Original Article
NRG Oncology/RTOG 0921: A Phase 2 Study of Postoperative Intensity-Modulated Radiotherapy With Concurrent Cisplatin and Bevacizumab Followed by Carboplatin and Paclitaxel for Patients With Endometrial Cancer Akila N. Viswanathan, MD, MPH1; Jennifer Moughan, MS2; Brigitte E. Miller, MD3; Ying Xiao, PhD4; Anuja Jhingran, MD5; Lorraine Portelance, MD6; Walter R. Bosch, DSc7; Ursula A. Matulonis, MD8; Neil S. Horowitz, MD9; Robert S. Mannel, MD10; Luis Souhami, MD11; Beth A. Erickson, MD12; Kathryn A. Winter, MS2; William Small Jr, MD13; and David K. Gaffney, MD, PhD14
BACKGROUND: The current study was conducted to assess acute and late adverse events (AEs), overall survival (OS), pelvic failure, regional failure, distant failure, and disease-free survival in a prospective phase 2 clinical trial of bevacizumab and pelvic intensitymodulated radiotherapy (IMRT) with chemotherapy in patients with high-risk endometrial cancer. METHODS: Patients underwent a hysterectomy and lymph node removal, and had 1 of the following high-risk factors: grade 3 carcinoma with >50% myometrial invasion, grade 2 or 3 disease with any cervical stromal invasion, or known extrauterine extension confined to the pelvis. Treatment included pelvic IMRT and concurrent cisplatin on days 1 and 29 of radiation and bevacizumab (at a dose of 5 mg/kg on days 1, 15, and 29 of radiation) followed by adjuvant carboplatin and paclitaxel for 4 cycles. The primary endpoint was grade 3 AEs occurring within the first 90 days (toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). RESULTS: A total of 34 patients were accrued from November 2009 through December 2011, 30 of whom were eligible and received study treatment. Seven of 30 patients (23.3%; 1-sided 95% confidence interval, 10.6%-36.0%) developed grade 3 treatment-related nonhematologic toxicities within 90 days; an additional 6 patients experienced grade 3 toxicities between 90 and 365 days after treatment. The 2-year OS rate was 96.7% and the disease-free survival rate was 79.1%. No patient developed a within-field pelvic failure and no patients with International Federation of Gynecology and Obstetrics stage I to IIIA disease developed disease recurrence after a median follow-up of 26 months. CONCLUSIONS: Postoperative bevacizumab added to chemotherapy and pelvic IMRT appears to be well tolerated and results in high OS rates at 2 years for patients with high-risk endometrial carcinoma. C 2015 American Cancer Society. Cancer 2015;121:2156-63. V KEYWORDS: endometrial cancer, radiation, bevacizumab, chemotherapy, intensity-modulated radiotherapy (IMRT).
INTRODUCTION Endometrial cancer is the most common cancer of the female reproductive organs diagnosed in the United States. Greater than 50,000 women are diagnosed annually, with the majority presenting with early-stage disease that is curable by surgery alone.1 Nevertheless, >8000 women die of the disease each year due to a combination of local and distant failures.1 Prior studies have indicated that pelvic external beam radiation may reduce the risk of local disease recurrence in high-risk patients, whereas chemotherapy may decrease the risk of distant metastasis. In the Gynecologic Oncology Group randomized trial, chemotherapy was associated with reduced distant metastases (22% vs. 18%) in patients with FIGO stage III/IV disease,2 but not in patients with stage I/II disease.3 The Radiation Therapy Oncology Group (RTOG) 9708 phase 2 clinical trial treated women with high-risk endometrial cancer with pelvic radiation and concurrent cisplatin, followed by additional chemotherapy with cisplatin and paclitaxel. Results demonstrated a low rate of local disease recurrence (2%), but a high rate of distant metastases (19%).4 Given these and other findings, it was postulated that the addition of
Corresponding author: Akila N. Viswanathan, MD, MPH, Department of Radiation Oncology, Brigham and Women’s Hospital, 75 Francis St; L2, Boston, MA 02115; Fax: (617) 278-6988; [email protected] 1 Department of Radiation Oncology, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; 2NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania; 3Carolinas Healthcare System NorthEast, Levine Cancer Institute, Concord, North Carolina; 4 Thomas Jefferson University Hospital, Philadelphia, Pennsylvania; 5The University of Texas MD Anderson Cancer Center, Houston, Texas; 6University of Miami Miller School of Medicine, Miami, Florida; 7Washington University, St. Louis, Missouri; 8Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; 9Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston, MA; 10University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; 11McGill University, Montreal, Quebec, Canada; 12Medical College of Wisconsin, Milwaukee, Wisconsin; 13Loyola University, Chicago, Illinois; 14University of Utah Health Science Center, Salt Lake City, Utah
DOI: 10.1002/cncr.29337, Received: December 29, 2014; Accepted: February 4, 2015, Published online April 6, 2015 in Wiley Online Library (wileyonlinelibrary. com)
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bevacizumab, an antiangiogenic agent, may further reduce the risk of distant metastases. With prior trials demonstrating the feasibility of using pelvic intensity-modulated radiotherapy (IMRT) in postoperative patients,5 IMRT was chosen in the hope of reducing the incidence or severity of bowel toxicity, which might be exacerbated by treatment with bevacizumab. The primary objective of the current trial was to assess the rates of grade 3, nonhematologic, treatmentrelated adverse events (AEs) within 90 days from the initiation of treatment when administering concurrent bevacizumab, cisplatin, and IMRT followed by chemotherapy with carboplatin and paclitaxel in patients with high-risk endometrial cancer. The secondary objectives were to evaluate treatment-related AEs occurring within 1 year from the initiation of treatment; all treatment-related AEs; disease-free survival (DFS) and overall survival (OS); and local, regional (RF), and distant (DF) failure. The 2year efficacy rates are reported.
