|Year : 2013 | Volume
| Issue : 1 | Page : 17-21
Image-guided intensity-modulated whole abdominal radiation therapy in relapsed epithelial ovarian cancers: A feasibility study
Umesh Mahant Shetty1, Srikant Shankar1, Reena Engineer1, Supriya Chopra1, Sudeep Gupta2, Amita Maheshwari3, Rajendra Kerkar3, Shyam Kishore Shrivastava1
1 Department of Radiation Oncology, Tata Memorial Centre, Mumbai, India
2 Department of Medical Oncology, Tata Memorial Centre, Mumbai, India
3 Department of Gynecologic Oncology, Tata Memorial Centre, Mumbai, India
|Date of Web Publication||10-Apr-2013|
Umesh Mahant Shetty
Department of Radiation Oncology, Tata Memorial Centre, Dr. E. Borges Marg, Mumbai
Source of Support: None, Conflict of Interest: None
Background and Purpose: Advanced epithelial ovarian cancer is associated with high relapse rates. Various consolidative therapies, including whole abdominal radiationtherapy (WAR), have been tried in the past with limited success. We report here a feasibility study and clinical outcome of WAR with helical tomotherapy (HT).
Materials and Methods: Eight patients with relapsed carcinoma ovary after standard treatment and deemed not suitable for further chemotherapy were treated with WAR using HT. All patients underwent intensity-modulated radiotherapy (IMRT) planning process and a dose of 25Gy/25#, at 1Gy/# to the whole of the abdomen [abdominal planning treatment volume (PTV)] with a simultaneous boost of 45Gy/25#, at 1.8Gy/# to the pelvic PTV was prescribed.
Results: There was an excellent coverage in both abdominal and pelvic PTVs.The V 95% (volume covered by the 95% isodose) and V 107% (volume receiving 107% dose) was 95.6 (±2.7)% and 2.6 (±0.5)% for abdominal PTV and 95.7 (±2.4)% and 0% for pelvic PTV, respectively. With a median follow-up of 15 months (10-24 months, mean: 14 months), 3patients developed disease recurrence. All 3recurred in the peritoneum, one progressed to intestinal obstruction and fatal septicemia.
Conclusion: WAR in recurrent/relapsed epithelial ovarian cancer is feasible with acceptable toxicities.
Keywords: Epithelial ovarian cancer, helical tomotherapy-based image-guided IMRT, whole abdominal radiation
|How to cite this article:|
Shetty UM, Shankar S, Engineer R, Chopra S, Gupta S, Maheshwari A, Kerkar R, Shrivastava SK. Image-guided intensity-modulated whole abdominal radiation therapy in relapsed epithelial ovarian cancers: A feasibility study. J Can Res Ther 2013;9:17-21
|How to cite this URL:|
Shetty UM, Shankar S, Engineer R, Chopra S, Gupta S, Maheshwari A, Kerkar R, Shrivastava SK. Image-guided intensity-modulated whole abdominal radiation therapy in relapsed epithelial ovarian cancers: A feasibility study. J Can Res Ther [serial online] 2013 [cited 2019 Sep 15];9:17-21. Available from: http://www.cancerjournal.net/text.asp?2013/9/1/17/110343
| > Introduction|| |
Epithelial ovarian cancer (EOC) is a surface malignancy with predilection for transperitoneal and transcoelomic spread. Despite multiple surgeries and chemotherapy (standard treatment), 60%-70% abdominopelvic recurrences has been reported.  Various consolidative therapies, including systemic or intraperitoneal chemotherapy, radiation therapy,and so on, have been tried. [2-4] Radiation in the form of whole abdomen radiation therapy (WAR), either as adjuvant treatment after maximal safe cytoreductive surgery or as salvage after chemotherapy failures has been tried in the past with limited success. , Only a randomized trial by Sorbe et al. has reported a potential benefit in recurrence rates, progression-free survival, and overall survival with WAR as consolidation.Although effective, concerns with the use of WAR were inadequate coverage of large target volume and poor sparing of organs at risk (OAR) due to poor technology leading to significantly higher toxicities. , Traditionally, anterior/posterior beam arrangement was used with partial kidney and liver blocks, which produces a highly inhomogeneous dose distribution. , Moving strip technique was another method thatwas used for improving dose homogeneity but no major breakthrough either. 
