The clinical efficacy and safety of single-agent pembrolizumab in patients with recurrent granulosa cell tumors of the ovary: a case series from a phase II basket trial.

Background Treatment of recurrent, unresectable granulosa cell tumor (GCT) of the ovary can be challenging. Given the rarity of the tumor, alternative therapies have been difficult to evaluate in large prospective clinical trials. Currently, to our knowledge, there are no reports of the use of immune checkpoint inhibitors in GCT patients. Here, we present a case series of GCT patients treated with pembrolizumab who were enrolled in a phase II basket trial in advanced, rare solid tumors (ClinicalTrials.gov: NCT02721732). Cases We identified 5 patients with recurrent GCT (4 adult and 1 juvenile type); they had an extensive history of systemic therapy at study enrollment (range, 3-10), with most regimens resulting in less than 12 months of disease control. Pembrolizumab was administered in these patients, as per trial protocol. Although there were no objective responses according to the irRECIST guidelines, 2 patients with adult-type GCT experienced disease control for ≥ 12 months (565 and 453 days). In one, pembrolizumab represented the longest duration of disease control compared to prior lines of systemic therapy (565 days vs. 13 months). In the other, pembrolizumab was the second longest systemic therapy associated with disease control (453 days vs. 22 months) compared to prior lines of therapy. In this patient, pembrolizumab was discontinued following withdrawal of consent. PD-L1 expression was not observed in any baseline tumor samples. Pembrolizumab was well tolerated, with no grade 3 or 4 treatment-related adverse events. Conclusions Although our results do not support the routine use of pembrolizumab monotherapy in unselected GCT patients, some patients with adult-type GCT may derive a clinical benefit, with a low risk of toxicity. Future studies should investigate the role of immunotherapy and predictors of clinical benefit in this patient population.

Management of recurrent granulosa cell tumor of the ovary: Contemporary literature review and a proposal of hyperthermic intraperitoneal chemotherapy as novel therapeutic option.

Granulosa cell tumors of the ovary (GCT) are the most common type of sex cord stromal tumors. Although most of patients are diagnosed at early stage and has favorable 5-year overall survival rate, 16-23% of GCT ultimately develop recurrent disease. Recurrences are characterized by disseminated peritoneal metastasis. The treatment options include systemic chemotherapy, secondary CRS or palliative localized radiation therapy have not yet standardized due to the rarity of disease. Aggressive CRS followed up by hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to provide benefit in other peritoneal disease but limited data available for recurrent GCT. We have a case of recurrent Adult-type GCT (AGCT) who was treated with CRS followed by HIPEC with mitomycin C and doxorubicin. The patient has no evidence of recurrence for approximately 11 years. An electronic search of the PubMed database with the following search terms: GCT, HIPEC showed that there were total 21 patients with recurrent GCT treated in seven different studies and 13 of 21 (61.9%) patients had no evidence of disease during follow-up ranging from 6 to 100 months. Three patients (14.2%) died of the disease. Six studies used cisplatin for HIPEC. At least 76.2% (16 of 21, data not available for five patients) had complete cytoreduction with total 16 cases of perioperative complications but no perioperative mortality was observed. Although further investigation is needed, we propose that CRS and HIPEC can be an effective therapeutic option for recurrent GCT at experienced institutions.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for management of recurrent/relapsed ovarian granulosa cell tumor: a single-center experience.

