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*Gynaecological Malignancies - Updates and Advances*

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**Chapter 5**

**Abstract**

exceeded.

**83**

**1. Introduction**

Dosimetric and Radiobiological

Radiotherapy of Cervical Cancer

*Evgeniia Sergeevna Sukhikh and Leonid Grigorievich Sukhikh*

A dosimetric and radiobiological investigation of the possibility to replace the traditional combined radiation therapy (3D-CRT + high-dose-rate brachytherapy (HDR-BT)) of cervical cancer with the following combinations, 60Co + VMAT, 3D-CRT + VMAT, and VMAT + VMAT, without change of total course dose and the number of fractions is described. For the investigation, the data of 11 patients with a diagnosis of cervical cancer (stages T2bNxM0 and T3NxM0) who received a course of combined radiotherapy was used. The 3D-CRT + high-dose-rate brachytherapy (HDR-BT) combination of dose delivery techniques was used as the basic one. The following fractionation regimes for combined radiotherapy were simulated: external beam radiation therapy (RT) (EBRT) of the first stage, total dose 50 Gy and fractional dose 2 Gy (25 fractions), and the second stage—total dose 28 Gy and fractional dose 7 Gy (4 fractions). Total combined RT course dose amounted to EQD2 = 89.7 Gy. Simulation results show that there is a technical possibility of replacing the second stage of combined RT of cervical cancer by EBRT based on the VMAT technique. Implementation of the VMAT technique allows increasing the uniformity of irradiated volume coverage compared with traditional high-dose rate. While using the VMAT technique, the tolerant levels of organs at risk are not

**Keywords:** intracavitary brachytherapy, external beam radiation therapy, cervical

In the treatment of cervical cancer, the main methods include surgical treatment, chemotherapy, and radiation therapy (RT), which can be used either separately or in combination with each other [1–3]. The combination of two consecutive stages of irradiation with different dose delivery techniques, i.e., external beam radiotherapy (EBRT) and intracavitary high-dose-rate brachytherapy, is called combined RT [1–6]. At the first stage of combined RT, the clinical tumor volume and regional lymph nodes are irradiated in total doses up to 44–50 Gy with fraction dose equal to 2 Gy depending on the widespread nature of the process. At the second stage of the combined RT, the clinical tumor volume is irradiated in the

cancer, intensity-modulated radiotherapy, combined radiotherapy

Based on the VMAT Technique

Evaluation of Combined

#### **Chapter 5**

## Dosimetric and Radiobiological Evaluation of Combined Radiotherapy of Cervical Cancer Based on the VMAT Technique

*Evgeniia Sergeevna Sukhikh and Leonid Grigorievich Sukhikh*

### **Abstract**

A dosimetric and radiobiological investigation of the possibility to replace the traditional combined radiation therapy (3D-CRT + high-dose-rate brachytherapy (HDR-BT)) of cervical cancer with the following combinations, 60Co + VMAT, 3D-CRT + VMAT, and VMAT + VMAT, without change of total course dose and the number of fractions is described. For the investigation, the data of 11 patients with a diagnosis of cervical cancer (stages T2bNxM0 and T3NxM0) who received a course of combined radiotherapy was used. The 3D-CRT + high-dose-rate brachytherapy (HDR-BT) combination of dose delivery techniques was used as the basic one. The following fractionation regimes for combined radiotherapy were simulated: external beam radiation therapy (RT) (EBRT) of the first stage, total dose 50 Gy and fractional dose 2 Gy (25 fractions), and the second stage—total dose 28 Gy and fractional dose 7 Gy (4 fractions). Total combined RT course dose amounted to EQD2 = 89.7 Gy. Simulation results show that there is a technical possibility of replacing the second stage of combined RT of cervical cancer by EBRT based on the VMAT technique. Implementation of the VMAT technique allows increasing the uniformity of irradiated volume coverage compared with traditional high-dose rate. While using the VMAT technique, the tolerant levels of organs at risk are not exceeded.

**Keywords:** intracavitary brachytherapy, external beam radiation therapy, cervical cancer, intensity-modulated radiotherapy, combined radiotherapy

#### **1. Introduction**

In the treatment of cervical cancer, the main methods include surgical treatment, chemotherapy, and radiation therapy (RT), which can be used either separately or in combination with each other [1–3]. The combination of two consecutive stages of irradiation with different dose delivery techniques, i.e., external beam radiotherapy (EBRT) and intracavitary high-dose-rate brachytherapy, is called combined RT [1–6]. At the first stage of combined RT, the clinical tumor volume and regional lymph nodes are irradiated in total doses up to 44–50 Gy with fraction dose equal to 2 Gy depending on the widespread nature of the process. At the second stage of the combined RT, the clinical tumor volume is irradiated in the

mode of dose boost when the dose per fraction is increased to 6–7.5 Gy delivered in 4 or 5 fractions resulting in the total dose equal to 28–30 Gy. The goal of the total combined RT course is to achieve a total EQD2 dose equal to 90 Gy delivered to the clinical tumor volume in less than 50 days of treatment [2–7].

The aim of this work was to carry out a dosimetric and radiobiological planning of the replacement of traditional combined radiation therapy (3D-CRT + HDR BT) by combinations of 60Co + VMAT, 3D-CRT + VMAT, and VMAT + VMAT while preserving the value of the total dose delivered and the number of fractions. The paper presents a comparison of radiation loads on tumor volumes and critical organs using different combinations of irradiation at the first and second stages, namely, 3D-CRT + HDR BT, conventional RT 60Co + VMAT, 3D-CRT + VMAT, and VMAT + VMAT. The study was conducted using tomographic data of 11 patients

*Dosimetric and Radiobiological Evaluation of Combined Radiotherapy of Cervical Cancer Based…*

Anatomical data of 11 patients with cervical cancer (squamous carcinoma) stages T2bN0M0 (six patients) and T3N0M0 (five patients) were used for investigation. The patients received no surgery due to the fact that for stages T2 and T3, the surgery is not the best treatment [13]. The patients were selected randomly between the patients who have received combined radiotherapy for half a year at Tomsk Regional Oncology Center. Patients' age was in the range from 55 to 57 years. All patients had received courses of standard combined radiotherapy using EBRT with 3D-CRT (Elekta Synergy linac, 10 MeV, AB Elekta) or conventional radiotherapy based on 60Co (Theratron Equinox 100) followed by HDR BT (Multisource HDR, Bebig). The prescribed total dose for EBRT amounted to 50 Gy given in 25 fractions

(2 Gy/fr). During the HDR BT, the total dose amounted to 28 Gy given in 4

equal to BED = 107.6 Gy and EQD2 = 89.7 Gy, which agreed with Refs. [2–7]. All

Different irradiation techniques were compared for dosimetric investigation. During the first stage of combined radiotherapy, we used conventional RT with 60Co, 3D-CRT using 10 MeV photons, and VMAT technique with 10 MeV photons. The second stage modalities included either HDR BT or VMAT with 10 MeV photons. The total dose values, as well as the fractionation regimen, were the same as

The OARs included bladder and rectum. The irradiation constraints are listed in

V59 < 50% V64 < 35% V69 < 25% V74 < 15%

V64 < 50% V69 < 35% V74 < 25% V79 < 15%

for the rectum [11]. The data were taken from the QUANTEC protocols [23, 24],

**Organ at risk QUANTEC [12, 13] RTOG 0415 [14] EBRT+BT**

*The tolerant levels of critical organs for all radiotherapy courses which include EBRT and BT or only the EBRT for two stages based on QUANTEC [23, 24], RTOG 0415 [25], GYN GES ESTRO [4], and other*

RTOG 0415 [25], GYN GES ESTRO [4], and other recommendations.

V60 < 35% V65 < 25% V70 < 20% V75 < 15%

V70 < 35% V75 < 25% V80 < 15% *<sup>b</sup>* ¼ 10 Gy for the tumor was

*<sup>β</sup>* ¼ 3*:*9 Gy

D2cc < 75Gy [3, 15] D2cc < 70Gy [2, 4]

D2cc < 90Gy [2–4, 15]

*<sup>β</sup>* <sup>¼</sup> 8 Gy for the bladder and *<sup>α</sup>*

fractions (7 Gy/fr). The total course dose assuming *<sup>a</sup>*

**Table 1**. During the study, we assumed that *<sup>α</sup>*

Rectum V50 < 50%

Bladder V65 < 50%

patients received concomitant cisplatin chemotherapy weekly.

with cervical cancer.

during irradiation.

**Table 1.**

**85**

*recommendations [26].*

**2. Combined radiotherapy**

*DOI: http://dx.doi.org/10.5772/intechopen.89734*

From the point of view of dose delivery technologies, the first stage of combined RT is EBRT based on one of the methods: conventional RT, 3D conformal RT (3D-CRT), or methods with intensity-modulated radiation (IMRT and VMAT) [8, 9]. The photon radiation sources used are gamma apparatus with 60Co sources and photon energy of 1.25 MeV or linear electron accelerators (linacs) with a photon energy equal to 6 or 10 MeV. When using conventional irradiation with gamma apparatus, there are difficulties in creating a conformal dose field that reduces the dose loads on critical organs, and, consequently, it is hard to improve the uniformity of coverage with a dose of the target volume; therefore, this technique, at present, is not very popular. However, from the point of view of operation and maintenance, the gamma apparatus is simpler and more convenient than linacs. According to IAEA, there are 240 gamma apparatuses in Russia and only 197 linacs. For comparison, in Germany, there are 523 linacs and only 20 gamma apparatuses [10]. From this point of view, the development of techniques for the best possible use of gamma apparatuses is an important task for Russia and other developing countries.

The second stage of combined RT is usually implemented using intracavitary HDR-BT based on gamma-emitting radionuclides 60Co or 192Ir [2–7]. The advantages of BT are the possibility of delivering a high dose to a clinical tumor volume with a relatively low dose load on OARs (bladder and rectum). Most of the radiotherapy departments in Russia are equipped with equipment that allows performing BT in HDR mode. However, BT has several significant drawbacks compared with EBRT. The main one is the substantial heterogeneity of the coverage of the clinical target volume, where doses in the range from 90 to 300% of the prescribed dose are delivered. BT is also a less comfortable procedure for patients because they experience painful sensations when inserting implants into the uterine cavity, which requires anesthesia. Dosimetric planning of BT needs conduction of topographic preparation using CT or magnetic resonance tomography (MRI) with implants inserted followed by a tight vaginal tamponade, to prevent their possible displacement inside the patient during transportation to the treatment table [2, 3, 5]. Optimization of the dose distribution in BT can be regulated only by introducing sectoral blocks into a Manchester (Fletcher)-type applicator (nozzle with an intrauterine endostat) or additional needles for interstitial implantation, which is even more complicated and requires anesthetic management. On the other hand, with BT, no additional margin from the clinical tumor volume (CTV) is required, which should consider the inaccuracy of dose delivery from fraction to fraction, i.e., creating a planned target volume (PTV), which is mandatory for EBRT. Because irradiation occurs from the inside, and not from the outside, in the case of movement of the organ with the implant inserted, the implant will move along with the organ [2–6].

The development of EBRT technologies has led to the widespread implementation of IMRT and VMAT dose delivery techniques, which allow delivery of single doses of up to 7 Gy to a target without exceeding tolerant levels for OARs. The VMAT method with large dose fractions is widely used, for example, in the treatment of prostate carcinomas [11–22]. The first investigations devoted to the study of the possibility of replacing BT with EBRT during the second stage of combined RT started in 2012 [18]. The goal of such investigations was to change BT with EBRT in hypofractionation mode for patients for whom BT was not possible for various reasons.

*Dosimetric and Radiobiological Evaluation of Combined Radiotherapy of Cervical Cancer Based… DOI: http://dx.doi.org/10.5772/intechopen.89734*

The aim of this work was to carry out a dosimetric and radiobiological planning of the replacement of traditional combined radiation therapy (3D-CRT + HDR BT) by combinations of 60Co + VMAT, 3D-CRT + VMAT, and VMAT + VMAT while preserving the value of the total dose delivered and the number of fractions. The paper presents a comparison of radiation loads on tumor volumes and critical organs using different combinations of irradiation at the first and second stages, namely, 3D-CRT + HDR BT, conventional RT 60Co + VMAT, 3D-CRT + VMAT, and VMAT + VMAT. The study was conducted using tomographic data of 11 patients with cervical cancer.

#### **2. Combined radiotherapy**

mode of dose boost when the dose per fraction is increased to 6–7.5 Gy delivered in 4 or 5 fractions resulting in the total dose equal to 28–30 Gy. The goal of the total combined RT course is to achieve a total EQD2 dose equal to 90 Gy delivered to the

From the point of view of dose delivery technologies, the first stage of combined RT is EBRT based on one of the methods: conventional RT, 3D conformal RT (3D-CRT), or methods with intensity-modulated radiation (IMRT and VMAT) [8, 9]. The photon radiation sources used are gamma apparatus with 60Co sources and photon energy of 1.25 MeV or linear electron accelerators (linacs) with a photon energy equal to 6 or 10 MeV. When using conventional irradiation with gamma apparatus, there are difficulties in creating a conformal dose field that reduces the dose loads on critical organs, and, consequently, it is hard to improve the uniformity of coverage with a dose of the target volume; therefore, this technique, at present, is not very popular. However, from the point of view of operation and maintenance, the gamma apparatus is simpler and more convenient than linacs. According to IAEA, there are 240 gamma apparatuses in Russia and only 197 linacs. For comparison, in Germany, there are 523 linacs and only 20 gamma apparatuses [10]. From this point of view, the development of techniques for the best possible use of gamma apparatuses is an important task for Russia and other developing

The second stage of combined RT is usually implemented using intracavitary HDR-BT based on gamma-emitting radionuclides 60Co or 192Ir [2–7]. The advantages of BT are the possibility of delivering a high dose to a clinical tumor volume with a relatively low dose load on OARs (bladder and rectum). Most of the radiotherapy departments in Russia are equipped with equipment that allows performing BT in HDR mode. However, BT has several significant drawbacks compared with EBRT. The main one is the substantial heterogeneity of the coverage of the clinical target volume, where doses in the range from 90 to 300% of the prescribed dose are delivered. BT is also a less comfortable procedure for patients because they experience painful sensations when inserting implants into the uterine cavity, which requires anesthesia. Dosimetric planning of BT needs conduction of topographic preparation using CT or magnetic resonance tomography (MRI) with implants inserted followed by a tight vaginal tamponade, to prevent their possible displacement inside the patient during transportation to the treatment table [2, 3, 5]. Optimization of the dose distribution in BT can be regulated only by introducing sectoral blocks into a Manchester (Fletcher)-type applicator (nozzle with an intrauterine endostat) or additional needles for interstitial implantation, which is even more complicated and requires anesthetic management. On the other hand, with BT, no additional margin from the clinical tumor volume (CTV) is required, which should consider the inaccuracy of dose delivery from fraction to fraction, i.e., creating a planned target volume (PTV), which is mandatory for EBRT. Because irradiation occurs from the inside, and not from the outside, in the case of movement of the organ with the implant inserted, the implant will move along with the

The development of EBRT technologies has led to the widespread implementation of IMRT and VMAT dose delivery techniques, which allow delivery of single doses of up to 7 Gy to a target without exceeding tolerant levels for OARs. The VMAT method with large dose fractions is widely used, for example, in the treatment of prostate carcinomas [11–22]. The first investigations devoted to the study of the possibility of replacing BT with EBRT during the second stage of combined RT started in 2012 [18]. The goal of such investigations was to change BT with EBRT in hypofractionation mode for patients for whom BT was not possible for

clinical tumor volume in less than 50 days of treatment [2–7].

*Gynaecological Malignancies - Updates and Advances*

countries.

organ [2–6].

various reasons.

**84**

Anatomical data of 11 patients with cervical cancer (squamous carcinoma) stages T2bN0M0 (six patients) and T3N0M0 (five patients) were used for investigation. The patients received no surgery due to the fact that for stages T2 and T3, the surgery is not the best treatment [13]. The patients were selected randomly between the patients who have received combined radiotherapy for half a year at Tomsk Regional Oncology Center. Patients' age was in the range from 55 to 57 years. All patients had received courses of standard combined radiotherapy using EBRT with 3D-CRT (Elekta Synergy linac, 10 MeV, AB Elekta) or conventional radiotherapy based on 60Co (Theratron Equinox 100) followed by HDR BT (Multisource HDR, Bebig). The prescribed total dose for EBRT amounted to 50 Gy given in 25 fractions (2 Gy/fr). During the HDR BT, the total dose amounted to 28 Gy given in 4 fractions (7 Gy/fr). The total course dose assuming *<sup>a</sup> <sup>b</sup>* ¼ 10 Gy for the tumor was equal to BED = 107.6 Gy and EQD2 = 89.7 Gy, which agreed with Refs. [2–7]. All patients received concomitant cisplatin chemotherapy weekly.

Different irradiation techniques were compared for dosimetric investigation. During the first stage of combined radiotherapy, we used conventional RT with 60Co, 3D-CRT using 10 MeV photons, and VMAT technique with 10 MeV photons. The second stage modalities included either HDR BT or VMAT with 10 MeV photons. The total dose values, as well as the fractionation regimen, were the same as during irradiation.

The OARs included bladder and rectum. The irradiation constraints are listed in **Table 1**. During the study, we assumed that *<sup>α</sup> <sup>β</sup>* <sup>¼</sup> 8 Gy for the bladder and *<sup>α</sup> <sup>β</sup>* ¼ 3*:*9 Gy for the rectum [11]. The data were taken from the QUANTEC protocols [23, 24], RTOG 0415 [25], GYN GES ESTRO [4], and other recommendations.


#### **Table 1.**

*The tolerant levels of critical organs for all radiotherapy courses which include EBRT and BT or only the EBRT for two stages based on QUANTEC [23, 24], RTOG 0415 [25], GYN GES ESTRO [4], and other recommendations [26].*

The data in **Table 1** are presented as Vx < y%, which means that the organ volume equal to y% of the total volume should not receive a dose greater than x Gy EQD2. Late third-grade radiation reactions are possible for the bladder if each of these levels is exceeded. For the rectum, second-grade (<15%) and third-grade reactions (<10%) are possible if the levels are exceeded [23, 24]. The data presented in **Table 1** for EBRT are taken from the statistics of radiation complications obtained during the treatment of prostate carcinomas. Because EBRT is widely used to treat this disease, we used these data, while we found no data for EBRT used along with treatment of cervical cancer due to the extremely rare use of EBRT for the second stage of combined radiotherapy.

#### **2.1 The first-stage EBRT**

Patient data for the first stage EBRT were obtained using the CT Toshiba Aquilion (Toshiba, Japan). The scanning step was equal to 3 mm. Patients were in the supine position due to the better immobilization possible [2–5]. A contrast substance was used during topometric preparation for the better identification of structures of interest: vessels, involved lymph nodes, tumor, bowel, bladder, and vagina. The rectosigmoid and the bladder were treated according to international recommendations [2–5] to minimize internal motion and ensure reproducibility during dose planning and treatment.

From **Table 2**, one can see that, as expected, the use of a more complex and higher gradient dose delivery technique (VMAT) leads to an increase in the irradiation of the tumor and the regional-iliac lymph nodes. The VMAT method allows reaching the level of coverage of 95% of the prescribed dose delivered in 97% of the irradiation volume, which can be considered a very good indicator of the coverage uniformity. It should be noted, however, that even the use of a conventional RT 60Co on a gamma device allows one to confidently exceed the coverage level of 90% of the prescribed dose delivered to 90% of the irradiation volume, ensuring even the level of 90% of the dose to 97.9% of the volume. At the same time, for 95% of the prescribed dose, the average irradiated volume is 89%, which should also be recognized as a good result for the conventional 60Co technique. The 3D-CRT technique allows obtaining a coverage level of 95–95%, which fully satisfies the prescription.