MATERIALS AND METHODS Eligibility Requirements for RTOG 0921
A hysterectomy and bilateral salpingo-oophorectomy must have been completed within 56 days before study entry with pathologic confirmation of uterine cancer meeting 1 of the following criteria: grade 3 carcinoma with >50% myometrial invasion (all papillary serous and clear cell carcinomas were considered to be grade 3); grade 2 or 3 carcinoma with any cervical stromal invasion; or known extrauterine disease confined to the pelvis, any grade. The following histologies were allowed: endometrioid endometrial adenocarcinoma, clear cell carcinoma, papillary serous adenocarcinoma, adenosquamous carcinoma, or other adenocarcinoma variant. All patients had a Zubrod performance status of 0 to 1, were 18 years old, and were able to provide study-specific informed consent. Patients must have had adequate bone marrow, renal, and hepatic function as indicated by the following laboratory assessments within 21 days before study entry: absolute neutrophil count 1500 cells/mm3 without the use of growth factors, platelet count 100,000/mm3, serum creatinine 1.5 mg/dL, total bilirubin 1.5 times the institutional upper normal limit, hemoglobin 10 g/ dL (transfusion may have been used to meet this criterion), aspartate aminotransferase and alanine aminotransferase 2 times the institutional upper normal limit, international normalized ratio 0.5, 24-hour urine protein was obtained and should have been 56 days before study registration, 1 had positive peritoneal cytology, and 1 had urinary protein creatinine >1 mg/dL). Detailed baseline patient characteristics of the 30 patients included in the analysis are listed in Table 1. A total of 29 of 30 patients underwent bilateral pelvic lymph node dissection and 19 had paraaortic lymph node removal. Protocol Treatment Compliance
Approximately 93% of patients were treated as per protocol with concurrent chemotherapy and 90% received their adjuvant chemotherapy as per protocol. All patients received bevacizumab in full and on time. RT compliance was assessed in terms of whether physician contours of the tumor volume and organs at risk, which underwent rapid review within 24 hours, followed the protocol-recommended contouring guidelines. For tumor volume contouring, 23 patients were as per protocol and 7 (23%) had an acceptable variation. For contouring of organs at risk, 27 patients were considered as per protocol whereas 3 patients (10%) had acceptable variations. Bladder, sigmoid, femur, and tumor volume were all contoured as per protocol on final submission (after rapid review for institutional first case). Barium contrast given by mouth to opacify the small bowel was allowed at the physician’s discretion. Two patients (6.7%) had unacceptable deviations on small-bowel contouring, in which the bowel loops were contoured instead of the bowel space; in the other 28 cases, the small bowel was contoured as per protocol. One patient had an acceptable variation on rectum contouring, with the inferior portion of the rectal contour overlapping the vaginal integrated target volume; the other 29 rectal contours were as per protocol. Compliance was also assessed with regard to treatment planning, with assessments of whether the lymph Cancer
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Concurrent Bev With Pelvic IMRT for Endometrial Ca/Viswanathan et al
TABLE 2. Tumor and Normal-Tissue Dose-Volume Analysis Criteria and Score Statistics Structure
Per Protocol
Variation Acceptable
Deviation Unacceptable
0.03 cc of PTV with 93% of prescribed dose
43% (13)
0.03 cc of PTV with 91% to 60% receives >45 Gy and 0.03 cc receives >65 Gy >35% receives >50 Gy and 0.03 cc receives >65 Gy >50% receives >35 Gy and 0.03 cc receives >65 Gy
PTV
0% (0)
0% (0)
0% (0)
Abbreviations: Gy, gray; PTV, planning target volume.
