What is the risk of bowel perforation associated with bevacizumab therapy in ovarian cancer?

BackgroundThere is a medical need in platinum resistant ovarian cancer patients. Median progression-free survival (PFS) is 3.4 months with chemotherapy and 6.7 months with chemotherapy-bevacizumab combination regimens.1 RECIST overall response rate (ORR) is 11.8% and 27.3%, respectively. The ORR is 15.9% for bevacizumab as a monotherapy with a median PFS of 4.4 months.2MethodsNCT03596281 An open-label phase 1b trial with a modified toxicity probability interval design to evaluate the combination of a flat dose of 400mg bevacizumab for 6 cycles and 200mg pembrolizumab until disease progression, unacceptable toxicity or completed 24 months of treatment in patients with platinum resistant ovarian cancer. The primary evaluation criteria is safety, the secondary endpoint is the efficacy.Results19 patients have been enrolled between January 2019 and February 2021 in 6 French centers. Patients‘ characteristics are reported (table 1). No dose limiting toxicities were observed. Grade 3 treatment related adverse events occurred in 3 patients (i.e. arterial thromboembolism, bowel perforation, proteinuria and sepsis). No grade 4/5 toxicities were induced. A median of 7 cycles (range 3–14) were administered. Median follow-up of patients was 4.1 months (1.8–23). The RECIST ORR was 26.3% (1 complete response and 4 partial responses) (table 2). The disease control rate was 78.9%. The time to progression was not yet reached in 6 patients. The ORR was equivalent whether patients have been pretreated or not with bevacizumab (27.3 and 25% respectively) (table 3). The ORR according to the combined positive score (CPS) for the evaluation of PD-L1 was 50.0% for CPS≥10% (n=4), 30.0% for a CPS≥1% (n=10) and 25.0% for CPS<1 (n=8) (table 4).ConclusionsA chemotherapy-free regimen combining pembrolizumab and bevacizumab was well tolerated and showed encouraging results in heavily pretreated platinum resistant ovarian cancer patients independent of their previous challenge with antiangiogenic agents.AcknowledgementsFunding for this research was provided by Fondation Cancer du Luxembourg and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationNCT03596281ReferencesPujade-Lauraine E, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Onco Off J Am Soc Clin Oncol 32,1302–1308 (2014).Cannistra SA, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol Off J Am Soc Clin Oncol 33,5180–5186 (2007).Ethics ApprovalThis study was approved by CPP Sud Méditerranée V institution’s Ethics Board; approval number 18.020 (EudraCT number 2017-004197-34).ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

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Comparison of toxicity and survival following intraperitoneal recombinant interleukin-2 for persistent ovarian cancer after platinum: twenty-four-hour versus 7-day infusion.

Journal of Clinical Oncology ◽

10.1200/jco.1997.15.11.3399 ◽

1997 ◽

Vol 15 (11) ◽

pp. 3399-3407 ◽

Cited By ~ 51

Author(s):

R P Edwards ◽

W Gooding ◽

B C Lembersky ◽

K Colonello ◽

R Hammond ◽

...

Keyword(s):

