ion recombination correction factor. The intercalibration with a second dose-per-pulse independent dosimeter is needed. Laitano (Laitano et al., 2006) proposed the evaluation of ksat starting from Boag's two voltages analysis (TVA), suggesting that the third of three Boag's models is more adequate. The latter approach has the advantage of being able to avoid any chamber calibration using, however, the calculated value of p as a function of chamber characteristics and experimental

In the general dosimetric characterization of the electron beams produced by an accelerator dedicated to IORT, the absolute dose in the point of the clinical prescription (buildup depth in water on the clinical axis) for the beveled applicators must also be determined. We refer

to this type of dosimetry as "in non reference conditions".

Dosimetric characteristics of the electron beams requires the knowledge of:

uncertainty in dose measurement has been evaluated to be 1.5% (1s).

The combined uncertainty in the measure is 1% (1s) for a test dose of 10 Gy.

factor Ksat.

conditions.

different expressions of ksat.

agreement, generally within 1% for plane-base applicators (De Angelis et al., 2006).


Table 2. Liac® system characteristics

#### **3. Dosimetry of the beam**

The IORT technique using the dedicated Linac machines requires special dosimetrical determinations, which are sometimes different in comparison to conventional external-beam radiotherapy. The main reason stems from the fact that a single high dose of radiation is delivered to a selectively defined volume of tissue, whose extension and depth are directly determined in the operating theatre. Particularly, the dosimetric data must allow the calculation of the Monitor Unit (MU) necessary to deliver the dose prescribed to the target volume. A further difference between IORT and external radiotherapy is related to the use of specific applicators that contribute to the determination of the physical-geometrical characteristics of the electron beams (quality, topology, homogeneity, etc.). All definitions are reported in the main international guideline (Istituto Superiore di Sanità [ISS], 2003; Palta et al. 1995; AAPM, 2006; Beddar et al., 2006).

A square applicator 10×10 cm2 or a circular applicator of diameter 10 cm with a plane basis is recommended for measurements in reference conditions and for each energy. This choice should allow, in most cases, to have a SSD = 100 cm or a nominal SSD when the length of the applicator does not allow it. The depth of Rmax (i.e. the depth at which the maximum dose is obtained) is recommended as reference depth for the dosimetry, both in reference and in no reference conditions.

The use of ionization chambers for the calibration of the beam in terms of dose per MU may be ineffective with dedicated machines because of the high density of electric charge produced in the chamber volume per radiation pulse. In particular the correction factor for ion recombination (Ksat) can be largely overestimated if the correction methods recommended by the international protocols are used. (AAPM, 1999; IAEA, 2001)

Italian guidelines (ISS, 2003) recommend the use of the absolute dosimetric system of Fricke for the measurement of the absorbed dose in water in reference conditions.

If other dosimetry systems are used, it is in any case required that all measurements can be traceable to national and international standards of the quantity "absorbed dose to water". This goal can be achieved through the calibration of the dosimeters at a Primary Metrological Institute or by a recognized Calibration Centre.

The Fricke dosimeter is a chemical dosimeter based on a solution of iron sulphate (Olszanski A. et al., 2002) and it consists of a glass-sealed ampoule (8.7 mm in diameter and 28 mm in

**Nominal Energy 4 – 6 – 8 – 10 6 – 8 – 10 – 12** Beam current 1.5 mA 1.5 mA

Dose rate 2-30 Gy/min 3-40 Gy/min

X-ray contamination < 0.5 % < 0.5 % Power dissipation 2 kW 2 kW

Table 2. Liac® system characteristics

Palta et al. 1995; AAPM, 2006; Beddar et al., 2006).

**3. Dosimetry of the beam** 

and in no reference conditions.

Frequency of emission 1 – 60 Hz (variabile) 1 – 60 Hz (variabile) Scattering foil 75 micron brass 850 micron aluminum

Field Diameter 3,4,5,6,7,8,10 & 12 opz 3,4,5,6,7,8,10 & 12 opz

The IORT technique using the dedicated Linac machines requires special dosimetrical determinations, which are sometimes different in comparison to conventional external-beam radiotherapy. The main reason stems from the fact that a single high dose of radiation is delivered to a selectively defined volume of tissue, whose extension and depth are directly determined in the operating theatre. Particularly, the dosimetric data must allow the calculation of the Monitor Unit (MU) necessary to deliver the dose prescribed to the target volume. A further difference between IORT and external radiotherapy is related to the use of specific applicators that contribute to the determination of the physical-geometrical characteristics of the electron beams (quality, topology, homogeneity, etc.). All definitions are reported in the main international guideline (Istituto Superiore di Sanità [ISS], 2003;

A square applicator 10×10 cm2 or a circular applicator of diameter 10 cm with a plane basis is recommended for measurements in reference conditions and for each energy. This choice should allow, in most cases, to have a SSD = 100 cm or a nominal SSD when the length of the applicator does not allow it. The depth of Rmax (i.e. the depth at which the maximum dose is obtained) is recommended as reference depth for the dosimetry, both in reference

The use of ionization chambers for the calibration of the beam in terms of dose per MU may be ineffective with dedicated machines because of the high density of electric charge produced in the chamber volume per radiation pulse. In particular the correction factor for ion recombination (Ksat) can be largely overestimated if the correction methods

Italian guidelines (ISS, 2003) recommend the use of the absolute dosimetric system of Fricke

If other dosimetry systems are used, it is in any case required that all measurements can be traceable to national and international standards of the quantity "absorbed dose to water". This goal can be achieved through the calibration of the dosimeters at a Primary

The Fricke dosimeter is a chemical dosimeter based on a solution of iron sulphate (Olszanski A. et al., 2002) and it consists of a glass-sealed ampoule (8.7 mm in diameter and 28 mm in

recommended by the international protocols are used. (AAPM, 1999; IAEA, 2001)

for the measurement of the absorbed dose in water in reference conditions.

Metrological Institute or by a recognized Calibration Centre.

**Model LIAC 10 MeV LIAC 12 MeV** 

length, thickness of glass 0.5 mm) filled with a ferrous sulphate acqueous solution. Dose assessment is performed through optical absorption measurements with a spectrophotometer at a wavelength of 304 nm. The perturbation introduced by the glass walls of the vial should be taken into account. The calibration in terms of dose to water is made using a 60Co gamma ray field in a Primary Standard Laboratory. The stated uncertainty in dose measurement has been evaluated to be 1.5% (1s).

An alternative dosimetric system with sensitivity independent from the dose-rate, from the beam energy and from the angle of incidence of the electron beam is the alanine dosimetry.

This type of dosimeter consists of a blend of alanine (95% by weight) and polyethylene (5% by weight) pressed into pellets of 4.9 mm in diameter and 2 mm in length (1.2 g/cm3 mass density) (De Angelis et al., 2006). The sample is measured with a spectrometer using the Electron Paramagnetic Resonance (EPR). Typically a set of five alanine pellets is used for each point of dose measurement. Each set is inserted into a quartz tube that is positioned in the microwave cavity for measurement. The alanine dosimeters should be calibrated in terms of dose to water in a 60Co gamma ray field against a Primary Standard Laboratory. The combined uncertainty in the measure is 1% (1s) for a test dose of 10 Gy.

Dose measurements performed using Fricke and alanine dosimeters have shown a good agreement, generally within 1% for plane-base applicators (De Angelis et al., 2006).

However, since the ionization chamber is the online absolute dose measurement device accepted as a reference dosimeter in clinical dosimetry, several authors have proposed corrections to take into account the free-electron fraction component which causes the overestimated value. The correction is introduced through the estimation of a saturation factor Ksat.

All the approaches are based on three improved theoretical models proposed by Boag (Boag et al., 1996). These authors did not provide particular criteria for choosing any of their three different expressions of ksat.

Italian researches propose two different experimental approaches. Di Martino (Di Martino et al., 2005) suggested a new equation for ksat in high dose-per-pulse beams based on the first Boag's formulas and experimentally derived the free-electron fraction p. The evaluation of some chamber-specific parameters is needed for calculation of ion recombination correction factor. The intercalibration with a second dose-per-pulse independent dosimeter is needed. Laitano (Laitano et al., 2006) proposed the evaluation of ksat starting from Boag's two voltages analysis (TVA), suggesting that the third of three Boag's models is more adequate. The latter approach has the advantage of being able to avoid any chamber calibration using, however, the calculated value of p as a function of chamber characteristics and experimental conditions.

In the general dosimetric characterization of the electron beams produced by an accelerator dedicated to IORT, the absolute dose in the point of the clinical prescription (buildup depth in water on the clinical axis) for the beveled applicators must also be determined. We refer to this type of dosimetry as "in non reference conditions".

Dosimetric characteristics of the electron beams requires the knowledge of:

Intra-Operative Radiotherapy with Electron Beam 155

Because of its high spatial resolution, weak energy dependence, and near tissue equivalence, Gafchromic films have been selected as the reference detector for relative measurements of the output factor, for applicators of various dimensions length, diameter and angle of incidence.

The final goal of IORT is an enhanced control in loco-regional tumor. IORT is feasible for intra-abdominal, retroperitoneal, pelvic and other malignancies. More recently, clinical experiences have shown that IORT may improve local control and disease-free survival, especially when used in adjuvant setting, combined with external beam irradiation in the

The rationale for the use of this segmental radiation therapy in place of whole-breast irradiation (WBI) is based on the results of some long-term studies reporting that local relapses after conservative surgery and External Beam Radio Therapy (EBRT) occur at the original tumor site at a rate of 80% or more, with few exceptions. This has been also confirmed by the results of the Milan III trial, which compared quadrantectomy alone with the same conservative surgery plus EBRT on the whole breast, have confirmed that 85% of local relapses were in, or close to, the previous index quadrant (Ivaldi et al., 2008). Another important advantage of the IORT is the avoidance of interaction with systemic therapy that may determine delays in the initiation or in performing conventional EBRT when CT, and

Widespread applications of IORT at various disease sites are feasible due to improvements in technology. By increasing the maximum energy of the linear accelerators of IORT and the total radiation dose it is possible to improve the therapeutic ratio and the tumor local control without increasing morbidity. Moreover, IORT is used as an adjuvant therapy, i.e., given as

IORT is generally given as a single fraction of 10 to 20 Gray (Gy). The single fraction is considered biologically equivalent from two to three times that of conventional fractionation for tumors while it is radiobiologically inferior due to impaired cellular repair of surrounding normal tissues, thus the protection of these tissues is mandatory. In fact the benefit in local recurrence needs to be carefully considered against the complications arising from the addition of IORT. This means that the appropriate entrance of the beam should be selected as well as the appropriate applicator diameter/kind and beam energy. This determines the Output factors (OFs) to be used and the monitor units evaluated using on an appropriate formula. In order to determine a dose-response effect a dosimeter could be placed within the field to be representative of the tumor bed or close to an Organ at Risk

The dose to be prescribed to target depends on the kind of disease, as well as on the microscopic spread expected in the tumor bed. This is particularly important when the resection margins are positive and depends on tumor stage and on radio-resistance of cells.