node and vaginal PTV and bladder, rectum, femoral heads, and bowel planned doses met the protocol-set dose limits. With regard to treatment planning, 5 cases had “deviation unacceptable” (>0.03 cc of PTV receiving 0.03 cc of PTV receiving 91%-93% of prescription) scores for the tumor dose-volume analysis, due to the minimum dose requirements. For normal tissues, only 1 “deviation unacceptable” score was recorded for small bowel and no “deviation unacceptable” cases were noted for bladder, rectum, or femoral heads, although 12 patients had acceptable variations for the dose-volume analysis recorded (Table 2). Primary Endpoint Acute adverse events
Of the 30 patients, 7 (23.3%; 1-sided 95% CI, 10.6%36.0%) developed grade 3, treatment-related, nonhematologic AEs 90 days from the initiation of concurrent treatment (ie, acute AEs). Table 3 lists the grade 3 and 4 side effects, including hematologic toxicity, in detail. Because the 1-sided, upper-bound CI for the rate of grade 3, treatment-related, nonhematologic AEs occurring 90 days from the initiation of concurrent treatment is 36%, there is 95% confidence that the true grade 3, nonhematologic, treatment-related AE rate is 90 days but 365 days from the initiation of concurrent treatment are Cancer
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listed in Table 4. Nine patients reported late AEs, 3 of whom also had acute toxicities. AEs occurring during concurrent treatment, during adjuvant chemotherapy treatment, and after the end of all treatments are shown in Table 5. One late toxicity, epistaxis, was considered possibly attributable to bevacizumab. Survival outcomes
The median follow-up for all patients was 25.9 months (range, 13.6-43.4 months). The 2-year estimate of OS was 96.7% (95% CI, 78.6%-99.5%) with a total of 4 deaths, all of which were from endometrial cancer. None of the 30 patients enrolled developed a within-field pelvic-only failure. The cumulative incidences for RF and DF at 2 years were 7.2% (95% CI, 0.0%-17.1%) and 17% (95% CI, 3.2%-30.9%), respectively. The 2-year estimate of DFS was 79.1% (95% CI, 59.2%-90.1%). A total of 6 patients developed recurrent disease. Two of the 6 had paraaortic lymph node failures; 1 of these patients also developed distant lymph node metastases and both patients subsequently died. One of the 2 patients with paraaortic lymph node failure had undergone a paraaortic lymph node dissection at the time of diagnosis; both had undergone pelvic lymph node lymphadenectomy at the time of diagnosis. Two of the other 4 patients died of distant disease. The remaining 2 patients were alive with DF at the time of last follow-up; 1 patient continued to receive chemotherapy and the other developed a 1-cm recurrence in the peritoneum above the pelvic field at a laparoscopic port site, which was resected laparoscopically with negative surgical margins. This individual continued to receive therapy with megestrol acetate and had been 2159
Original Article TABLE 3. Adverse Events Grade 3 Occurring Within the First 90 Days From the Initiation of Concurrent Treatment (Acute Events) System Organ Class Nervous system disorders General disorders and administration site conditions Nervous system disorders Vascular disorders Metabolism and nutrition disorders Infections and infestations Reproductive system and breast disorders Investigations Blood and lymphatic system disorders General disorders and administration site conditions
Term
Gradea
Relationship to Treatment
Days From Concurrent Rx Start
Headache Fatigue Syncope Thromboembolic eventb Hyponatremia Hyperglycemia Vaginal infection Vaginal inflammation ALT increased Febrile neutropenia Fatigue
3 3 3 4 3 3 3 3 3 4 3
Probable Probable Possible Probable Probable Possible Probable Possible Possible Probable Possible
78 85 89 42 55 90 28 27 12 88 4
Abbreviations: ALT, alanine aminotransferase; Rx, treatment. a Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). b Most likely attributable to bevacizumab.
TABLE 4. Adverse Events Grade 3 Occurring Within >90 Days But 365 Days From the Initiation of Concurrent Treatment (Late Events) System Organ Class General disorders and administration site conditions Metabolism and nutrition disorders Respiratory, thoracic, and mediastinal disorders Nervous system disorders Metabolism and nutrition disorders Vascular disorders General disorders and administration site conditions Ear and labyrinth disorders Metabolism and nutrition disorders Nervous system disorders Infections and infestations
Term
Gradea
Relationship to Treatment
Days From Concurrent Rx Start
Fatigue Hypomagnesemia Hypokalemia Epistaxisb Headache Hyponatremia Hot flashes Pain Hearing impaired Hypokalemia Neuralgia Skin infection
3 4 3 3 3 3 3 3 3 4 3 3
Probable Possible Possible Probable Probable Possible Definite Possible Probable Probable Possible Possible
105 183 168 176 98 98 300 180 333 136 126 126
Abbreviation: Rx, treatment. a Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). b Most likely attributable to bevacizumab.
