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Radiation therapy for vaginal and perirectal lesions in recurrent ovarian cancer

Highlights • Radiation to isolated vaginal and perirectal ovarian cancer recurrences provides effective in-field control.• Complete response of targeted lesions after radiation was 88%.• Radiation increased the chemotherapy-free interval without associated grade 3/4 toxicities.• Platinum sensitivity prior to radiation may be associated with improved overall survival.


Introduction
Despite recent advances in primary and maintenance therapies for patients with ovarian carcinoma (OC), over 80% will recur and experience treatment-related toxicities. The landscape of therapeutic options in the recurrent setting is driven by platinum response, and most commonly includes systemic therapies such as chemotherapy, biologic targeted therapies, immunotherapy, and even endocrine therapy (NCCN Guidelines, 2020). Prior to the development of effective palliative chemotherapy options, pelvic radiation was used for local control (Firat and Erickson, 2001). However, this modality fell out of favor because it failed to address upper abdominal disease, while whole abdomen radiation produced toxicities that outweighed its limited benefits. Nevertheless, while current guidelines reserve a role for localized radiation to palliate symptoms, (NCCN Guidelines, 2020) it remains unclear who benefits most from this localized treatment modality.
The small, but growing body of literature on radiation for recurrent OC has documented responses in heterogeneous populations with oligometastatic disease (i.e. vaginal/rectal implants vs. localized nodal and extranodal recurrences in the abdomen and/or pelvis) with limited insight into which subgroups experience clinical benefit (Firat and Erickson, 2001;Albuquerque et al., 2016;Chundury et al., 2016;Westhoff et al., 2016;Kim et al., 2019;Brown et al., 2013;Yahara et al., 2013;Chang et al., 2018;Smart et al., 2019;Onal et al., 2020). Though the reported incidence of oligometastatic vaginal/perirectal OC recurrences appears low, (Casey et al., 1996) these areas are unique in that they may be salvaged with targeted radiation to improve not only local control and long-term survival, but also to effectively palliate symptoms. Thus, we aimed to better define the patient population with vaginal/ perirectal oligometastatic OC recurrences who benefits from radiation and what toxicities may result from this treatment modality. Here, we describe our institutional experience utilizing intensity modulated radiation therapy (IMRT) +/-high dose-rate (HDR) brachytherapy to treat vaginal and perirectal recurrences in OC patients. Our primary objectives were to evaluate complete response rates of targeted lesions after radiation and calculate the 5-year in-field local control (IFC) rate. Secondary objectives were to assess radiation-related toxicities, as well as post-radiation progression-free survival (PFS) and overall survival (OS).

Methods
This case series included 17 patients with recurrent OC who received IMRT, HDR brachytherapy, or both for vaginal and/or perirectal recurrences at Washington University School of Medicine from January 2006 to November 2019. Eligible patients were identified from our Radiation Oncology institutional database. Initial treatment planning, simulation, treatment devices, and radiation treatment plans were individualized at the discretion of the treating radiation oncologist. This retrospective review was approved by the Washington University Institutional Review Board (#202005019).
We included patients with recurrent OC, regardless of stage or histology, with a vaginal and/or perirectal recurrence as determined by computed tomography (CT), 18-fluoro-deoxyglucose positron emission tomography (FDG-PET), and/or magnetic resonance imaging (MRI). Patients were subdivided by oligometastatic, defined as 1-5 metastatic lesions, (Lievens et al., 2020) or multi-site recurrence prior to radiation.
Following radiation, patients were seen for 6-week post-radiation exams by either a radiation oncologist or gynecologic oncologist, and thereafter according to systemic treatment schedules, but at least every 3 months. Radiation related toxicities were categorized as acute (≤28 days) or late (>28 days) and graded per common terminology criteria for adverse events (CTCAE) version 5.0 (Cancer Therapy Evaluation Program (CTEP), 2017). All patients were followed until death or time of analysis.
OS was defined from start of radiation to death or last follow-up at time of analysis. PFS was defined from start of radiation to progression (evidenced by imaging or initiation systemic therapy), death, or last follow-up at time of analysis. IFC was defined as no recurrence within the radiated field as determined by PET/CT, CT, MRI, or clinical exam. Those suspected of recurrence following radiation did not require biopsy for histologic confirmation. Chemotherapy-free interval (CFI) was calculated as the time between radiation start and next line of chemotherapy. OS, PFS, and IFC were calculated using Kaplan-Meier method. The log rank test was used to compare PFS and OS after radiation stratified by pre-radiation platinum status. All tests were two-sided with a significance level of 0.05. SAS Version 9.4 (Cary, NC) was used to perform all statistical analyses.