Treatment planning is the process in which a team of radiation oncologists, surgeons and physicists plan the most appropriate radiation treatment for the patient using an external

**4. Decision parameters during surgery** 

particularly anthracyclin-based cycles, are given.

a boost after conventional fractionated radiotherapy.

(OAR) near the applicator or under an additional shield.

beam or by means of an internal beam such as IORT.

**5. Simulation of treatment plans** 

stomach, pancreas, colon-rectum cancer and soft tissue sarcoma.


Values of the output expressed as dose per Monitor Units (MU) (cGy/MU), measured in a point at the reference depth on the clinical axis of the beam;

Such characteristics must be measured for every applicator, energy and SSD of clinical interest.

For low energy electron beams (4-10 MeV), as suggested by international protocol, a parallel-plate ionization chamber should be used. Ross, Markus and advanced Markus types (PTW Freiburg Germany) are the most utilized (PTW, 2011). But the response of these types of chamber is angle dependent so their use with a beveled applicator is not possible.

Because of its high spatial resolution and independence on beam direction, a small cylindrical chamber, such as CC01 (Wellhofer, 2011) or Pin point (PTW), seems to be particularly suitable to perform absolute dose measurements for electron beams collimated with inclined applicators (Karaj et al 2007, Iaccarino et al. 2011).

Due to the presence of electrons scattered by the applicator, the electron fields obtained with IORT-dedicated applicators are characterized by a wider energy spectrum and a wider angular distribution than electron beams collimated with conventional systems. This implies a higher surface dose (especially for the lower nominal energies) and less steep dose gradients (especially for the higher nominal energies).

For this reason, a dosimetry system must be selected characterized by a minimum dependence of the response from the beam energy and from the angle of incidence of electrons. It is recommended that, when measuring the dose distribution, the same dose-rate (MU/min) should be used during the determination of the output and during the treatment of the patients. It is also recommended to investigate and determine the percentage of the radiation scattered through the applicator's walls, as a function of the beam energy and of the distance from the walls and from the base of the applicator.

For PDDs and Profiles diodes or diamond detectors should be used in water phantom. Relative absorbed dose measurements, i.e. percentage depth doses (PDDs) and off-axis profiles (OAPs) could be performed using a p-type diode in the water phantom. The signal from the diode detector is stated to be approximately proportional to the absorbed dose to water. The uncertainty in the diode position is typically less than 0.2 mm and PDDs and OAPs are acquired with a spatial resolution of 1.0 mm.

For the Output measurements, in no reference conditions and in particular in the case of small and or beveled applicators, a solid phantom and radiographic or radiochromic films (Fiandra et al., 2008), or TLD (Palta et al., 1995) may be employed.



Values of the output expressed as dose per Monitor Units (MU) (cGy/MU), measured in a

Such characteristics must be measured for every applicator, energy and SSD of clinical

For low energy electron beams (4-10 MeV), as suggested by international protocol, a parallel-plate ionization chamber should be used. Ross, Markus and advanced Markus types (PTW Freiburg Germany) are the most utilized (PTW, 2011). But the response of these types of chamber is angle dependent so their use with a beveled applicator is not possible. Because of its high spatial resolution and independence on beam direction, a small cylindrical chamber, such as CC01 (Wellhofer, 2011) or Pin point (PTW), seems to be particularly suitable to perform absolute dose measurements for electron beams collimated

Due to the presence of electrons scattered by the applicator, the electron fields obtained with IORT-dedicated applicators are characterized by a wider energy spectrum and a wider angular distribution than electron beams collimated with conventional systems. This implies a higher surface dose (especially for the lower nominal energies) and less steep dose

For this reason, a dosimetry system must be selected characterized by a minimum dependence of the response from the beam energy and from the angle of incidence of electrons. It is recommended that, when measuring the dose distribution, the same dose-rate (MU/min) should be used during the determination of the output and during the treatment of the patients. It is also recommended to investigate and determine the percentage of the radiation scattered through the applicator's walls, as a function of the beam energy and of

For PDDs and Profiles diodes or diamond detectors should be used in water phantom. Relative absorbed dose measurements, i.e. percentage depth doses (PDDs) and off-axis profiles (OAPs) could be performed using a p-type diode in the water phantom. The signal from the diode detector is stated to be approximately proportional to the absorbed dose to water. The uncertainty in the diode position is typically less than 0.2 mm and PDDs and

For the Output measurements, in no reference conditions and in particular in the case of small and or beveled applicators, a solid phantom and radiographic or radiochromic films

bremsstrahlung radiation);

point at the reference depth on the clinical axis of the beam;

with inclined applicators (Karaj et al 2007, Iaccarino et al. 2011).

the distance from the walls and from the base of the applicator.

(Fiandra et al., 2008), or TLD (Palta et al., 1995) may be employed.

OAPs are acquired with a spatial resolution of 1.0 mm.

gradients (especially for the higher nominal energies).

R80 and of R50;

interest.

Because of its high spatial resolution, weak energy dependence, and near tissue equivalence, Gafchromic films have been selected as the reference detector for relative measurements of the output factor, for applicators of various dimensions length, diameter and angle of incidence.

#### **4. Decision parameters during surgery**

The final goal of IORT is an enhanced control in loco-regional tumor. IORT is feasible for intra-abdominal, retroperitoneal, pelvic and other malignancies. More recently, clinical experiences have shown that IORT may improve local control and disease-free survival, especially when used in adjuvant setting, combined with external beam irradiation in the stomach, pancreas, colon-rectum cancer and soft tissue sarcoma.

The rationale for the use of this segmental radiation therapy in place of whole-breast irradiation (WBI) is based on the results of some long-term studies reporting that local relapses after conservative surgery and External Beam Radio Therapy (EBRT) occur at the original tumor site at a rate of 80% or more, with few exceptions. This has been also confirmed by the results of the Milan III trial, which compared quadrantectomy alone with the same conservative surgery plus EBRT on the whole breast, have confirmed that 85% of local relapses were in, or close to, the previous index quadrant (Ivaldi et al., 2008). Another important advantage of the IORT is the avoidance of interaction with systemic therapy that may determine delays in the initiation or in performing conventional EBRT when CT, and particularly anthracyclin-based cycles, are given.

Widespread applications of IORT at various disease sites are feasible due to improvements in technology. By increasing the maximum energy of the linear accelerators of IORT and the total radiation dose it is possible to improve the therapeutic ratio and the tumor local control without increasing morbidity. Moreover, IORT is used as an adjuvant therapy, i.e., given as a boost after conventional fractionated radiotherapy.

IORT is generally given as a single fraction of 10 to 20 Gray (Gy). The single fraction is considered biologically equivalent from two to three times that of conventional fractionation for tumors while it is radiobiologically inferior due to impaired cellular repair of surrounding normal tissues, thus the protection of these tissues is mandatory. In fact the benefit in local recurrence needs to be carefully considered against the complications arising from the addition of IORT. This means that the appropriate entrance of the beam should be selected as well as the appropriate applicator diameter/kind and beam energy. This determines the Output factors (OFs) to be used and the monitor units evaluated using on an appropriate formula. In order to determine a dose-response effect a dosimeter could be placed within the field to be representative of the tumor bed or close to an Organ at Risk (OAR) near the applicator or under an additional shield.

The dose to be prescribed to target depends on the kind of disease, as well as on the microscopic spread expected in the tumor bed. This is particularly important when the resection margins are positive and depends on tumor stage and on radio-resistance of cells.

#### **5. Simulation of treatment plans**

Treatment planning is the process in which a team of radiation oncologists, surgeons and physicists plan the most appropriate radiation treatment for the patient using an external beam or by means of an internal beam such as IORT.

Intra-Operative Radiotherapy with Electron Beam 157

Several types of dosimeters have been developed to measure the precise dose and the percentage depth dose (PDD) using detectors such as ion chambers, silicon-diode detectors, diamond detectors, liquid ion chambers and radiographic films. They are partially ineffective, considering requests for new approaches to therapy such as: small sensitive volume, dose rate independence, measurements in real-time, use of high doses, no dependence on environmental conditions, such as temperature, humidity and pressure. For this reason new dosimetric systems have been studied and proposed in recent years (Aoyama et al., 1997; Staub et al., 2004; Archambault et al., 2005; Consorti et al. 2005).

These include dosimeters based on scintillating fibers. Difficulties arising in the conventional techniques have been overcome by providing features such as: small sensitive volume, high spatial resolution, water or tissue equivalent material, linear response, independence from energy and from dose rate, independence from environmental conditions such as temperature, pressure and humidity, high resistance to radiation

One of the first works that showed the potential of scintillating fibers to measure the depthdose for electron beams was published in 1997 (Takahiko et al., 1997). Over the past 10 years several proposals have appeared in literature with the use of scintillating fibers. Some of these have used small volumes of scintillating fibers coupled to light guides for reading the response to light (Archambault & Arsenault, 2005 ; Frelin & Fontbonne, 2006 ; Bongsoo et al., 2008 ; Staub, 2004). In others, detector elements have been incorporated in a water phantom equivalent in order to have a 3D representation (Fontbonne et al., 2002; Guillot et al., 2010; Lacroix et al., 2008). In all these approaches, the technique of elimination of Cerenkov light was needed. This contribution is very small and negligible compared to the scintillation light in the scintillating fibers. However the Cerenkov light becomes dominant, in the light guides, connecting the scintillating fibers to the electronic readout, when the

The approach described in this paragraph is different because it is very similar to that adopted in X-ray diagnostics (Bartesaghi et al., 2007a, 2007b). The dose absorbed along the beam is read by scintillating fibers assembled in homogeneous planes orthogonal to the beam axis. The light produced is integrated and collected for the read out at the end of each fiber, giving the projection of the signal in one dimension. The fibers assembled in each homogeneous plane are ready at one end. The approach is similar to the reading of onedimensional Radon transformation of the dose absorbed. In a previous work (Lamanna et al., 2009) we studied the basic elements constituting the device. In this chapter we present the results of the study of the therapeutic beam of electrons (the system can be used for other particles, photons, protons etc.) with a homogeneous layer of plastic scintillating

According to the clinical dosimetry, the absorbed dose is calculated in the biological tissue. For this reason, dosimeters built with equivalent tissue are more suitable. Water is the source material for phantoms taken as equivalent tissue in all electron beam dosimetry protocols. This choice comes from the fact that approximately 2/3 of the human body is

**6. Use of scintillating fibers for dosimetry** 

guides are subject to radiation (Archambault et al., 2006).

exposure, real-time response.

fibers.