TABLE 5. Summary of Worst Adverse Event per Patient (Definitely, Probably, or Possibly Related to Treatment) Comparing RTOG 9708 With RTOG 0921 AEs 90 Days From the Initiation of All Rxa Gradee 1 2 3 4 5
AEs >90 Days From the Initiation of All Rxb
AEs Occurring During Concurrent Rxc
RTOG 0921
RTOG 0921
RTOG 9708
RTOG 0921
0 (0%) 10 (33%) 11 (37%) 5 (17%) 0 (0%)
3 (10%) 10 (33%) 9 (30%) 6 (20%) 0 (0%)
9 (20%) 17 (39%) 7 (16%) 1 (2%) 0 (0%)
1 (3%) 9 (30%) 7 (23%) 2 (7%) 0 (0%)
RTOG 9708 12 19 12 1 0
AEs Occurring During Adjuvant Chemotherapyd RTOG 0921
RTOG 9708
0 (0%) 6 (20%) 12 (40%) 6 (20%) 0 (0%)
3 (7%) 3 (7%) 9 (21%) 26 (62%) 0 (0%)
(27%) (43%) (27%) (2%) (0%)
Abbreviations: AE, adverse event; RTOG, Radiation Therapy Oncology Group; Rx, treatment. a The AE date was the start of all treatment 190 days. b The AE date was > the start of all treatment 190 days. c Concurrent treatment start date AE date concurrent treatment end date. d Adjuvant treatment start date AE date adjuvant treatment end date. e Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0).
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TABLE 6. Characteristics of Patients With Recurrent Disease Patient No.
FIGO Stage
Histology
First Disease Recurrence
1 2 3 4 5 6
IIIC1 IIIC1 IIIC1G2 IIIC1G3 IIIBG3 IIIAG1
UPSC UPSC EAC EAC EAC EAC
Regional Regional Distant Distant Distant Distant
Areas of Spread
Time From First Disease Recurrence to Death, Months
Paraaortic lymph node Paraaortic lymph node Lung, bone, brain Lung Lung Abdominal
10 4 8 6 Alive Alive
Abbreviations: EAC, endometrioid endometrial adenocarcinoma; FIGO, International Federation of Gynecology and Obstetrics; UPSC, uterine papillary serous adenocarcinoma.
disease free for 2 years at the time of last follow-up. Detailed characteristics of the patients with disease recurrence are shown in Table 6. DISCUSSION This phase 2 prospective trial demonstrates the feasibility of administering bevacizumab with pelvic IMRT followed by combination chemotherapy with carboplatin and paclitaxel in patients with high-risk endometrial cancer. The rate of acute grade 3, nonhematologic, treatmentrelated toxicity was 23.3% and the hypothesis that the true rate of such AEs is 45 Gy is smaller with IMRT than with wholepelvic radiation. Portelance et al reported a >60% reduction in the volume of small bowel irradiated to >45 Gy with IMRT.18 A study by Roeske et al demonstrated a 50% reduction in the volume of small bowel irradiated to >45 Gy.19 Overall, the rate of grade 3 toxicity reported during concurrent treatment in the RTOG 9708 trial (3dimensional conformal pelvic radiation and concurrent cisplatin chemotherapy followed by adjuvant cisplatin and paclitaxel) was 30%. To determine whether IMRT may be of benefit in reducing this rate, toxicities occurring during RT in the current study (RTOG 0921) were compared with those of the precursor trial RTOG 9708. In RTOG 9708, during the concurrent portion of the treatment, 43% of participants had grade 2, 27% had grade 3, and 2% had grade 4 acute toxicity; in the current RTOG 0921 trial, these rates were 30%, 23%, and 7%, respectively. It is interesting to note that although the systems are similar, toxicity in RTOG 9708 was assessed according to the Cooperative Group Common Toxicity Criteria (1989), the Acute Radiation Morbidity Scoring Criteria, and the Late Radiation Morbidity Scoring 2162
Scheme of the RTOG and the European Organisation for Research and Treatment of Cancer, whereas the current trial used the subsequent the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0), which developed from the preceding scales. Prospective results from the ongoing RTOG 1203 TIME-C randomized trial may help to clarify whether IMRT reduces toxicity compared with 3-dimensional conformal radiation. Compared with the RTOG 0418 trial, which was a prospective series of patients treated with postoperative pelvic IMRT, the less strict dose-volume histogram (DVH) criteria used in the current trial resulted in higher compliance for constraints. In the RTOG 0418 trial, dose criteria were not met in 67% of cases for the bladder, in 76% of cases for the rectum, and in 17% of cases for the bowel. In comparison, in the current trial, dose criteria were not met in 14% of cases (4 of 29 cases) for the bladder, in 24% of cases (7 of 29 cases) for the rectum, and in 14% of cases (4 of 28 cases) for the bowel. To illustrate the effect of stringency, the femoral head constraint in the RTOG 0921 trial was met in all cases (all had a DVH value of 15% receiving
NRG Oncology/RTOG 0921: A Phase 2 Study of Postoperative Intensity-Modulated Radiotherapy With Concurrent Cisplatin and Bevacizumab Followed by Carboplatin and Paclitaxel for Patients With Endometrial Cancer Akila N. Viswanathan, MD, MPH1; Jennifer Moughan, MS2; Brigitte E. Miller, MD3; Ying Xiao, PhD4; Anuja Jhingran, MD5; Lorraine Portelance, MD6; Walter R. Bosch, DSc7; Ursula A. Matulonis, MD8; Neil S. Horowitz, MD9; Robert S. Mannel, MD10; Luis Souhami, MD11; Beth A. Erickson, MD12; Kathryn A. Winter, MS2; William Small Jr, MD13; and David K. Gaffney, MD, PhD14