In the past two decades, there have been significant advances in imaging and radiation technology (planning software and delivery), which are available for clinical use. Linear accelerator (LA)-based intensity-modulated radiotherapy (IMRT), volumetric intensity-modulated arc therapy (IMAT), and helical tomotherapy (HT) have shown potential to achieve uniform dose delivery to the target with significant sparing of OARs. ,,
A dosimetric outcome of HT-based IMRT for WAR in epithelial ovarian cancers has been reported by us recently.  HT achieves an excellent coverage with simultaneous pelvic boost and better organ sparing.  Also, HT has the advantages of treating longer field lengths, larger and complex volumes, including whole abdominal radiation fields.As part of a feasibility study, we report here the clinical outcome of epithelial ovarian cancer patients treated with WAR using HT-based IMRT with megavoltage computed tomography (MVCT) image guidance.
| > Materials and Methods|| |
Between April 2008 and June 2009 eight patients with relapsed carcinoma ovary were treated with WAR using HT-based IMRT with MVCT image guidance. Patients with relapse after definitive planned standard treatment who had disease confined to abdominopelvic region were considered for WAR. These patients received second-/third-line chemotherapy and were assessed for resection. Patients who underwent debulking surgery or deemed technically unresectable were consented for WAR. Out of 8 patients, 6 had firstrelapse and were treated with second-line chemotherapy and referred for radiation in view of small residual disease, whereas the remaining 2 had unresectable residual disease after neoadjuvant chemotherapy, maximal debulking surgery, and adjuvant chemotherapy. The first-line chemotherapy was paclitaxel (175mg/m 2 ) and carboplatin (area under the curve = 5) in all patients. As second-line, the CAP regimen (cyclophosphamide, doxorubicin, cisplatin) was used in 4 patients, and gemcitabine in 4. One patient had Cap etoposide as third-line treatment. Relapsed patients had a median disease-free interval of 10 months after first radical therapy. Residual disease/relapse/recurrence in the peritoneal cavity were diagnosed by 18-Fluorodeoxyglucose (18-FDG) Positron emission tomography-computed tomography (PET-CT) scans, and/or serum CA-125 levels. None of these patients had any extra-abdominal disease. Patient characteristics are detailed in [Table 1]. After obtaining a written informed consent, all these patients were planned for WAR with IMRT using HT. This study was approved by the ethics committee.
Whole abdominal radiation therapy
The protocol has been described in our previous report.  Patients were instructed about the planning process, bladder filling protocol (750-1000mL of oral water intake after emptying the bladder) and daily treatments.All these patients were positioned supine, immobilized in a vacuum cradle with knee rest. Forty-five minutes after emptying the bladder and water intake, a 5 mm planning CT imaging (Siemens Multi-slice Scanner) from mid-thorax to mid-thigh was performed.The CT datasets were transferred to Coherence Dosimetrist Planning Workstation and various target volumes and the organs at risk were contoured. The volumes defined were in keeping with the International Commission of Radiation Units and Measurements 50 and 62 definitions. The clinical target volume (CTV) consisted of the whole peritoneal cavity from the diaphragm to the vaginal vault/pouch of Douglas. It was divided into abdomen and pelvis. The abdominal CTV consisted of the capsule of the liver (1 cm rim), the undersurface of the liver, the mesentery and bowel, anterolateral surfaces of both kidneys, and the abdominal surface of the diaphragm. The planning treatment volume (PTV) was drawn with differential margins, 1.5 cm cranially (to account for diaphragm movements) and 0.5-0.7 cm in the other directions. The pelvic CTV consisted of the peritoneal cavity from L5-S1 junction to include the pouch of Douglas, the pelvic lymph nodes, and the vaginal vault. The PTV was created by adding a 1cm margin in the caudal direction, and 0.5-0.7cm in the others. The organs at risk were the kidneys (minus the anterolateral surfaces included in the CTV) the rectum, bladder and bone marrow (of ribs, vertebrae, femoral heads, and pelvic bones). A structure called "Normal liver" was drawn just inside the liver PTV to account (or control) for doses in the liver. These contoured CT datasets were then transferred to the Hi-Art Tomotherapy Treatment Planning Workstation (Version 2.2, TomoTherapy Inc., Madison, WI, USA). IMRT plans were made based on HT in all the 8 patients. The prescribed dose was 25Gy/25#, at 1Gy/# to the whole of the abdomen (abdominal PTV), with a simultaneous boost of 45Gy/25#, at 1.8Gy/# to the pelvic PTV. Treatment was given 5#/week over 5 weeks. HT plans were obtained using a field width of 2.5 and 5.0 cm and a modulation factor of 3.0 and 3.5, respectively. A pitch factor of 0.3 was used for all the plans. Daily megavoltage CT scans using 3.5 MV were obtained for registration and positioning accuracy and matched for the kidneys and vertebral bodies [Figure 1].