**6.1 Dosimeter characteristics** 

Currently, it is very complicated to plan the radiotherapy process beforehand, this is because the team of specialists must choose at the very moment of operation the cone dimension, its positioning, the bevel angle and the electron beam energy according to its medical and surgical experience and the information gathered during surgery. One of the main limitations of IORT is due to the removal of diseased tissue from the patient during surgery which will change the geometric shape. In this way it is difficult to carry out a feasible dosimetry calculation using pre-operative images.

This aspect highlights two main problems for the planning of the intervention:


Today, treatment planning is entirely focused on the use of specific software. This software uses algorithms that exploit the patient's images, by means of the computed tomography (CT), for extremely realistic simulations.

Systems like Novac11 and Radiance are now a single integrated platform, which include not only the dedicated mobile accelerator, but also simulation software (NRT, 2011).

Radiance (Radiance, 2011) is the only available Radiotherapy Treatment Planning System (RTPS) that has been specifically designed for Intraoperative Radiotherapy (IORT) and the only one that works in such a field of radiotherapy. Radiance allows the specialists to simulate the whole IORT workflow. The operator can simulate the full delivery of the dose loading and visualizing CT images of the patient. The best choice of the parameters needed may be taken (applicator geometry, accelerator energy, number of MU …) to maximize the dose on the tumor or tumor bed and to minimize the contribution to the healthy tissues.

A new step in the IORT procedure has been introduced, the preplanning phase. In this presimulation, it is possible to modify the different parameters of the procedure to evaluate the outcome without stress in the real treatment decision-making process. Thus, it improves the safety of the global procedure. Radiance is a state-of-the-art development unrivalled today worldwide. It uses advanced visualization, simulation and dosimetry algorithms that are far ahead, concerning performance, of any current software. DICOM images are loaded and their volumetric representation built online. The computation of both graphics and dosimetry computation algorithms is almost in real time. The capability of simulation of different tissue densities opens a new era in the planning of IORT. At the same time the measurements required for commissioning a linear accelerator have been reduced considerably.

The dose calculation is carried out by means of two dosimetry computation engines which are available in radiance:


In the future built-in tools that make use of advanced simulation software, as described, will be increasingly used. This software will be able to improve not only the quality of the radiosurgery procedure, and therefore the results on patients, but also the interaction of the various specialists involved (radiation oncologists, surgeons and Physicists) through simulations of different scenarios.

Currently, it is very complicated to plan the radiotherapy process beforehand, this is because the team of specialists must choose at the very moment of operation the cone dimension, its positioning, the bevel angle and the electron beam energy according to its medical and surgical experience and the information gathered during surgery. One of the main limitations of IORT is due to the removal of diseased tissue from the patient during surgery which will change the geometric shape. In this way it is difficult to carry out a

 After the operation: since such images are not available, the results cannot be assessed. Today, treatment planning is entirely focused on the use of specific software. This software uses algorithms that exploit the patient's images, by means of the computed tomography

Systems like Novac11 and Radiance are now a single integrated platform, which include not

Radiance (Radiance, 2011) is the only available Radiotherapy Treatment Planning System (RTPS) that has been specifically designed for Intraoperative Radiotherapy (IORT) and the only one that works in such a field of radiotherapy. Radiance allows the specialists to simulate the whole IORT workflow. The operator can simulate the full delivery of the dose loading and visualizing CT images of the patient. The best choice of the parameters needed may be taken (applicator geometry, accelerator energy, number of MU …) to maximize the dose on the tumor or tumor bed and to minimize the contribution to the healthy tissues.

A new step in the IORT procedure has been introduced, the preplanning phase. In this presimulation, it is possible to modify the different parameters of the procedure to evaluate the outcome without stress in the real treatment decision-making process. Thus, it improves the safety of the global procedure. Radiance is a state-of-the-art development unrivalled today worldwide. It uses advanced visualization, simulation and dosimetry algorithms that are far ahead, concerning performance, of any current software. DICOM images are loaded and their volumetric representation built online. The computation of both graphics and dosimetry computation algorithms is almost in real time. The capability of simulation of different tissue densities opens a new era in the planning of IORT. At the same time the measurements

The dose calculation is carried out by means of two dosimetry computation engines which

An adapted and validated fast implementation of the Pencil Beam algorithm used in

In the future built-in tools that make use of advanced simulation software, as described, will be increasingly used. This software will be able to improve not only the quality of the radiosurgery procedure, and therefore the results on patients, but also the interaction of the various specialists involved (radiation oncologists, surgeons and Physicists) through

feasible dosimetry calculation using pre-operative images.

(CT), for extremely realistic simulations.

are available in radiance:

external radiotherapy.

simulations of different scenarios.

A parallel implementation of Monte Carlo algorithm.

This aspect highlights two main problems for the planning of the intervention:

only the dedicated mobile accelerator, but also simulation software (NRT, 2011).

required for commissioning a linear accelerator have been reduced considerably.

Before the operation: it is difficult to estimate the dose to be received;

#### **6. Use of scintillating fibers for dosimetry**

Several types of dosimeters have been developed to measure the precise dose and the percentage depth dose (PDD) using detectors such as ion chambers, silicon-diode detectors, diamond detectors, liquid ion chambers and radiographic films. They are partially ineffective, considering requests for new approaches to therapy such as: small sensitive volume, dose rate independence, measurements in real-time, use of high doses, no dependence on environmental conditions, such as temperature, humidity and pressure. For this reason new dosimetric systems have been studied and proposed in recent years (Aoyama et al., 1997; Staub et al., 2004; Archambault et al., 2005; Consorti et al. 2005).

These include dosimeters based on scintillating fibers. Difficulties arising in the conventional techniques have been overcome by providing features such as: small sensitive volume, high spatial resolution, water or tissue equivalent material, linear response, independence from energy and from dose rate, independence from environmental conditions such as temperature, pressure and humidity, high resistance to radiation exposure, real-time response.

One of the first works that showed the potential of scintillating fibers to measure the depthdose for electron beams was published in 1997 (Takahiko et al., 1997). Over the past 10 years several proposals have appeared in literature with the use of scintillating fibers. Some of these have used small volumes of scintillating fibers coupled to light guides for reading the response to light (Archambault & Arsenault, 2005 ; Frelin & Fontbonne, 2006 ; Bongsoo et al., 2008 ; Staub, 2004). In others, detector elements have been incorporated in a water phantom equivalent in order to have a 3D representation (Fontbonne et al., 2002; Guillot et al., 2010; Lacroix et al., 2008). In all these approaches, the technique of elimination of Cerenkov light was needed. This contribution is very small and negligible compared to the scintillation light in the scintillating fibers. However the Cerenkov light becomes dominant, in the light guides, connecting the scintillating fibers to the electronic readout, when the guides are subject to radiation (Archambault et al., 2006).

The approach described in this paragraph is different because it is very similar to that adopted in X-ray diagnostics (Bartesaghi et al., 2007a, 2007b). The dose absorbed along the beam is read by scintillating fibers assembled in homogeneous planes orthogonal to the beam axis. The light produced is integrated and collected for the read out at the end of each fiber, giving the projection of the signal in one dimension. The fibers assembled in each homogeneous plane are ready at one end. The approach is similar to the reading of onedimensional Radon transformation of the dose absorbed. In a previous work (Lamanna et al., 2009) we studied the basic elements constituting the device. In this chapter we present the results of the study of the therapeutic beam of electrons (the system can be used for other particles, photons, protons etc.) with a homogeneous layer of plastic scintillating fibers.

#### **6.1 Dosimeter characteristics**

According to the clinical dosimetry, the absorbed dose is calculated in the biological tissue. For this reason, dosimeters built with equivalent tissue are more suitable. Water is the source material for phantoms taken as equivalent tissue in all electron beam dosimetry protocols. This choice comes from the fact that approximately 2/3 of the human body is

Intra-Operative Radiotherapy with Electron Beam 159

The system is thus a solid phantom having a density approaching 1 g/cm3, with sensitive layers of scintillating fibers set at fixed positions in a calorimetric configuration for the containment of electrons of energy 4-12 MeV. The prototype is able to define the physical and geometrical characteristics of the electron beam (energy, isotropy, homogeneity, etc) and to measure the parameters needed to select the energy, the intensity and the Monitor Units (MU) for the exposure: the Percentage Depth Dose (PDD); the Beam profiles; the

Another important thing that must be considered is spatial resolution. The spatial resolution is a key feature for next-generation dosimeters. This feature will become more important in the next few years, in fact next-generation accelerators have a beam size up to 3 mm. DOSIORT responds fully to the demands of new approaches to radiotherapy. Its innovative detection system, made up of optical fibers which provide high spatial resolution and photodiodes with a sensitive area of 0.3×0.6 mm2 with pitch of 0.4 mm, gives a high spatial

The materials used to make the detector and the operations needed before the data taking have been studied and described in details in previous papers (Lamanna et al., 2009a, 2009b). The sequence of the most relevant steps before beginning are: electronic noise measurement to be subtracted; choice of the integration time to ensure a dynamic range large enough to have a linear response from the detector electronic; evaluation of calibration factor for each Phd response by exposing the fibers homogeneously to the same beam.

In this paragraph we include the results obtained from testing the system with a photon beam of 6 MV and an electron beam of energy 9 MeV generated through a Varian Clinac 2100 DHX. The data are compared to the measurements obtained using the PTW Freiburg TM31010 ionization chamber and the PTW MP3 water phantom, when they are available. The data taken through DOSIORT may be selected and elaborated considering the full detector or only part of the system. There are three different configurations for applying the dosimeter: using one layer (1D) at fixed depth and rotating it around the beam axis , using one double layers (2D) at different depths and using all six double layers (3D) at different depths. All the configurations are able to get the results in real time but the first system gives a more accurate measurement of the dose at fixed depth and it provides a series of measurements at different angles, the second one gives the results in depth more quickly but is less accurate in the reconstruction of the dose outside the FOV (field of view) region, the third is able to give a 3D estimation of the beam in depth into a single measure. However, all configurations require the acquisition of a number of measurements in a time that is in any case about a tenth of that needed to obtain the results with the ionization chambers or other traditional dosimeters. The

The response of the detector was tested through exposure to a beam orthogonal to the layer surface using only one layer. The photon beam of 6 MV was selected with a FOV of 8x8 cm2. The system was rotated manually around the beam axis and the projected data were

The projection of the dose in arbitrary units at different angles and positions along the

choice is connected to the level of accuracy needed in the measurements.

collected every 5 degrees for a total of 37 positions from -87.5 to 92.5 degrees.

**6.2 Results using one layer of DOSIORT** 

rotating axes is shown in Fig. 3,a.

Isodose curves; the values of dose per MU (cGy/MU).

resolution approximately 0.5 mm.

made up water. The dose distribution curves in water and in tissues are very similar, because water is an excellent image of diffusion and absorption properties of the human body. However, in many cases the employment of water as a test phantom is not very useful. Thus it can be replaced by solid materials with similar physical properties like polystyrene and perspex (PMMA). In theory, water tissue-equivalent materials should have effective atomic number Zeff (electron number per gram), and a density equal to water. In clinical applications, however, a material with electron density as close as possible to water is fairly suitable (McLaughlin & Chalkey, 1965).