BACKGROUND: The current study was conducted to assess acute and late adverse events (AEs), overall survival (OS), pelvic failure, regional failure, distant failure, and disease-free survival in a prospective phase 2 clinical trial of bevacizumab and pelvic intensitymodulated radiotherapy (IMRT) with chemotherapy in patients with high-risk endometrial cancer. METHODS: Patients underwent a hysterectomy and lymph node removal, and had 1 of the following high-risk factors: grade 3 carcinoma with >50% myometrial invasion, grade 2 or 3 disease with any cervical stromal invasion, or known extrauterine extension confined to the pelvis. Treatment included pelvic IMRT and concurrent cisplatin on days 1 and 29 of radiation and bevacizumab (at a dose of 5 mg/kg on days 1, 15, and 29 of radiation) followed by adjuvant carboplatin and paclitaxel for 4 cycles. The primary endpoint was grade 3 AEs occurring within the first 90 days (toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). RESULTS: A total of 34 patients were accrued from November 2009 through December 2011, 30 of whom were eligible and received study treatment. Seven of 30 patients (23.3%; 1-sided 95% confidence interval, 10.6%-36.0%) developed grade 3 treatment-related nonhematologic toxicities within 90 days; an additional 6 patients experienced grade 3 toxicities between 90 and 365 days after treatment. The 2-year OS rate was 96.7% and the disease-free survival rate was 79.1%. No patient developed a within-field pelvic failure and no patients with International Federation of Gynecology and Obstetrics stage I to IIIA disease developed disease recurrence after a median follow-up of 26 months. CONCLUSIONS: Postoperative bevacizumab added to chemotherapy and pelvic IMRT appears to be well tolerated and results in high OS rates at 2 years for patients with high-risk endometrial carcinoma. C 2015 American Cancer Society. Cancer 2015;121:2156-63. V KEYWORDS: endometrial cancer, radiation, bevacizumab, chemotherapy, intensity-modulated radiotherapy (IMRT).
INTRODUCTION Endometrial cancer is the most common cancer of the female reproductive organs diagnosed in the United States. Greater than 50,000 women are diagnosed annually, with the majority presenting with early-stage disease that is curable by surgery alone.1 Nevertheless, >8000 women die of the disease each year due to a combination of local and distant failures.1 Prior studies have indicated that pelvic external beam radiation may reduce the risk of local disease recurrence in high-risk patients, whereas chemotherapy may decrease the risk of distant metastasis. In the Gynecologic Oncology Group randomized trial, chemotherapy was associated with reduced distant metastases (22% vs. 18%) in patients with FIGO stage III/IV disease,2 but not in patients with stage I/II disease.3 The Radiation Therapy Oncology Group (RTOG) 9708 phase 2 clinical trial treated women with high-risk endometrial cancer with pelvic radiation and concurrent cisplatin, followed by additional chemotherapy with cisplatin and paclitaxel. Results demonstrated a low rate of local disease recurrence (2%), but a high rate of distant metastases (19%).4 Given these and other findings, it was postulated that the addition of
Corresponding author: Akila N. Viswanathan, MD, MPH, Department of Radiation Oncology, Brigham and Women’s Hospital, 75 Francis St; L2, Boston, MA 02115; Fax: (617) 278-6988; [email protected] 1 Department of Radiation Oncology, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; 2NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania; 3Carolinas Healthcare System NorthEast, Levine Cancer Institute, Concord, North Carolina; 4 Thomas Jefferson University Hospital, Philadelphia, Pennsylvania; 5The University of Texas MD Anderson Cancer Center, Houston, Texas; 6University of Miami Miller School of Medicine, Miami, Florida; 7Washington University, St. Louis, Missouri; 8Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; 9Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston, MA; 10University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; 11McGill University, Montreal, Quebec, Canada; 12Medical College of Wisconsin, Milwaukee, Wisconsin; 13Loyola University, Chicago, Illinois; 14University of Utah Health Science Center, Salt Lake City, Utah
DOI: 10.1002/cncr.29337, Received: December 29, 2014; Accepted: February 4, 2015, Published online April 6, 2015 in Wiley Online Library (wileyonlinelibrary. com)
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bevacizumab, an antiangiogenic agent, may further reduce the risk of distant metastases. With prior trials demonstrating the feasibility of using pelvic intensity-modulated radiotherapy (IMRT) in postoperative patients,5 IMRT was chosen in the hope of reducing the incidence or severity of bowel toxicity, which might be exacerbated by treatment with bevacizumab. The primary objective of the current trial was to assess the rates of grade 3, nonhematologic, treatmentrelated adverse events (AEs) within 90 days from the initiation of treatment when administering concurrent bevacizumab, cisplatin, and IMRT followed by chemotherapy with carboplatin and paclitaxel in patients with high-risk endometrial cancer. The secondary objectives were to evaluate treatment-related AEs occurring within 1 year from the initiation of treatment; all treatment-related AEs; disease-free survival (DFS) and overall survival (OS); and local, regional (RF), and distant (DF) failure. The 2year efficacy rates are reported.