|Figure 1: Illustration showing a helical tomotherapy based intensity-modulated radiotherapywhole abdominal radiation therapy plan|
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The patients were monitored weekly during radiotherapy.Complete blood counts/renal function tests/liver function tests/serum electrolytes were obtained weekly. Toxicities, whether acute or late, were classified according to the CTC Version 3. All these patients were followed up at intervals of 3 months after the completion of radiotherapy, with CA-125 levels and 18-FDG PET-CT scans.
| > Results|| |
All the 8 patients completed the planned treatment and were available for outcome analysis. None of the patients had any major treatment-related breaks (radiation treatment break>4 consecutive fractions). The dosimetric outcome has been reported in detail elsewhere.  The mean (range) abdominal and pelvic PTV volumes were 6630 (6190-7135) cm 3 , and 1235 (1100-1456) cm 3 , respectively. There was an excellent coverage in both abdominal and pelvic PTVs. The V 95% [volume covered by the 95% isodose ± standard deviation (SD)] and V 107% (volume receiving 107% dose± SD) was 95.6 (±2.7)% and 2.6 (±0.5)% for abdominal PTV and 95.7 (±2.4)% and 0% for pelvic PTV, respectively. Mean and median doses received by the kidneys were 10.8 (±0.8) Gy and 9.6 (±1.2) Gy, whereasthe median dose received by the "normal liver" and whole liver were 17 (±2.7) Gy and 24.1 (±2.6) Gy, respectively. The meanand median of bone marrow were 24.1(±1.6) Gy and 22 (±1.4) Gy, respectively. The mean and median doses to heart were14 (±2.2) Gy and 13.1(±1.2) Gy, respectively. The mean dosesofthe bladder and rectum werefound to be 39.3 (±2.1) Gy and 40.5 (±1.2) Gy, respectively. The spinal cord received a mean dose of 11.5±1.7Gy and a median of 12.8±1.1Gy [Figure 2].
[Table 2] shows the details of acute toxicities. No treatment-related deaths were reported. Acute toxicities were essentially hematologic and gastrointestinal. Hematologic toxicity was seen in 3 patients. Two patients developed thrombocytopenia one each with grades 3 and 4, while 1 patient had Grade 3 leukopenia.Patient with Grade 4 thrombocytopenia had a radiation treatment break of 2 days and received platelet transfusions. Acute Grade 2 nausea and vomiting was seen in 3 patients. Two patients had deranged (Grade 2 CTC) liver functions during the 3 rd -4 th week of radiation and resolved spontaneously. None of the patients developed any renal dysfunction on weekly monitoring during treatment. One patient underwent surgical exploration for intestinal obstruction at 14 months postradiation period, which turned out to be due to disease and died.
With a median follow-up of 15 months (10-24 months, mean: 14 months), 3 patients developed disease recurrence [Table 3]. All the 3 patients had a component of abdominal relapse, one progressed to intestinal obstruction and fatal septicemia at 14 months posttreatment. The second patient developed lung metastases in 6 months posttreatment period and defaulted for any further treatment (considered dead due to disease). The third patient progressed in the vaginal vault and also showed a portocaval node on imaging at 8 months posttreatment period. She is currently on palliative chemotherapy. CA-125 levels in these 3 patients initially came down to baseline, but only to rise again consistent with their disease relapse/progression. All the other 5 patients (assessed by PET-CT and CA-125 levels) were diseasefree at last follow-up.