AIM: The aim of this study was to retrospectively report our experience (efficacy/morbidity) with cytoreductive surgery+hyperthermic intraperitoneal chemotherapy (CRS+HIPEC) for the management of recurrent/relapsed ovarian granulosa cell tumors (OGCT). MATERIAL AND METHODS: From 2010 to 2013, six patients underwent CRS+HIPEC. CRS was performed with standard peritonectomy procedures and visceral resections directed towards complete elimination of tumors from the abdominopelvic cavity. HIPEC was performed with cisplatin (50 mg/m²) and doxorubicin (15 mg/m²) and allowed to circulate in the abdominopelvic cavity for 90 min at 41.0-42.2°C. RESULTS: Cytoreduction completeness (CC-0) was achieved in all except one patient (CC-1). Five patients had OGCT recurrences in abdomen+pelvis and one patient in abdomen only. No grade V morbidity (Clavien-Dindo classification) occurred. Two patients developed lung atelectasis, which was managed by mere chest physiotherapy (grade I). One patient developed urinary tract infection (grade II) and another patient developed pneumonia (grade II) - both of which were managed by antibiotics. One patient developed splenic bed and anterior abdominal wall collections requiring ultrasound-guided aspiration without general anesthesia (grade III). One patient developed pulmonary embolism requiring intensive care-unit management (grade IV). Four chemo-naïve patients received adjuvant chemotherapy whereas the remaining two previously chemo-exposed patients received no adjuvant therapy. All patients were alive and disease-free without proof of recurrence/relapse at 40, 32, 27, 24, 20 and 16 months. The average interval of follow-up after CRS+HIPEC was roughly 27 months (range: 16-40 months). CONCLUSION: CRS+HIPEC appears to be an efficacious and morbidly well-tolerated therapeutic modality for recurrent/relapsed OGCT. Long-term follow-up data and further research are needed.

Results of oxaliplatin-based hyperthermic intraperitoneal chemotherapy in recurrent ovarian granulosa cell tumors.

OBJECTIVES: To assess the efficacy and morbidity of cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) for relapsed ovarian granulosa cell tumors (OGCT). STUDY DESIGN: Between 2007 and 2009, patients with relapsed OGCT who had been treated with HIPEC after CRS in our institution were retrospectively analyzed. RESULTS: We identified 7 patients who had undergone CRS plus HIPEC. Macroscopically complete cytoreduction had been performed in all patients. The location of the recurrence was exclusively the pelvis in 2 cases and both the pelvis and abdomen in 5 cases. We had administered an intraperitoneal perfusion of oxaliplatin (460 mg/m(2)) or oxaliplatin (360 mg/m(2)) plus irinotecan (360 mg/m(2)) heated up to 41-43°C for 30 min. No post-operative mortality nor any grade IV morbidity (according to the Clavien and Dindo classification) had occurred. One lymphocyst (grade III) had appeared which had twice required percutaneous drainage. Six patients had experienced extra-abdominal complications (all grade II). Median follow-up after CRS plus HIPEC was 32 months (range, 25-56). Among the 7 patients, 2 are disease free, 3 had relapsed with peritoneal carcinomatosis and 2 had relapsed with liver metastases. CONCLUSIONS: HIPEC (using oxaliplatin or oxaliplatin plus irinotecan) should not be recommended to treat relapsed OGCT.

Continuous Intraoperative Intraperitoneal Hyperthermic Chemoperfusion (CIIPHCP) in the treatment of advanced stage and recurrent granulosa cell tumors. Report of two cases.

BACKGROUND: Treatment of advanced stages and recurrent ovarian granulosa cell tumors, has not been established yet. The effectiveness of radiation therapy could not be proven. Systemic chemotherapy has shown promising results, but with severe side effects and high incidence of relapse. CASE REPORTS: We report of one patient with advanced stage III C, and one patient with bulky recurrent ovarian granulosa cell tumors. Both patients were treated with a combination of surgical debulking, Continuous Intraoperative Intraperitoneal Hyperthermic Chemoperfusion (CIIPHCP) with Cisplatin and one of them with adjuvant systemic chemotherapy. CONCLUSION: CIIPHCP appears to offer a promising procedure in addition to surgical debulking and systemic chemotherapy for treatment of advanced or recurrent ovarian granulosa cell tumors. The present report is the first concerning the question of adding Intraoperative Hyperthermic Chemoperfusion in the treatment of advanced or recurrent ovarian granulosa cell tumors.