MATERIALS AND METHODS Eligibility Requirements for RTOG 0921
A hysterectomy and bilateral salpingo-oophorectomy must have been completed within 56 days before study entry with pathologic confirmation of uterine cancer meeting 1 of the following criteria: grade 3 carcinoma with >50% myometrial invasion (all papillary serous and clear cell carcinomas were considered to be grade 3); grade 2 or 3 carcinoma with any cervical stromal invasion; or known extrauterine disease confined to the pelvis, any grade. The following histologies were allowed: endometrioid endometrial adenocarcinoma, clear cell carcinoma, papillary serous adenocarcinoma, adenosquamous carcinoma, or other adenocarcinoma variant. All patients had a Zubrod performance status of 0 to 1, were 18 years old, and were able to provide study-specific informed consent. Patients must have had adequate bone marrow, renal, and hepatic function as indicated by the following laboratory assessments within 21 days before study entry: absolute neutrophil count 1500 cells/mm3 without the use of growth factors, platelet count 100,000/mm3, serum creatinine 1.5 mg/dL, total bilirubin 1.5 times the institutional upper normal limit, hemoglobin 10 g/ dL (transfusion may have been used to meet this criterion), aspartate aminotransferase and alanine aminotransferase 2 times the institutional upper normal limit, international normalized ratio 0.5, 24-hour urine protein was obtained and should have been 56 days before study registration, 1 had positive peritoneal cytology, and 1 had urinary protein creatinine >1 mg/dL). Detailed baseline patient characteristics of the 30 patients included in the analysis are listed in Table 1. A total of 29 of 30 patients underwent bilateral pelvic lymph node dissection and 19 had paraaortic lymph node removal. Protocol Treatment Compliance
Approximately 93% of patients were treated as per protocol with concurrent chemotherapy and 90% received their adjuvant chemotherapy as per protocol. All patients received bevacizumab in full and on time. RT compliance was assessed in terms of whether physician contours of the tumor volume and organs at risk, which underwent rapid review within 24 hours, followed the protocol-recommended contouring guidelines. For tumor volume contouring, 23 patients were as per protocol and 7 (23%) had an acceptable variation. For contouring of organs at risk, 27 patients were considered as per protocol whereas 3 patients (10%) had acceptable variations. Bladder, sigmoid, femur, and tumor volume were all contoured as per protocol on final submission (after rapid review for institutional first case). Barium contrast given by mouth to opacify the small bowel was allowed at the physician’s discretion. Two patients (6.7%) had unacceptable deviations on small-bowel contouring, in which the bowel loops were contoured instead of the bowel space; in the other 28 cases, the small bowel was contoured as per protocol. One patient had an acceptable variation on rectum contouring, with the inferior portion of the rectal contour overlapping the vaginal integrated target volume; the other 29 rectal contours were as per protocol. Compliance was also assessed with regard to treatment planning, with assessments of whether the lymph Cancer
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Concurrent Bev With Pelvic IMRT for Endometrial Ca/Viswanathan et al
TABLE 2. Tumor and Normal-Tissue Dose-Volume Analysis Criteria and Score Statistics Structure
Per Protocol
Variation Acceptable
Deviation Unacceptable
0.03 cc of PTV with 93% of prescribed dose
43% (13)
0.03 cc of PTV with 91% to 60% receives >45 Gy and 0.03 cc receives >65 Gy >35% receives >50 Gy and 0.03 cc receives >65 Gy >50% receives >35 Gy and 0.03 cc receives >65 Gy
PTV
0% (0)
0% (0)
0% (0)
Abbreviations: Gy, gray; PTV, planning target volume.