**Dose, % 60Co, V% 3D-CRT, V% VMAT, V%** 97.9 [96.9–99.0] 99.2 [99.0–99.4] 98.8 [98.4–99.2] 89.0 [85.6–92.3] 95.7 [95.2–96.2] 97.0 [96.1–97.9] 72.7 [64.0–81.4] 87.2 [85.3–89.0] 93.5 [91.5–95.5] 62.1 [50.8–73.4] 81.5 [78.5–84.4] 90.4 [87.0–93.7] 47.9 [34.8–60.9] 71.8 [66.5–77.1] 84.5 [78.9–90.1] 0 [0–0] 0 [0–0] 1.5 [0–4.4]

*Dosimetric and Radiobiological Evaluation of Combined Radiotherapy of Cervical Cancer Based…*

To prepare for HDR BT, the patients were scanned using the CT scanner in a supine position with inserted Manchester-type CT-compatible implants (rigid direct central intrauterine endostat and two rigid lateral intrauterine endostats with

CT scans give poor visualization of the tumor, which is why the whole uterus (whole cervix) was chosen as CTV for BT (CTV-B). No additional safety margins are needed to take into account internal movement during BT because the applicator moves together with the CTV [2–5]. Although there are some uncertainties for setup (applicator reconstruction), these seem to be rather negligible, if the systematic error can be kept below 2 mm and the slice thickness below 5 mm (random error) [3]. In the present study, we assumed that no margins should be added to

For compensation of possible changes of target and OAR localization with respect to the position of the applicator, each BT implant insertion was followed by

The treatment planning goal for HDR BT was prescribed to deliver more than 90% of the dose to 90% of the volume (D90% ≥ V90%). DVHs were used for the

The dose limitations to OARs were set for the bladder and rectum according to the limits listed in **Table 1**. The whole organs were contoured based on CT images

For OAR, it was important to specify the position of the hot spots in the bladder (D2cc) because this small volume may have an impact on the clinical outcome, and

a new CT study with the applicator in situ and a new dose plan calculation. Contouring for both CTV and OARs was performed for each insertion/implant of

**2.2 HDR for the second stage**

*PTV-TN dose coverage for the first stage of combined RT.*

*DOI: http://dx.doi.org/10.5772/intechopen.89734*

**Table 2.**

ovoid) that were sufficiently fixed.

CTV-B, resulting in CTV-B = PTV-B.

analysis of the planning results.

without division on parts.

BT applicators.

**87**

Because of the use of CT, only the CTV-T included the whole uterus. The PTV-T safety margin was approximately equal to 10 mm to ensure full coverage of the CTV during treatment course [2–5].

The pelvic lymph node (CTV-N) region included parametrial, para-rectal, internal iliac, external iliac, presacral, and iliaca communis. PTV-N included CTV-N plus an additional 10 mm margin. In the case of anatomical barriers such as the bone or uninvolved muscle/fascia, a smaller margin value was used [2–5].

PTV-T and PTV-N were joined to PTV-TN, and the prescription was defined for PTV-TN as follows: D95 ≥ V95% and D107 ≤ V2%. The average volumes amounted to CTV-T = 198 120 cm3 , PTV-T = 475 180 cm3 , CTV-N = 334 140 cm3 , and PTV-TN = 1323 300 cm3 .

The first-stage EBRT dosimetric treatment planning was carried out in the XIO dosimetry planning system (version 5.1, Elekta AB) using the conventional RT 60Co with Theratron Equinox 100 gamma apparatus and 3D-CRT technique at the Elekta Synergy linac at 10 MeV. Dosimetric planning of conventional RT 60Co and 3D-CRT was carried out using the superposition calculation algorithm based on modified four-field irradiation. For conventional RT, lateral irradiation on the right and left was complemented by the "field-in-field" irradiation technique and the distribution of weight dose loads to improve the target coverage. For 3D-CRT, the upper and lower fields were divided into subfields with turns at gantry angles of 340° and 20° to reduce the radiation load on the OARs while keeping an acceptable level of target coverage.

The first-stage EBRT dosimetric treatment planning based on the VMAT technique was carried out using the Monaco dosimetric planning system (v. 5.10.04, Elekta) at the Elekta Synergy linac at 10 MeV. For the VMAT technique, the inverse algorithms based on the Monte Carlo method were used. The dose delivery was realized using three full arches. The grid step was 0.3 cm, the minimum width of the segment was 1 cm, and the uncertainty of the entire calculation was 0.8% during the dose simulation.

In **Table 2**, one can see the results of dosimetric planning of the first-stage EBRT averaged over all patients.

*Dosimetric and Radiobiological Evaluation of Combined Radiotherapy of Cervical Cancer Based… DOI: http://dx.doi.org/10.5772/intechopen.89734*


**Table 2.**

The data in **Table 1** are presented as Vx < y%, which means that the organ volume equal to y% of the total volume should not receive a dose greater than x Gy EQD2. Late third-grade radiation reactions are possible for the bladder if each of these levels is exceeded. For the rectum, second-grade (<15%) and third-grade reactions (<10%) are possible if the levels are exceeded [23, 24]. The data

presented in **Table 1** for EBRT are taken from the statistics of radiation complications obtained during the treatment of prostate carcinomas. Because EBRT is widely used to treat this disease, we used these data, while we found no data for EBRT used along with treatment of cervical cancer due to the extremely rare use of EBRT for

Patient data for the first stage EBRT were obtained using the CT Toshiba Aquilion (Toshiba, Japan). The scanning step was equal to 3 mm. Patients were in the supine position due to the better immobilization possible [2–5]. A contrast substance was used during topometric preparation for the better identification of structures of interest: vessels, involved lymph nodes, tumor, bowel, bladder, and vagina. The rectosigmoid and the bladder were treated according to international recommendations [2–5] to minimize internal motion and ensure reproducibility

Because of the use of CT, only the CTV-T included the whole uterus. The PTV-T safety margin was approximately equal to 10 mm to ensure full coverage of the CTV

PTV-T and PTV-N were joined to PTV-TN, and the prescription was defined for PTV-TN as follows: D95 ≥ V95% and D107 ≤ V2%. The average volumes amounted

The first-stage EBRT dosimetric treatment planning was carried out in the XIO dosimetry planning system (version 5.1, Elekta AB) using the conventional RT 60Co with Theratron Equinox 100 gamma apparatus and 3D-CRT technique at the Elekta Synergy linac at 10 MeV. Dosimetric planning of conventional RT 60Co and 3D-CRT was carried out using the superposition calculation algorithm based on modified four-field irradiation. For conventional RT, lateral irradiation on the right and left was complemented by the "field-in-field" irradiation technique and the distribution of weight dose loads to improve the target coverage. For 3D-CRT, the upper and lower fields were divided into subfields with turns at gantry angles of 340° and 20° to reduce the radiation load on the OARs while keeping an acceptable level of target

The first-stage EBRT dosimetric treatment planning based on the VMAT technique was carried out using the Monaco dosimetric planning system (v. 5.10.04, Elekta) at the Elekta Synergy linac at 10 MeV. For the VMAT technique, the inverse algorithms based on the Monte Carlo method were used. The dose delivery was realized using three full arches. The grid step was 0.3 cm, the minimum width of the segment was 1 cm, and the uncertainty of the entire calculation was 0.8% during the

In **Table 2**, one can see the results of dosimetric planning of the first-stage EBRT

, CTV-N = 334 140 cm3

, and

The pelvic lymph node (CTV-N) region included parametrial, para-rectal, internal iliac, external iliac, presacral, and iliaca communis. PTV-N included CTV-N plus an additional 10 mm margin. In the case of anatomical barriers such as the bone

, PTV-T = 475 180 cm3

or uninvolved muscle/fascia, a smaller margin value was used [2–5].

.

the second stage of combined radiotherapy.

*Gynaecological Malignancies - Updates and Advances*

during dose planning and treatment.

during treatment course [2–5].

to CTV-T = 198 120 cm3

PTV-TN = 1323 300 cm3

coverage.

dose simulation.

**86**

averaged over all patients.

**2.1 The first-stage EBRT**

*PTV-TN dose coverage for the first stage of combined RT.*

From **Table 2**, one can see that, as expected, the use of a more complex and higher gradient dose delivery technique (VMAT) leads to an increase in the irradiation of the tumor and the regional-iliac lymph nodes. The VMAT method allows reaching the level of coverage of 95% of the prescribed dose delivered in 97% of the irradiation volume, which can be considered a very good indicator of the coverage uniformity. It should be noted, however, that even the use of a conventional RT 60Co on a gamma device allows one to confidently exceed the coverage level of 90% of the prescribed dose delivered to 90% of the irradiation volume, ensuring even the level of 90% of the dose to 97.9% of the volume. At the same time, for 95% of the prescribed dose, the average irradiated volume is 89%, which should also be recognized as a good result for the conventional 60Co technique. The 3D-CRT technique allows obtaining a coverage level of 95–95%, which fully satisfies the prescription.

#### **2.2 HDR for the second stage**

To prepare for HDR BT, the patients were scanned using the CT scanner in a supine position with inserted Manchester-type CT-compatible implants (rigid direct central intrauterine endostat and two rigid lateral intrauterine endostats with ovoid) that were sufficiently fixed.

CT scans give poor visualization of the tumor, which is why the whole uterus (whole cervix) was chosen as CTV for BT (CTV-B). No additional safety margins are needed to take into account internal movement during BT because the applicator moves together with the CTV [2–5]. Although there are some uncertainties for setup (applicator reconstruction), these seem to be rather negligible, if the systematic error can be kept below 2 mm and the slice thickness below 5 mm (random error) [3]. In the present study, we assumed that no margins should be added to CTV-B, resulting in CTV-B = PTV-B.

For compensation of possible changes of target and OAR localization with respect to the position of the applicator, each BT implant insertion was followed by a new CT study with the applicator in situ and a new dose plan calculation. Contouring for both CTV and OARs was performed for each insertion/implant of BT applicators.

The treatment planning goal for HDR BT was prescribed to deliver more than 90% of the dose to 90% of the volume (D90% ≥ V90%). DVHs were used for the analysis of the planning results.

The dose limitations to OARs were set for the bladder and rectum according to the limits listed in **Table 1**. The whole organs were contoured based on CT images without division on parts.

For OAR, it was important to specify the position of the hot spots in the bladder (D2cc) because this small volume may have an impact on the clinical outcome, and

so delineation of full organs based on CT images and dose was estimated in any location whose accordance did not exceed the tolerance level (see **Table 1**).

The dosimetric planning of the HDR BT of the second stage was carried out using the HDRplus 3D BT dose-planning system (version 3.4) for the MultiSource HDR apparatus with 60Co source (Bebig, Germany).

combined therapy in the EBRT + VMAT format, the EQD2 DVHs from the EBRT

*Dosimetric and Radiobiological Evaluation of Combined Radiotherapy of Cervical Cancer Based…*

**Figure 1** shows examples of the planned dose distribution for the first and

Let us further consider the results of the total combined RT course. **Figure 1** shows an example of DVHs for CTV-T, for one of the patients. **Figure 2** shows all considered irradiation combinations (3D-CRT + HDR-BT, 60Co + VMAT,

In **Figure 2**, one can see that with the use of HDR BT, the dose distribution over the target volume is nonuniform, i.e., there are proportions of the volume of radia-

**Table 3** shows the resulting dose coverage for the total treatment course as the

From **Table 3**, one can see that combined RT based on HDR BT results in 90% of prescribed dose delivered to 95.9% of the target volume, which is a rather good result. However, HDR BT results in irradiation of the significant target volumes by doses that are significantly higher than the prescribed dose. In this case, 150–200% of the prescribed dose was delivered to 44.6 and 19.7% of the volume, respectively. The use of VMAT as the second stage of the combined RT significantly improves the situation. Regardless of the dose delivery technique used during the first stage dose, 95% of the prescribed dose is delivered to 97% of the volume. The hot spots do not exceed 110% of the prescribed dose delivered in less than 9% of the volume for the VMAT + VMAT combination. It should be noted that even the use of the conventional RT based on 60Co in combination with VMAT allows one to achieve

**Figure 3** shows examples of bladder and rectum DVHs in the case of the VMAT technique used as the second stage of combined RT. Statistical data on the irradiation of critical organs are given in **Table 4** for the bladder and in **Table 5** for the

From **Table 4**, one can see that the dose load on the bladder using 60Co + VMAT or VMAT + VMAT combinations allows meeting the tolerant levels, avoiding thirddegree radiation complications (see **Table 1**). For the combination of 3D-CRT + VMAT, there is a slight exceeding of the tolerant levels for the dose levels of 65 Gy and 70 Gy. This dose overload is caused by the high level of the dose coverage during the first stage when 95% of the prescribed dose was delivered to 95% of the volume (see **Table 2**). In the case of conventional irradiation, the dose load meets the tolerant levels because the first-stage dose coverage is lower than the 95–95% prescription. The use of VMAT techniques reduces the dose loads due to modula-

According to the criterion of the maximum dose delivered to the volume of 2 cm3 of the bladder, all the methods of dose delivery meet the constraints, although the best result was obtained with the use of HDR BT. When using VMAT + VMAT technology, there are individual cases exceeding the tolerant dose of 90 Gy per 2 cm3 volume, which is caused by escalation of the dose in the target. In this case, it is difficult to judge whether this will lead to radiation complications because the irradiation levels of parts of the bladder do not exceed the tolerant levels of QUANTEC. **Table 5** shows the radiation loads on the rectum for the different combinations of dose delivery techniques. From **Table 5**, one can see that the use of the VMAT +

VMAT combination does not exceed the tolerance levels established by the

and VMAT course were summed up for CTV-T and OARs.

tion that receive doses substantially higher than prescribed.

mean value obtained for 11 patients and a confidence interval [27].

**3. Results and discussion**

second stages of combined radiotherapy.

*DOI: http://dx.doi.org/10.5772/intechopen.89734*

3D-CRT + VMAT, VMAT + VMAT).

such a high level of target coverage.

tion of the radiation intensity.

rectum.

**89**

During the planning procedure, the implant was carefully reconstructed, and the conventional standard loading pattern matching the prescribed dose to point A was applied. From this starting point, dose optimization was performed with the goal of adapting the dose to the CTV-B. The optimization of CTV-B dose coverage and OAR dose constraints was carried out using the following steps:


There is the task of summation of the doses from the first-stage EBRT and the second-stage HDR BT. This was done based on the assumptions given by GYN GEC ESTRO recommendation [3]. According to Ref. [3], it is assumed that CTV and OARs receive the full dose from the EBRT course. Thus, it was assumed that the dose in the small volumes of interest for BT (anterior-lateral walls of the rectum and sigmoid, posterior-inferior wall of the bladder, and wall of the vagina adjacent to macroscopic disease) receives the EBRT prescribed dose for CTV-T and CTV-N.

#### **2.3 VMAT for the second stage**

The VMAT technique with three full arches was used as EBRT of the second stage. The dosimetric planning was carried out using the same CT scans as for the first-stage EBRT because no specific patient scanning was done after the first-stage EBRT. The PTV tumor for the second stage was assumed to be equal to CTV-T of the first stage plus 5 mm safety margin. In our opinion, it is sufficient estimation, taking into account the fact that the tumor shrinks after the first-stage EBRT.

The second-stage VMAT dosimetric planning was carried out using the Monaco dosimetric planning system (v. 5.10.04, Elekta) at the Elekta Synergy linac at 10 MeV. For the VMAT technique, the inverse algorithms based on the Monte Carlo method were used. The dose delivery was realized using three full arches. The grid step was 0.3 cm, the minimum width of the segment was 1 cm, and the uncertainty of the entire calculation was 0.8% during the dose simulation.

#### **2.4 Summation of the first- and second-stage results**

When planning a combined RT in the EBRT + BT format, the question of DVH summation arises because the DVHs were calculated by different planning systems that are completely incompatible. Therefore, we assumed that during the first stage, the CTV-T was irradiated uniformly up to the prescribed dose of 50 Gy. The DVH from the second-stage HDR BT was added to that dose value [2–6]. The damage to the OARs was assessed by the criterion of the total EQD2 delivered to 2 cm3 from both courses of EBRT and HDR BT because the summation of DVHs for OARs is illegal because of OAR shape changes while inserting the implants [2–5, 18]. For

*Dosimetric and Radiobiological Evaluation of Combined Radiotherapy of Cervical Cancer Based… DOI: http://dx.doi.org/10.5772/intechopen.89734*

combined therapy in the EBRT + VMAT format, the EQD2 DVHs from the EBRT and VMAT course were summed up for CTV-T and OARs.

#### **3. Results and discussion**

so delineation of full organs based on CT images and dose was estimated in any location whose accordance did not exceed the tolerance level (see **Table 1**). The dosimetric planning of the HDR BT of the second stage was carried out using the HDRplus 3D BT dose-planning system (version 3.4) for the MultiSource

During the planning procedure, the implant was carefully reconstructed, and the conventional standard loading pattern matching the prescribed dose to point A was applied. From this starting point, dose optimization was performed with the goal of adapting the dose to the CTV-B. The optimization of CTV-B dose coverage and

• Graphical optimization ("dose shaping") combined with manual verification and adjustments for unnecessarily large deviations from standard loading

There is the task of summation of the doses from the first-stage EBRT and the second-stage HDR BT. This was done based on the assumptions given by GYN GEC ESTRO recommendation [3]. According to Ref. [3], it is assumed that CTV and OARs receive the full dose from the EBRT course. Thus, it was assumed that the dose in the small volumes of interest for BT (anterior-lateral walls of the rectum and sigmoid, posterior-inferior wall of the bladder, and wall of the vagina adjacent to macroscopic disease) receives the EBRT prescribed dose for CTV-T and CTV-N.

The VMAT technique with three full arches was used as EBRT of the second stage. The dosimetric planning was carried out using the same CT scans as for the first-stage EBRT because no specific patient scanning was done after the first-stage EBRT. The PTV tumor for the second stage was assumed to be equal to CTV-T of the first stage plus 5 mm safety margin. In our opinion, it is sufficient estimation, taking into account the fact that the tumor shrinks after the first-stage EBRT.

The second-stage VMAT dosimetric planning was carried out using the Monaco

When planning a combined RT in the EBRT + BT format, the question of DVH summation arises because the DVHs were calculated by different planning systems that are completely incompatible. Therefore, we assumed that during the first stage, the CTV-T was irradiated uniformly up to the prescribed dose of 50 Gy. The DVH from the second-stage HDR BT was added to that dose value [2–6]. The damage to the OARs was assessed by the criterion of the total EQD2 delivered to 2 cm3 from both courses of EBRT and HDR BT because the summation of DVHs for OARs is illegal because of OAR shape changes while inserting the implants [2–5, 18]. For

dosimetric planning system (v. 5.10.04, Elekta) at the Elekta Synergy linac at 10 MeV. For the VMAT technique, the inverse algorithms based on the Monte Carlo method were used. The dose delivery was realized using three full arches. The grid step was 0.3 cm, the minimum width of the segment was 1 cm, and the uncertainty

of the entire calculation was 0.8% during the dose simulation.

**2.4 Summation of the first- and second-stage results**

HDR apparatus with 60Co source (Bebig, Germany).

*Gynaecological Malignancies - Updates and Advances*

• Dose point optimization

**2.3 VMAT for the second stage**

patterns

**88**

OAR dose constraints was carried out using the following steps:

• Manual dwell time or dwell weight optimization

**Figure 1** shows examples of the planned dose distribution for the first and second stages of combined radiotherapy.

Let us further consider the results of the total combined RT course. **Figure 1** shows an example of DVHs for CTV-T, for one of the patients. **Figure 2** shows all considered irradiation combinations (3D-CRT + HDR-BT, 60Co + VMAT, 3D-CRT + VMAT, VMAT + VMAT).

In **Figure 2**, one can see that with the use of HDR BT, the dose distribution over the target volume is nonuniform, i.e., there are proportions of the volume of radiation that receive doses substantially higher than prescribed.

**Table 3** shows the resulting dose coverage for the total treatment course as the mean value obtained for 11 patients and a confidence interval [27].

From **Table 3**, one can see that combined RT based on HDR BT results in 90% of prescribed dose delivered to 95.9% of the target volume, which is a rather good result. However, HDR BT results in irradiation of the significant target volumes by doses that are significantly higher than the prescribed dose. In this case, 150–200% of the prescribed dose was delivered to 44.6 and 19.7% of the volume, respectively.

The use of VMAT as the second stage of the combined RT significantly improves the situation. Regardless of the dose delivery technique used during the first stage dose, 95% of the prescribed dose is delivered to 97% of the volume. The hot spots do not exceed 110% of the prescribed dose delivered in less than 9% of the volume for the VMAT + VMAT combination. It should be noted that even the use of the conventional RT based on 60Co in combination with VMAT allows one to achieve such a high level of target coverage.

**Figure 3** shows examples of bladder and rectum DVHs in the case of the VMAT technique used as the second stage of combined RT. Statistical data on the irradiation of critical organs are given in **Table 4** for the bladder and in **Table 5** for the rectum.

From **Table 4**, one can see that the dose load on the bladder using 60Co + VMAT or VMAT + VMAT combinations allows meeting the tolerant levels, avoiding thirddegree radiation complications (see **Table 1**). For the combination of 3D-CRT + VMAT, there is a slight exceeding of the tolerant levels for the dose levels of 65 Gy and 70 Gy. This dose overload is caused by the high level of the dose coverage during the first stage when 95% of the prescribed dose was delivered to 95% of the volume (see **Table 2**). In the case of conventional irradiation, the dose load meets the tolerant levels because the first-stage dose coverage is lower than the 95–95% prescription. The use of VMAT techniques reduces the dose loads due to modulation of the radiation intensity.