Ovarian Cancer ◽

Survival Time ◽

Median Survival ◽

Median Survival Time ◽

Bowel Perforation ◽

Interleukin 2 ◽

Maximum Tolerated Dose ◽

Eligibility Criteria ◽

Platinum Based Chemotherapy ◽

Number Of Patients

PURPOSE To compare the toxicity, pharmacokinetics, and efficacy seen in ovarian cancer patients treated with escalating doses of intraperitoneal (I.P.) interleukin-2 (IL-2) by two different infusion schedules. PATIENTS AND METHODS Forty-five patients were sequentially entered onto a phase I/II study in groups of four at fixed dosage tiers of 6 x 10(4), 6 x 10(5), 6 x 10(6), and 3 x 10(7) IU/m2/d in either of two schedules: (A) intermittent weekly infusions of 24 hours' duration; or (B) alternating continuous 7-day infusions followed by 7-day intervals without therapy. Eligibility criteria included > or = six courses of prior platinum-based chemotherapy and laparotomy-confirmed persistent or recurrent ovarian cancer. RESULTS Forty-one eligible patients received I.P. IL-2 and were assessable for toxicity, but six patients were not assessable for response, which left 35 patients assessable for response. Significant locoregional dose-limiting toxicity was seen with the 7-day infusions (including bowel perforation), with 600,000 IU/m2 as the maximum-tolerated dose (MTD), but catheter infection was the only significant complication seen with the 24-hour infusions, for which an MTD was not established. Among 35 assessable patients, there were six laparotomy-confirmed complete responses (CRs) and three partial responses, for an overall response rate of 25.7% (nine of 35). The median survival time of the cohort was 13.7 months and the overall 5-year survival probability was 13.9%. For the nine patients who demonstrated responses (six on the 24-hour infusion and three on the 7-day infusion), the median survival time has not been reached (range, 27 to 90+ months). CONCLUSION I.P. IL-2 is better tolerated as a weekly infusion as compared with a 7-day infusion and demonstrates evidence of possible long-term efficacy in a modest number of patients. A randomized trial is indicated to determine if the prolonged survival seen in this study is a due to I.P. IL-2 therapy or other factors that cannot be controlled for in a single-arm study.

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Should Bevacizumab Be Continued After Progression on Bevacizumab in Recurrent Ovarian Cancer?

International Journal of Gynecological Cancer ◽

10.1097/igc.0b013e318290ea69 ◽

2013 ◽

Vol 23 (5) ◽

pp. 833-838 ◽

Cited By ~ 5

Author(s):

Floor J. Backes ◽

Debra L. Richardson ◽

Georgia A. McCann ◽

Blair Smith ◽

Ritu Salani ◽

...

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Bowel Perforation ◽

Objective Response ◽

Retrospective Chart Review ◽

Progression Free Survival ◽

Response Rates ◽

Recurrent Ovarian Cancer ◽

Median Number ◽

Cytotoxic Chemotherapy

ObjectiveThe optimal role of bevacizumab (Bev) in the treatment of ovarian cancer has not yet been established. Furthermore, it is unclear whether there is a benefit of Bev after progression on a Bev-containing regimen in ovarian cancer. The objective of this study was to compare response rates, progression-free survival (PFS), and overall survival between patients who were treated with chemotherapy and Bev after progression on Bev (BAB) versus patients who were treated with chemotherapy without Bev (CWOB).MethodsWe conducted a retrospective chart review of all patients who received treatment with Bev (with or without cytotoxic chemotherapy) for recurrent ovarian cancer at a single institution. Patients who received additional therapy after progression while on Bev were included.ResultsForty-six patients were included (16 CWOB group and 30 BAB). The median number of previous chemotherapy regimens was 2.5 for CWOB compared with 4 for BAB (P= 0.11). Fifty-two percent of patients had an objective response to the first Bev regimen before progressing on Bev. Response rates for the regimen after progression on Bev were 19% (3/16) in the CWOB group and 23% (7/30) in the BAB group (P= 1). Twenty-five percent of the patients who responded to the first Bev regimen and 18% of those who did not respond to the first Bev regimen responded to the second Bev regimen (P= 0.72). The median PFS for patients in the CWOB group was 2.6 months (95% confidence interval [CI], 1.3–5 months), compared with 5.0 months (95% CI, 3.5–7.3 months) for patients in the BAB group (P= 0.01). Overall survival was similar, 9.4 months (95% CI, 5.0–12.0 months) for CWOB versus 8.6 months (95% CI, 5.8–15.5 months) for BAB (P= 0.19). One patient in the BAB group died of a bowel perforation.ConclusionsIn patients previously treated with Bev for recurrent ovarian cancer, the subsequent addition of Bev to cytotoxic chemotherapy increased the PFS compared with patients not receiving a second course of Bev, but did so without an impact on overall survival. The response to the first Bev regimen did not predict whether a patient would respond again to the next Bev regimen. Randomized, larger studies will have to be performed to confirm this observation.