node and vaginal PTV and bladder, rectum, femoral heads, and bowel planned doses met the protocol-set dose limits. With regard to treatment planning, 5 cases had “deviation unacceptable” (>0.03 cc of PTV receiving 0.03 cc of PTV receiving 91%-93% of prescription) scores for the tumor dose-volume analysis, due to the minimum dose requirements. For normal tissues, only 1 “deviation unacceptable” score was recorded for small bowel and no “deviation unacceptable” cases were noted for bladder, rectum, or femoral heads, although 12 patients had acceptable variations for the dose-volume analysis recorded (Table 2). Primary Endpoint Acute adverse events
Of the 30 patients, 7 (23.3%; 1-sided 95% CI, 10.6%36.0%) developed grade 3, treatment-related, nonhematologic AEs 90 days from the initiation of concurrent treatment (ie, acute AEs). Table 3 lists the grade 3 and 4 side effects, including hematologic toxicity, in detail. Because the 1-sided, upper-bound CI for the rate of grade 3, treatment-related, nonhematologic AEs occurring 90 days from the initiation of concurrent treatment is 36%, there is 95% confidence that the true grade 3, nonhematologic, treatment-related AE rate is 90 days but 365 days from the initiation of concurrent treatment are Cancer
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listed in Table 4. Nine patients reported late AEs, 3 of whom also had acute toxicities. AEs occurring during concurrent treatment, during adjuvant chemotherapy treatment, and after the end of all treatments are shown in Table 5. One late toxicity, epistaxis, was considered possibly attributable to bevacizumab. Survival outcomes
The median follow-up for all patients was 25.9 months (range, 13.6-43.4 months). The 2-year estimate of OS was 96.7% (95% CI, 78.6%-99.5%) with a total of 4 deaths, all of which were from endometrial cancer. None of the 30 patients enrolled developed a within-field pelvic-only failure. The cumulative incidences for RF and DF at 2 years were 7.2% (95% CI, 0.0%-17.1%) and 17% (95% CI, 3.2%-30.9%), respectively. The 2-year estimate of DFS was 79.1% (95% CI, 59.2%-90.1%). A total of 6 patients developed recurrent disease. Two of the 6 had paraaortic lymph node failures; 1 of these patients also developed distant lymph node metastases and both patients subsequently died. One of the 2 patients with paraaortic lymph node failure had undergone a paraaortic lymph node dissection at the time of diagnosis; both had undergone pelvic lymph node lymphadenectomy at the time of diagnosis. Two of the other 4 patients died of distant disease. The remaining 2 patients were alive with DF at the time of last follow-up; 1 patient continued to receive chemotherapy and the other developed a 1-cm recurrence in the peritoneum above the pelvic field at a laparoscopic port site, which was resected laparoscopically with negative surgical margins. This individual continued to receive therapy with megestrol acetate and had been 2159
Original Article TABLE 3. Adverse Events Grade 3 Occurring Within the First 90 Days From the Initiation of Concurrent Treatment (Acute Events) System Organ Class Nervous system disorders General disorders and administration site conditions Nervous system disorders Vascular disorders Metabolism and nutrition disorders Infections and infestations Reproductive system and breast disorders Investigations Blood and lymphatic system disorders General disorders and administration site conditions
Term
Gradea
Relationship to Treatment
Days From Concurrent Rx Start
Headache Fatigue Syncope Thromboembolic eventb Hyponatremia Hyperglycemia Vaginal infection Vaginal inflammation ALT increased Febrile neutropenia Fatigue
3 3 3 4 3 3 3 3 3 4 3
Probable Probable Possible Probable Probable Possible Probable Possible Possible Probable Possible
78 85 89 42 55 90 28 27 12 88 4
Abbreviations: ALT, alanine aminotransferase; Rx, treatment. a Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). b Most likely attributable to bevacizumab.
TABLE 4. Adverse Events Grade 3 Occurring Within >90 Days But 365 Days From the Initiation of Concurrent Treatment (Late Events) System Organ Class General disorders and administration site conditions Metabolism and nutrition disorders Respiratory, thoracic, and mediastinal disorders Nervous system disorders Metabolism and nutrition disorders Vascular disorders General disorders and administration site conditions Ear and labyrinth disorders Metabolism and nutrition disorders Nervous system disorders Infections and infestations
Term
Gradea
Relationship to Treatment
Days From Concurrent Rx Start
Fatigue Hypomagnesemia Hypokalemia Epistaxisb Headache Hyponatremia Hot flashes Pain Hearing impaired Hypokalemia Neuralgia Skin infection
3 4 3 3 3 3 3 3 3 4 3 3
Probable Possible Possible Probable Probable Possible Definite Possible Probable Probable Possible Possible
105 183 168 176 98 98 300 180 333 136 126 126
Abbreviation: Rx, treatment. a Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). b Most likely attributable to bevacizumab.