According to the criterion of the maximum dose delivered to the volume of 2 cm3 of the bladder, all the methods of dose delivery meet the constraints, although the best result was obtained with the use of HDR BT. When using VMAT + VMAT technology, there are individual cases exceeding the tolerant dose of 90 Gy per 2 cm3 volume, which is caused by escalation of the dose in the target. In this case, it is difficult to judge whether this will lead to radiation complications because the irradiation levels of parts of the bladder do not exceed the tolerant levels of QUANTEC.

**Table 5** shows the radiation loads on the rectum for the different combinations of dose delivery techniques. From **Table 5**, one can see that the use of the VMAT + VMAT combination does not exceed the tolerance levels established by the

#### **Figure 1.**

*Dose distributions of treatment plans: (a) 60Co, (b) 3D-CRT, (c) VMAT for the first stage, (d) VMAT for the second stage, and (e) HDR.*

QUANTEC protocol. In the case of 60Co + VMAT and 3D-CRT + VMAT combinations, there is an exceeding of tolerant levels. In these cases, 60 Gy EQD2 is delivered to more than 35% of the volume and 50 Gy EQD2 to more than 50%. This can lead to late second- and third-grade complications. Such results appear due to large irradiation volumes. During the first-stage irradiation, PTV is close to the anterior rectal wall, which leads to its irradiation. The use of the VMAT technique allows reducing the radiation load during the implementation of high-gradient plans. To reduce the exposure of the rectum, it is necessary to reduce the margin between

*Example of DVHs calculated for target volume for different variants of combined therapy at prescribed dose*

*Dosimetric and Radiobiological Evaluation of Combined Radiotherapy of Cervical Cancer Based…*

**3D-CRT + VMAT, volume %**

> 99.6 [99.4–99.8]

98.0 [97.4–98.5]

94.7 [93.3–96.0]

92.5 [90.6–94.4]

89.2 [86.6–91.8]

> 2.6 [1.2–4.1]

—— —

—— —

—— —

**VMAT+VMAT, volume %**

> 99.7 [99.6–99.8]

> 98.8 [98.4–99.3]

97.0 [96.1–97.9]

95.8 [94.6–97.0]

93.9 [92.2–95.5]

8.8 [5.4–12.1]

**60Co + VMAT, v %**

> 99.3 [98.9–99.6]

> 97.1 [96.1–98.0]

92.4 [90.4–94.3]

89.4 [86.8–91.9]

85.0 [81.4–88.7]

2.1 [0.9–3.4]

**Figure 2.**

*EQD2 = 89.7 Gy.*

**Dose, %**

90 95.9

95 91.8

98 88.8

99 87.7

100 86.7

110 75.7

150 44.6

200 27.4

250 19.7

**Table 3.**

**91**

**3D-CRT + BT, volume %**

*DOI: http://dx.doi.org/10.5772/intechopen.89734*

[94.8–96.9]

[90.5–93.2]

[87.2–90.3]

[86.1–89.4]

[85.0–88.4]

[73.3–78.2]

[41.8–47.4]

[25.2–29.6]

[17.7–21.6]

*Target coverage for different courses of combined RT.*

*Dosimetric and Radiobiological Evaluation of Combined Radiotherapy of Cervical Cancer Based… DOI: http://dx.doi.org/10.5772/intechopen.89734*

#### **Figure 2.**

*Example of DVHs calculated for target volume for different variants of combined therapy at prescribed dose EQD2 = 89.7 Gy.*


#### **Table 3.**

*Target coverage for different courses of combined RT.*

QUANTEC protocol. In the case of 60Co + VMAT and 3D-CRT + VMAT combinations, there is an exceeding of tolerant levels. In these cases, 60 Gy EQD2 is delivered to more than 35% of the volume and 50 Gy EQD2 to more than 50%. This can lead to late second- and third-grade complications. Such results appear due to large irradiation volumes. During the first-stage irradiation, PTV is close to the anterior rectal wall, which leads to its irradiation. The use of the VMAT technique allows reducing the radiation load during the implementation of high-gradient plans. To reduce the exposure of the rectum, it is necessary to reduce the margin between

**Figure 1.**

**90**

*second stage, and (e) HDR.*

*Gynaecological Malignancies - Updates and Advances*

*Dose distributions of treatment plans: (a) 60Co, (b) 3D-CRT, (c) VMAT for the first stage, (d) VMAT for the*

PTV-T and CTV-T for the displacement of organs, which requires fixing the position of the target, the rectum, and the stability of the filling of the bladder.

*Dosimetric and Radiobiological Evaluation of Combined Radiotherapy of Cervical Cancer Based…*

estimate.

increases.

**4. Conclusion**

**93**

ing the dose loads to OARs.

tolerant levels for all critical organs.

*DOI: http://dx.doi.org/10.5772/intechopen.89734*

of the patient after the first-stage irradiation.

In **Table 5**, one can see that there is no exceeding of the rectum tolerant level by 2 cm3 parameter for any combination of the techniques simulated. It should again be noted that the criterion of 2 cm3 has a much lower accuracy than the DVH

The combined RT for cervical cancer can be realized using different combinations of the first- and second-stage irradiation techniques. The efficiency of the total course can be analyzed using two parameters, which are dose coverage of the target (both tumor and nodes during the first stage) and the dose loads on the OARs. Thus, from the point of view of target coverage, the 60Co + VMAT and 3D-CRT + VMAT combinations are very similar because with 60Co + VMAT, coverage is 95% of the prescribed dose, 97.1% of the volume, and with 3D-CRT + VMAT, 95% of the dose, 98% of the volume. Unfortunately, the use of the gamma apparatus loses in the first stage of the combined RT because the coverage of the volume of PTV is only 95% of the dose—89% of the volume—and with 3D-CRT 95% of the dose, 95.1% of the volume. Despite this, it can be pointed out that using a gamma apparatus for EBRT can be effective for a combined RT when followed by VMAT, providing good coverage of the target with a 10–15% chance of late second- and third-grade complications to the rectum and bladder. When using the VMAT + VMAT combination, a coverage level of 98–97% is achieved without exceeding the

Obviously, the values of radiation loads will depend on the accuracy of contour creation for both the target and for critical organs, as well as the offset space used. Therefore, the results of irradiation substantially depend on the degree of immobilization of the patient, which includes maintaining the mutual position of the internal organs by introducing a Foley catheter, as well as minimizing and control-

The main advantage of using the VMAT technique for the second stage of combined RT is to simplify the treatment procedure, to reduce the painful sensations typical for BT in the process of topometric preparation and treatment, as well as to reduce the time of the irradiation session. When using VMAT technology, the radiotherapist's labor costs (no need for implants) are reduced, but the work of the topometrist (the need for more accurate contouring) and the medical physicist (more complex dosimetric planning and the need for dosimetry quality assurance)

One of the effective ways to implement the use of the VMAT technique for the second-stage irradiation is to use both CT and MRI for the topographic preparation

In the considered examples, it can be seen that the use of the VMAT dose delivery technique for the second stage of combined RT of cervical cancer allows a significant increase in the irradiation uniformity, to exclude overexposure of large volumes with high doses (more than 115% of the prescribed dose) and to deliver the prescribed dose to the target with a high coverage level (95.8% of the target volume can be irradiated with a dose higher than 99% of the prescribed dose), not exceed-

In Tomsk Regional Oncology Center, HDR brachytherapy is not fully equipped by implants of different types needed for effective treatment of the cervical cancer. Also we do not have the equipment for the gynecological interstitial brachytherapy

ling their displacement during breathing (e.g., abdominal press).

**Figure 3.** *Example of DVHs calculated for bladder and rectum for one of the patients.*


#### **Table 4.**

*Bladder dose loads for different courses of combined RT.*


#### **Table 5.**

*Rectum dose loads for different courses of combined RT.*

*Dosimetric and Radiobiological Evaluation of Combined Radiotherapy of Cervical Cancer Based… DOI: http://dx.doi.org/10.5772/intechopen.89734*

PTV-T and CTV-T for the displacement of organs, which requires fixing the position of the target, the rectum, and the stability of the filling of the bladder.

In **Table 5**, one can see that there is no exceeding of the rectum tolerant level by 2 cm3 parameter for any combination of the techniques simulated. It should again be noted that the criterion of 2 cm3 has a much lower accuracy than the DVH estimate.

The combined RT for cervical cancer can be realized using different combinations of the first- and second-stage irradiation techniques. The efficiency of the total course can be analyzed using two parameters, which are dose coverage of the target (both tumor and nodes during the first stage) and the dose loads on the OARs.

Thus, from the point of view of target coverage, the 60Co + VMAT and 3D-CRT + VMAT combinations are very similar because with 60Co + VMAT, coverage is 95% of the prescribed dose, 97.1% of the volume, and with 3D-CRT + VMAT, 95% of the dose, 98% of the volume. Unfortunately, the use of the gamma apparatus loses in the first stage of the combined RT because the coverage of the volume of PTV is only 95% of the dose—89% of the volume—and with 3D-CRT 95% of the dose, 95.1% of the volume. Despite this, it can be pointed out that using a gamma apparatus for EBRT can be effective for a combined RT when followed by VMAT, providing good coverage of the target with a 10–15% chance of late second- and third-grade complications to the rectum and bladder. When using the VMAT + VMAT combination, a coverage level of 98–97% is achieved without exceeding the tolerant levels for all critical organs.

Obviously, the values of radiation loads will depend on the accuracy of contour creation for both the target and for critical organs, as well as the offset space used. Therefore, the results of irradiation substantially depend on the degree of immobilization of the patient, which includes maintaining the mutual position of the internal organs by introducing a Foley catheter, as well as minimizing and controlling their displacement during breathing (e.g., abdominal press).

The main advantage of using the VMAT technique for the second stage of combined RT is to simplify the treatment procedure, to reduce the painful sensations typical for BT in the process of topometric preparation and treatment, as well as to reduce the time of the irradiation session. When using VMAT technology, the radiotherapist's labor costs (no need for implants) are reduced, but the work of the topometrist (the need for more accurate contouring) and the medical physicist (more complex dosimetric planning and the need for dosimetry quality assurance) increases.

One of the effective ways to implement the use of the VMAT technique for the second-stage irradiation is to use both CT and MRI for the topographic preparation of the patient after the first-stage irradiation.

#### **4. Conclusion**

**Figure 3.**

**EQD2/volume % QUANTEC**

2 cm<sup>3</sup> < 90 Gy EQD2

**EQD2/volume % QUANTEC**

**Table 4.**

**Table 5.**

**92**

*Example of DVHs calculated for bladder and rectum for one of the patients.*

**60Co + VMAT, volume %**

[7.1–17.0]

[13.6–25.9]

[22.1–36.1]

[31.4–49.5]

60Co + VMAT, EQD2, Gy

87.2 [84.4–90.0]

**60Co + VMAT, volume %**

[0.9–4.3]

[3.9–15.0]

[12.4–33.3]

[30.1–54.2]

[67.9–86.8]

60Co + VMAT, EQD2, Gy

> 71.9 [69.5–74.4]

**3D-CRT + VMAT, volume %**

> 12.7 [7.4–18.0]

23.3 [15.3–31.4]

37.0 [26.5–47.5]

52.3 [41.4–63.2]

3D-CRT + VMAT, EQD2, Gy

> 87.7 [85.0–90.4]

**3D-CRT + VMAT, volume %**

> 2.5 [0.9–4.0]

8.5 [3.3–13.7]

20.3 [9.8–30.7]

38.4 [25.5–51.3]

73.3 [65.0–81.7]

3D-CRT + VMAT, EQD2, Gy

> 72.4 [69.9–74.9]

**VMAT+VMAT, volume %**

> 11.8 [7.0–16.6]

18.6 [12.5–24.7]

26.0 [19.1–32.8]

33.5 [26.2–40.8]

VMAT+VMAT, EQD2, Gy

> 88.9 [85.8–92.2]

**VMAT+VMAT, volume %**

> 2.1 [1.2–3.0]

6 [3.4–8.6]

13.2 [7.8–18.5]

22.6 [15.4–29.9]

44.3 [35.4–53.1]

VMAT+VMAT, EQD2, Gy

> 71.5 [69.3–73.7]

**3D-CRT + BT, volume %**

80 Gy/15% — 12.1

*Gynaecological Malignancies - Updates and Advances*

75 Gy/25% — 19.7

70 Gy/35% — 29.1

65 Gy/50% — 40.4

*Bladder dose loads for different courses of combined RT.*

75 Gy/15% — 2.6

70 Gy/20% — 9.4

65 Gy/25% — 22.3

60 Gy/ 35% — 42.1

50 Gy/ 50% — 77.3

*Rectum dose loads for different courses of combined RT.*

EQD2, Gy

[67.1–74.7]

Volume 3D-CRT + BT,

2 cm<sup>3</sup> < 75 Гр EQD2 70.9

EQD2, Gy

82.2 [74.6–89.8]

**3D-CRT + BT, volume %**

Volume 3D-CRT + BT,

In the considered examples, it can be seen that the use of the VMAT dose delivery technique for the second stage of combined RT of cervical cancer allows a significant increase in the irradiation uniformity, to exclude overexposure of large volumes with high doses (more than 115% of the prescribed dose) and to deliver the prescribed dose to the target with a high coverage level (95.8% of the target volume can be irradiated with a dose higher than 99% of the prescribed dose), not exceeding the dose loads to OARs.

In Tomsk Regional Oncology Center, HDR brachytherapy is not fully equipped by implants of different types needed for effective treatment of the cervical cancer. Also we do not have the equipment for the gynecological interstitial brachytherapy

that significantly limits our possibilities. At the same time, Tomsk Regional Oncology Center has good competences in the EBRT VMAT treatment planning, QA, and delivery. The results of presented study show that the VMAT dose delivery could be effective enough to replace HDR brachytherapy in some case.

**References**

[1] Kravchenko GR, Zharov AV, Vazhenin AV, et al. Results of

2009;**33**(3):20-23. Russian

**33**(2):10-17. Russian

22 July 2019]

[2] Kravets OA, Andreeva YV, Kozlov OV, Nechushkin MI. Clinical and radiobiological planning of brachytherapy of locally advanced cervical cancer. Medical Physics. 2009;

multicomponent treatment of patients with locally advanced forms of cervical cancer. Siberian Oncological Journal.

*DOI: http://dx.doi.org/10.5772/intechopen.89734*

[8] Bucci МК, Bevan A, Roach М. Advances in radiation therapy:

PMID: 15761080

*Dosimetric and Radiobiological Evaluation of Combined Radiotherapy of Cervical Cancer Based…*

Conventional to 3D, to IMRT, to 4D and beyond. CA: A Cancer Journal for Clinicians. 2005;**55**(2):117-134. PubMed

[9] Roeske JC, Lujan A, Rotmensch J, Waggoner SE, Yamada D, Mundt AJ. Intensity-modulated whole pelvic radiation therapy in patients with gynecologic malignancies. International Journal of Radiation Oncology, Biology,

Physics. 2000;**48**(5):1613-1621

[10] Chernyaev AP, Popodko AI, Lykova EN. Medical Equipment in the Modern Radiotherapy. Moscow, Russian: MSU Physical Faculty Publishing; 2019. 101 p

[11] Roitberg GE, Usychkin SV,

[12] Ghandour S, Matzinger O,

**61**(1):47-59. Russian

Boyko AV. Large-scale remote radiation therapy for prostate cancer. Medical Radiology and Radiation Safety. 2016;

Pachouda M. Volumetric-modulated arc therapy planning using multicriteria optimization for localized prostate cancer. Journal of Applied Clinical Medical Physics. 2015;**16**(3):258-269. DOI: 10.1120/jacmp.v16i3.5410

[13] Rodríguez Villalba S, Planell CD, Grau JM. Current opinion in cervix carcinoma. Clinical and Translational Oncology. 2011;**13**:378-384. DOI: 10.1007/s12094-011-0671-4

[14] Chan P, Yeo I, Perkins G, Fyles A, Milosevic M. Dosimetric comparison of intensity-modulated, conformal, and four-field pelvic radiotherapy boost plans for gynecologic cancer: A retrospective planning study. Radiation Oncology. 2006;**1**:13. DOI: 10.1186/1748-717X-1-13

[15] Cozzia L, Dinshawc KA, Shrivastavac SK, Mahantshettyc U,

[3] A European Study on MRI-Guided Brachytherapy in Locally Advanced Cervical Cancer EMBRACE. 2009. Available from: https://www.embrace study.dk/UserUpload/PublicDocume nts/EmbraceProtocol.pdf [Accessed:

[4] Hellebust TA, Kirisits C, Berger D. Recommendations for gynaecological (GYN) GEC ESTRO working group: Considerations and pitfalls in commissioning and applicator reconstruction in 3D image-based treatment planning of cervix cancer brachytherapy. Radiotherapy and Oncology. 2010;**96**(2):153-160. DOI: 10.1016/j.radonc.2010.06.004

[5] Kravets OA, Kozlov OV,

[6] Banerjee R, Kamrava M.

Women's Health. 2014;**6**:555-564

10.1016/j.brachy.2011.07.002

**95**

Fedyanina AA, et al. Methodical aspects of contact radiation therapy of cervical cancer using 3D-planning. Medical Physics. 2017;**73**(1):16-24. Russian

Brachytherapy in the treatment of cervical cancer: A review. International Journal of

[7] Vishwanathan AN, Beriwal S, De Los Santos JF. American brachytherapy society consensus guidelines for locally advanced carcinoma of the cervix. Part II: High-dose-rate brachytherapy. Brachytherapy. 2012;**11**(1):47-52. DOI:

There are different patients that could benefit from the change of HDR BT to VMAT. These are the patients with challenging cervical dilation, perforation risk, patients with asymmetric tumor invasion, and patients with personal reasons to avoid the BT procedure.

The results of this study that have shown the technical possibility of HDR BT replacement were the basis to start this method in the clinical practice. These days, five patients are treated with VMAT for the second stage of combined radiotherapy with cisplatin chemotherapy. The patients chosen have intolerance to procedure, asymmetric tumor invasion, and religious contradictions to the intracavitary BT.

Due to the focus of the present study on the dosimetric and radiobiological evaluation of the radiotherapy using different dose delivery techniques, we cannot discuss the advantages of the different treatment methods that include surgery, adjuvant or neoadjuvant therapy, etc. These treatment modalities should be carefully examined for each patient. In the case when RT can be performed, the HDR BT could be examined to the possibility to be replaced by the VMAT technique. In this case, it does not matter which treatment modality is used, postsurgery + EBRT, chemotherapy + EBRT, etc.

#### **Author details**

Evgeniia Sergeevna Sukhikh1,2\* and Leonid Grigorievich Sukhikh2

1 Medical Physics Department, Tomsk Regional Oncology Centre, Tomsk, Russia

2 Research School of Physics of High-Energy Processes, Tomsk Polytechnic University, Tomsk, Russia

\*Address all correspondence to: e.s.sukhikh@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Dosimetric and Radiobiological Evaluation of Combined Radiotherapy of Cervical Cancer Based… DOI: http://dx.doi.org/10.5772/intechopen.89734*

#### **References**

that significantly limits our possibilities. At the same time, Tomsk Regional Oncology Center has good competences in the EBRT VMAT treatment planning, QA, and delivery. The results of presented study show that the VMAT dose delivery could be

There are different patients that could benefit from the change of HDR BT to VMAT. These are the patients with challenging cervical dilation, perforation risk, patients with asymmetric tumor invasion, and patients with personal reasons to

The results of this study that have shown the technical possibility of HDR BT replacement were the basis to start this method in the clinical practice. These days, five patients are treated with VMAT for the second stage of combined radiotherapy with cisplatin chemotherapy. The patients chosen have intolerance to procedure, asymmetric tumor invasion, and religious contradictions to the intracavitary BT. Due to the focus of the present study on the dosimetric and radiobiological evaluation of the radiotherapy using different dose delivery techniques, we cannot discuss the advantages of the different treatment methods that include surgery, adjuvant or neoadjuvant therapy, etc. These treatment modalities should be carefully examined for each patient. In the case when RT can be performed, the HDR BT could be examined to the possibility to be replaced by the VMAT technique. In this case, it does not matter which treatment modality is used, postsurgery + EBRT,

effective enough to replace HDR brachytherapy in some case.

*Gynaecological Malignancies - Updates and Advances*

Evgeniia Sergeevna Sukhikh1,2\* and Leonid Grigorievich Sukhikh2

\*Address all correspondence to: e.s.sukhikh@gmail.com

provided the original work is properly cited.

1 Medical Physics Department, Tomsk Regional Oncology Centre, Tomsk, Russia

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Research School of Physics of High-Energy Processes, Tomsk Polytechnic

avoid the BT procedure.

chemotherapy + EBRT, etc.