For these reasons the system DOSIORT (IORT Dosimeter) is conceived as a box made of a tissue-equivalent material (polystyrene) with a density = 1.05 g/cm3. Inside the box there are six sensitive layers spaced 4 mm apart and set perpendicularly to the Z direction of the incident beam, as shown in Fig 2.

Each layer is composed of a grid consisting of two bundles of 190 scintillating optical fibers having a square cross section of 0.5×0.5 mm2 and crossing one over another so as to define a XY layer with an area of approximately 10×10 cm2. We use 380 BCF-60 scintillating optical fibers produced by Saint Gobain Crystals.

The light emitted in the fibers is read-out by two photodiode (Phd) arrays Hamamatsu S8865-128 for each bundle. The Phd are read sequentially using the Hamamatsu driver C9118 and the signal is digitized and processed by a computer with dedicated software.

The read-out system is therefore composed of 24 arrays. A dedicated electronic system is able to acquire, process and display the reconstructed electron beam image in real time (within a few seconds).

Fig. 2. Scintillating fiber dosimeter. On the left the characteristics of the layers are shown. On the right the photo of the dosimeter and of one double ribbon are shown.

made up water. The dose distribution curves in water and in tissues are very similar, because water is an excellent image of diffusion and absorption properties of the human body. However, in many cases the employment of water as a test phantom is not very useful. Thus it can be replaced by solid materials with similar physical properties like polystyrene and perspex (PMMA). In theory, water tissue-equivalent materials should have effective atomic number Zeff (electron number per gram), and a density equal to water. In clinical applications, however, a material with electron density as close as possible to water

For these reasons the system DOSIORT (IORT Dosimeter) is conceived as a box made of a tissue-equivalent material (polystyrene) with a density = 1.05 g/cm3. Inside the box there are six sensitive layers spaced 4 mm apart and set perpendicularly to the Z direction of the

Each layer is composed of a grid consisting of two bundles of 190 scintillating optical fibers having a square cross section of 0.5×0.5 mm2 and crossing one over another so as to define a XY layer with an area of approximately 10×10 cm2. We use 380 BCF-60 scintillating optical

The light emitted in the fibers is read-out by two photodiode (Phd) arrays Hamamatsu S8865-128 for each bundle. The Phd are read sequentially using the Hamamatsu driver C9118 and the signal is digitized and processed by a computer with dedicated software.

The read-out system is therefore composed of 24 arrays. A dedicated electronic system is able to acquire, process and display the reconstructed electron beam image in real time

Fig. 2. Scintillating fiber dosimeter. On the left the characteristics of the layers are shown. On

the right the photo of the dosimeter and of one double ribbon are shown.

is fairly suitable (McLaughlin & Chalkey, 1965).

incident beam, as shown in Fig 2.

(within a few seconds).

fibers produced by Saint Gobain Crystals.

The system is thus a solid phantom having a density approaching 1 g/cm3, with sensitive layers of scintillating fibers set at fixed positions in a calorimetric configuration for the containment of electrons of energy 4-12 MeV. The prototype is able to define the physical and geometrical characteristics of the electron beam (energy, isotropy, homogeneity, etc) and to measure the parameters needed to select the energy, the intensity and the Monitor Units (MU) for the exposure: the Percentage Depth Dose (PDD); the Beam profiles; the Isodose curves; the values of dose per MU (cGy/MU).

Another important thing that must be considered is spatial resolution. The spatial resolution is a key feature for next-generation dosimeters. This feature will become more important in the next few years, in fact next-generation accelerators have a beam size up to 3 mm. DOSIORT responds fully to the demands of new approaches to radiotherapy. Its innovative detection system, made up of optical fibers which provide high spatial resolution and photodiodes with a sensitive area of 0.3×0.6 mm2 with pitch of 0.4 mm, gives a high spatial resolution approximately 0.5 mm.

The materials used to make the detector and the operations needed before the data taking have been studied and described in details in previous papers (Lamanna et al., 2009a, 2009b). The sequence of the most relevant steps before beginning are: electronic noise measurement to be subtracted; choice of the integration time to ensure a dynamic range large enough to have a linear response from the detector electronic; evaluation of calibration factor for each Phd response by exposing the fibers homogeneously to the same beam.

In this paragraph we include the results obtained from testing the system with a photon beam of 6 MV and an electron beam of energy 9 MeV generated through a Varian Clinac 2100 DHX. The data are compared to the measurements obtained using the PTW Freiburg TM31010 ionization chamber and the PTW MP3 water phantom, when they are available.

The data taken through DOSIORT may be selected and elaborated considering the full detector or only part of the system. There are three different configurations for applying the dosimeter: using one layer (1D) at fixed depth and rotating it around the beam axis , using one double layers (2D) at different depths and using all six double layers (3D) at different depths. All the configurations are able to get the results in real time but the first system gives a more accurate measurement of the dose at fixed depth and it provides a series of measurements at different angles, the second one gives the results in depth more quickly but is less accurate in the reconstruction of the dose outside the FOV (field of view) region, the third is able to give a 3D estimation of the beam in depth into a single measure. However, all configurations require the acquisition of a number of measurements in a time that is in any case about a tenth of that needed to obtain the results with the ionization chambers or other traditional dosimeters. The choice is connected to the level of accuracy needed in the measurements.

#### **6.2 Results using one layer of DOSIORT**

The response of the detector was tested through exposure to a beam orthogonal to the layer surface using only one layer. The photon beam of 6 MV was selected with a FOV of 8x8 cm2. The system was rotated manually around the beam axis and the projected data were collected every 5 degrees for a total of 37 positions from -87.5 to 92.5 degrees.

The projection of the dose in arbitrary units at different angles and positions along the rotating axes is shown in Fig. 3,a.

Intra-Operative Radiotherapy with Electron Beam 161

acquired values is calculated. This parameter is taken as the error to minimize iterating the method. Each value difference is projected back on the reconstructed image to correct the values along the fiber and then a new difference between reconstructed and acquired data is calculated. This method, described in (Brancaccio et al., 2004), is able to converge into seven/eight steps and in less than a second. The reconstructed image seems to be more precise (Fig. 3,c). A more accurate comparison is shown in Fig. 4 where the reconstructed dose profiles are superimposed on the profile obtained using the ionization chamber around

Fig. 4. Dose profile measured using Ionizing chamber superimposed on the reconstructed

The reconstruction using the back projection with ramp filter reproduces quite accurately the dose profile from the maximum to about 10%. Some fluctuations are visible in the flat region. The iterative approach describes quite well the profile in the FOV used [-40 to +40

The energy 9 MeV was selected for the test of 1 double layer (XY) of DOSIORT. The FOV was set at 4×4 cm2 in order to study the energy response containing the doses absorbed.

The data were taken in different acquisition tests. In each test we changed the geometry of the setup superimposing over the previous configuration a sheet of polystyrene of 4.2 mm in water equivalent thickness. In this way we simulated a homogeneous phantom with

The double layer 2D was used for the reconstruction of the XY map of dose absorption at different depths. The XY projections collected for each acquisition, after correction for noise and calibration, were used to reconstruct the dose through the iterative method used for 1D

In Fig. 5 isodose curves at four fixed depths are shown for electrons of 9 MeV. The performance is similar to the reconstructions obtained in medical imaging using only two projections. The results are acceptable in a region coinciding with the FOV, [-20 to +20 mm]

dose profiles using the iterative and the back projection with and without filters.

mm] where the dose varies from 100% to 50%.

measurements at different depths.

detector and explained in (Brancaccio, 2004).

in the pictures. Outside this region the reproduction is poor.

**6.3 2D Results using one double layer of DOSIORT** 

the centre of the beam.

Fig. 3. a) Projected dose at 37 rotating angles around the beam axis; b) Back Projection without filter; c) Iterative reconstruction; d) Filtered Back Projection with ramp filter.

The plot shows the typical behaviour of a square FOV with maximum values around the diagonal at -45 and 45 degrees.

The 37 projections were used to reconstruct the transverse profile of the dose. The fibers collect the light generated along their axis, thus each acquired profile corresponds to the projection of the beam delivered along an axis. This system is not dissimilar to image reconstruction problems in tomography, where several projections have to be composed to trace them back to the original image. For this reason the first reconstruction method chosen was the back-projection algorithm widely used in tomography. Nevertheless using a backprojection approach without a filter we obtained a poor profile (Fig.3,b) while with the introduction of a ramp filter (Fig. 3,d) a better reconstructed image can be obtained. We additionally developed a dedicated algorithm based on the principle of the tomographic iterative methods.

The iterative method uses only two orthogonal projections. The choice of the two projections is very important to determine a good result in the reconstruction. We have selected the projections at 0 and 90 degrees. The idea is to sum the data collected by each fiber along an axis with the corresponding fiber for each of the two different angles, weighing the projection contribution on the basis of its concordance with the other projections results.

The image obtained in this way is a weighted sum of the contributions of two projections. Then the difference between the sum along an axis of the reconstructed image and the

Fig. 3. a) Projected dose at 37 rotating angles around the beam axis; b) Back Projection without filter; c) Iterative reconstruction; d) Filtered Back Projection with ramp filter.

diagonal at -45 and 45 degrees.

iterative methods.

The plot shows the typical behaviour of a square FOV with maximum values around the

The 37 projections were used to reconstruct the transverse profile of the dose. The fibers collect the light generated along their axis, thus each acquired profile corresponds to the projection of the beam delivered along an axis. This system is not dissimilar to image reconstruction problems in tomography, where several projections have to be composed to trace them back to the original image. For this reason the first reconstruction method chosen was the back-projection algorithm widely used in tomography. Nevertheless using a backprojection approach without a filter we obtained a poor profile (Fig.3,b) while with the introduction of a ramp filter (Fig. 3,d) a better reconstructed image can be obtained. We additionally developed a dedicated algorithm based on the principle of the tomographic

The iterative method uses only two orthogonal projections. The choice of the two projections is very important to determine a good result in the reconstruction. We have selected the projections at 0 and 90 degrees. The idea is to sum the data collected by each fiber along an axis with the corresponding fiber for each of the two different angles, weighing the projection contribution on the basis of its concordance with the other projections results.

The image obtained in this way is a weighted sum of the contributions of two projections. Then the difference between the sum along an axis of the reconstructed image and the acquired values is calculated. This parameter is taken as the error to minimize iterating the method. Each value difference is projected back on the reconstructed image to correct the values along the fiber and then a new difference between reconstructed and acquired data is calculated. This method, described in (Brancaccio et al., 2004), is able to converge into seven/eight steps and in less than a second. The reconstructed image seems to be more precise (Fig. 3,c). A more accurate comparison is shown in Fig. 4 where the reconstructed dose profiles are superimposed on the profile obtained using the ionization chamber around the centre of the beam.