TABLE 5. Summary of Worst Adverse Event per Patient (Definitely, Probably, or Possibly Related to Treatment) Comparing RTOG 9708 With RTOG 0921 AEs 90 Days From the Initiation of All Rxa Gradee 1 2 3 4 5
AEs >90 Days From the Initiation of All Rxb
AEs Occurring During Concurrent Rxc
RTOG 0921
RTOG 0921
RTOG 9708
RTOG 0921
0 (0%) 10 (33%) 11 (37%) 5 (17%) 0 (0%)
3 (10%) 10 (33%) 9 (30%) 6 (20%) 0 (0%)
9 (20%) 17 (39%) 7 (16%) 1 (2%) 0 (0%)
1 (3%) 9 (30%) 7 (23%) 2 (7%) 0 (0%)
RTOG 9708 12 19 12 1 0
AEs Occurring During Adjuvant Chemotherapyd RTOG 0921
RTOG 9708
0 (0%) 6 (20%) 12 (40%) 6 (20%) 0 (0%)
3 (7%) 3 (7%) 9 (21%) 26 (62%) 0 (0%)
(27%) (43%) (27%) (2%) (0%)
Abbreviations: AE, adverse event; RTOG, Radiation Therapy Oncology Group; Rx, treatment. a The AE date was the start of all treatment 190 days. b The AE date was > the start of all treatment 190 days. c Concurrent treatment start date AE date concurrent treatment end date. d Adjuvant treatment start date AE date adjuvant treatment end date. e Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0).
2160
Cancer
July 1, 2015
Concurrent Bev With Pelvic IMRT for Endometrial Ca/Viswanathan et al
TABLE 6. Characteristics of Patients With Recurrent Disease Patient No.
FIGO Stage
Histology
First Disease Recurrence
1 2 3 4 5 6
IIIC1 IIIC1 IIIC1G2 IIIC1G3 IIIBG3 IIIAG1
UPSC UPSC EAC EAC EAC EAC
Regional Regional Distant Distant Distant Distant
Areas of Spread
Time From First Disease Recurrence to Death, Months
Paraaortic lymph node Paraaortic lymph node Lung, bone, brain Lung Lung Abdominal
10 4 8 6 Alive Alive
Abbreviations: EAC, endometrioid endometrial adenocarcinoma; FIGO, International Federation of Gynecology and Obstetrics; UPSC, uterine papillary serous adenocarcinoma.
disease free for 2 years at the time of last follow-up. Detailed characteristics of the patients with disease recurrence are shown in Table 6. DISCUSSION This phase 2 prospective trial demonstrates the feasibility of administering bevacizumab with pelvic IMRT followed by combination chemotherapy with carboplatin and paclitaxel in patients with high-risk endometrial cancer. The rate of acute grade 3, nonhematologic, treatmentrelated toxicity was 23.3% and the hypothesis that the true rate of such AEs is 45 Gy is smaller with IMRT than with wholepelvic radiation. Portelance et al reported a >60% reduction in the volume of small bowel irradiated to >45 Gy with IMRT.18 A study by Roeske et al demonstrated a 50% reduction in the volume of small bowel irradiated to >45 Gy.19 Overall, the rate of grade 3 toxicity reported during concurrent treatment in the RTOG 9708 trial (3dimensional conformal pelvic radiation and concurrent cisplatin chemotherapy followed by adjuvant cisplatin and paclitaxel) was 30%. To determine whether IMRT may be of benefit in reducing this rate, toxicities occurring during RT in the current study (RTOG 0921) were compared with those of the precursor trial RTOG 9708. In RTOG 9708, during the concurrent portion of the treatment, 43% of participants had grade 2, 27% had grade 3, and 2% had grade 4 acute toxicity; in the current RTOG 0921 trial, these rates were 30%, 23%, and 7%, respectively. It is interesting to note that although the systems are similar, toxicity in RTOG 9708 was assessed according to the Cooperative Group Common Toxicity Criteria (1989), the Acute Radiation Morbidity Scoring Criteria, and the Late Radiation Morbidity Scoring 2162
Scheme of the RTOG and the European Organisation for Research and Treatment of Cancer, whereas the current trial used the subsequent the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0), which developed from the preceding scales. Prospective results from the ongoing RTOG 1203 TIME-C randomized trial may help to clarify whether IMRT reduces toxicity compared with 3-dimensional conformal radiation. Compared with the RTOG 0418 trial, which was a prospective series of patients treated with postoperative pelvic IMRT, the less strict dose-volume histogram (DVH) criteria used in the current trial resulted in higher compliance for constraints. In the RTOG 0418 trial, dose criteria were not met in 67% of cases for the bladder, in 76% of cases for the rectum, and in 17% of cases for the bowel. In comparison, in the current trial, dose criteria were not met in 14% of cases (4 of 29 cases) for the bladder, in 24% of cases (7 of 29 cases) for the rectum, and in 14% of cases (4 of 28 cases) for the bowel. To illustrate the effect of stringency, the femoral head constraint in the RTOG 0921 trial was met in all cases (all had a DVH value of 15% receiving