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Does repeat usage of bevacizumab in patients with progressive recurrent ovarian cancer offer a survival advantage?

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e16510 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e16510-e16510

Author(s):

D. L. Richardson ◽

F. J. Backes ◽

L. G. Seamon ◽

J. D. Hurt ◽

...

Keyword(s):

Ovarian Cancer ◽

Treatment Regimen ◽

Bowel Perforation ◽

Group Versus ◽

Progression Free Survival ◽

Recurrent Ovarian Cancer ◽

Median Number ◽

Cytotoxic Chemotherapy ◽

Group 13 ◽

Additional Therapy

e16510 Background: Many studies show bevacizumab (BEV) has activity in the treatment of recurrent ovarian cancer, especially when combined with cytotoxic chemotherapy. However, it is uncertain whether BEV should be continued if a patient progressives on treatment which includes BEV. Therefore, our objective is to compare response rates (RR), progression-free survival (PFS), and overall survival (OS) between patients who continued on BEV after progression on BEV (BPB) versus patients who were treated with cytotoxic chemotherapy without BEV (no BPB). Methods: All patients who received treatment with BEV (with or without cytotoxic chemotherapy) for recurrent ovarian cancer at a single institution were identified. Patients who received additional therapy after progression on BEV were included. Patients who were treated on GOG 218 or received first-line BEV or had their first BEV therapy discontinued due to side effects from BEV were excluded. RR were assessed using RECIST criteria, CA125 levels, or progressive disease symptoms. PFS was defined as the period from initiation of the treatment regimen until progression or date of last contact. OS was defined as the period from initiation of the second treatment regimen until death or date of last contact. Results: 35 patients met inclusion criteria. The median number of previous chemotherapy regimens was 4 (range 1–8). About 50% of the patients had a CR or PR prior to progressing on BEV. There were 27 patients in the BPB group, and 8 patients in the no BPB group. 13% (1/7) of patients responded to cytotoxic chemo after BEV, and 15% (4/27) of patients responded to repeat treatment with BEV, p = 1. The median PFS for patients in the no BPB group was 4.6 months (95% CI 1.6–5 mo), compared to 4.8 months (2.7–7.5 mo) for patients in the BPB group, p = 0.11. There was no difference in OS, 9.8 months (95% CI 2.73- ∞) versus 8.4 months (95% CI 5.8–15.6 months) p = 0.43 for patients in the no BPB group versus the BPB group. One patient in the BPB group died of a bowel perforation. Conclusions: We offer the first comparison of PFS and OS in patients treated with cytotoxic chemotherapy ± BEV after progression on BEV. After progressing on a BEV regimen, there was no difference in the PFS, OS or RR in those pts treated with or without BEV with an overall OS < 1 year. [Table: see text]

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Spontaneous massive duodenal perforation after ovarian cancer treatment with bevacizumab

Journal of Surgical Case Reports ◽

10.1093/jscr/rjaa174 ◽

2020 ◽

Vol 2020 (6) ◽

Author(s):

Michael Karanikas ◽

Konstantinia Kofina ◽

Dimitrios Potolidis ◽

Soultana Foutzitzi ◽

Savas Deftereos ◽

...

Keyword(s):

Ovarian Cancer ◽

Adverse Effects ◽

Cancer Treatment ◽

Bowel Perforation ◽

Gastrointestinal Perforation ◽

Duodenal Perforation ◽

Life Threatening ◽

Life Threatening Complication ◽

Caucasian Female

Abstract Bevacizumab has been used as an effective drug for ovarian cancer. However, serious adverse effects, such as gastrointestinal perforation, can occur. Spontaneous gastrointestinal perforation is an uncommon, yet life-threatening complication related to bevacizumab administration. We present the case of a 65-year-old Caucasian female who presented with acute abdomen 10 days after the first administration of bevacizumab for ovarian cancer treatment, and she was diagnosed intraoperatively with a massive duodenal perforation. Bowel perforation after bevacizumab administration is a serious and potentially lethal complication. Careful follow-up of the patients is necessary in order to detect any signs of this condition in time.