| > Discussion|| |
Advanced (Stage II and III) epithelial ovarian cancer has an aggressive course, and inspite of equally aggressive initial treatments, is associated with high relapse rates, especially in the abdominal cavity. Consolidative therapies attempted in the past have had limited success. , As detailed in the introduction, WAR with old radiation technology had its limitations. , Nevertheless, the only randomized trial in WAR till date by Sorbe et al.,  has reported a 20% benefit in progression-free survival (PFS) in patients treated with WAR and pelvic boost (56% PFS at 5years) compared withpatients treated with consolidation chemotherapy (36% PFS at 5 years) and untreated patients (35% at 5 years), but had a high incidence of treatment-related toxicities due to conventional radiotherapy techniques. The lack of power of this study led to the conclusion that further larger randomized studies are needed to explore the role of WAR in epithelial ovarian cancers. Also, NIH Consensus Development Conference recommended that WAR be re-evaluated and newer radiation techniques be assessed in the treatment of optimally debulked Stage II and III ovarian cancers. WAR with newer radiation technology has been sparingly reported. ,,,,,
Patients with epithelial ovarian cancers receive chemotherapy after surgery. They receive further second-/third-/fourth-line chemotherapy for relapses subsequently. Hence preservation of hepatorenal functions and bone marrow reserves become vital for patients being planned for large field abdominal radiation. Although Duthoy et al. pioneered the use of IMRT for WAR,  Rochetet al. were the first to report WAR using HT, and have shown that IMRT is feasible both in terms of organ sparing (liver, bones,and kidneys), target coverage, and good early clinical outcome. 
In our experience so far, HT-based IMRT with MVCT image guidance enabled proper documentation, compilation, and correction of set-up errors andintrafraction and interfraction errors as reported by Rochet et al. In our series, we obtained highly conformal dose distributions covering the whole peritoneal cavity, including the capsule of the liver, the undersurface of the liver, and a simultaneous pelvic boost. In our previous report, the dosimetric parameters achieved have been discussed in detail.  In summary, our dosimetric data showed an excellent sparing of the OARs, including liver, kidneys, bone marrow (except pelvic region), which was essentially our goal and is comparable to reported literature so far. ,,,
The acute hematologic and gastrointestinaltoxicities were similar, except that 1 patient in our protocol had Grade 4 thrombocytopenia. These patients recovered with supportive care, none requiring active intervention. In late toxicities, however, we seem to have had better results with only 1of 8 patients had to be surgically explored for intestinal obstruction (more due to disease), whereas Rochet et al. reported in 3 of 10 patients.  However, longer follow-up is necessary to report late sequelae. Various dose levels for varying indications (consolidation/salvage/palliative) have been used in the past. , The current feasibility study has reported WAR as salvage therapy in 8 patients. A dose of 45Gy was prescribed to the pelvis, as the pelvis is the major site of relapse and higher radiation doses are welltolerated by it. The literature review of dose-response suggests that WAR of more than 22.5Gy is associated with higher small bowel complications requiring surgeries. , Hence a dose of 25Gy to whole abdomen and simultaneous boost to pelvis to a total dose of 45Gy was planned. Although in our series we used 25Gy to the whole abdomen, the clinical outcome was comparable to the reported series,  with 3 of 8(37.5%) patients relapsed in our study as compared with 4/10 (40%) patients as reported by Rochet et al.
In our series, whole abdominal dose of 25Gy may not be sufficient to palliate the disease in the relapse setting; however, this dose may be sufficient in the consolidation setting thatis being tested in our ongoing phase II study. Recently, the Ghent group have reported on the clinical outcome in a series of 13 patients (who had been pretreated with surgery and chemotherapy) treated with IMAT to a dose of 33Gy/22# and showed a 70% response rate. Six patients with subacute or acute intestinal obstruction were also included, and of these 4 had complete symptom response. The 6-month abdominopelvicPFS rate was 29%, whereas the 6-month overall survival rate was 60%. 
WAR in recurrent/relapsed epithelial ovarian cancer is feasible with acceptable toxicities. Although we report its use in recurrent/relapse ovarian cancers confined to abdominopelvic region, the outcome is still modest and encouraging reiterating the principle that WAR with newer radiation techniques is feasible. With these encouraging results, WAR with IMRT using HT, as consolidation therapy is ongoing in Stage III epithelial ovarian cancers.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]