**Author details**

**94**

University, Tomsk, Russia

[1] Kravchenko GR, Zharov AV, Vazhenin AV, et al. Results of multicomponent treatment of patients with locally advanced forms of cervical cancer. Siberian Oncological Journal. 2009;**33**(3):20-23. Russian

[2] Kravets OA, Andreeva YV, Kozlov OV, Nechushkin MI. Clinical and radiobiological planning of brachytherapy of locally advanced cervical cancer. Medical Physics. 2009; **33**(2):10-17. Russian

[3] A European Study on MRI-Guided Brachytherapy in Locally Advanced Cervical Cancer EMBRACE. 2009. Available from: https://www.embrace study.dk/UserUpload/PublicDocume nts/EmbraceProtocol.pdf [Accessed: 22 July 2019]

[4] Hellebust TA, Kirisits C, Berger D. Recommendations for gynaecological (GYN) GEC ESTRO working group: Considerations and pitfalls in commissioning and applicator reconstruction in 3D image-based treatment planning of cervix cancer brachytherapy. Radiotherapy and Oncology. 2010;**96**(2):153-160. DOI: 10.1016/j.radonc.2010.06.004

[5] Kravets OA, Kozlov OV, Fedyanina AA, et al. Methodical aspects of contact radiation therapy of cervical cancer using 3D-planning. Medical Physics. 2017;**73**(1):16-24. Russian

[6] Banerjee R, Kamrava M. Brachytherapy in the treatment of cervical cancer: A review. International Journal of Women's Health. 2014;**6**:555-564

[7] Vishwanathan AN, Beriwal S, De Los Santos JF. American brachytherapy society consensus guidelines for locally advanced carcinoma of the cervix. Part II: High-dose-rate brachytherapy. Brachytherapy. 2012;**11**(1):47-52. DOI: 10.1016/j.brachy.2011.07.002

[8] Bucci МК, Bevan A, Roach М. Advances in radiation therapy: Conventional to 3D, to IMRT, to 4D and beyond. CA: A Cancer Journal for Clinicians. 2005;**55**(2):117-134. PubMed PMID: 15761080

[9] Roeske JC, Lujan A, Rotmensch J, Waggoner SE, Yamada D, Mundt AJ. Intensity-modulated whole pelvic radiation therapy in patients with gynecologic malignancies. International Journal of Radiation Oncology, Biology, Physics. 2000;**48**(5):1613-1621

[10] Chernyaev AP, Popodko AI, Lykova EN. Medical Equipment in the Modern Radiotherapy. Moscow, Russian: MSU Physical Faculty Publishing; 2019. 101 p

[11] Roitberg GE, Usychkin SV, Boyko AV. Large-scale remote radiation therapy for prostate cancer. Medical Radiology and Radiation Safety. 2016; **61**(1):47-59. Russian

[12] Ghandour S, Matzinger O, Pachouda M. Volumetric-modulated arc therapy planning using multicriteria optimization for localized prostate cancer. Journal of Applied Clinical Medical Physics. 2015;**16**(3):258-269. DOI: 10.1120/jacmp.v16i3.5410

[13] Rodríguez Villalba S, Planell CD, Grau JM. Current opinion in cervix carcinoma. Clinical and Translational Oncology. 2011;**13**:378-384. DOI: 10.1007/s12094-011-0671-4

[14] Chan P, Yeo I, Perkins G, Fyles A, Milosevic M. Dosimetric comparison of intensity-modulated, conformal, and four-field pelvic radiotherapy boost plans for gynecologic cancer: A retrospective planning study. Radiation Oncology. 2006;**1**:13. DOI: 10.1186/1748-717X-1-13

[15] Cozzia L, Dinshawc KA, Shrivastavac SK, Mahantshettyc U, Engineerc R, Deshpandec DD, et al. A treatment planning study comparing volumetric arc modulation with RapidArc and fixed field IMRT for cervix uteri radiotherapy. Radiotherapy and Oncology. 2008;**89**:180-191

[16] Khosla D, Patel FD, Oinam AS, Tomar P, Sharma SC. Dosimetric comparison of vaginal vault ovoid brachytherapy versus intensitymodulated radiation therapy plans in postoperative patients of cervical carcinoma following whole pelvic radiotherapy. Journal of Cancer Research and Therapeutics. 2014;**10**(1): 153-158. DOI: 10.4103/ 0973-1482.131449

[17] Pedicini P, Caivano R, Fiorentino A, Strigari L, Califano G, Barbieri V, et al. Comparative dosimetric and radiobiological assessment among a nonstandard RapidArc, standard RapidArc, classical intensity-modulated radiotherapy, and 3D brachytherapy for the treatment of the vaginal vault in patients affected by gynecologic cancer. Medical Dosimetry. 2012;**37**(4):347-352. DOI: 10.1016/j.meddos.2011.11.009

[18] Mahmoud O, Kilic S, Khan AJ, Beriwal S, Small W Jr. External beam techniques to boost cervical cancer when brachytherapy is not an option— Theories and applications. The Annals of Translational Medicine. 2017;**5**(10): 207. DOI: 10.21037/atm.2017.03.102

[19] Cihoric N, Tsikkinis A, Miguelez CG, Strnad V, Soldatovic I, Ghadjar P, et al. Portfolio of prospective clinical trials including brachytherapy: An analysis of the ClinicalTrials.gov database. Radiation Oncology. 2016; **22**(11):48. DOI: 10.1186/s13014-016- 0624-8.

[20] Mell LK, Mundt AJ. Intensitymodulated radiation therapy in gynecologic cancers: Growing support, growing acceptance. Cancer Journal.

2008;**14**(3):198-199. DOI: 10.1097/ PPO.0b013e318178dda1

Oncology, Biology, Physics. 2012;**82**(2): 653. DOI: 10.1016/j.ijrobp.2010.12.029

*DOI: http://dx.doi.org/10.5772/intechopen.89734*

*Dosimetric and Radiobiological Evaluation of Combined Radiotherapy of Cervical Cancer Based…*

[27] Gmurman VE. Theory of Probability and Mathematical Statistics. 9th ed. Moscow: Higher School; 2003. 479 p.

Russian

**97**

[21] Cilla S, Macchia G, Sabatino D, Digesù C, Deodato F, Piermattei A, De Spirito M, Morganti AG. Applicatorguided volumetric-modulated arc therapy for low-risk endometrial cancer. Medical Dosimetry 2013;38(1):5–11. DOI: 10.1016/j.meddos.2012.04.004

[22] Assenholt MS, Petersen JB, Nielsen SK, Lindegaard JC, Tanderup K. A dose planning study on applicator guided stereotactic IMRT boost in combination with 3D MRI based brachytherapy in locally advanced cervical cancer. Acta Oncologica. 2008; **47**(7):1337. DOI: 10.1080/028418608 02266698

[23] Michalski JM, Gay H, Jackson A, Tucker SL, Deasy JO. Radiation dosevolume effects in radiation-induced rectal injury. International Journal of Radiation Oncology, Biology, Physics. 2010;**76**(3):123. DOI: 10.1016/j.ijrobp. 2009.03.078

[24] Viswanathan AN, Yorke ED, Marks LB, Eifel PJ, Shipley WU. Radiation dose–volume effects of the urinary bladder. International Journal of Radiation Oncology, Biology, Physics. 2010;**76**(3):116-S122. DOI: 10.1016/j. ijrobp.2009.02.090

[25] RTOG/EORTC Late Radiation Morbidity Scoring Schema. Available from: https://www.rtog.org/Research Associates/AdverseEventReporting/ RTOGEORTCLateRadiationMorbid ityScoringSchema.aspx [Accessed: 22 July 2019]

[26] Georg P, Pötter R, Georg D, Lang S, Dimopoulos JC, Sturdza AE, et al. Dose effect relationship for late side effects of the rectum and urinary bladder in magnetic resonance image-guided adaptive cervix cancer brachytherapy. International Journal of Radiation

*Dosimetric and Radiobiological Evaluation of Combined Radiotherapy of Cervical Cancer Based… DOI: http://dx.doi.org/10.5772/intechopen.89734*

Oncology, Biology, Physics. 2012;**82**(2): 653. DOI: 10.1016/j.ijrobp.2010.12.029

Engineerc R, Deshpandec DD, et al. A treatment planning study comparing volumetric arc modulation with RapidArc and fixed field IMRT for cervix uteri radiotherapy. Radiotherapy

*Gynaecological Malignancies - Updates and Advances*

2008;**14**(3):198-199. DOI: 10.1097/

[21] Cilla S, Macchia G, Sabatino D, Digesù C, Deodato F, Piermattei A, De Spirito M, Morganti AG. Applicatorguided volumetric-modulated arc therapy for low-risk endometrial cancer. Medical Dosimetry 2013;38(1):5–11. DOI: 10.1016/j.meddos.2012.04.004

[22] Assenholt MS, Petersen JB,

02266698

2009.03.078

ijrobp.2009.02.090

22 July 2019]

Nielsen SK, Lindegaard JC, Tanderup K. A dose planning study on applicator guided stereotactic IMRT boost in combination with 3D MRI based brachytherapy in locally advanced cervical cancer. Acta Oncologica. 2008; **47**(7):1337. DOI: 10.1080/028418608

[23] Michalski JM, Gay H, Jackson A, Tucker SL, Deasy JO. Radiation dosevolume effects in radiation-induced rectal injury. International Journal of Radiation Oncology, Biology, Physics. 2010;**76**(3):123. DOI: 10.1016/j.ijrobp.

[24] Viswanathan AN, Yorke ED, Marks LB, Eifel PJ, Shipley WU. Radiation dose–volume effects of the urinary bladder. International Journal of Radiation Oncology, Biology, Physics. 2010;**76**(3):116-S122. DOI: 10.1016/j.

[25] RTOG/EORTC Late Radiation Morbidity Scoring Schema. Available from: https://www.rtog.org/Research Associates/AdverseEventReporting/ RTOGEORTCLateRadiationMorbid ityScoringSchema.aspx [Accessed:

[26] Georg P, Pötter R, Georg D, Lang S, Dimopoulos JC, Sturdza AE, et al. Dose effect relationship for late side effects of the rectum and urinary bladder in magnetic resonance image-guided adaptive cervix cancer brachytherapy. International Journal of Radiation

PPO.0b013e318178dda1

and Oncology. 2008;**89**:180-191

[16] Khosla D, Patel FD, Oinam AS, Tomar P, Sharma SC. Dosimetric comparison of vaginal vault ovoid brachytherapy versus intensitymodulated radiation therapy plans in postoperative patients of cervical carcinoma following whole pelvic radiotherapy. Journal of Cancer

Research and Therapeutics. 2014;**10**(1):

[17] Pedicini P, Caivano R, Fiorentino A, Strigari L, Califano G, Barbieri V, et al.

153-158. DOI: 10.4103/ 0973-1482.131449

Comparative dosimetric and radiobiological assessment among a nonstandard RapidArc, standard RapidArc, classical intensity-modulated radiotherapy, and 3D brachytherapy for the treatment of the vaginal vault in patients affected by gynecologic cancer. Medical Dosimetry. 2012;**37**(4):347-352. DOI: 10.1016/j.meddos.2011.11.009

[18] Mahmoud O, Kilic S, Khan AJ, Beriwal S, Small W Jr. External beam techniques to boost cervical cancer when brachytherapy is not an option— Theories and applications. The Annals of Translational Medicine. 2017;**5**(10): 207. DOI: 10.21037/atm.2017.03.102

[19] Cihoric N, Tsikkinis A,

0624-8.

**96**

Miguelez CG, Strnad V, Soldatovic I, Ghadjar P, et al. Portfolio of prospective clinical trials including brachytherapy: An analysis of the ClinicalTrials.gov database. Radiation Oncology. 2016; **22**(11):48. DOI: 10.1186/s13014-016-

[20] Mell LK, Mundt AJ. Intensitymodulated radiation therapy in

gynecologic cancers: Growing support, growing acceptance. Cancer Journal.

[27] Gmurman VE. Theory of Probability and Mathematical Statistics. 9th ed. Moscow: Higher School; 2003. 479 p. Russian

**99**

**Chapter 6**

**Abstract**

**1. Background**

Intraoperative Radiation Therapy

Gynecological malignancies, mainly cervical uterine cancer, continue to present a high number of pelvic and para-aortic recurrences. Intraoperative radiation therapy (IORT) allows a precise therapeutic boost in the surgical bed in the cases in which removal of the tumor relapse is feasible. At the same time, IORT permits the exclusion of the radiosensitive organs from the irradiation field. While the first published gynecological IORT took place in 1905, the number of patients per year became stable and the published series are retrospective and limited. Recurrences are located in different areas with non-homogeneous prognostic and most of the published manuscripts are retrospective including a mix of primaries, sites and different types and results of salvage surgery. We have revised the present knowledge in this field and the main conclusion is that IORT increases the local control and, in selected cases, probably slightly the survival. Also, the quality of life is probably increased. Randomized trials that allow a breakthrough in the conclusions are highly unlikely to be performed in recurrent gynecological malignancies.

**Keywords:** gynecological cancer, radiotherapy, intraoperative radiation therapy,

Intraoperative radiation therapy (IORT) is a boosting technique that delivers a single high dose fraction of radiation directly to the resection bed during surgery. The purpose is to selectively irradiate anatomical areas that have been identified as high risk of persistence of subclinical disease or even macroscopic unresectable residual disease. This identification is easily achieved by the direct vision of the area of interest through the surgical field. At the same time, IORT protects or avoids damage to surrounding structures or organs at risk (OAR) because they are radiosensitive. This allows good protection of pelvic organs, such as urinary bladder, ureter, rectum, bowel, etc., and, consequently, decreases the incidence of secondary undesired effects including enteritis, proctitis or cystitis. IORT can be delivered using a dedicated linear accelerator producing electron beams of different energies and penetration degrees, X-ray sources delivering low-energy radiation or high dose-rate brachytherapy sources. All of them can also be conveniently used for IORT procedures in primary or recurrent gynecological tumors. All techniques have different advantages and disadvantages. In the initial period, conventional radiotherapy linear accelerators were used, which meant that the patient had to be moved from the operating room to the radiotherapy room, which

uterine cancer, ovarian cancer, endometrial cancer

in Gynecological Cancer

*Albert Biete, Angeles Rovirosa and Gabriela Oses*

#### **Chapter 6**

## Intraoperative Radiation Therapy in Gynecological Cancer

*Albert Biete, Angeles Rovirosa and Gabriela Oses*

#### **Abstract**

Gynecological malignancies, mainly cervical uterine cancer, continue to present a high number of pelvic and para-aortic recurrences. Intraoperative radiation therapy (IORT) allows a precise therapeutic boost in the surgical bed in the cases in which removal of the tumor relapse is feasible. At the same time, IORT permits the exclusion of the radiosensitive organs from the irradiation field. While the first published gynecological IORT took place in 1905, the number of patients per year became stable and the published series are retrospective and limited. Recurrences are located in different areas with non-homogeneous prognostic and most of the published manuscripts are retrospective including a mix of primaries, sites and different types and results of salvage surgery. We have revised the present knowledge in this field and the main conclusion is that IORT increases the local control and, in selected cases, probably slightly the survival. Also, the quality of life is probably increased. Randomized trials that allow a breakthrough in the conclusions are highly unlikely to be performed in recurrent gynecological malignancies.

**Keywords:** gynecological cancer, radiotherapy, intraoperative radiation therapy, uterine cancer, ovarian cancer, endometrial cancer

#### **1. Background**

Intraoperative radiation therapy (IORT) is a boosting technique that delivers a single high dose fraction of radiation directly to the resection bed during surgery. The purpose is to selectively irradiate anatomical areas that have been identified as high risk of persistence of subclinical disease or even macroscopic unresectable residual disease. This identification is easily achieved by the direct vision of the area of interest through the surgical field. At the same time, IORT protects or avoids damage to surrounding structures or organs at risk (OAR) because they are radiosensitive. This allows good protection of pelvic organs, such as urinary bladder, ureter, rectum, bowel, etc., and, consequently, decreases the incidence of secondary undesired effects including enteritis, proctitis or cystitis. IORT can be delivered using a dedicated linear accelerator producing electron beams of different energies and penetration degrees, X-ray sources delivering low-energy radiation or high dose-rate brachytherapy sources. All of them can also be conveniently used for IORT procedures in primary or recurrent gynecological tumors. All techniques have different advantages and disadvantages. In the initial period, conventional radiotherapy linear accelerators were used, which meant that the patient had to be moved from the operating room to the radiotherapy room, which was sometimes far away. Apart from inconveniences to transfer the patient at the time of surgery, there was also a risk of infections and a substantial prolongation of surgery time. As a result, compact mobile electron accelerators were designed that could be installed in a radio-protected operating room to avoid patient transfer (Mobetron and LIAC are the best known). Low kilovoltage X-ray tubes, such as Intrabeam, have a more specific design for intraoperative breast radiotherapy and do not have collimators of sufficient diameter. Another added difficulty is that the irradiation time is too long, about 20–40 minutes as compared to a few minutes in electron accelerators. Also, several dosimetric considerations are favoring the use of accelerated electron beams over 50 kV X-ray beams, the description of which is out of the scope of this chapter.

In the Radiation Oncology literature, the first description of an IORT procedure has been consistently attributed to Beck [1] but Casals et al. [2] from Barcelona documented a case of an IORT treatment in the gynecological area some years before. Comas and Prio [3] reported the case of a 33-year-old woman diagnosed with a cervical squamous cell carcinoma treated by radical surgery and intrapelvic roentgen therapy to the left parametria. The patient survived at least 6 years after the treatment was completed (**Figure 1**). Results were very limited for much of the century, but through the introduction of megavoltage linear accelerators and later specifically designed units as previously explained, studies of IORT delivery procedures began to be published.

IORT has been used in the primary management, as well as in the salvage setting, for many solid tumors of different locations. Conservative treatment of breast cancer has been the most common indication, but many treatments have been done in other sites such as the pancreas, the rectum, the cardio-esophageal junction, etc.

#### **Figure 1.**

*Original picture of the first published IORT treatment. The patient was irradiated to the distant parametrial area and survived at least 7 years. Drs. C. comas and A. Prio signed the image. Barcelona, 1905.*

**101**

*Intraoperative Radiation Therapy in Gynecological Cancer*

**2. Biological and technical considerations**

more unfavorable (**Figure 2**).

maximum inhibition in the luminal subtypes.

related to the dose.

Two reviews on IORT in gynecological tumors have been previously published. The first one, from Backes and Martin [4], comprises all gynecological malignancies, including separate sections focused on uterine primary tumors and recurrent cervical cancer. A total amount of 276 cases of cervical cancer (primary and recurrent) were collected. The main conclusion is that if the surgical margins are positive or close, IORT appears to increase local control of the disease, with an acceptable toxicity profile. The second review, recently published by Krengly et al. [5], focuses on endometrial, cervical, renal, bladder and prostate cancers. A total of 153 patients (primary and recurrent cervical cancer) from 4 studies are analyzed in detail. They conclude as follows: in recurrent cervical cancer from these studies, it emerged that the status of the margins is the most important risk factor for treatment and the association of IORT seems to improve the probability of local control. In contrast, they do not recommend surgery and IORT for primary tumors. They state: "The available data suggests that this aggressive strategy is not advantageous in particular for the risk of severe side effects and that concomitant radio-chemotherapy alone

should be considered the best treatment strategy in this patient setting."