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A Comparison of Thermal Plasma Energy Versus Argon Beam Coagulator-Induced Intestinal Injury After Vaporization in a Porcine Model

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000000849 ◽

2016 ◽

Vol 27 (1) ◽

pp. 177-182 ◽

Cited By ~ 4

Author(s):

Edward J. Tanner ◽

Erica Dun ◽

Yukio Sonoda ◽

Alexander B. Olawaiye ◽

Dennis S. Chi

Keyword(s):

Ovarian Cancer ◽

Inflammatory Response ◽

Thermal Plasma ◽

Thermal Injury ◽

Porcine Model ◽

Bowel Perforation ◽

Plasma Energy ◽

Mucosal Necrosis ◽

Consistent Treatment ◽

Argon Beam Coagulator

ObjectivesComplete cytoreduction of ovarian cancer often requires excision or ablation of bowel serosa implants. Both argon beam coagulator (ABC) and thermal plasma energy (TPE) (PlasmaJet; PlasmaSurgical, Roswell, Ga) have been used to ablate bowel serosa implants. Our objective was to identify comparable power settings as well as determine the rate of bowel perforation, depth of thermal injury, and extent of inflammatory response with ABC versus TPE in a porcine model.Materials and MethodsNine pigs underwent vaporization of small bowel and colon serosa according to assigned treatment group (TPE vs ABC) and settings (ABC: 30, 50, and 70 W; TPE: Cut 10U, 20U, and 30U and Coagulation 10U, 20U, and 30U). Animals underwent necropsy with blinded histomorphologic evaluation on days 0, 3, and 10 postprocedure to assess for presence of bowel perforation, depth of thermal injury, and extent of inflammatory response.ResultsAt necropsy, bowel perforation was not identified in any animals. Depth of treatment with ABC in the porcine colon was variable and unrelated to power settings whereas TPE was associated with a consistent treatment depth of 1.0 mm regardless of location or power. Treatment with ABC resulted in greater tissue coagulation and desiccation as well as increased rates of mucosal necrosis, especially at higher settings (>50 W). Treatment with TPE primarily resulted in tissue ablation and minimal mucosal necrosis at low settings (Coag 10U–20U). The inflammatory response associated with TPE treatments was interpreted as biologically benign, and less than that observed with the ABC regardless of treatment settings.ConclusionsBoth ABC and TPE effectively ablate bowel serosa in a porcine model. The TPE seems to result in a more predictable tissue effect with less inflammatory response, especially when used at low power settings such as Coag 10U or 20U. These characteristics are appealing for ablation of bowel serosa implants during ovarian cancer surgery and warrant further investigation.

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Intraperitoneal Chemotherapy with Mitoxanthrone in Ovarian Cancer

Tumori Journal ◽

10.1177/030089169708300513 ◽

1997 ◽

Vol 83 (5) ◽

pp. 837-840 ◽

Cited By ~ 1

Author(s):

Maria Le Donne ◽

Giovanna Messina ◽

Concetta Buda ◽

Francesco Corrado ◽

Giuseppe Pettineo ◽

...