Fig. 4. Dose profile measured using Ionizing chamber superimposed on the reconstructed dose profiles using the iterative and the back projection with and without filters.

The reconstruction using the back projection with ramp filter reproduces quite accurately the dose profile from the maximum to about 10%. Some fluctuations are visible in the flat region. The iterative approach describes quite well the profile in the FOV used [-40 to +40 mm] where the dose varies from 100% to 50%.

#### **6.3 2D Results using one double layer of DOSIORT**

The energy 9 MeV was selected for the test of 1 double layer (XY) of DOSIORT. The FOV was set at 4×4 cm2 in order to study the energy response containing the doses absorbed.

The data were taken in different acquisition tests. In each test we changed the geometry of the setup superimposing over the previous configuration a sheet of polystyrene of 4.2 mm in water equivalent thickness. In this way we simulated a homogeneous phantom with measurements at different depths.

The double layer 2D was used for the reconstruction of the XY map of dose absorption at different depths. The XY projections collected for each acquisition, after correction for noise and calibration, were used to reconstruct the dose through the iterative method used for 1D detector and explained in (Brancaccio, 2004).

In Fig. 5 isodose curves at four fixed depths are shown for electrons of 9 MeV. The performance is similar to the reconstructions obtained in medical imaging using only two projections. The results are acceptable in a region coinciding with the FOV, [-20 to +20 mm] in the pictures. Outside this region the reproduction is poor.

Intra-Operative Radiotherapy with Electron Beam 163

The system, optimized through Monte Carlo simulation as explained in (Lamanna et al., 2009a), is able to contain the full shower produced with electrons of energy 6 to 9 MeV. Greater energies may be measured using the same technique as in the previous paragraph: by superimposing sheets of polystyrene over the detector. The thickness of the sheets must be selected to position the build-up inside the detector. The isodose curves measured in each double layer for a beam of electrons of energy 9 MeV, using a FOV of 40×40 mm2 without external sheets are shown in Fig. 7. The dose is reconstructed using the iterative method described previously. The curves are well described in the FOV region. Outside some

The central X slice of the isodoses shown in Fig. 7 are represented on the left side of Fig. 8. The dose profile in depth is well reconstructed. The comparison with the ionization chamber results is done in the right part of the same figure, using the average of the dose in a central surface of area 2×2 mm2, corresponding to 4×4 scintillating fibers. The measurement through DOSIORT reproduces the PDD curve obtained through the ionization chamber.

Fig. 7. Isodose curves reconstructed through the iterative method described in the test using

data taken with 6 double layers of DOSIORT.

The full detector DOSIORT may be used to measure the dose in three dimensions.

Also in this picture the region inside the FOV is well represented.

artefacts connected to the reconstruction method are visible.

**6.4 3D Results using DOSIORT** 

Fig. 5. Isodose at four fixed depths for electrons of energy 9 MeV. A FOV 40×40 mm2 was selected.

The reconstructed doses may be used to visualize the depth dose profiles, selecting one central slice for each fixed step. The performance obtained is shown in Fig. 6.

Fig. 6. Depth dose profile for electrons of energy 9 MeV. A (FOV) 40×40 mm2 was selected.

Also in this picture the region inside the FOV is well represented.

#### **6.4 3D Results using DOSIORT**

162 Modern Practices in Radiation Therapy

Fig. 5. Isodose at four fixed depths for electrons of energy 9 MeV. A FOV 40×40 mm2 was

central slice for each fixed step. The performance obtained is shown in Fig. 6.

The reconstructed doses may be used to visualize the depth dose profiles, selecting one

Fig. 6. Depth dose profile for electrons of energy 9 MeV. A (FOV) 40×40 mm2 was selected.

selected.

The full detector DOSIORT may be used to measure the dose in three dimensions.

The system, optimized through Monte Carlo simulation as explained in (Lamanna et al., 2009a), is able to contain the full shower produced with electrons of energy 6 to 9 MeV. Greater energies may be measured using the same technique as in the previous paragraph: by superimposing sheets of polystyrene over the detector. The thickness of the sheets must be selected to position the build-up inside the detector. The isodose curves measured in each double layer for a beam of electrons of energy 9 MeV, using a FOV of 40×40 mm2 without external sheets are shown in Fig. 7. The dose is reconstructed using the iterative method described previously. The curves are well described in the FOV region. Outside some artefacts connected to the reconstruction method are visible.

The central X slice of the isodoses shown in Fig. 7 are represented on the left side of Fig. 8. The dose profile in depth is well reconstructed. The comparison with the ionization chamber results is done in the right part of the same figure, using the average of the dose in a central surface of area 2×2 mm2, corresponding to 4×4 scintillating fibers. The measurement through DOSIORT reproduces the PDD curve obtained through the ionization chamber.

Fig. 7. Isodose curves reconstructed through the iterative method described in the test using data taken with 6 double layers of DOSIORT.

Intra-Operative Radiotherapy with Electron Beam 165

The implementation of the new Linac for the production of electron beams dedicated to IORT in the last 10 years has allowed a diffusion of the therapeutic approach in a large number of health facilities by making the approach easier to use. Its use has facilitated the possibility to carry out clinical trials in international contexts for different types of tumor. Accelerators available on the market are today excellent for use in operating rooms. The improvements of the IORT technique pass through the proposal of means that include devices and methods to cover completely the therapeutic intervention. In particular through introduction of tools that help operators to select parameters required for this radio-surgical technique. Among these the most important are: a specific treatment planning system, and an efficient distribution map of the beam dosimetry. Today effort is devoted to introducing

GMV-RADIANCE (GMV, 2011) has recently introduced on the market a Proposal for IORT treatment planning. This package is included in the method ELIOT (Electron Beam

The Dosimetry of the beam is assessed using conventional systems with some difficulties to provide all the necessary measurements. In this chapter a method based on scintillating fibers is described. The results of the tests performed using a Varian electron beam are promising. The system allows, quickly and in detail, the measurements of the dosimetric distributions of the beam. The evolution of the system will be the engineering of the

We are grateful to the Italian INFN (National Institute of Nuclear Physics) for supporting the study of scintillating fiber dosimeters and the '"Hospital of Cosenza" for allowing the use

Intraoperative Radiotherapy) of the NRT (NRT, 2011) and it is really promising.

prototype to improve the electronic read-out and its stability.

of the accelerator Varian to test the dosimeter.

**10. Abbreviations used in this chapter** 

ADCB: Automatic Dose Control Board;

IORT: Intra-Operative RadioTherapy; IAEA: International Atomic Energy Agency; INFN: National Institute of Nuclear Physics;

ISS: Istituto Superiore di Sanità;

NRT: New Radiant Technology;

Linac: Linear Accelerator; MU: Monitor Unit;

OFs: Output factors; PDD: Per cent Depth Dose;

Phd: Photodiode;

EBRT: External Beam Radiation Therapy;

AAPM: American Association of Physicists in Medicine;

DICOM: Digital Imaging and COmmunications in Medicine;

Ksat: Correction factor for ion recombination in ionization chamber;

**8. Conclusion** 

improvements in these two fields.

**9. Acknowledgment** 

FOV: Field Of View;

Fig. 8. Depth dose X profile on the left and PDD curve on the right: DOSIORT compared to the results of the Ionization Chamber.

#### **7. Current activities and future clinical perspectives**

Many efforts have been made by physicists and physicians in order to improve this therapeutic approach. In the main, medical physicists have conducted many studies to determine the dosimetric characteristics of the beams produced by these dedicated devices, in order to overcome the limits of the dosimetric systems, such as ionization chambers. In particular, dosimetric data and the OFs of flat and bevelled applicators for all available applicator/angle combinations have been investigated using Monte Carlo simulation. The aim was to predict with higher accuracy the dose distributions delivered to the target and Organs at Risks, and to use this information in modern treatment planning systems, which are mandatory to improve the knowledge of dose-effect relationships.

In fact, even if the Monte Carlo method requires longer computing time, it is capable of accurately calculating the dose distribution under almost all circumstances and can be employed as a benchmark of conventional treatment planning systems.

Another future clinical perspective is based on the deep investigation of radiobiology of IORT. In fact, the current radiobiological models should be applied up to 16-18 Gy, i.e. for higher doses the validity of Linear Quadratic model should be proven. Because IORT is used as an adjuvant therapy, i.e. given as a boost after conventional fractionated radiotherapy, the modality to combine the expected effects of fractionated and single dose fraction should be tested and verified in a clinical setting.

Moreover, the development of on-line systems to monitor the three dimensional dose distributions should be encouraged in order to reduce the time of verification and quality assurance before treatment delivery; as well as during the acceptance tests in order to reduce the time of the physical characterization of these machines for each combination of energy and applicator diameter or collimator systems.

Finally, the availability of large field sizes (larger than 10 cm), as well as of beam modifiers should prove to be more efficacious for larger targets such as sarcomas, while sparing normal tissues.

#### **8. Conclusion**

164 Modern Practices in Radiation Therapy

Fig. 8. Depth dose X profile on the left and PDD curve on the right: DOSIORT compared to

Many efforts have been made by physicists and physicians in order to improve this therapeutic approach. In the main, medical physicists have conducted many studies to determine the dosimetric characteristics of the beams produced by these dedicated devices, in order to overcome the limits of the dosimetric systems, such as ionization chambers. In particular, dosimetric data and the OFs of flat and bevelled applicators for all available applicator/angle combinations have been investigated using Monte Carlo simulation. The aim was to predict with higher accuracy the dose distributions delivered to the target and Organs at Risks, and to use this information in modern treatment planning systems, which

In fact, even if the Monte Carlo method requires longer computing time, it is capable of accurately calculating the dose distribution under almost all circumstances and can be

Another future clinical perspective is based on the deep investigation of radiobiology of IORT. In fact, the current radiobiological models should be applied up to 16-18 Gy, i.e. for higher doses the validity of Linear Quadratic model should be proven. Because IORT is used as an adjuvant therapy, i.e. given as a boost after conventional fractionated radiotherapy, the modality to combine the expected effects of fractionated and single dose

Moreover, the development of on-line systems to monitor the three dimensional dose distributions should be encouraged in order to reduce the time of verification and quality assurance before treatment delivery; as well as during the acceptance tests in order to reduce the time of the physical characterization of these machines for each combination of

Finally, the availability of large field sizes (larger than 10 cm), as well as of beam modifiers should prove to be more efficacious for larger targets such as sarcomas, while sparing

the results of the Ionization Chamber.

**7. Current activities and future clinical perspectives** 

are mandatory to improve the knowledge of dose-effect relationships.

employed as a benchmark of conventional treatment planning systems.

fraction should be tested and verified in a clinical setting.

energy and applicator diameter or collimator systems.

normal tissues.