IORT using a linear accelerator of mobile electrons is given by applying a set of collimators of different diameters to the area of interest. The distal end may be perpendicular to the longitudinal or oblique axis, facilitating access to areas in the pelvic wall. The rotation of the accelerator head makes it easier to adapt the collimator to the area to be irradiated. If a risk organ cannot move out of the irradiation field, it can be protected by a metal disc, which is interposed between it and the radiation beam. The available accelerated electron energies are in a range of 4–12 MeV and the available collimator diameters are between 4 and 8 cm. The electron beams deposit their energy to a depth between 1.5 and 4 cm depending on the energy used. The dose refers to the 90% isodoses and from the determined depth falls sharply, which protects the organs located deeper. IORT can also be given employing Ir-192 thread brachytherapy, but it is a more complex procedure and requires more time, and radioprotection, as well as the surface dose/dose ratio at the desired depth, is

The carcinogenic effect depends not only on the nature of the radiation but also on the total dose and the time in which it is given (relative biological efficacy, RBE). The conventional dose per session in external pelvic radiotherapy is 1.8–2 Grays (Gy). In IORT, the doses usually used are 10–20 Gy and it is estimated that the RBE of this single large dose is equivalent up to 2–3 times the dose if delivered as standard external beam radiotherapy. Consequently, IORT can deliver more effective radiotherapy than an external beam, because the antineoplastic efficacy is strongly

Also, there is probably an extra benefit coming from diminishing the release of cell growth-stimulating cytokines. This has been well reported by Belletti et al. [6] in 2008 and later by Zaleska et al. [7] in 2016. It was shown that the growth of cell cultures of breast cancer lines could be stimulated by adding the fluid collected from the operative field to cell cultures. By contrast, if the fluid was collected after irradiation of the surgical site, no such stimulus was elicited. This may help to explain the high effectiveness of IORT in preventing tumor recurrence in the treated area. Also, it has been shown that irradiation blocks the proliferative cascade induced by surgical wound repair. Moreover, Zaleska et al. [7] showed that inhibition patterns vary according to the different histological types of breast cancer, with

*DOI: http://dx.doi.org/10.5772/intechopen.91641*

*Intraoperative Radiation Therapy in Gynecological Cancer DOI: http://dx.doi.org/10.5772/intechopen.91641*

*Gynaecological Malignancies - Updates and Advances*

out of the scope of this chapter.

procedures began to be published.

was sometimes far away. Apart from inconveniences to transfer the patient at the time of surgery, there was also a risk of infections and a substantial prolongation of surgery time. As a result, compact mobile electron accelerators were designed that could be installed in a radio-protected operating room to avoid patient transfer (Mobetron and LIAC are the best known). Low kilovoltage X-ray tubes, such as Intrabeam, have a more specific design for intraoperative breast radiotherapy and do not have collimators of sufficient diameter. Another added difficulty is that the irradiation time is too long, about 20–40 minutes as compared to a few minutes in electron accelerators. Also, several dosimetric considerations are favoring the use of accelerated electron beams over 50 kV X-ray beams, the description of which is

In the Radiation Oncology literature, the first description of an IORT procedure has been consistently attributed to Beck [1] but Casals et al. [2] from Barcelona documented a case of an IORT treatment in the gynecological area some years before. Comas and Prio [3] reported the case of a 33-year-old woman diagnosed with a cervical squamous cell carcinoma treated by radical surgery and intrapelvic roentgen therapy to the left parametria. The patient survived at least 6 years after the treatment was completed (**Figure 1**). Results were very limited for much of the century, but through the introduction of megavoltage linear accelerators and later specifically designed units as previously explained, studies of IORT delivery

IORT has been used in the primary management, as well as in the salvage setting, for many solid tumors of different locations. Conservative treatment of breast cancer has been the most common indication, but many treatments have been done in other sites such as the pancreas, the rectum, the cardio-esophageal junction, etc.

*Original picture of the first published IORT treatment. The patient was irradiated to the distant parametrial* 

*area and survived at least 7 years. Drs. C. comas and A. Prio signed the image. Barcelona, 1905.*

**100**

**Figure 1.**

Two reviews on IORT in gynecological tumors have been previously published. The first one, from Backes and Martin [4], comprises all gynecological malignancies, including separate sections focused on uterine primary tumors and recurrent cervical cancer. A total amount of 276 cases of cervical cancer (primary and recurrent) were collected. The main conclusion is that if the surgical margins are positive or close, IORT appears to increase local control of the disease, with an acceptable toxicity profile. The second review, recently published by Krengly et al. [5], focuses on endometrial, cervical, renal, bladder and prostate cancers. A total of 153 patients (primary and recurrent cervical cancer) from 4 studies are analyzed in detail. They conclude as follows: in recurrent cervical cancer from these studies, it emerged that the status of the margins is the most important risk factor for treatment and the association of IORT seems to improve the probability of local control. In contrast, they do not recommend surgery and IORT for primary tumors. They state: "The available data suggests that this aggressive strategy is not advantageous in particular for the risk of severe side effects and that concomitant radio-chemotherapy alone should be considered the best treatment strategy in this patient setting."

#### **2. Biological and technical considerations**

IORT using a linear accelerator of mobile electrons is given by applying a set of collimators of different diameters to the area of interest. The distal end may be perpendicular to the longitudinal or oblique axis, facilitating access to areas in the pelvic wall. The rotation of the accelerator head makes it easier to adapt the collimator to the area to be irradiated. If a risk organ cannot move out of the irradiation field, it can be protected by a metal disc, which is interposed between it and the radiation beam. The available accelerated electron energies are in a range of 4–12 MeV and the available collimator diameters are between 4 and 8 cm. The electron beams deposit their energy to a depth between 1.5 and 4 cm depending on the energy used. The dose refers to the 90% isodoses and from the determined depth falls sharply, which protects the organs located deeper. IORT can also be given employing Ir-192 thread brachytherapy, but it is a more complex procedure and requires more time, and radioprotection, as well as the surface dose/dose ratio at the desired depth, is more unfavorable (**Figure 2**).

The carcinogenic effect depends not only on the nature of the radiation but also on the total dose and the time in which it is given (relative biological efficacy, RBE). The conventional dose per session in external pelvic radiotherapy is 1.8–2 Grays (Gy). In IORT, the doses usually used are 10–20 Gy and it is estimated that the RBE of this single large dose is equivalent up to 2–3 times the dose if delivered as standard external beam radiotherapy. Consequently, IORT can deliver more effective radiotherapy than an external beam, because the antineoplastic efficacy is strongly related to the dose.

Also, there is probably an extra benefit coming from diminishing the release of cell growth-stimulating cytokines. This has been well reported by Belletti et al. [6] in 2008 and later by Zaleska et al. [7] in 2016. It was shown that the growth of cell cultures of breast cancer lines could be stimulated by adding the fluid collected from the operative field to cell cultures. By contrast, if the fluid was collected after irradiation of the surgical site, no such stimulus was elicited. This may help to explain the high effectiveness of IORT in preventing tumor recurrence in the treated area. Also, it has been shown that irradiation blocks the proliferative cascade induced by surgical wound repair. Moreover, Zaleska et al. [7] showed that inhibition patterns vary according to the different histological types of breast cancer, with maximum inhibition in the luminal subtypes.

#### **Figure 2.**

*Operating room designed for IORT and equipped with a mobile electron linear accelerator (LIAC). Hospital clinic. The University of Barcelona.*

#### **3. Intraoperative radiotherapy in locally advanced cervical cancer**

The elective treatment in advanced cervical cancer is simultaneous radiochemotherapy followed by brachytherapy plus/minus parametrial depending on the extend of the tumor after chemoradiation. Nevertheless, in some cases, brachytherapy could not be performed and then these patients could be treated using SBRT (Stereotaxic radiotherapy) techniques but with lower results in comparison to the elective treatment. Although in 2/3 of the patients the clinical results are satisfactory, there are some cases in which the tumor remains out of control. IORT has been considered a novel approach after the removal of the persistent tumor to boost with irradiation of the surgical bed at risk and mainly performed in FIGO stages IIB.

Martinez-Monge et al. [8] described in 31 patients the results of IORT after surgery in resectable cervical cancer. These patients were treated from 1986 to 1999 with cisplatin plus fluorouracil chemotherapy simultaneously with pelvic irradiation (dose: 45 Gy). After tumor removal, IORT was delivered to the risk areas [mainly pelvic sidewalls with a median dose of 12 Gy (range between 10 and 25 Gy)]. Patients were irradiated using electrons of 9 or 12 MeV and the median field size was 6.4 cm (range between 5 and 12 cm). The 10-year local control obtained in the irradiation field was 92.8% and the pelvic control 78.6%. Attributable to IORT, toxicity was found in 14% of the patients manifested as transient pelvic pain and only one patient had neuropathy. The authors considered IORT as a boosting technique feasible and valuable in advanced resectable cervical tumors.

Giorda et al. [9] reported the results of a phase II trial in 42 patients that underwent surgery (radical hysterectomy) after 6–8 weeks of simultaneous

**103**

histology.

*Intraoperative Radiation Therapy in Gynecological Cancer*

chemotherapy and pelvic irradiation (50.4 Gy, 1.8 Gy/fraction). After the pathological study, only 5/35 (23%) of the patients achieved a complete response and gross macroscopical disease was present in 10/35 (26%) patients. After tumor removal, IORT was administered in 83% of the patients to parametria (82%), pelvic sidewalls, obturator fossa, iliac vessels, macroscopic residual tumor or macroscopic lymph nodes. IORT median given dose was 11 Gy (range between 10 and 15 Gy), being the median field size diameter 6.3 cm (range from 5.7 to 8.3 cm). At 5 years, the overall survival (OS) was 49% and the disease-free survival (DFS) was 46% with a median time to recurrence of 22 months. In this phase II trial, it was difficult to correlate the detected complications to IORT. Although the authors concluded that IORT was mainly effective in patients with a pathological complete response and in those with residual tumor limited to the cervix, this statement became very

In a report from Foley et al. [10], 32 patients were treated with IORT after surgery over a period of 17 years (1994–2011) and 21 (65.6%) of them had a diagnosis of cervical cancer (locally advanced and recurrent cervical cancer). After surgery, 84.4% of the primary cervical cancer patients had microscopically positive margins. Patients were treated using electrons from IORT with a median dose of 13.5 Gy (range 10–22.5 Gy). The higher doses were delivered in the patients with gross tumor persistence. The mean cone size was 6.6 cm with diameters ranging between 4 and 10 cm. The pelvic sidewall was treated in 59.4%, central pelvis in 21.8% and para-aortic areas in 18.8%, respectively. Only one patient developed a grade 3 peripheral neuropathy and no other relevant complications were reported. The authors concluded on the usefulness of IORT after surgery in advanced cases and relapses from cervical cancer and remark the need for clinical trials to better

Gao et al. [11] reported the results of a series of 27 cases presenting a stage II cervical adenocarcinoma collected between 1999 and 2002. The rationale of the study was on the worse prognosis of this raising histological subtype. The patients underwent HDR (high dose rate) brachytherapy (overall dose of 12–14 Gy in 2 applications) and followed 1–2 weeks thereafter by surgery (total hysterectomy and selective lymphadenectomy). IORT given dose was 18–20 Gy using 12 MeV electrons and the diameter of the treatment field size was 10–12 cm with the protection of bowels, sigma, rectum and bladder. The obturator nerve was also partially shielded. Positive or close surgical margins were found in 8 of 27 cases (29.6%). About 4–6 courses of cisplatin and 5-fluorouracil adjuvant chemotherapy were administered 2 weeks after the surgery. The 5-year overall survival and disease-free survival were 77.8 and 70.4%, respectively. With a mean follow-up of 81 months, 2 patients developed local relapse (7.4%), but outside of the treatment field. The main complication was the peripheral neuropathy that appeared in 2 patients (7.4%) at 8 and 17 months, respectively. The authors concluded that IORT was safe and feasible, achieving an optimal local control benefit in stage II patients. The same group published in 2002 [12] a previous study describing the results of delivering IORT as a boosting irradiation technique after tumor resection in stage IIB patients. The 5-year survival was 95% and they conclude that this approach is a new and effective therapy method for this stage, mainly in adenocarcinoma

According to the authors' conclusions, it is very difficult or perhaps near impossible to asses if adding IORT to extensive surgery in cervical cancer stage II has any advantage. Improving the results of standard therapies is not easy because the high control rates obtained. Even with a randomized trial, a large number of cases would be mandatory to have good discrimination and to be sure of a real benefit. We do

not think that a study like that will be planned in a short future.

*DOI: http://dx.doi.org/10.5772/intechopen.91641*

difficult to be demonstrated.

analyze the benefit to add IORT to the surgery.

*Gynaecological Malignancies - Updates and Advances*

**3. Intraoperative radiotherapy in locally advanced cervical cancer**

The elective treatment in advanced cervical cancer is simultaneous radiochemotherapy followed by brachytherapy plus/minus parametrial depending on the extend of the tumor after chemoradiation. Nevertheless, in some cases, brachytherapy could not be performed and then these patients could be treated using SBRT (Stereotaxic radiotherapy) techniques but with lower results in comparison to the elective treatment. Although in 2/3 of the patients the clinical results are satisfactory, there are some cases in which the tumor remains out of control. IORT has been considered a novel approach after the removal of the persistent tumor to boost with irradiation of the surgical bed at risk and mainly performed in FIGO stages IIB. Martinez-Monge et al. [8] described in 31 patients the results of IORT after surgery in resectable cervical cancer. These patients were treated from 1986 to 1999 with cisplatin plus fluorouracil chemotherapy simultaneously with pelvic irradiation (dose: 45 Gy). After tumor removal, IORT was delivered to the risk areas [mainly pelvic sidewalls with a median dose of 12 Gy (range between 10 and 25 Gy)]. Patients were irradiated using electrons of 9 or 12 MeV and the median field size was 6.4 cm (range between 5 and 12 cm). The 10-year local control obtained in the irradiation field was 92.8% and the pelvic control 78.6%. Attributable to IORT, toxicity was found in 14% of the patients manifested as transient pelvic pain and only one patient had neuropathy. The authors considered IORT as a boosting technique feasible and valuable in advanced resectable

*Operating room designed for IORT and equipped with a mobile electron linear accelerator (LIAC). Hospital* 

Giorda et al. [9] reported the results of a phase II trial in 42 patients that underwent surgery (radical hysterectomy) after 6–8 weeks of simultaneous

**102**

**Figure 2.**

*clinic. The University of Barcelona.*

cervical tumors.

chemotherapy and pelvic irradiation (50.4 Gy, 1.8 Gy/fraction). After the pathological study, only 5/35 (23%) of the patients achieved a complete response and gross macroscopical disease was present in 10/35 (26%) patients. After tumor removal, IORT was administered in 83% of the patients to parametria (82%), pelvic sidewalls, obturator fossa, iliac vessels, macroscopic residual tumor or macroscopic lymph nodes. IORT median given dose was 11 Gy (range between 10 and 15 Gy), being the median field size diameter 6.3 cm (range from 5.7 to 8.3 cm). At 5 years, the overall survival (OS) was 49% and the disease-free survival (DFS) was 46% with a median time to recurrence of 22 months. In this phase II trial, it was difficult to correlate the detected complications to IORT. Although the authors concluded that IORT was mainly effective in patients with a pathological complete response and in those with residual tumor limited to the cervix, this statement became very difficult to be demonstrated.

In a report from Foley et al. [10], 32 patients were treated with IORT after surgery over a period of 17 years (1994–2011) and 21 (65.6%) of them had a diagnosis of cervical cancer (locally advanced and recurrent cervical cancer). After surgery, 84.4% of the primary cervical cancer patients had microscopically positive margins. Patients were treated using electrons from IORT with a median dose of 13.5 Gy (range 10–22.5 Gy). The higher doses were delivered in the patients with gross tumor persistence. The mean cone size was 6.6 cm with diameters ranging between 4 and 10 cm. The pelvic sidewall was treated in 59.4%, central pelvis in 21.8% and para-aortic areas in 18.8%, respectively. Only one patient developed a grade 3 peripheral neuropathy and no other relevant complications were reported. The authors concluded on the usefulness of IORT after surgery in advanced cases and relapses from cervical cancer and remark the need for clinical trials to better analyze the benefit to add IORT to the surgery.

Gao et al. [11] reported the results of a series of 27 cases presenting a stage II cervical adenocarcinoma collected between 1999 and 2002. The rationale of the study was on the worse prognosis of this raising histological subtype. The patients underwent HDR (high dose rate) brachytherapy (overall dose of 12–14 Gy in 2 applications) and followed 1–2 weeks thereafter by surgery (total hysterectomy and selective lymphadenectomy). IORT given dose was 18–20 Gy using 12 MeV electrons and the diameter of the treatment field size was 10–12 cm with the protection of bowels, sigma, rectum and bladder. The obturator nerve was also partially shielded. Positive or close surgical margins were found in 8 of 27 cases (29.6%). About 4–6 courses of cisplatin and 5-fluorouracil adjuvant chemotherapy were administered 2 weeks after the surgery. The 5-year overall survival and disease-free survival were 77.8 and 70.4%, respectively. With a mean follow-up of 81 months, 2 patients developed local relapse (7.4%), but outside of the treatment field. The main complication was the peripheral neuropathy that appeared in 2 patients (7.4%) at 8 and 17 months, respectively. The authors concluded that IORT was safe and feasible, achieving an optimal local control benefit in stage II patients. The same group published in 2002 [12] a previous study describing the results of delivering IORT as a boosting irradiation technique after tumor resection in stage IIB patients. The 5-year survival was 95% and they conclude that this approach is a new and effective therapy method for this stage, mainly in adenocarcinoma histology.

According to the authors' conclusions, it is very difficult or perhaps near impossible to asses if adding IORT to extensive surgery in cervical cancer stage II has any advantage. Improving the results of standard therapies is not easy because the high control rates obtained. Even with a randomized trial, a large number of cases would be mandatory to have good discrimination and to be sure of a real benefit. We do not think that a study like that will be planned in a short future.

#### **4. IORT in recurrent cervical cancer**

Most of the IORT treatments in gynecological tumors have been performed in cervical cancer recurrences. The main locations of them are central pelvis (cervix or vaginal vault if previous radical hysterectomy), pelvic walls, parametria and nodal areas (pelvic or para-aortic). The IORT has been performed on the surgical bed after complete resection or over the remaining unresectable recurrence, mainly because of infiltration or adherence to vascular or other anatomical structures. Facing the optimal efficacy, the goal always will be to achieve a complete resection with surgical margin free (R0) or at least only microscopically invaded (R1). Clinical results became worse if residual gross tumor remains after surgery.

When we made a short review of published clinical data on IORT in cervical cancer recurrences, we found that all studies are retrospectives series. The recruitment periods are very long, with a low year rate and large heterogeneity in doses, irradiation fields, energies and duration of follow-up.

One of the historical series was published in 1997 by Garton et al. [13] from the Mayo Clinic. In a large group of 449 patients treated with IORT, 39 patients had gynecological tumors and 22 were cervical relapses. The median dose administered was 17.5 Gy (range 10– 25 Gy) and its variation was due to the different degrees of surgical radicality and tumor persistence (R0, R1 or R2). Most of the irradiated locations were lymph nodes followed by the pelvic wall. In a few cases, both sites were treated simultaneously. The 5-year actuarial local control rate on the irradiated area was 81% but decreased to 67% if the whole pelvic and nodal areas were registered. The 5-year DFS was 40.5% mainly due to the appearance of distant metastasis. The authors concluded that the association of surgery, IORT and, if possible, external beam radiotherapy was the right therapeutic approach, but with an uncertain benefit of including IORT.

One of the largest trials on recurrent cervical cancer is the study by Mahe et al. [14]. Due to the short survival registered in these patients, they made a retrospective revision of IORT-treated cases. Between 1985 and 1993, a cohort of 70 patients presenting with pelvic recurrences underwent IORT with or without external radiotherapy. The clinical series were collected from seven French institutions and results were reported in 1996. In most of the patients, the relapse location was on the pelvic sidewall (59/70) and central pelvis in the remaining patients. Lymph node relapses were not reported. Five patients underwent 100 kV X-rays IORT and electrons were used in the rest of the group. The median energy was 12 MeV (range 6–20 MeV) in R0/R1 cases and somewhat higher, 14 MeV (range 7–24 MeV), when macroscopic tumor persisted after surgery. The median IORT doses were similar (18–19 Gy) in both subgroups (R0/R1 vs. R2) but the broad range (10–30 Gy). The cone median diameter was 7.5 cm (range 4–9 cm). The median follow-up was 15 months and the 5-year actuarial local control was 21%, with an OS of only 8%. This study reported one of the lowest local control and survival rates in the literature. Five of seventy patients (7.1%) developed late peripheral neuropathy, presenting with pain and paresthesia. The authors concluded that IORT seems feasible in recurrent cervical cancer but cannot dramatically improve prognosis.