Results
A total of 17 patients were included in the analysis, 4 with oligometastatic disease and 13 with multi-site disease. Table 1 summarizes patient clinical characteristics. All but 2 patients were white, the median age at diagnosis was 58 (range 38-77), and most had stage III disease and high-grade serous histology. Of the 12 patients with available genetic testing results, 2 had germline mutations in BRCA2, 1 in BRCA1, and 1 in MLH1. All 4 (23.5%) patients (ID 10, 11, 16, and 17) with oligometastatic disease confined to the vagina/rectum were initially platinum sensitive, but only 3 were platinum sensitive immediately preceding radiation. Table 2 summarizes treatment characteristics of patients stratified by oligometastatic and multi-site recurrence. Overall, this was a heavily pretreated population. Patients had received a median of 3 lines of chemotherapy prior to radiation (range 1-9), including 3 who received concurrent chemoradiation. Eleven of the 17 patients received definitive radiation; median time for radiation completion was 41 days (range 11-105). One patient (ID 17) experienced extended time to completion of a total of 105 elapsed days-45 days for initial photon treatment, 6000 cGy in 30 fractions, followed by proton boost, 30 cobalt gray equivalents (CGE) in 15 fractions. This plan was specifically individualized for this patient, as she was the only one in our series who received proton therapy. The two patients with the longest CFI after radiation included a BRCA2 mutation carrier (ID 11) with isolated disease to the vagina, while the other (ID 14) had a mismatch repair deficient (MLH1) tumor treated with concurrent radiation and pembrolizumab.
Median follow-up after radiation was 28.4 months (range 4.5-166.4). Fifteen (88.2%) patients achieved a complete response of targetable lesion(s) after radiation. Four (23.5%) patients (ID 8, 6, 11 and 10) had in-field failures at 3.7, 11.2, 24.5, and 27.5 months after start of radiation ( Fig. 1). Two were BRCA carriers, and 3 received additional radiation to the vaginal cuff/perirectal area. A detailed narrative of these 4 patients and their management strategies are provided in Supplemental Table 1. Eleven women were treated with curative intent, and among them, 7 (64%) were free of disease within the treatment field at last follow-up. Ten patients were evaluable for 5-year follow-up after radiation, contributing to a 5-year IFC rate of 70%.
At the time of this analysis, 3 (17.6%) patients were alive with no evidence of disease, 2 (11.8%) were alive with disease, and 12 (58.8%) were dead of disease. Overall median PFS post-radiation was 11.0 months (range 2.6-27.5). Patients treated with definitive intent (n = 11), had a 13.4 month longer median PFS than those treated with palliative doses (18.6 vs 5.2 months, p = 0.01). PFS did not differ when stratified by platinum status prior to radiation. The 9 patients who were platinum-sensitive prior to radiation had similar median PFS (6.5 vs. 13.4 months, log-rank p = 0.75), but longer OS (71.1 vs 18.8 months, log-rank p = 0.05, Fig. 2) compared to their platinum-resistant counterparts. Excluding patients with low-grade serous histology and those who were treated with palliative intent, the median CFI was 14.2 months (range 4.70-33.0) with no impact on PFS or OS when stratified by CFI < 12 months vs. ≥ 12 months.
Overall radiation was well tolerated with 2 patients experiencing grade 3/4 toxicities. Patient 12 had a vesicovaginal fistula repair 5 months prior to radiation and the fistula recurred during her last week of radiation for multisite disease (vaginal cuff and retroperitoneal adenopathy). Patient 5 was diagnosed with a parastomal hernia and bowel perforation outside of the radiated field approximately 4 weeks after completing palliative pelvic IMRT + HDR brachytherapy for multi-site disease. This was thought to be due to a 10 cm mass eroding into the colon and she eventually succumbed from this event.