The implementation of the new Linac for the production of electron beams dedicated to IORT in the last 10 years has allowed a diffusion of the therapeutic approach in a large number of health facilities by making the approach easier to use. Its use has facilitated the possibility to carry out clinical trials in international contexts for different types of tumor. Accelerators available on the market are today excellent for use in operating rooms. The improvements of the IORT technique pass through the proposal of means that include devices and methods to cover completely the therapeutic intervention. In particular through introduction of tools that help operators to select parameters required for this radio-surgical technique. Among these the most important are: a specific treatment planning system, and an efficient distribution map of the beam dosimetry. Today effort is devoted to introducing improvements in these two fields.

GMV-RADIANCE (GMV, 2011) has recently introduced on the market a Proposal for IORT treatment planning. This package is included in the method ELIOT (Electron Beam Intraoperative Radiotherapy) of the NRT (NRT, 2011) and it is really promising.

The Dosimetry of the beam is assessed using conventional systems with some difficulties to provide all the necessary measurements. In this chapter a method based on scintillating fibers is described. The results of the tests performed using a Varian electron beam are promising. The system allows, quickly and in detail, the measurements of the dosimetric distributions of the beam. The evolution of the system will be the engineering of the prototype to improve the electronic read-out and its stability.

#### **9. Acknowledgment**

We are grateful to the Italian INFN (National Institute of Nuclear Physics) for supporting the study of scintillating fiber dosimeters and the '"Hospital of Cosenza" for allowing the use of the accelerator Varian to test the dosimeter.

#### **10. Abbreviations used in this chapter**

AAPM: American Association of Physicists in Medicine;

ADCB: Automatic Dose Control Board;


Intra-Operative Radiotherapy with Electron Beam 167

Boag J.W. ; Hochhauser, E. ; & Balk, O.A. (1996) The effect of free-electron collection on the

Bongsoo L. et al. (2008) Measurement of Two-Dimensional Photon Beam Distributions

Brancaccio, R. et al. (2004) Study of an appropriate reconstruction algorithm for an

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**10** 

 *Japan* 

 **Intraoperative Radiotherapy** 

The standard treatment for early breast cancer is breast-conserving therapy (BCT) with whole breast external irradiation therapy (WBI), and local control plays crucial role on survival (Clarke et al., 2005). It has been established that there is no significant difference in disease-free or overall survival rates between treatment by mastectomy or by lumpectomy with WBI for women with early breast cancer (Fisher et al., 2002; Veronesi et al., 2002). WBI actually provides statistically significant local control and survival data out to 15 years in favor of WBI compared to none (Clarke, et al., 2005). In actuality many women are still encouraged to proceed to mastectomy, because of the lack of access to radiotherapy centers or the long course of treatment of WBI. On the other hand, local recurrences after BCT with or without WBI arise most in the same quadrant as the primary cancer (Veronesi et al., 2001). The main objective of radiotherapy after BCT is considered to be the destruction of residual cancer cells in the operative field. Partial breast irradiation (PBI) has been tested in clinical trials for selected patients, and these studies have shown adequate local control, minimal toxicity, and good cosmetic appearance (Njeh et al., 2010). Intraoperative radiotherapy (IORT) is one of these PBI methods, which has recently been used in early stage breast cancer. Partial breast radiation therapy administered around the tumor bed has been comparable to WBI in selected patients (Antonucci et al., 2009; Benitez et al., 2007; Vicini et al., 2001; Vicini et al., 2003). Many phase II or III trials evaluating adjuvant IORT are actively accruing patients in the United States (NSABP-B39), Europe, United Kingdom, and Australia (Holmes et al., 2007). The standard treatment for early breast cancer is BCT with WBI, and outside the setting of a clinical trial, use of IORT as well as accelerated partial breast irradiation (APBI) is not yet recommended (Njeh, et al., 2010; Skandarajah et al., 2009). Then, particularly in practice setting, patients' selection is critical to the successful application of

This review concentrates on the eligibility, methods, outcome, and the point at issue of IORT for early breast cancer. With regard to terms, I defined IORT as the delivery of single fractional dose irradiation directly to the tumor bed during operation, and PBI as irradiation

**1. Introduction** 

PBI (Polgár et al., 2010; Vicini et al., 2011).

confined to the tumor bed either during operation or after surgery.

 **for Early Breast Cancer** 

Masataka Sawaki

*Department of Breast Oncology, Aichi Cancer Center Hospital,* 


## **Intraoperative Radiotherapy for Early Breast Cancer**

#### Masataka Sawaki

*Department of Breast Oncology, Aichi Cancer Center Hospital, Japan* 

#### **1. Introduction**

168 Modern Practices in Radiation Therapy

Istituto Superiore di Sanità [ISS] (2003), Guidelines for quality assurance in intra-operative

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Lamanna, E. et al. (2009b) Calorimetric approach for 3D dosimetry of high intensity

McLaughlin, L.; Chalkey, L. (1965) Low atomic numbered dye systems for ionising radiation

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Medicine. *Int. J. Radiat. Oncol., Biol., Phys.* Vol.33, pp.725–746.

*Accelerator*. Chicago, IL , USA Vol. 4, pp.2494-2496

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Ronsivalle, C.; Picardi, L.; Vignati, A.; Tata, A.; Benassi, M. (2001). Accelerators development

Soriani A., Felici G., Fantini M. et al. (2010) Radiation protection measurements around a 12 MeV mobile dedicated IORT accelerator. *Med Phys*. ; Vol.37(3), pp.995-1003 Staub, D. (2004) Real-time radio-transparent dosimeter for X-ray imaging system. *Nuclear* 

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NRT (2011). SpA - New Radiant Technology Italy. Available from http://www.newrt.it/ Olszanski, A.; Klassen, N.V.; C. K. Ross, C.K.; & Shortt K.R. (2002) The IRS Fricke Dosimetry

Luini, A.; Veronesi, P.; Ciocca, M.; Sangalli, C.; Fodor, C.; Veronesi, U. (2008) Preliminary results of electron intraoperative therapy boost and hypofractionated external beam radiotherapy after breast-conserving surgery in premenopausal

cylindrical ionization chamber for very high dose per pulse high energy electron

Dedicated Accelerators in Intra-Operative Radiation Therapy (IORT). *Ieee* 

therapeutic electron beams. *Nuclear Physics B - Proceedings Supplements* Vol.197 (1),

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measurements. *Photo.Sci.Eng.* Vol.9, pp.159-165.

*National Research Council* Ottawa, Ontario

The standard treatment for early breast cancer is breast-conserving therapy (BCT) with whole breast external irradiation therapy (WBI), and local control plays crucial role on survival (Clarke et al., 2005). It has been established that there is no significant difference in disease-free or overall survival rates between treatment by mastectomy or by lumpectomy with WBI for women with early breast cancer (Fisher et al., 2002; Veronesi et al., 2002). WBI actually provides statistically significant local control and survival data out to 15 years in favor of WBI compared to none (Clarke, et al., 2005). In actuality many women are still encouraged to proceed to mastectomy, because of the lack of access to radiotherapy centers or the long course of treatment of WBI. On the other hand, local recurrences after BCT with or without WBI arise most in the same quadrant as the primary cancer (Veronesi et al., 2001). The main objective of radiotherapy after BCT is considered to be the destruction of residual cancer cells in the operative field. Partial breast irradiation (PBI) has been tested in clinical trials for selected patients, and these studies have shown adequate local control, minimal toxicity, and good cosmetic appearance (Njeh et al., 2010). Intraoperative radiotherapy (IORT) is one of these PBI methods, which has recently been used in early stage breast cancer. Partial breast radiation therapy administered around the tumor bed has been comparable to WBI in selected patients (Antonucci et al., 2009; Benitez et al., 2007; Vicini et al., 2001; Vicini et al., 2003). Many phase II or III trials evaluating adjuvant IORT are actively accruing patients in the United States (NSABP-B39), Europe, United Kingdom, and Australia (Holmes et al., 2007). The standard treatment for early breast cancer is BCT with WBI, and outside the setting of a clinical trial, use of IORT as well as accelerated partial breast irradiation (APBI) is not yet recommended (Njeh, et al., 2010; Skandarajah et al., 2009). Then, particularly in practice setting, patients' selection is critical to the successful application of PBI (Polgár et al., 2010; Vicini et al., 2011).

This review concentrates on the eligibility, methods, outcome, and the point at issue of IORT for early breast cancer. With regard to terms, I defined IORT as the delivery of single fractional dose irradiation directly to the tumor bed during operation, and PBI as irradiation confined to the tumor bed either during operation or after surgery.

Intraoperative Radiotherapy for Early Breast Cancer 171

been shown to involve higher risk for local recurrence than luminal A or B-types (Kyndi et al., 2008; Nguyen et al., 2008; Veronesi, et al., 2010), then tailored local-regional treatment for

There has been only limited study of IORT including PBI in patients receiving neoadjuvant or concurrent chemotherapy. For patients who will receive adjuvant chemotherapy, it is recommended that APBI be performed first and that there should be an interval of at least 2 to 3 weeks between completion of APBI and initiation of chemotherapy (Smith, et al., 2009). Thus, IORT including PBI allows radiotherapy to be given without delaying administration of chemotherapy or hormonal therapy. But careful observation is needed; a retrospective analysis from MammoSite registry single arm trial reported an association between initiation of adjuvant chemotherapy within 3 weeks of the last MammoSite treatment and an increased risk of both radiation recall skin retraction and suboptimal cosmetics (Haffty et al., 2008). There is no data when adjuvant endocrine therapy with APBI should be started.

early-stage breast cancer has been reported to be mandatory now (Solin, 2010).

**2.5 Oncology** 

We show recommendation for APBI in Table 1.

Factors Suitable group

Multicentricity Unicentric only

 Pure DCIS Not allowed EIC Not allowed Associated LCIS Allowed Nodal status pN0

 Nodal surgery SN Bx or ALND Neoadjuvant Therapy Not allowed

ASTRO Consensus Statement (Smith, et al., 2009)

**3. Radiation methods** 

techniques for IORT in Table 2.

Margins Negative by at least 2 mm

 Mutifocally Clinically unifocal with total size ≤2 cm Histology Invasive ductal or other favorable subtypes

Table 1. Suitable patient group recommendation selections for APBI outside of clinical trials;

Several radiation methods are commonly in use for IORT. We show various radiation

 BRCA1/2 mutation Not present Tumor size ≤2 cm T stage T1

Age ≥60

 Grade Any LVSI No ER statis Positive

#### **2. Eligibility for IORT – Who is suitable for IORT?**

Many attempts have been made to identify subgroups of patients who might avoid radiotherapy after BCT, but these are not distinct factors. In general, the risk factors for local recurrence after BCT are larger tumor size, higher tumor grade, younger age, lymph nodepositive, and close surgical margin (Clarke, et al., 2005; Fisher, 1997; Park et al., 2000). Then, we review clinical questions of which patients can be considered for IORT. Some points are discussed separately as below.