A second paper from the Mayo Clinic was published some years later, in 2013, by Barney et al. [15]. The recruiting period was extended 9 years, with a total of 86 patients treated between 1983 and 2010. Eight-five percent of patients had locally recurrent tumors and the remaining patients locally advanced primary cervical cancer. The most commonly performed surgery associated with IORT was pelvic exenteration (30%) followed by pelvic side wall resection (26%). In 20% of the patients, IORT was delivered to metastatic para-aortic nodes. During the surgical

**105**

*Intraoperative Radiation Therapy in Gynecological Cancer*

procedure, 67% of the cases were found involving the pelvic sidewall but maximal debulking surgery was performed. Surgical margins were free (R0) in 41% of cases, microscopically involved (R1) in 35% and gross residual tumor (R2) in 24%. The patients underwent IORT with an electron beam from a conventional linear accelerator. The median given dose was 15 Gy (range 6–25 Gy) according to the resection margin (R0, R1 or R2). Site and R status were the parameters used to select the appropriate beam energies, and 9 and 12 MeV were the most commonly employed. In the previous study from the same institution [13], the median dose was a little higher (17.5 Gy vs. 15 Gy) and the irradiated volume slightly smaller in the present series. The authors considered that combining IORT and pelvic exenteration, the best results were achieved, improving the probability of local control. After surgery, an R0 or R1 pathological result was obtained only in half of the patients, but the 3-year actuarial local control was 56%. Also, only 43% of patients underwent external beam irradiation after surgery. About IORT-related toxicity, 16/89 (18%) patients experienced peripheral neuropathy, 4/89 (4.5%) ureteral stenosis and also 4.5% bowel perforation or fistula. We must point out that, keeping in mind that both studies from the Mayo Clinic share most of the patients, local control rates are rather different (70% at 5 years vs. 56% at 3 years). The authors concluded that long-term survival is possible with combined modality therapy including IORT for advanced and recurrences of cervical cancer, but distant relapse is common. A Spanish study by Sole et al. [16] published in 2014 evaluated a series of 31 patients with recurrent cervical cancer. Because all patients had undergone previous external irradiation, the management of relapse was limited to complete or debulking surgical resection and IORT. The mean electron given dose was 12.5 Gy (range 10 to 15 Gy) and the median beam energy 12 Mev from a standard linear accelerator. Circular cones most beveled ranged from 5 to 12 cm in diameter. The 5-year actuarial local control, OS and DFS were 65, 42, and 44%, respectively. Secondary effects directly associated with IORT were not reported. The authors concluded that patients presenting with local or nodal relapse were safely treated and had improved local control by adding IORT to the surgical resection. The largest benefit

Tran et al. [17] conducted a study at Stanford University and reported the clinical results of a retrospective series of 36 consecutive patients treated from 1986 to 2005. Cervical recurrent tumors were present in 17 (47%) patients, and all of them had negative margins (R0) on the perioperative pathological examination. IORT was delivered with an orthovoltage X-ray equipment (200–250 kV), using circular cones with diameters from 2.5 to 10 cm and bevels between 0° and 45°. Doses were referred to as the surface of the surgical bed. In some patients, customized lead shielding was designed to protect neighboring radiosensitive organs. The median dose given was 11.5 Gy (range 6–17.5 Gy). The 5-year actuarial local control was 45% and the DSF 46%. These results, which were more favorable than those reported elsewhere, should be interpreted taking into account that IORT was only administered in patients with R0 resections. Another explanation was the lower rate of sidewall pelvic location, 32% vs. 84% in the French study [16]. As previously commented on, recurrences on the pelvic sidewall have the worst prognosis compared with other sites such as the central pelvis or isolated metastatic lymph nodes. A very low reported rate of secondary effects due to IORT may be explained by shielding the organs at risk and limiting the peripheral nerve dose below 12.5 Gy. As a conclusion and remarking the importance of wisely selecting the candidates to IORT, the authors colloquially wrote: "It is a question of fishing in the right hole". A few years ago, in 2014, Backes et al. [18] published an article investigating whether the association of pelvic exenteration and IORT in recurrent gynecological cancer could improve survival. A total of 21 patients out of 32 (65.6%) with

*DOI: http://dx.doi.org/10.5772/intechopen.91641*

was detected in the R0 cases.

#### *Intraoperative Radiation Therapy in Gynecological Cancer DOI: http://dx.doi.org/10.5772/intechopen.91641*

*Gynaecological Malignancies - Updates and Advances*

**4. IORT in recurrent cervical cancer**

tumor remains after surgery.

irradiation fields, energies and duration of follow-up.

an uncertain benefit of including IORT.

cancer but cannot dramatically improve prognosis.

Most of the IORT treatments in gynecological tumors have been performed in cervical cancer recurrences. The main locations of them are central pelvis (cervix or vaginal vault if previous radical hysterectomy), pelvic walls, parametria and nodal areas (pelvic or para-aortic). The IORT has been performed on the surgical bed after complete resection or over the remaining unresectable recurrence, mainly because of infiltration or adherence to vascular or other anatomical structures. Facing the optimal efficacy, the goal always will be to achieve a complete resection with surgical margin free (R0) or at least only microscopically invaded (R1). Clinical results became worse if residual gross

When we made a short review of published clinical data on IORT in cervical cancer recurrences, we found that all studies are retrospectives series. The recruitment periods are very long, with a low year rate and large heterogeneity in doses,

One of the historical series was published in 1997 by Garton et al. [13] from the Mayo Clinic. In a large group of 449 patients treated with IORT, 39 patients had gynecological tumors and 22 were cervical relapses. The median dose administered was 17.5 Gy (range 10– 25 Gy) and its variation was due to the different degrees of surgical radicality and tumor persistence (R0, R1 or R2). Most of the irradiated locations were lymph nodes followed by the pelvic wall. In a few cases, both sites were treated simultaneously. The 5-year actuarial local control rate on the irradiated area was 81% but decreased to 67% if the whole pelvic and nodal areas were registered. The 5-year DFS was 40.5% mainly due to the appearance of distant metastasis. The authors concluded that the association of surgery, IORT and, if possible, external beam radiotherapy was the right therapeutic approach, but with

One of the largest trials on recurrent cervical cancer is the study by Mahe et al. [14]. Due to the short survival registered in these patients, they made a retrospective revision of IORT-treated cases. Between 1985 and 1993, a cohort of 70 patients presenting with pelvic recurrences underwent IORT with or without external radiotherapy. The clinical series were collected from seven French institutions and results were reported in 1996. In most of the patients, the relapse location was on the pelvic sidewall (59/70) and central pelvis in the remaining patients. Lymph node relapses were not reported. Five patients underwent 100 kV X-rays IORT and electrons were used in the rest of the group. The median energy was 12 MeV (range 6–20 MeV) in R0/R1 cases and somewhat higher, 14 MeV (range 7–24 MeV), when macroscopic tumor persisted after surgery. The median IORT doses were similar (18–19 Gy) in both subgroups (R0/R1 vs. R2) but the broad range (10–30 Gy). The cone median diameter was 7.5 cm (range 4–9 cm). The median follow-up was 15 months and the 5-year actuarial local control was 21%, with an OS of only 8%. This study reported one of the lowest local control and survival rates in the literature. Five of seventy patients (7.1%) developed late peripheral neuropathy, presenting with pain and paresthesia. The authors concluded that IORT seems feasible in recurrent cervical

A second paper from the Mayo Clinic was published some years later, in 2013, by Barney et al. [15]. The recruiting period was extended 9 years, with a total of 86 patients treated between 1983 and 2010. Eight-five percent of patients had locally recurrent tumors and the remaining patients locally advanced primary cervical cancer. The most commonly performed surgery associated with IORT was pelvic exenteration (30%) followed by pelvic side wall resection (26%). In 20% of the patients, IORT was delivered to metastatic para-aortic nodes. During the surgical

**104**

procedure, 67% of the cases were found involving the pelvic sidewall but maximal debulking surgery was performed. Surgical margins were free (R0) in 41% of cases, microscopically involved (R1) in 35% and gross residual tumor (R2) in 24%. The patients underwent IORT with an electron beam from a conventional linear accelerator. The median given dose was 15 Gy (range 6–25 Gy) according to the resection margin (R0, R1 or R2). Site and R status were the parameters used to select the appropriate beam energies, and 9 and 12 MeV were the most commonly employed. In the previous study from the same institution [13], the median dose was a little higher (17.5 Gy vs. 15 Gy) and the irradiated volume slightly smaller in the present series. The authors considered that combining IORT and pelvic exenteration, the best results were achieved, improving the probability of local control. After surgery, an R0 or R1 pathological result was obtained only in half of the patients, but the 3-year actuarial local control was 56%. Also, only 43% of patients underwent external beam irradiation after surgery. About IORT-related toxicity, 16/89 (18%) patients experienced peripheral neuropathy, 4/89 (4.5%) ureteral stenosis and also 4.5% bowel perforation or fistula. We must point out that, keeping in mind that both studies from the Mayo Clinic share most of the patients, local control rates are rather different (70% at 5 years vs. 56% at 3 years). The authors concluded that long-term survival is possible with combined modality therapy including IORT for advanced and recurrences of cervical cancer, but distant relapse is common.

A Spanish study by Sole et al. [16] published in 2014 evaluated a series of 31 patients with recurrent cervical cancer. Because all patients had undergone previous external irradiation, the management of relapse was limited to complete or debulking surgical resection and IORT. The mean electron given dose was 12.5 Gy (range 10 to 15 Gy) and the median beam energy 12 Mev from a standard linear accelerator. Circular cones most beveled ranged from 5 to 12 cm in diameter. The 5-year actuarial local control, OS and DFS were 65, 42, and 44%, respectively. Secondary effects directly associated with IORT were not reported. The authors concluded that patients presenting with local or nodal relapse were safely treated and had improved local control by adding IORT to the surgical resection. The largest benefit was detected in the R0 cases.

Tran et al. [17] conducted a study at Stanford University and reported the clinical results of a retrospective series of 36 consecutive patients treated from 1986 to 2005. Cervical recurrent tumors were present in 17 (47%) patients, and all of them had negative margins (R0) on the perioperative pathological examination. IORT was delivered with an orthovoltage X-ray equipment (200–250 kV), using circular cones with diameters from 2.5 to 10 cm and bevels between 0° and 45°. Doses were referred to as the surface of the surgical bed. In some patients, customized lead shielding was designed to protect neighboring radiosensitive organs. The median dose given was 11.5 Gy (range 6–17.5 Gy). The 5-year actuarial local control was 45% and the DSF 46%. These results, which were more favorable than those reported elsewhere, should be interpreted taking into account that IORT was only administered in patients with R0 resections. Another explanation was the lower rate of sidewall pelvic location, 32% vs. 84% in the French study [16]. As previously commented on, recurrences on the pelvic sidewall have the worst prognosis compared with other sites such as the central pelvis or isolated metastatic lymph nodes. A very low reported rate of secondary effects due to IORT may be explained by shielding the organs at risk and limiting the peripheral nerve dose below 12.5 Gy. As a conclusion and remarking the importance of wisely selecting the candidates to IORT, the authors colloquially wrote: "It is a question of fishing in the right hole".

A few years ago, in 2014, Backes et al. [18] published an article investigating whether the association of pelvic exenteration and IORT in recurrent gynecological cancer could improve survival. A total of 21 patients out of 32 (65.6%) with

recurrence of cervical cancer underwent surgical resection and IORT. The median radiation dose was 17.5 Gy (range 10–20 Gy). The selected electron beam energy ranged from 6 to 12 MeV and the dose depth prescription was, as usual, at 90% isodose curve. In eight patients, the intraoperative radiation was delivered with HDR brachytherapy catheters. It is difficult to understand the results given only 66% (21/32) of patients received IORT and the origin of the primary tumor (cervix, endometrium) was unclear. Probably the reason for that may be explained because the review has been focused to evaluate the efficacy of pelvic exenteration in the whole series. The 5-year actuarial local control rate differs according to the extension of surgery: pelvic exenteration and IORT (64%) vs. laterally extended endopelvic resection (69%). The authors' conclusions remarked that IORT fails to ameliorate local control and survival outcomes. Nevertheless, the cohort treated with pelvic exenteration and IORT had a worse prognosis compared with patients treated only with pelvis lateral wall surgery. It would reasonable to conclude that if the local control rates are similar in both arms the addition of IORT may contribute to raising the local control in the worst prognosis subgroup.

To our knowledge, the most recent reported study on gynecological malignancies treated with surgery and IORT is the German study of Arians et al. [19] published in 2016. This retrospective series included 36 patients, 18 (50%) of whom presented with cervical cancer recurrence. The recruitment period was 12 years (2002–2014). IORT was performed with a mobile linear accelerator delivering a range of electron beam energies between 6 and 18 MeV. Radiosensitive organs (bowel, ureters and peripheral nerves) were displaced out of the irradiated field or using radiation protection lead shields. The median given dose was 15 Gy (range 10–18 Gy) and the median energy 8 MeV (range 6–15 MeV). The maximum dose permitted to the nerves was always below 10–12 Gy. With a median follow-up of 14 months, the actuarial 5-year OS rate was 6.4% and the DFS 0%. The results of local control were even worse, with a rate of 0% at 2 years. The reported neural toxicity was 11%. Based on these unfavorable results, the authors concluded that surgical resection and IORT in cervical cancer recurrence should be considered a rather palliative procedure, suggesting a careful selection of patients to identify those who may benefit from this combined approach.

Our institutional experience is still limited and has been partially reported [20]. The IORT program started in 2013 with a mobile electron linear accelerator (LIAC) installed in a specifically designed operation room. Treatment objectives are mainly focused on conservative breast cancer but a series of patients with gynecological cancer recurrence have also been included as candidates to receive IORT. At present, 16 patients have been enrolled. Primary tumors included uterine cervix in 11 patients, uterine corpus in 4 and ovarian cancer in 1. The mean age was 53 years (range 40–68). The most common histological type has been squamous cell carcinoma (10/16) followed by different types of adenocarcinoma (5/16) and one carcinosarcoma. Hysterectomy was performed in six cases, resection of local recurrence lesions in five and pelvic exenteration in five. A negative pathological margin (R0) was obtained in 9/16 cases, microscopically involved margins (R1) in 6/16 and macroscopic residual tumor in 1. IORT was administered to the surgical bed using an electron beam with energy ranges from 4 to 12 MeV and a mean diameter field of 5 cm (range 4–6). The median prescribed dose has been 11 Gy (range 8–15 Gy). We consider that beyond 15 Gy the probability of peripheral nerve damage is not acceptable. All the irradiated patients presented with pelvic recurrences (central in eight, the pelvic wall in four and both sites in four) but the involvement of paraaortic nodes was also present in two patients. At follow-up, there were five cancer deaths and two patients were lost. Eight patients are in complete remission without any recurrence in the irradiated area. Only one marginal relapse has appeared.

**107**

tumors.

endometrial cancer.

*Intraoperative Radiation Therapy in Gynecological Cancer*

Taken all these data together, the difficulties of obtaining valid and objective conclusions should be emphasized. The heterogeneity of the data, size, location, and extent of the relapses, the different therapeutic approaches, IORT doses, different surgical procedures, etc. must be taken into account before inadequate conclusions. Probably, adding IORT to the debulking surgery may give an extra benefit in terms of local control, particularly if the resection is R0 or R1. But the influence on survival seems, if any, poor because of the high probability to develop pelvic

The experience with IORT in endometrial cancer is still more limited than in cervical cancer. Firstly, the pattern of recurrence is different, with very infrequent isolated relapses in the vaginal fundus fulfilling surgical indication. Most are usually controlled by external radiotherapy and brachytherapy. In other cases, the recurrence is in the form of peritoneal carcinomatosis, which already rules out combined

When reviewing the literature, it is observed that the majority of revisions do not include cases of endometrial cancer or do not allow their identification because they are mixed with the most numerous of the cervix or even vagina and vulva. For example, Solé et al. [16] in a series of 62 cases recruited over 17 years acknowledge that they have not included the origin of the primary tumor in the analysis criteria. In a subsequent article published 1 year later (2015) [21] dedicated specifically to IORT in oligometastases of gynecological cancer, it is surprising that it refers to more cases of endometrial than of cervical origin (18 vs. 14). With an average follow-up of 55 months, local control was 79% and DFS 44%, which stimulates the addition of IORT to external radiotherapy. In the multivariate analysis, surgery with a positive margin (R1) was the only independent prognostic factor. In a historical series of the Mayo Clinic, published in 1997 by Garton et al. [22] that includes 39 gynecological neoplasms (recurrent or advanced), only 7 are primary endometrial

In the aforementioned review carried out by Backes et al. [4], 276 cases of cervical cancer with IORT from 8 institutions were collected, but there were only 52 cases of endometrial cancer. This can be explained by the encouraging results of the primary treatment and even of the few isolated vaginal recurrences registered, which through a combination of external radiotherapy and brachytherapy reached control rates between 60% and 70%. Dowdy et al. [23] described a series of 25 patients with recurrence of endometrial cancer treated by external radiotherapy, surgical resection and IORT. The probability of local control was 84% but dropped to 47% if residual tumor persisted. For this reason, they insisted on the need to achieve surgery with negative margins. The two cases with isolated para-aortic relapses achieved control of the disease. Awtrey et al. [24] in 2006, 26 months after that study of Dowdy et al. [23], published a second specific study of IORT and

One of the main difficulties to get any valid conclusion about the usefulness of IORT is the great disparity between different studies. Nowadays, endometrial cancer has a good prognosis in most of the treated cases. Recurrences are scarce and 80% of them are located in the vaginal vault. Standard treatment of brachytherapy with or without external radiotherapy obtains satisfactory results. The cases that underwent surgery may benefit from the addition of IORT. The IORT published results in endometrium-isolated relapses are better than in cervical cancer and the toxicity is assumable if doses are under 15 Gy. We must keep in mind that a

*DOI: http://dx.doi.org/10.5772/intechopen.91641*

carcinomatosis or distant metastasis.

management of surgery and IORT.

**5. Endometrial cancer**

Taken all these data together, the difficulties of obtaining valid and objective conclusions should be emphasized. The heterogeneity of the data, size, location, and extent of the relapses, the different therapeutic approaches, IORT doses, different surgical procedures, etc. must be taken into account before inadequate conclusions. Probably, adding IORT to the debulking surgery may give an extra benefit in terms of local control, particularly if the resection is R0 or R1. But the influence on survival seems, if any, poor because of the high probability to develop pelvic carcinomatosis or distant metastasis.

#### **5. Endometrial cancer**

*Gynaecological Malignancies - Updates and Advances*

to raising the local control in the worst prognosis subgroup.

those who may benefit from this combined approach.

recurrence of cervical cancer underwent surgical resection and IORT. The median radiation dose was 17.5 Gy (range 10–20 Gy). The selected electron beam energy ranged from 6 to 12 MeV and the dose depth prescription was, as usual, at 90% isodose curve. In eight patients, the intraoperative radiation was delivered with HDR brachytherapy catheters. It is difficult to understand the results given only 66% (21/32) of patients received IORT and the origin of the primary tumor (cervix, endometrium) was unclear. Probably the reason for that may be explained because the review has been focused to evaluate the efficacy of pelvic exenteration in the whole series. The 5-year actuarial local control rate differs according to the extension of surgery: pelvic exenteration and IORT (64%) vs. laterally extended endopelvic resection (69%). The authors' conclusions remarked that IORT fails to ameliorate local control and survival outcomes. Nevertheless, the cohort treated with pelvic exenteration and IORT had a worse prognosis compared with patients treated only with pelvis lateral wall surgery. It would reasonable to conclude that if the local control rates are similar in both arms the addition of IORT may contribute

To our knowledge, the most recent reported study on gynecological malignancies treated with surgery and IORT is the German study of Arians et al. [19] published in 2016. This retrospective series included 36 patients, 18 (50%) of whom presented with cervical cancer recurrence. The recruitment period was 12 years (2002–2014). IORT was performed with a mobile linear accelerator delivering a range of electron beam energies between 6 and 18 MeV. Radiosensitive organs (bowel, ureters and peripheral nerves) were displaced out of the irradiated field or using radiation protection lead shields. The median given dose was 15 Gy (range 10–18 Gy) and the median energy 8 MeV (range 6–15 MeV). The maximum dose permitted to the nerves was always below 10–12 Gy. With a median follow-up of 14 months, the actuarial 5-year OS rate was 6.4% and the DFS 0%. The results of local control were even worse, with a rate of 0% at 2 years. The reported neural toxicity was 11%. Based on these unfavorable results, the authors concluded that surgical resection and IORT in cervical cancer recurrence should be considered a rather palliative procedure, suggesting a careful selection of patients to identify

Our institutional experience is still limited and has been partially reported [20]. The IORT program started in 2013 with a mobile electron linear accelerator (LIAC) installed in a specifically designed operation room. Treatment objectives are mainly focused on conservative breast cancer but a series of patients with gynecological cancer recurrence have also been included as candidates to receive IORT. At present, 16 patients have been enrolled. Primary tumors included uterine cervix in 11 patients, uterine corpus in 4 and ovarian cancer in 1. The mean age was 53 years (range 40–68). The most common histological type has been squamous cell carcinoma (10/16) followed by different types of adenocarcinoma (5/16) and one carcinosarcoma. Hysterectomy was performed in six cases, resection of local recurrence lesions in five and pelvic exenteration in five. A negative pathological margin (R0) was obtained in 9/16 cases, microscopically involved margins (R1) in 6/16 and macroscopic residual tumor in 1. IORT was administered to the surgical bed using an electron beam with energy ranges from 4 to 12 MeV and a mean diameter field of 5 cm (range 4–6). The median prescribed dose has been 11 Gy (range 8–15 Gy). We consider that beyond 15 Gy the probability of peripheral nerve damage is not acceptable. All the irradiated patients presented with pelvic recurrences (central in eight, the pelvic wall in four and both sites in four) but the involvement of paraaortic nodes was also present in two patients. At follow-up, there were five cancer deaths and two patients were lost. Eight patients are in complete remission without any recurrence in the irradiated area. Only one marginal relapse has appeared.

**106**

The experience with IORT in endometrial cancer is still more limited than in cervical cancer. Firstly, the pattern of recurrence is different, with very infrequent isolated relapses in the vaginal fundus fulfilling surgical indication. Most are usually controlled by external radiotherapy and brachytherapy. In other cases, the recurrence is in the form of peritoneal carcinomatosis, which already rules out combined management of surgery and IORT.