Discussion
Focused radiation therapy led to durable IFC for most OC patients with recurrence involving the vaginal apex and/or perirectal area. As expected, genitourinary and gastrointestinal side effects were most frequent, but grade 3-4 complications were uncommon. However, OS was determined by platinum sensitivity, suggesting that subsequent chemotherapy plays a role in determining survival. Our results support continuing our ongoing institutional practice to evaluate patients with limited metastatic burden for targeted radiation with the goal of providing treatment breaks from systemic therapy, palliation of symptoms, and effective locoregional control.
Prior studies exploring localized radiotherapy, including our own institutional data from 2016, historically included heterogeneous populations of OC patients, many with localized nodal and extranodal recurrences in the abdomen and/or pelvis (Albuquerque et al., 2016;Chundury et al., 2016;Westhoff et al., 2016;Kim et al., 2019;Brown et al., 2013;Yahara et al., 2013;Chang et al., 2018;Smart et al., 2019;Onal et al., 2020). Nevertheless, rates of local control at 2 and 3 years after radiation are > 80% and 5-year IFC rates as high as 71% (Albuquerque et al., 2016;Brown et al., 2013). More recently, the SABR-COMET trial reported a 5-year OS benefit among patients with metastatic solid tumors treated with palliative radiation vs ablative therapy (17.7% vs. 42.3% ,95% CI, 28-56%; p = 0.006), with no new grade 2-5 adverse events or differences in quality of life . Though this study excluded gynecologic oncology patients, our study results show comparable rates of 5-year in-field control (70%) when targeted local radiation therapy is employed in this patient population. Importantly, due to the anatomic location of tumors in this study, patients experiencing in-field recurrence were frequently salvaged with additional radiation. Of the 17 patients in our case series, four had undergone a diverting ostomy prior to initiation of radiation, either as a part of their upfront staging surgery (n = 1) or during a secondary cytoreductive surgery (n = 3). Nevertheless, no patients underwent a diverting procedure after radiation completion. Collectively, this data suggests that in carefully selected women with recurrent OC localized to the pelvis and involving the vagina and/or perirectal area, there may be a potential advantage to delivering aggressive local radiation. This can be administered with limited toxicity, and provide heavily pretreated patients treatment breaks from systemic therapy. Furthermore, we show a median CFI post-radiation of 14.2 months, which for platinum-resistant patients, could lead to re-challenge with a platinum or additional agents. LG: low-grade; LN: lymph node; RP: retroperitoneal. * Patients were screened with a multi-gene panel.

Table 2
Treatment and outcomes.
Our case series has several limitations impacting interpretation of data and extrapolation to the recurrent OC patient population at large. Given the small sample size and high rates of complete response to radiation, we were unable to perform subgroup analyses to better understand predictors of complete response to radiation and 5-year IFC. Though platinum status prior to radiation was collected, subgroup analysis was not feasible to further explore the impact of platinumsensitivity to radiation response and IFC. Our small sample size also did not allow for meaningful comparisons between different radiation modalities (IMRT versus brachytherapy), dose, and volumes for optimal tumor response, nor could we stratify by important clinical characteristics such as tumor number, size, or location (vaginal apex/perirectal area vs other), histology, number of therapies prior to radiation, and genetic status. Additionally, although radiation was generally well tolerated, we do not have quality of life data for this cohort to determine symptomatic benefit from radiation.
Future studies should examine utilization of other modalities to deliver aggressive local radiation to locally recurrent OC patients as employed in this study. Our institution is actively examining stereotactic radiation utilizing MRI-guidance and adaptive treatment planning to test whether this approach can provide patients with shortened treatment times (days instead of weeks) while maintaining desired clinical outcomes for treatment sites throughout the body without increasing adverse events. Additionally, the timing of radiation in relation to chemotherapy should be investigated. At present, there is no consensus regarding initiation of radiation in patients with locoregional recurrence. In our study, time from diagnosis to first round of radiation therapy was > 5 years. Potentially, initiation of local therapy earlier in the treatment course could provide greater therapeutic benefit, while simultaneously reducing cumulative treatment-related toxicity and improving quality of life outcomes. Finally, it will be important to identify any clinical (platinum sensitivity, histology, etc.) or genetic markers (tumor mutational burden, BRCA status) within the population that may predispose patients to greater benefit from aggressive local therapy.
In conclusion, our data suggests that utilization of aggressive local therapy with radiation for patients with locoregional pelvic recurrence is safe, provides effective IFC, leading to increased CFI, with minimal gastrointestinal/genitourinary side effects. We propose that radiation should be considered for appropriately selected patients at the time of locoregional pelvic recurrence as it may lead to improved clinical outcomes. Author

Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.