#### **2.1 Age**

Cumulative incidence of recurrence of tumor in the ispilateral breast after WBI with a boost is different among age, younger women have higher incidence (Bartelink et al., 2007). Age ≥ 50 years has been selected in most prospective trials, and studies have shown that elderly patients treated with WBI (Antonini et al., 2007; Bartelink, et al., 2007) or MammoSite® (Chao et al., 2007) were low risk. Few women younger than 50 has been treated with PBI in prospective single arm studies.

#### **2.2 Tumor size**

A maximum tumor size of 2cm has been selected in most prospective trials. T2 tumors (>2cm, ≤5cm) or T0 (ductal carcinoma *in situ*; DCIS) tumors are cautionary recommended (Smith et al., 2009). Patients with T3 or T4 tumors should not receive PBI. An extensive intraductal component should be treated with caution. Patients with multicentric tumors; i.e. presence of foci of cancer in different quadrants, should not receive PBI because of the extent of disease. Patients of clinically unifocal or multifocal tumors with a total tumor size no greater than 2 cm could be suitable for PBI (Smith, et al., 2009).

#### **2.3 Nodal status**

Node positive is one of the risk factor for ispilateral breast cancer (Clarke, et al., 2005). Then, majority of patients who have been treated in prospective single arm APBI trials had pathologically node negative disease. Patients who do not undergo surgical nodal assessment or who have pathologic evidence of nodal involvements should not receive PBI.

#### **2.4 Pathology**

One area of concern in the use of IORT is the management of positive surgical margins as positivity is discovered at the final histology, a few days after surgery and IORT. Attention should be paid to ensure negative margins on final pathology (Beal et al., 2007), although margin positivity does not always influence the rate of local recurrences if effective radiotherapy is delivered (Chism et al., 2006; Mariani et al., 1998; Veronesi et al., 2010). Intraoperative frozen sections may be used to reduce positive margins (Fukamachi et al., 2010). Patients with close but negative margins (<2 mm) may be treated with caution (Smith, et al., 2009). Tumors with higher tumor grade is not suitable for PBI, because it is one of risk factors for local recurrence and most prospective trials have not considered as eligibility criteria. As for the tumor characteristics biologically, such as HER2-type or basal-type have been shown to involve higher risk for local recurrence than luminal A or B-types (Kyndi et al., 2008; Nguyen et al., 2008; Veronesi, et al., 2010), then tailored local-regional treatment for early-stage breast cancer has been reported to be mandatory now (Solin, 2010).

#### **2.5 Oncology**

170 Modern Practices in Radiation Therapy

Many attempts have been made to identify subgroups of patients who might avoid radiotherapy after BCT, but these are not distinct factors. In general, the risk factors for local recurrence after BCT are larger tumor size, higher tumor grade, younger age, lymph nodepositive, and close surgical margin (Clarke, et al., 2005; Fisher, 1997; Park et al., 2000). Then, we review clinical questions of which patients can be considered for IORT. Some points are

Cumulative incidence of recurrence of tumor in the ispilateral breast after WBI with a boost is different among age, younger women have higher incidence (Bartelink et al., 2007). Age ≥ 50 years has been selected in most prospective trials, and studies have shown that elderly patients treated with WBI (Antonini et al., 2007; Bartelink, et al., 2007) or MammoSite® (Chao et al., 2007) were low risk. Few women younger than 50 has been treated with PBI in

A maximum tumor size of 2cm has been selected in most prospective trials. T2 tumors (>2cm, ≤5cm) or T0 (ductal carcinoma *in situ*; DCIS) tumors are cautionary recommended (Smith et al., 2009). Patients with T3 or T4 tumors should not receive PBI. An extensive intraductal component should be treated with caution. Patients with multicentric tumors; i.e. presence of foci of cancer in different quadrants, should not receive PBI because of the extent of disease. Patients of clinically unifocal or multifocal tumors with a total tumor size

Node positive is one of the risk factor for ispilateral breast cancer (Clarke, et al., 2005). Then, majority of patients who have been treated in prospective single arm APBI trials had pathologically node negative disease. Patients who do not undergo surgical nodal assessment or who have pathologic evidence of nodal involvements should not receive PBI.

One area of concern in the use of IORT is the management of positive surgical margins as positivity is discovered at the final histology, a few days after surgery and IORT. Attention should be paid to ensure negative margins on final pathology (Beal et al., 2007), although margin positivity does not always influence the rate of local recurrences if effective radiotherapy is delivered (Chism et al., 2006; Mariani et al., 1998; Veronesi et al., 2010). Intraoperative frozen sections may be used to reduce positive margins (Fukamachi et al., 2010). Patients with close but negative margins (<2 mm) may be treated with caution (Smith, et al., 2009). Tumors with higher tumor grade is not suitable for PBI, because it is one of risk factors for local recurrence and most prospective trials have not considered as eligibility criteria. As for the tumor characteristics biologically, such as HER2-type or basal-type have

no greater than 2 cm could be suitable for PBI (Smith, et al., 2009).

**2. Eligibility for IORT – Who is suitable for IORT?** 

discussed separately as below.

prospective single arm studies.

**2.2 Tumor size** 

**2.3 Nodal status** 

**2.4 Pathology** 

**2.1 Age** 

There has been only limited study of IORT including PBI in patients receiving neoadjuvant or concurrent chemotherapy. For patients who will receive adjuvant chemotherapy, it is recommended that APBI be performed first and that there should be an interval of at least 2 to 3 weeks between completion of APBI and initiation of chemotherapy (Smith, et al., 2009). Thus, IORT including PBI allows radiotherapy to be given without delaying administration of chemotherapy or hormonal therapy. But careful observation is needed; a retrospective analysis from MammoSite registry single arm trial reported an association between initiation of adjuvant chemotherapy within 3 weeks of the last MammoSite treatment and an increased risk of both radiation recall skin retraction and suboptimal cosmetics (Haffty et al., 2008). There is no data when adjuvant endocrine therapy with APBI should be started.


We show recommendation for APBI in Table 1.

Table 1. Suitable patient group recommendation selections for APBI outside of clinical trials; ASTRO Consensus Statement (Smith, et al., 2009)

#### **3. Radiation methods**

Several radiation methods are commonly in use for IORT. We show various radiation techniques for IORT in Table 2.

Intraoperative Radiotherapy for Early Breast Cancer 173

The largest randomized clinical trial to date is now in progress at the Milan Institute. The goal of the trial is to determine the equivalence of local recurrence rates between quadrantectomy with conventional WBI and that with IORT. To date, they remain investigational until information on its long-term efficacy and safety becomes available (Buchholz, 2009). In the trial at the Milan Institute, 21 Gy, which is recommended through more than 1000 IORT procedures (Intra, et al., 2006), was used for the IORT arm. In the most update data, local recurrence rate was 1.3% (24/1,822) (Veronesi, et al., 2010). In addition, IORT can achieve early initiation of radiotherapy (RT). Delay in the initiation of RT is

With regard to another concept of full-dose intraoperative radiotherapy, an anticipated boost during operation has been studied (Reitsamer et al., 2002; Reitsamer et al., 2006). A single dose of 9 Gy was applied to the 90% reference isodose with energies ranging from 4 to 15 MeV, using round applicator tubes 4–8 cm in diameter. After wound healing, the patients received additional 51 – 56 Gy external boost radiation (EBRT) to the whole breast (Reitsamer, et al., 2002). The advantages are follows. 1) To complete skin sparing, 2) the precise application of the boost directly to the tumor bed with a homogeneous tissue radiation and 3) to reduce postoperative radiation time for 7-10 days (time of postoperative

Nipple sparing mastectomy can be applied for treatment of breast cancer when mastectomy is indicated. To reduce the risk of retro areolar recurrence, radio-surgical treatment combining subcutaneous mastectomy with intraoperative radiotherapy (ELIOT) is proposed (Petit et al., 2009; Petit et al., 2009). The IORT with electrons of 16 Gy in one shot was delivered on the nipple areolar area. Local recurrence rate was not higher than the usual rate

associated with a decrease in local recurrence rate (Huang, 2003).

boost radiotherapy) (Reitsamer, et al., 2002; Reitsamer, et al., 2006).

observed in the literature, although longer follow up is needed.

**3.1.2 As a boost** 

**3.1.3 Nipple sparing mastectomy** 


Table 2. Clinical studies using full-dose Intraoperative radiation therapy (IORT)

#### **3.1 Electrons Intraoperative Therapy (ELIOT)**

#### **3.1.1 As a single fractional dose**

ELIOT is one of these PBI methods, which has recently been used in early stage breast cancer, mainly at the European Institute of Oncology (Italian: *Istituto Europeo di Oncologia*; IEO) in Milan since 1999 (Intra et al., 2006; Luini et al., 2005; Veronesi et al., 2005; Veronesi, et al., 2010; Veronesi et al., 2001). They have been promoted to prospective trials to investigate tolerance to increased IORT doses and ultimately to introduce the use of 21 Gy in the context of breast conserving surgery. A single dose of 21 Gy at 90% isodose has been shown to be feasible in European breast cancer patients and biologically equivalent to a full dose of conventional WBI (Intra, et al., 2006; Luini, et al., 2005; Veronesi, et al., 2005; Veronesi, et al., 2001). The main advantages are follows. 1) To be able to deliver the radiation before tumor cells have a chance to proliferate under surgical intervention have a rich vascularization, which makes them more sensitive to the action of the radiation. 2) To be able to deliver under direct visualization at the time of surgery. It has the potential for accurate dose delivery by permitting delivery of the radiation dose directly to the surgical margins. 3) IORT could minimize some potential side effects, since skin and the subcutaneous tissue can be displaced. 4) The spread of irradiation to lung and heart is reduced significantly. 5) IORT allows radiotherapy to be given without delaying administration of chemotherapy or hormonal therapy. 6) There is potential for decreasing healthcare cost, because it is one fraction as opposed to 25 fractions. For elderly patients, it is feasible and corresponded to acceptable quality index criteria (Lemanski et al., 2010). In Asian breast cancer patients 21 Gy was recommended as a result of phase I study, which had been used a scheme of dose-escalation from 19, 20, and 21 Gy. (Sawaki et al., 2009), and subsequent phase II study indicated feasibility at 21 Gy (Sawaki et al., 2011). In this technique a disk should be needed to reduce the spread of irradiation to lung and heart. The disk is located between gland and pectoralis muscle. The aluminum and lead disk has been used in Italy (Intra, et al., 2006; Mussari et al., 2006). As for an another kind of disk, two layers disk; a first layer (source side) of polymethyl methacrylate (PMMA) and a second layer of copper was designed and selected from metals such as aluminum, copper and lead after testing for their shielding capabilities and the range of the backscatter (Oshima et al., 2009).