When reviewing the literature, it is observed that the majority of revisions do not include cases of endometrial cancer or do not allow their identification because they are mixed with the most numerous of the cervix or even vagina and vulva. For example, Solé et al. [16] in a series of 62 cases recruited over 17 years acknowledge that they have not included the origin of the primary tumor in the analysis criteria. In a subsequent article published 1 year later (2015) [21] dedicated specifically to IORT in oligometastases of gynecological cancer, it is surprising that it refers to more cases of endometrial than of cervical origin (18 vs. 14). With an average follow-up of 55 months, local control was 79% and DFS 44%, which stimulates the addition of IORT to external radiotherapy. In the multivariate analysis, surgery with a positive margin (R1) was the only independent prognostic factor. In a historical series of the Mayo Clinic, published in 1997 by Garton et al. [22] that includes 39 gynecological neoplasms (recurrent or advanced), only 7 are primary endometrial tumors.

In the aforementioned review carried out by Backes et al. [4], 276 cases of cervical cancer with IORT from 8 institutions were collected, but there were only 52 cases of endometrial cancer. This can be explained by the encouraging results of the primary treatment and even of the few isolated vaginal recurrences registered, which through a combination of external radiotherapy and brachytherapy reached control rates between 60% and 70%. Dowdy et al. [23] described a series of 25 patients with recurrence of endometrial cancer treated by external radiotherapy, surgical resection and IORT. The probability of local control was 84% but dropped to 47% if residual tumor persisted. For this reason, they insisted on the need to achieve surgery with negative margins. The two cases with isolated para-aortic relapses achieved control of the disease. Awtrey et al. [24] in 2006, 26 months after that study of Dowdy et al. [23], published a second specific study of IORT and endometrial cancer.

One of the main difficulties to get any valid conclusion about the usefulness of IORT is the great disparity between different studies. Nowadays, endometrial cancer has a good prognosis in most of the treated cases. Recurrences are scarce and 80% of them are located in the vaginal vault. Standard treatment of brachytherapy with or without external radiotherapy obtains satisfactory results. The cases that underwent surgery may benefit from the addition of IORT. The IORT published results in endometrium-isolated relapses are better than in cervical cancer and the toxicity is assumable if doses are under 15 Gy. We must keep in mind that a

significant number of patients will present later on peritoneal carcinomatosis and/ or lung metastasis, mainly the grade III tumors. Finally, it is slightly surprising that, in the cases presenting bad prognostic factors, IORT is not used more, because local control in endometrial cancer is mandatory.

#### **6. Ovarian cancer**

In most published studies, the cases of IORT in ovarian cancer are marginal and scarce, so that it is difficult to achieve any conclusions. As far as we are aware, there are only four relevant studies on the role of IORT in ovarian cancer.

One of the oldest series is that of Konski et al. [25] in 1990. They performed IORT on nine patients with recurrence of ovarian cancer and compared their evolution with a similar group without IORT. Survival was similar in both groups.

Yap et al. [26] present a series of 24 patients undergoing cytoreductive surgery with which IORT was delivered to the areas at high risk of residual disease. Interestingly, IORT was given by using a 200 kV X-ray beam instead of an electron beam. The average dose was 12 Gy (range 9–14 Gy). At 2 years follow-up, only 5 of the 24 patients were in complete remission, but only 5 showed relapse in the irradiated surgical bed, and the remaining relapse occurred in other areas. Because of the results, they concluded that IORT had some activity but its influence on the prognosis was very limited.

A more extensive series is the experience of Gao et al. [27] with 45 patients enrolled along 11 years (2000–2010) and undergoing cytoreductive surgery. IORT was performed on the pelvis using larger than usual fields (10–12 cm in diameter) and higher than usual doses, 18–20 Gy except in two cases with 10 Gy. They register local faults by 32% but the majority outside the irradiated field (10/14). The DFS was 55% at 5 years. The authors reported a rate of peripheral neuropathy of 11%, with an average time elapsed period of 11 months (range 8–22). They also register 4% of hydronephrosis. It was concluded that IORT was effective in advanced cases or recurrences undergoing surgery, as well as it appears to discreetly increase survival and quality of life. Toxicity attributable to given doses greater than 15 Gy was not mentioned.

Barney et al. [28] from the Mayo Clinic published in 2011 a series of 20 cases treated between 1987 and 2009 because of relapses after surgery and chemotherapy. The IORT zones were pelvis (14/20), para-aortic (6/20) and inguinal fields. The average electron dose was 12.5 Gy (range 10–22.5 Gy). The probability of global-local control at 5 years was 59%, with 76% in the irradiated volume. In all cases of recurrence in the irradiation field, surgeries were R1. Survival at 5 years was 49%, similar to that in the previous study. Neural toxicity was recorded in three cases (15%).

Finally, Albuquerque et al. [29] reported a series of 27 localized extraperitoneal recurrences of ovarian cancer. In 17 cases (63%), surgical results R0 or R1 were obtained. At 5 years, the probability of local control in the irradiated area was 70% and DFS was 33%. It should be noted that in this series 37% of patients had macroscopic disease after surgery. The authors make a comparison with a similar group of relapsed patients treated only with surgery and chemotherapy without finding significant differences in survival, but they concluded "suggesting a role for locoregional therapies in selected patients presenting recurrences in ovarian cancer."

The role and possible benefit of adding IORT to the surgical resection in ovarian cancers' localized recurrences are still under debate. These kinds of recurrences, tumoral or nodal, are infrequent. Survival is not modified and probably the local control is more related to the quality of life. As we consider ovarian cancer as more

**109**

surgical resections.

*Intraoperative Radiation Therapy in Gynecological Cancer*

Peripheral neural toxicity occurred in 7% of the cases.

appeared to fare as well as those previously non-irradiated.

a systemic disease and focus more on systemic therapy, we can assess than IORT would have only a role in the scarce cases presenting an isolated and resectable

In this section, we would like to comment briefly on three publications as a whole, in which no distinction has been made according to the origin of the gynecological neoplasia. The first one, from Coelho et al. [30], retrospectively analyzed 41 patients with isolated or retroperitoneal recurrences of colorectal, gynecological or retroperitoneal primary tumors. Following salvage surgery, all patients underwent tumor bed IORT with an electron beam or brachytherapy. The median dose of IORT was 12 Gy. A total of 15 gynecological cancers (36%) were included, including tumors of the cervix in 8 cases, uterine corpus in 6 and ovary in 1. Patients were enrolled along 11 years, between 2004 and 2015, with a rate of 1.3 cases per year. The 5-year local control rate was 81%. Surgery R1 was the worst prognostic factor.

Haddock et al. [31] reported the results of a retrospective series of 63 patients treated during a period of 12 years (1983–1995). The recruiting rate was 5.25 cases/ year. IORT was administered in 8 primary gynecological tumors and 55 relapses. Most of the patients (n = 40) had cervical cancer. There were 16 patients with tumors of the endometrium, 5 with vaginal and 2 with ovarian. Most patients had been previously treated with external beam radiotherapy. IORT was given with electrons with a range of energies between 9 and 18 MeV. When macroscopic residual persisted after surgery, the median dose administered was 20 Gy (R2) and 15 Gy in R0-R1 cases. The actuarial 5-year local control was 74% but the probability to survive was 27%. The authors concluded that long-term disease control is obtainable in a significant number of carefully selected patients with locally advanced or recurrent gynecological malignancies with aggressive multimodality treatment, including IORT. Disease control was better when gross total resection was possible. Patients with local or regional relapse after previous external beam radiotherapy

Finally, Gemignani et al. [32] reported a short series of 17 patients diagnosed with gynecological tumor recurrences. They were treated over a period of 5 years (1993–1998) with an inclusion rate of 3.4 cases per year, quite similar to our recruiting rate. Surprisingly, they are very young, with a median age of only 49 years (range 27 to 72). The origin of neoplasms was the cervix in nine patients, the endometrium in seven and the vagina in one. R0-R1 surgical resections were obtained in 76% of cases and the median IORT dose was 14 Gy. The actuarial 3-year local control reached 67% but if gross tumor remains after surgery the local control decreased to 25%. In R0-R1 cases, the actuarial 3-year control was the highest, with an 85% rate, but the DFS rate was 54%. Peripheral neuropathy occurred in 18% of cases and ureteral stenosis in 12%. The authors concluded the need to obtain R0-R1

The results of different series obtained in clinical practice with the use of IORT in patients with gynecological cancer are shown in **Table 1**. Most of the experience comes from resected recurrences in various locations, mainly in the central pelvis. Cervical cancer is the most frequent diagnosis followed by endometrium and ovary. The most relevant published experience since 1995 includes 727 patients. The median number of patients per institution is 36, taking into account that the 70 cases described by the French collaborative study [16] came from 7 institutions. The median given dose has been 14.8 Gy but with large differences (range between 27

*DOI: http://dx.doi.org/10.5772/intechopen.91641*

pelvic recurrence.

**7. Miscellaneous**

a systemic disease and focus more on systemic therapy, we can assess than IORT would have only a role in the scarce cases presenting an isolated and resectable pelvic recurrence.

### **7. Miscellaneous**

*Gynaecological Malignancies - Updates and Advances*

control in endometrial cancer is mandatory.

**6. Ovarian cancer**

prognosis was very limited.

was not mentioned.

three cases (15%).

significant number of patients will present later on peritoneal carcinomatosis and/ or lung metastasis, mainly the grade III tumors. Finally, it is slightly surprising that, in the cases presenting bad prognostic factors, IORT is not used more, because local

In most published studies, the cases of IORT in ovarian cancer are marginal and scarce, so that it is difficult to achieve any conclusions. As far as we are aware, there

One of the oldest series is that of Konski et al. [25] in 1990. They performed IORT on nine patients with recurrence of ovarian cancer and compared their evolu-

A more extensive series is the experience of Gao et al. [27] with 45 patients enrolled along 11 years (2000–2010) and undergoing cytoreductive surgery. IORT was performed on the pelvis using larger than usual fields (10–12 cm in diameter) and higher than usual doses, 18–20 Gy except in two cases with 10 Gy. They register local faults by 32% but the majority outside the irradiated field (10/14). The DFS was 55% at 5 years. The authors reported a rate of peripheral neuropathy of 11%, with an average time elapsed period of 11 months (range 8–22). They also register 4% of hydronephrosis. It was concluded that IORT was effective in advanced cases or recurrences undergoing surgery, as well as it appears to discreetly increase survival and quality of life. Toxicity attributable to given doses greater than 15 Gy

Barney et al. [28] from the Mayo Clinic published in 2011 a series of 20 cases treated between 1987 and 2009 because of relapses after surgery and chemotherapy. The IORT zones were pelvis (14/20), para-aortic (6/20) and inguinal fields. The average electron dose was 12.5 Gy (range 10–22.5 Gy). The probability of global-local control at 5 years was 59%, with 76% in the irradiated volume. In all cases of recurrence in the irradiation field, surgeries were R1. Survival at 5 years was 49%, similar to that in the previous study. Neural toxicity was recorded in

Finally, Albuquerque et al. [29] reported a series of 27 localized extraperitoneal recurrences of ovarian cancer. In 17 cases (63%), surgical results R0 or R1 were obtained. At 5 years, the probability of local control in the irradiated area was 70% and DFS was 33%. It should be noted that in this series 37% of patients had macroscopic disease after surgery. The authors make a comparison with a similar group of relapsed patients treated only with surgery and chemotherapy without finding significant differences in survival, but they concluded "suggesting a role for locoregional therapies in selected patients presenting recurrences in ovarian cancer."

The role and possible benefit of adding IORT to the surgical resection in ovarian cancers' localized recurrences are still under debate. These kinds of recurrences, tumoral or nodal, are infrequent. Survival is not modified and probably the local control is more related to the quality of life. As we consider ovarian cancer as more

tion with a similar group without IORT. Survival was similar in both groups. Yap et al. [26] present a series of 24 patients undergoing cytoreductive surgery with which IORT was delivered to the areas at high risk of residual disease. Interestingly, IORT was given by using a 200 kV X-ray beam instead of an electron beam. The average dose was 12 Gy (range 9–14 Gy). At 2 years follow-up, only 5 of the 24 patients were in complete remission, but only 5 showed relapse in the irradiated surgical bed, and the remaining relapse occurred in other areas. Because of the results, they concluded that IORT had some activity but its influence on the

are only four relevant studies on the role of IORT in ovarian cancer.

**108**

In this section, we would like to comment briefly on three publications as a whole, in which no distinction has been made according to the origin of the gynecological neoplasia. The first one, from Coelho et al. [30], retrospectively analyzed 41 patients with isolated or retroperitoneal recurrences of colorectal, gynecological or retroperitoneal primary tumors. Following salvage surgery, all patients underwent tumor bed IORT with an electron beam or brachytherapy. The median dose of IORT was 12 Gy. A total of 15 gynecological cancers (36%) were included, including tumors of the cervix in 8 cases, uterine corpus in 6 and ovary in 1. Patients were enrolled along 11 years, between 2004 and 2015, with a rate of 1.3 cases per year. The 5-year local control rate was 81%. Surgery R1 was the worst prognostic factor. Peripheral neural toxicity occurred in 7% of the cases.

Haddock et al. [31] reported the results of a retrospective series of 63 patients treated during a period of 12 years (1983–1995). The recruiting rate was 5.25 cases/ year. IORT was administered in 8 primary gynecological tumors and 55 relapses. Most of the patients (n = 40) had cervical cancer. There were 16 patients with tumors of the endometrium, 5 with vaginal and 2 with ovarian. Most patients had been previously treated with external beam radiotherapy. IORT was given with electrons with a range of energies between 9 and 18 MeV. When macroscopic residual persisted after surgery, the median dose administered was 20 Gy (R2) and 15 Gy in R0-R1 cases. The actuarial 5-year local control was 74% but the probability to survive was 27%. The authors concluded that long-term disease control is obtainable in a significant number of carefully selected patients with locally advanced or recurrent gynecological malignancies with aggressive multimodality treatment, including IORT. Disease control was better when gross total resection was possible. Patients with local or regional relapse after previous external beam radiotherapy appeared to fare as well as those previously non-irradiated.

Finally, Gemignani et al. [32] reported a short series of 17 patients diagnosed with gynecological tumor recurrences. They were treated over a period of 5 years (1993–1998) with an inclusion rate of 3.4 cases per year, quite similar to our recruiting rate. Surprisingly, they are very young, with a median age of only 49 years (range 27 to 72). The origin of neoplasms was the cervix in nine patients, the endometrium in seven and the vagina in one. R0-R1 surgical resections were obtained in 76% of cases and the median IORT dose was 14 Gy. The actuarial 3-year local control reached 67% but if gross tumor remains after surgery the local control decreased to 25%. In R0-R1 cases, the actuarial 3-year control was the highest, with an 85% rate, but the DFS rate was 54%. Peripheral neuropathy occurred in 18% of cases and ureteral stenosis in 12%. The authors concluded the need to obtain R0-R1 surgical resections.

The results of different series obtained in clinical practice with the use of IORT in patients with gynecological cancer are shown in **Table 1**. Most of the experience comes from resected recurrences in various locations, mainly in the central pelvis. Cervical cancer is the most frequent diagnosis followed by endometrium and ovary. The most relevant published experience since 1995 includes 727 patients. The median number of patients per institution is 36, taking into account that the 70 cases described by the French collaborative study [16] came from 7 institutions. The median given dose has been 14.8 Gy but with large differences (range between 27


#### **Table 1.**

*Selected studies of the use of IORT for gynecologic malignancies.*

and 6 Gy). We have divided all groups into two periods: 1995–2007 and 2008–2018. The median dose in the first period has been 15.5 Gy (range 6–27 Gy), whereas the median dose in the second period was 14.1 Gy (range 6–25 Gy). Differences are minor but a tendency to slightly lower doses is detected. The higher doses were administered when gross residual tumor persisted after surgery (R2) assuming that doses over 15 Gy increase the risk of peripheral neural toxicity and may cause ureteral stenosis and pelvic fibrosis if these structures are irradiated. However, in daily clinical practice, it is difficult to determine the precise cause of secondary effects: surgery, radiation or both. Broad differences in local control results are also registered. The probability to be free of the treated recurrence at 5 years switched around 30 and 100%, but most percentages are about 70–80%. No comparisons are allowed due to the high degree of heterogeneity among studies. **Table 2** shows the

**111**

**8. Conclusions**

**Table 2.**

or simply debulking.

*Intraoperative Radiation Therapy in Gynecological Cancer*

different recruiting rates from 18 studies, with a median study period of 10.7 years, although there is a large variation between a minimum of 5 years and a maximum of 27 years. The total number of cases included in this table is 626 and the median of cases per institution is 34.7 (range 15–86). The median recruitment rate is low (3.2 cases/year) and ranges between a maximum of 5.2 cases/year and a minimum of 1.4 cases/year. The previously cited French study raises a rate of 8.7 cases/year, but if we consider the 7 different institutions, then the rate lowers to 1.2 cases/year per hospital. Recruitment rates have been stable over the years, and also a strong

**Author Period Years N Rate/year** Coelho et al. [30] 2004–2005 11 15 1.4 Foley et al. [10] 1994–2011 17 32 1.9 Sole et al. [16] 1997–2012 15 35 2.3 Garton et al. [13] 1983–1991 8 39 4.9 Backes and Martin [4] 2000–2012 13 21 1.6 Arians et al. [19] 2002–2014 12 36 3.0 Tran et al. [17] 1986–2005 20 36 1.8 Giorda et al. [9] 2000–2007 8 42 5.2 Gao et al. [11] 1999–2006 7 27 3.8 Barney et al. [15] 1983–2010 27 86 3.2 Mahe et al. [14] 1985–1993 8 70 8.7 Gemignani et al. [32] 1993–1998 6 17 2.8 Garton et al. [22] 1981–1992 11 42 3.8 Martinez-Monge et al. [8] 1985–1992 8 26 3.2 Haddock et al. [31] 1983–1995 13 63 4.8 Dowdy et al. [23] 1986–2002 16 25 1.6 Yap et al. [26] 1994–2002 9 24 2.7 Biete and Oses [20] 2013–2017 5 16 3.2

The published studies on IORT have many parameters of heterogeneity. Some of them are as follows: recurrence sites of different prognosis such as pelvic sidewalls or central pelvic, margin status on resection (R0, R1 or R2), tumor initial and residual burden, high level of heterogeneity according to the different techniques, energies, fields, doses, etc. Even more, the conclusions of the referred studies are frequently different. It is not easy to demonstrate the efficacy and the benefit of IORT in these retrospective limited series. IORT is a radiation boost in a surgical procedure. In well-designed randomized prospective studies, it is frequently difficult to demonstrate the degree of local control benefit of postoperative radiotherapy. This is particularly difficult in IORT because it is necessarily associated with different degrees of radicality in surgery, from local resection to pelvic exenteration

*DOI: http://dx.doi.org/10.5772/intechopen.91641*

heterogeneity in the published series persists.

*Recruitment period and year rate of different authors' published studies.*


#### *Intraoperative Radiation Therapy in Gynecological Cancer DOI: http://dx.doi.org/10.5772/intechopen.91641*

#### **Table 2.**

*Gynaecological Malignancies - Updates and Advances*

2001 Martinez-Monge

2001 Martinez-Monge

2001 Gemignani

2002 Liu and

2014 Backes and

Martin [4]

*OS, overall survival; DFS, disease-free survival; LC, local control.*

*Selected studies of the use of IORT for gynecologic malignancies.*

et al. [8]

et al. [8]

et al. [32]

Chen [12]

2005 Yap et al. [26] 24 Recurrent-

**YEAR Reference N Classification IORT** 

**median dose and range in Grays**

36 Recurrent 15 14% 16% 42%

31 Primary-cervix 12 67% 70% 79%

17 Recurrent 14 (12–15) 54% 3y 54% 3y 83% 3y

97 Primary-cervix 19 (18–20) 88% — —

21 Recurrent 17.5 (10–20) 30% — 59%

12 (9–14) 22% — 68%

 Stelzer et al. [33] 22 Recurrent 22 (14–27) 43% — 48% Mahe et al. [14] 70 Recurrent 18 (10–25) 8%(3y) — 30% Haddock et al. [31] 63 Mix 15 (8–25) 26% — 67% Garton et al. [13] 39 Mix 17 (10–25) 40% 32% 76%

ovary

 Dowdy et al. [23] 25 Recurrent 15 (10–25) 71% — — Tran et al. [17] 36 Recurrent 11 (6–17) — 47% 44% Giorda et al. [9] 35 Primary-cervix 11 (10–15) 49% 46% 89% Gao et al. [27] 27 Primary-cervix 19 (18–20) 78% 70% 100% Barney et al. [15] 73 Recurrent 15 (6–25) — 31% 61% Barney et al. [15] 13 Primary-cervix 15 (6–25) — — 70% Foley et al. [10] 21 Recurrent 13.5 (10–22) 69% 30% 59%

 Sole et al. [21] 61 Recurrent 12 (10–15) 42% 44% 65% Arians et al. [19] 36 Recurrent 15 (10–18) 22% — 44% Biete and Oses [20] 16 Recurrent 11 (8–15) 79% — 86% Coelho et al. [30] 15 Recurrent 12 (9–15) 56% — 81%

**5y OS 5y DFS 5y LC**

and 6 Gy). We have divided all groups into two periods: 1995–2007 and 2008–2018. The median dose in the first period has been 15.5 Gy (range 6–27 Gy), whereas the median dose in the second period was 14.1 Gy (range 6–25 Gy). Differences are minor but a tendency to slightly lower doses is detected. The higher doses were administered when gross residual tumor persisted after surgery (R2) assuming that doses over 15 Gy increase the risk of peripheral neural toxicity and may cause ureteral stenosis and pelvic fibrosis if these structures are irradiated. However, in daily clinical practice, it is difficult to determine the precise cause of secondary effects: surgery, radiation or both. Broad differences in local control results are also registered. The probability to be free of the treated recurrence at 5 years switched around 30 and 100%, but most percentages are about 70–80%. No comparisons are allowed due to the high degree of heterogeneity among studies. **Table 2** shows the

**110**

**Table 1.**

*Recruitment period and year rate of different authors' published studies.*

different recruiting rates from 18 studies, with a median study period of 10.7 years, although there is a large variation between a minimum of 5 years and a maximum of 27 years. The total number of cases included in this table is 626 and the median of cases per institution is 34.7 (range 15–86). The median recruitment rate is low (3.2 cases/year) and ranges between a maximum of 5.2 cases/year and a minimum of 1.4 cases/year. The previously cited French study raises a rate of 8.7 cases/year, but if we consider the 7 different institutions, then the rate lowers to 1.2 cases/year per hospital. Recruitment rates have been stable over the years, and also a strong heterogeneity in the published series persists.