Keyword(s):

Ovarian Cancer ◽

Ovarian Carcinoma ◽

Minimal Residual Disease ◽

Drug Exposure ◽

Residual Disease ◽

Radical Surgery ◽

Bowel Perforation ◽

Cost Benefit ◽

Toxic Effects ◽

Minimal Residual

Aims and background Ovarian carcinoma remains confined to the peritoneal cavity for the greater part of its natural history, so intraperitoneal (IP) administration of chemotherapy could result in greater total drug exposure of the tumor and minimize systemic antiblastic drug side effects. The aim of this study was to evaluate the therapeutic efficacy and toxic effects of intraperitoneal mitoxanthrone in patients affected by ovarian carcinoma with macroscopic absence of disease or minimal residual disease. Methods Ten patients were enrolled (stage II and III) who had been previously treated with neoadjuvant systemic chemotherapy (CDDP or CBDCA + CTX) and radical surgery resulting in macroscopic absence of disease or minimal residual disease (<1 cm). Mitoxanthrone (25 mg/m2) was instilled in 2 liters of normal saline every four weeks for 2-4 cycles. Results A total of 26 courses was administered; two patients discontinued IP therapy, one for chemoperitonitis and another for bowel perforation requiring catheter removal. Of the 10 patients receiving IP chemotherapy, 7 are alive at 5 years from radical surgery, and 3 had relapses at 13, 14 and 57 months, respectively, from radical surgery. Conclusions Intraperitoneal mitoxanthrone appears to be an effective second-line therapy in ovarian cancer; it is well tolerated as far as toxic effects are concerned, allowing cost reduction and improved patient compliance. For those cases requiring a limited number of peritoneal accesses traditional percutaneous systems have a more favorable cost/benefit ratio.

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A multi-institutional evaluation of the safety and efficacy of bevacizumab for recurrent, platinum-resistant ovarian cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.5019 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 5019-5019 ◽

Cited By ~ 2

Author(s):

J. D. Wright ◽

A. Alvarezsecord ◽

T. M. Numnum ◽

R. P. Rocconi ◽

M. A. Powell ◽

...

Keyword(s):

Ovarian Cancer ◽

Stable Disease ◽

Bowel Perforation ◽

Single Agent ◽

Recurrent Ovarian Cancer ◽

Significant Activity ◽

Recent Trial ◽

Platinum Resistant ◽

Heavily Pretreated ◽

Grade 3

5019 Background: Bevacizumab has shown activity in recurrent ovarian cancer with an acceptable adverse event profile. However, the incidence of bowel perforation in a recent trial of heavily pretreated ovarian cancer patients was higher than expected from prior experience with bevacizumab. Whether the difference in the rate of bowel perforation was due to refractory disease, treatment history, disease burden, or location of tumor is uncertain. We sought to review our multi-institutional experience with bevacizumab in patients with recurrent ovarian cancer. Methods: A retrospective review of patients with recurrent ovarian cancer treated with single agent or combination bevacizumab therapy was undertaken. Toxicity was assessed using standard criteria. Response was determined radiographically and through serial CA125 measurements. Statistical analysis to determine factors associated with toxicity and response was performed. Results: Sixty-two eligible patients were identified. All had failed prior platinum-based therapy and had received a median of 5 prior chemotherapy regimens and 2 prior platinum-containing regimens. Single agent bevacizumab was administered to 12 (19%) women, while 50 (81%) received the drug in combination with a cytotoxic agent. The most common toxicities were myelosuppression (60%), proteinuria (19%) and hypertension (16%). Grade 3–5 toxicities occurred in 15 (24%) patients, including grade 3–4 hypertension in 4 (7%). Gastrointestinal perforations were identified in 4 (7%) subjects. Nine (15%) patients discontinued therapy due to toxicity. Fifty-eight patients were assessable for response. The overall response rate was 36% (4 CR, 17 PR) with stable disease in 40%. Clinical benefit (CR, PR, stable disease) was seen in 83% of patients treated with single agent therapy and 74% of those treated with bevacizumab-combination regimens. Conclusions: Bevacizumab demonstrates significant activity for recurrent, platinum-resistant ovarian cancer. Life threatening bowel perforations were noted in 7% of our subjects. The frequency of perforations in our cohort suggests that this complication is more likely to occur in heavily pretreated patients. No significant financial relationships to disclose.

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