IORT extends the primary operation only for an additional 15 minutes plus approximately 30 minutes of a radiotherapy physicist's time to prepare the device(Sawaki, et al., 2009), although conventional WBI radiotherapy usually requires 5 weeks of outpatient treatment.

The largest randomized clinical trial to date is now in progress at the Milan Institute. The goal of the trial is to determine the equivalence of local recurrence rates between quadrantectomy with conventional WBI and that with IORT. To date, they remain investigational until information on its long-term efficacy and safety becomes available (Buchholz, 2009). In the trial at the Milan Institute, 21 Gy, which is recommended through more than 1000 IORT procedures (Intra, et al., 2006), was used for the IORT arm. In the most update data, local recurrence rate was 1.3% (24/1,822) (Veronesi, et al., 2010). In addition, IORT can achieve early initiation of radiotherapy (RT). Delay in the initiation of RT is associated with a decrease in local recurrence rate (Huang, 2003).

#### **3.1.2 As a boost**

172 Modern Practices in Radiation Therapy

ELIOT is one of these PBI methods, which has recently been used in early stage breast cancer, mainly at the European Institute of Oncology (Italian: *Istituto Europeo di Oncologia*; IEO) in Milan since 1999 (Intra et al., 2006; Luini et al., 2005; Veronesi et al., 2005; Veronesi, et al., 2010; Veronesi et al., 2001). They have been promoted to prospective trials to investigate tolerance to increased IORT doses and ultimately to introduce the use of 21 Gy in the context of breast conserving surgery. A single dose of 21 Gy at 90% isodose has been shown to be feasible in European breast cancer patients and biologically equivalent to a full dose of conventional WBI (Intra, et al., 2006; Luini, et al., 2005; Veronesi, et al., 2005; Veronesi, et al., 2001). The main advantages are follows. 1) To be able to deliver the radiation before tumor cells have a chance to proliferate under surgical intervention have a rich vascularization, which makes them more sensitive to the action of the radiation. 2) To be able to deliver under direct visualization at the time of surgery. It has the potential for accurate dose delivery by permitting delivery of the radiation dose directly to the surgical margins. 3) IORT could minimize some potential side effects, since skin and the subcutaneous tissue can be displaced. 4) The spread of irradiation to lung and heart is reduced significantly. 5) IORT allows radiotherapy to be given without delaying administration of chemotherapy or hormonal therapy. 6) There is potential for decreasing healthcare cost, because it is one fraction as opposed to 25 fractions. For elderly patients, it is feasible and corresponded to acceptable quality index criteria (Lemanski et al., 2010). In Asian breast cancer patients 21 Gy was recommended as a result of phase I study, which had been used a scheme of dose-escalation from 19, 20, and 21 Gy. (Sawaki et al., 2009), and subsequent phase II study indicated feasibility at 21 Gy (Sawaki et al., 2011). In this technique a disk should be needed to reduce the spread of irradiation to lung and heart. The disk is located between gland and pectoralis muscle. The aluminum and lead disk has been used in Italy (Intra, et al., 2006; Mussari et al., 2006). As for an another kind of disk, two layers disk; a first layer (source side) of polymethyl methacrylate (PMMA) and a second layer of copper was designed and selected from metals such as aluminum, copper and lead after testing for their

Technique Ispilateral breast cancer recurrence (%)

Median follow up (months)

Author Year

(publish)

**3.1 Electrons Intraoperative Therapy (ELIOT)** 

**3.1.1 As a single fractional dose** 

No. of cases

Sawaki M 2011 32 26 Electrons 0 Veronesi U 2010 1,822 36.1 Electrons 1.3 Vaidya JS 2010 854 48 Photons 1.2 Lemanski C 2010 42 30 Electrons 4.8 Mussari S 2006 47 48 Electrons 0

Table 2. Clinical studies using full-dose Intraoperative radiation therapy (IORT)

shielding capabilities and the range of the backscatter (Oshima et al., 2009).

IORT extends the primary operation only for an additional 15 minutes plus approximately 30 minutes of a radiotherapy physicist's time to prepare the device(Sawaki, et al., 2009), although conventional WBI radiotherapy usually requires 5 weeks of outpatient treatment.

With regard to another concept of full-dose intraoperative radiotherapy, an anticipated boost during operation has been studied (Reitsamer et al., 2002; Reitsamer et al., 2006). A single dose of 9 Gy was applied to the 90% reference isodose with energies ranging from 4 to 15 MeV, using round applicator tubes 4–8 cm in diameter. After wound healing, the patients received additional 51 – 56 Gy external boost radiation (EBRT) to the whole breast (Reitsamer, et al., 2002). The advantages are follows. 1) To complete skin sparing, 2) the precise application of the boost directly to the tumor bed with a homogeneous tissue radiation and 3) to reduce postoperative radiation time for 7-10 days (time of postoperative boost radiotherapy) (Reitsamer, et al., 2002; Reitsamer, et al., 2006).

#### **3.1.3 Nipple sparing mastectomy**

Nipple sparing mastectomy can be applied for treatment of breast cancer when mastectomy is indicated. To reduce the risk of retro areolar recurrence, radio-surgical treatment combining subcutaneous mastectomy with intraoperative radiotherapy (ELIOT) is proposed (Petit et al., 2009; Petit et al., 2009). The IORT with electrons of 16 Gy in one shot was delivered on the nipple areolar area. Local recurrence rate was not higher than the usual rate observed in the literature, although longer follow up is needed.

Intraoperative Radiotherapy for Early Breast Cancer 175

Antonini N, Jones H, Horiot JC et al (2007) Effect of age and radiation dose on local control

Antonucci JV, Wallace M, Goldstein NS et al (2009) Differences in Patterns of Failure in

Bartelink H, Horiot JC, Poortmans PM et al (2007) Impact of a higher radiation dose on local

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after breast conserving treatment: EORTC trial 22881-10882. *Radiother Oncol* 82:265-

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control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881-10882 trial. *J Clin* 

for Breast Cancer: Early Cosmetic Results. *International Journal of Radiation* 

Mammosite balloon brachytherapy for partial breast irradiation in early-stage

**5. Conflict of Interest** 

The author states that I have no conflict of interest.

**6. Acronyms and abbreviations**  ALND; Axillary lymph node dissection APBI; Accelerated partial breast irradiation ASTRO; American Society for Radiation Oncology

BCT; Breast conserving therapy DCIS; Ductal carcinoma *in situ*  EBRT; External boost radiation EIC; Extensive intraductal component ELIOT; Electrons intraoperative therapy

IORT; Intraoperative radiotherapy LCIS; lobular carcinoma *in situ*

PBI; Partial breast irradiation PMMA; polymethyl methacrylate

LVSI; Lymph-vascular space invasion

SN Bx; Sentinel lymph node biopsy

*Oncol* 25:3259-3265

*OncologyBiologyPhysics* 69:19-24

surgery. *N Engl J Med* 360:63-70

TARGIT; Targeted intraoperative radiotherapy WBI; Whole breast external irradiation therapy

*of Radiation OncologyBiologyPhysics* 74:447-452

ER; Estrogen receptor

RT; Radiotherapy

**7. References** 

271

Fig. 1. Intraoperative radiotherapy (electrons)

#### **3.2 Targeted intraoperative radiotherapy (TARGIT)**

This device is inserted intraopetatively into the tumor cavity after excision of the tumor and emits X-rays from within the breast (Vaidya et al., 2010). The authors used a miniature electron-beam-driven X-ray source called Intrabeam®, which emits low energetic X-rays with 50 kV from the point source. In large randomized clinical trial, TARGIT trial for selected patients with early breast cancer, a single dose of radiotherapy delivered at the time of surgery by use of targeted intraoperative radiotherapy is considered as an alternative to external beam radiotherapy delivered over several weeks (Vaidya, et al., 2010), although it needs longer follow up to conclude the no inferiority to the WBI (Reitsamer et al., 2010).

#### **4. Conclusion**

In conclusion, IORT is an option applied for breast conserving therapy in the selected patients. TARGIT trial has been considered as an alternative to external beam radiotherapy delivered over several weeks (Vaidya, et al., 2010). And also ELIOT appears a promising feature in early breast cancer treated with breast conserving surgery, reducing the exposure of normal tissues to radiations and shortening the radiation course from 6 weeks to one single session (Veronesi, et al., 2010). These clinical studies have shown adequate local control, minimal toxicity, and good cosmetic appearance, although a longer follow up is needed for the evaluation of the late side effects. In practice setting, careful management is needed because patients' selection is critical to the successful application of IORT.

#### **5. Conflict of Interest**

174 Modern Practices in Radiation Therapy

This device is inserted intraopetatively into the tumor cavity after excision of the tumor and emits X-rays from within the breast (Vaidya et al., 2010). The authors used a miniature electron-beam-driven X-ray source called Intrabeam®, which emits low energetic X-rays with 50 kV from the point source. In large randomized clinical trial, TARGIT trial for selected patients with early breast cancer, a single dose of radiotherapy delivered at the time of surgery by use of targeted intraoperative radiotherapy is considered as an alternative to external beam radiotherapy delivered over several weeks (Vaidya, et al., 2010), although it needs longer follow up to conclude the no inferiority to the WBI (Reitsamer et al., 2010).

In conclusion, IORT is an option applied for breast conserving therapy in the selected patients. TARGIT trial has been considered as an alternative to external beam radiotherapy delivered over several weeks (Vaidya, et al., 2010). And also ELIOT appears a promising feature in early breast cancer treated with breast conserving surgery, reducing the exposure of normal tissues to radiations and shortening the radiation course from 6 weeks to one single session (Veronesi, et al., 2010). These clinical studies have shown adequate local control, minimal toxicity, and good cosmetic appearance, although a longer follow up is needed for the evaluation of the late side effects. In practice setting, careful management is

needed because patients' selection is critical to the successful application of IORT.

Fig. 1. Intraoperative radiotherapy (electrons)

**4. Conclusion** 

**3.2 Targeted intraoperative radiotherapy (TARGIT)** 

The author states that I have no conflict of interest.

#### **6. Acronyms and abbreviations**

ALND; Axillary lymph node dissection APBI; Accelerated partial breast irradiation ASTRO; American Society for Radiation Oncology BCT; Breast conserving therapy DCIS; Ductal carcinoma *in situ*  EBRT; External boost radiation EIC; Extensive intraductal component ELIOT; Electrons intraoperative therapy ER; Estrogen receptor IORT; Intraoperative radiotherapy LCIS; lobular carcinoma *in situ* LVSI; Lymph-vascular space invasion PBI; Partial breast irradiation PMMA; polymethyl methacrylate RT; Radiotherapy SN Bx; Sentinel lymph node biopsy TARGIT; Targeted intraoperative radiotherapy WBI; Whole breast external irradiation therapy

#### **7. References**


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**Part 4** 

**Scope of Radiation** 

**Therapy for Specific Diseases** 