#### **8. Conclusions**

The published studies on IORT have many parameters of heterogeneity. Some of them are as follows: recurrence sites of different prognosis such as pelvic sidewalls or central pelvic, margin status on resection (R0, R1 or R2), tumor initial and residual burden, high level of heterogeneity according to the different techniques, energies, fields, doses, etc. Even more, the conclusions of the referred studies are frequently different. It is not easy to demonstrate the efficacy and the benefit of IORT in these retrospective limited series. IORT is a radiation boost in a surgical procedure. In well-designed randomized prospective studies, it is frequently difficult to demonstrate the degree of local control benefit of postoperative radiotherapy. This is particularly difficult in IORT because it is necessarily associated with different degrees of radicality in surgery, from local resection to pelvic exenteration or simply debulking.

However, most of the referred studies agree that adding IORT to surgical resection is the right strategy for raising the local control rate. There are more doubts about the influence on survival and probably there is a little impact. Nevertheless, in cervical cancer, local control has a strong impact on the quality of life. We must keep in mind that half of the mortality in cervical cancer is due to a non-controlled pelvic disease.

By contrast, the therapeutic approach in primary tumors, including surgery and IORT, is strongly debated. It seems there is no clear advantage over the standard well-established approach, including chemoradiotherapy and brachytherapy. But there is some agreement that, if surgery is the therapeutic option, IORT is an effective tool adding extra safety and increasing the local control rate. Nevertheless, IORT is a therapeutical option still not included in the clinical guides.

Finally, we must point out the difficulty and the low probability to design and conduct randomized prospective trials. The experienced low accrual of enough number of patients in a reasonable time and the heterogeneity of recurrences and surgical procedures are hard difficulties to overcome.

#### **9. Concluding remarks**

Most of the published studies on IORT on gynecological cancer collected small and non-homogeneous series of patients with the additional difficulty of the long enrolment period. Cervical cancer, as primary or recurrence, is the most analyzed tumor, but many studies include a blend of recurrences from different sites: endometrium, ovary and vagina. At the same time, there is a broad variety of recurrence locations: central pelvis, pelvic walls, retroperitoneal or pelvic nodes are the most common. There is also a great variation of the surgical radicality and margin status: R0, R1 or R2.

Nowadays, knowledge comes from retrospective and heterogeneous series. High survival achieved on the primary treatment, mainly in the cervix and endometrium, results in the onset of a few local recurrences. Then, candidates for IORT are scarce and the recruitment rate becomes low in all the institutions. On the other hand, IORT is not a standard option at the initial treatment. Even taken into account all the difficulties explained before, there is a broad consensus that IORT as a radiation boost after salvage surgery adds an extra benefit to achieve better local control. Also, some authors assess that survival may also be slightly increased. There is no doubt about the benefit of IORT on quality of life. Even in patients presenting with the metastatic disease, local control is a valuable goal and has a substantial impact on the quality of life.

An important challenge for the future is the control of the tumor spreading in the peritoneal cavity, and in this case, the impact of the recurrence local control utilizing surgery and IORT would raise. Probably there will be in the near future little changes in IORT technique delivery excepting smaller units with better mobility and versatility. A significant increase in the treated patients' rate is not expected, quite different from conservative breast cancer treatment.

Finally, the limited side effects of this radiation modality if doses do not exceed 15 Gy must stick out. However, after nearly 30 years, IORT remains a technique of uneasy availability due to the limited number of institutions where it is available.

**113**

**Author details**

\*, Angeles Rovirosa1

Hospital Clinic, University of Barcelona, Spain

\*Address all correspondence to: abiete@ub.edu

provided the original work is properly cited.

University of Barcelona, Spain

and Gabriela Oses2

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

1 Radiation Oncology Department and Gynecological Oncology Unit,

2 Radiation Oncology Department and Breast Unit, Hospital Clinic,

Albert Biete1

*Intraoperative Radiation Therapy in Gynecological Cancer*

*DOI: http://dx.doi.org/10.5772/intechopen.91641*

*Intraoperative Radiation Therapy in Gynecological Cancer DOI: http://dx.doi.org/10.5772/intechopen.91641*

*Gynaecological Malignancies - Updates and Advances*

pelvic disease.

**9. Concluding remarks**

R0, R1 or R2.

on the quality of life.

However, most of the referred studies agree that adding IORT to surgical resection is the right strategy for raising the local control rate. There are more doubts about the influence on survival and probably there is a little impact. Nevertheless, in cervical cancer, local control has a strong impact on the quality of life. We must keep in mind that half of the mortality in cervical cancer is due to a non-controlled

By contrast, the therapeutic approach in primary tumors, including surgery and IORT, is strongly debated. It seems there is no clear advantage over the standard well-established approach, including chemoradiotherapy and brachytherapy. But there is some agreement that, if surgery is the therapeutic option, IORT is an effective tool adding extra safety and increasing the local control rate. Nevertheless,

Finally, we must point out the difficulty and the low probability to design and conduct randomized prospective trials. The experienced low accrual of enough number of patients in a reasonable time and the heterogeneity of recurrences and

Most of the published studies on IORT on gynecological cancer collected small and non-homogeneous series of patients with the additional difficulty of the long enrolment period. Cervical cancer, as primary or recurrence, is the most analyzed tumor, but many studies include a blend of recurrences from different sites: endometrium, ovary and vagina. At the same time, there is a broad variety of recurrence locations: central pelvis, pelvic walls, retroperitoneal or pelvic nodes are the most common. There is also a great variation of the surgical radicality and margin status:

Nowadays, knowledge comes from retrospective and heterogeneous series. High

An important challenge for the future is the control of the tumor spreading in the peritoneal cavity, and in this case, the impact of the recurrence local control utilizing surgery and IORT would raise. Probably there will be in the near future little changes in IORT technique delivery excepting smaller units with better mobility and versatility. A significant increase in the treated patients' rate is not expected,

Finally, the limited side effects of this radiation modality if doses do not exceed 15 Gy must stick out. However, after nearly 30 years, IORT remains a technique of uneasy availability due to the limited number of institutions where it is available.

quite different from conservative breast cancer treatment.

survival achieved on the primary treatment, mainly in the cervix and endometrium, results in the onset of a few local recurrences. Then, candidates for IORT are scarce and the recruitment rate becomes low in all the institutions. On the other hand, IORT is not a standard option at the initial treatment. Even taken into account all the difficulties explained before, there is a broad consensus that IORT as a radiation boost after salvage surgery adds an extra benefit to achieve better local control. Also, some authors assess that survival may also be slightly increased. There is no doubt about the benefit of IORT on quality of life. Even in patients presenting with the metastatic disease, local control is a valuable goal and has a substantial impact

IORT is a therapeutical option still not included in the clinical guides.

surgical procedures are hard difficulties to overcome.

**112**

### **Author details**

Albert Biete1 \*, Angeles Rovirosa1 and Gabriela Oses2

1 Radiation Oncology Department and Gynecological Oncology Unit, Hospital Clinic, University of Barcelona, Spain

2 Radiation Oncology Department and Breast Unit, Hospital Clinic, University of Barcelona, Spain

\*Address all correspondence to: abiete@ub.edu

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

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[6] Belletti B, Vaidya S, D'Andrea S, Entschladen F, et al. Targeted intraoperative radiotherapy impairs the stimulation of breast cancer cell proliferation and invasion caused by surgical wounding. Clinical Cancer Research. 2008;**14**:1325-1331

[7] Zaleska K, Suchorska WM, Przybyla A, Murawa D. Effect of surgical wound fluids after intraoperative electron radiotherapy on the cancer stem cell phenotype in a panel of human breast cancer cell lines. Oncology Letters. 2016;**12**:3707-3714

[8] Martinez-Monge R, Jurado M, Aristu JJ, Moreno M, et al. Intraoperative electron beam radiotherapy during radical surgery for locally advanced and recurrent cervical cancer. Gynecologic Oncology. 2001;**82**:538-543

[9] Giorda G, Boz G, Gadducci A, Lucia E, et al. Multimodality approach in extra-cervical locally advanced cervical cancer: Chemoradiation, surgery and intra-operative radiation therapy. A phase II trial. EJSO. 2011;**37**:442-447

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[12] Liu Z, Chen X. Preliminary results of intraoperative radiation therapy for cervical carcinoma IIB. Zhonghua Fu Chan Ke Za Zhi. 2002;**37**:553-555

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Physics. 2005;**63**:1114-1121

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surgical resection and intraoperative electron beam radiation therapy for oligorecurrent gynecological cancer. Long-term outcome. Strahlentherapie und Onkologie. 2014;**190**:171-180

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[18] Backes F, Billingsley C, Martin D, Tierney B, et al. Does intra-operative radiation at the time of pelvic exenteration improve survival for patients for recurrent previously irradiated cervical, vaginal or vulvar cancer? Gynecologic Oncology.

[19] Arians N, Foerster R, Rom J, Uhl M, et al. Outcome of patients with local recurrent gynecological malignancies after resection combined with intraoperative electron radiation therapy (IOERT). Radiation Oncology.

[20] Biete A, Oses G. Radiation therapy in uterine cervical cancer: A review. Reports of Practical Oncology and Radiotherapy. 2018;**23**:589-594

[21] Sole CV, Calvo FA, Lizarraga S, Gonzalez-Bayon L, Garcia-Sabrido JL. Intraoperative electron-beam radiation therapy with or without external beam radiotherapy in the management of paraaortic lymph-node oligometastases from gynecological malignancies. Clinical & Translational Oncology.

[22] Garton GR, Gunderson LL, Webb MJ, Wilson TO, Cha SS, Podrazt KC. Intraoperative radiation therapy in gynecologic cancer:

504-511

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2016;**11**:44-54

2015;**17**:910-916

*Intraoperative Radiation Therapy in Gynecological Cancer DOI: http://dx.doi.org/10.5772/intechopen.91641*

[16] Sole CV, Calvo FA, Lozano MA, Gonzalez-Bayon L, et al. Externalbeam radiation therapy after surgical resection and intraoperative electron beam radiation therapy for oligorecurrent gynecological cancer. Long-term outcome. Strahlentherapie und Onkologie. 2014;**190**:171-180

[17] Tran P, Su Z, Hara W, Husain M, et al. Long-term survivors using intraoperative radiotherapy for recurrent gynecological malignancies. International Journal of Radiation Oncology, Biology, Physics. 2007;**69**(2): 504-511

[18] Backes F, Billingsley C, Martin D, Tierney B, et al. Does intra-operative radiation at the time of pelvic exenteration improve survival for patients for recurrent previously irradiated cervical, vaginal or vulvar cancer? Gynecologic Oncology. 2014;**135**:95-99

[19] Arians N, Foerster R, Rom J, Uhl M, et al. Outcome of patients with local recurrent gynecological malignancies after resection combined with intraoperative electron radiation therapy (IOERT). Radiation Oncology. 2016;**11**:44-54

[20] Biete A, Oses G. Radiation therapy in uterine cervical cancer: A review. Reports of Practical Oncology and Radiotherapy. 2018;**23**:589-594

[21] Sole CV, Calvo FA, Lizarraga S, Gonzalez-Bayon L, Garcia-Sabrido JL. Intraoperative electron-beam radiation therapy with or without external beam radiotherapy in the management of paraaortic lymph-node oligometastases from gynecological malignancies. Clinical & Translational Oncology. 2015;**17**:910-916

[22] Garton GR, Gunderson LL, Webb MJ, Wilson TO, Cha SS, Podrazt KC. Intraoperative radiation therapy in gynecologic cancer:

Update of the experience at a single institution. International Journal of Radiation Oncology, Biology, Physics. 1997;**37**:839-843

[23] Dowdy SC, Mariani A, Clibby VA, Haddock MG, Petersen IA, Sim FH, et al. Radical pelvic resection and intraoperative radiotherapy for recurrent endometrial cancer: Technique and analysis of outcomes. Gynecologic Oncology. 2006;**101**:280-286

[24] Awtrey C, Cadungog M, Leitao M, et al. Surgical resection for endometrial carcinoma. Gynecologic Oncology. 2006;**102**:480-488

[25] Konski A, Neisler J, Phibbs B, et al. A pilot study investigating intraoperative electron beam irradiation in the treatment of ovarian malignancies. Gynecologic Oncology. 1990;**38**:121-124

[26] Yap OW, Kapp DS, Teng NN, et al. Intraoperative radiation therapy in recurrent ovarian cancer. International Journal of Radiation Oncology, Biology, Physics. 2005;**63**:1114-1121

[27] Gao Y, Liu Z, Chen X, et al. Intraoperative radiotherapy electron boost in advanced and recurrent ovarian epithelial carcinoma: A retrospective study. BMC Cancer. 2011;**11**:439

[28] Barney BM, Petersen IA, Dowdy SC, et al. Intraoperative electron beam radiotherapy in the management of recurrent ovarian malignancies. International Journal of Gynecological Cancer. 2011;**21**:1225-1231

[29] Albuquerque K, Patel M, Liotta M, et al. Long-term benefit of tumorvolume directed involved field radiation therapy in the management of recurrent ovarian cancer. International Journal of Gynecological Cancer. 2016;**26**:4

[30] Coelho TM, Fogaroli RC, Pellizzon AC, et al. Intraoperative

**114**

*Gynaecological Malignancies - Updates and Advances*

electron beam radiotherapy during radical surgery for locally advanced and recurrent cervical cancer. Gynecologic

[9] Giorda G, Boz G, Gadducci A,

Lucia E, et al. Multimodality approach in extra-cervical locally advanced cervical cancer: Chemoradiation, surgery and intra-operative radiation therapy. A phase II trial. EJSO. 2011;**37**:442-447

[10] Foley O, Rauh-Hain JA, Clark R, Goodman A, et al. Intraoperative radiation therapy in the management

American Journal of Clinical Oncology.

[12] Liu Z, Chen X. Preliminary results of intraoperative radiation therapy for cervical carcinoma IIB. Zhonghua Fu Chan Ke Za Zhi. 2002;**37**:553-555

[13] Garton GR, Gunderson L, Webb M, Wilson T, et al. Intraoperative radiation therapy in gynecologic cancer: The Mayo Clinic experience. Gynecologic

[14] Mahe MA, Gerard JP, Dubois JB, Roussel A, et al. Intraoperative radiation therapy in recurrent carcinoma of the uterine cervix: Report of the French intraoperative group on 70 patients. International Journal of Radiation Oncology, Biology, Physics.

[15] Barney B, Petersen I, Dowdy S, Bakkum-Gamez N, et al. Intraoperative electron beam radiotherapy (IOERT) in the management of locally advanced or recurrent cervical cancer. Radiation

Oncology. 2013;**8**:80-89

of gynecologic malignancies.

[11] Gao Y, Liu Z, Gao F, Chen X. Intraoperative radiotherapy in stage IIB adenocarcinoma of the uterine cervix: A retrospective study. Oncotargets and

Therapy. 2013;**6**:1695-1700

Oncology. 1993;**48**:328-332

1996;**34**:21-26

2016;**39**:329-334

Oncology. 2001;**82**:538-543

[1] Beck C. On external roentgen treatment of internal structures. New York Medical Journal. 1909;**89**:

[2] Casas F, Ferrer C, Calvo FA. European historical note of

and Oncology. 1997;**43**:323-324

[3] Comas C, Prio A. Irradiation roentgen preventive intra-abdominal, après l'intervention chirurgicale dans un cas de cancer de l'uterus: Communication au III Congrés International d'Electro-radiologie. Barcelona: Francisco Badia; 1906.

[4] Backes F, Martin D. Intraoperative

gynecologic malignancies. Gynecologic

[5] Krengli M, Pisani C, Deantonio L,

[6] Belletti B, Vaidya S, D'Andrea S, Entschladen F, et al. Targeted intraoperative radiotherapy impairs the stimulation of breast cancer cell proliferation and invasion caused by surgical wounding. Clinical Cancer Research. 2008;**14**:1325-1331

[7] Zaleska K, Suchorska WM, Przybyla A, Murawa D. Effect of surgical wound fluids after

intraoperative electron radiotherapy on the cancer stem cell phenotype in a panel of human breast cancer cell lines. Oncology Letters. 2016;**12**:3707-3714

[8] Martinez-Monge R, Jurado M, Aristu JJ, Moreno M, et al. Intraoperative

radiation therapy (IORT) for

Oncology. 2015;**138**:449-456

Surico D, et al. Intraoperative radiotherapy for gynecological and genitourinary malignancies: Focus on endometrial, cervical, renal, bladder and prostate cancers. Radiation

Oncology. 2017;**12**:18-27

intraoperative radiation therapy (IORT). A case report from 1905. Radiotherapy

621-622

**References**

p. 1907

radiation therapy for the treatment of recurrent retroperitoneal and pelvic tumors: A single-institution analysis. Radiation Oncology. 2018;**13**:224-237

[31] Haddock MG, Petersen IA, Webb MJ. IORT for locally advanced malignancies. Frontiers of Radiation Therapy and Oncology. 1997;**31**:256-259

[32] Gemignani ML, Alektiar KM, Leitao M, et al. Radical surgical resection and high dose intraoperative radiotherapy in patients with recurrent gynecologic cancers. International Journal of Radiation Oncology, Biology, Physics. 2001;**50**:687-694

[33] Stelzer KJ, Kohn WJ, Greer BE, et al. The use of intraoperative radiotherapy in radical salvage surgery for recurrent cervical cancer: Outcome and toxicity. American Journal of Obstetrics and Gynecology. 1995;**172**:1881-1886

*Gynaecological Malignancies - Updates and Advances*

radiation therapy for the treatment of recurrent retroperitoneal and pelvic tumors: A single-institution analysis. Radiation Oncology. 2018;**13**:224-237

[31] Haddock MG, Petersen IA, Webb MJ. IORT for locally advanced malignancies. Frontiers of Radiation Therapy and Oncology. 1997;**31**:256-259

[32] Gemignani ML, Alektiar KM, Leitao M, et al. Radical surgical resection and high dose intraoperative radiotherapy in patients with recurrent gynecologic cancers. International Journal of Radiation Oncology, Biology,

[33] Stelzer KJ, Kohn WJ, Greer BE, et al. The use of intraoperative radiotherapy in radical salvage surgery for recurrent cervical cancer: Outcome and toxicity. American Journal of Obstetrics and Gynecology. 1995;**172**:1881-1886

Physics. 2001;**50**:687-694

**116**

### *Edited by Gwo Yaw Ho and Sophia Frentzas*

*"Gynaecological Malignancies - Updates and Advances"* aims to present a review of the significant advances in the understanding and management of gynaecological malignancies. Major areas of importance in this field will be covered, incorporating new knowledge that has arisen due to the advancements in molecular techniques and the ability to correlate these molecular changes with clinical behaviour of gynaecologic tumours. The therapeutic implications of molecular subtyping to match appropriate therapies and the appreciation of the use of up to date radiotherapy techniques will be explored.

Published in London, UK © 2020 IntechOpen © CIPhotos / iStock

Gynaecological Malignancies - Updates and Advances

Gynaecological Malignancies

Updates and Advances

*Edited by Gwo Yaw Ho and Sophia Frentzas*