Intraperitoneal Chemotherapy as a Maintenance Treatment for Advanced Ovarian Cancer: Early Experience from Tertiary Care Center in India

Abstract

Introduction

Ovarian cancer is the eighth leading cause of death among women worldwide, accounting for 1.6% of new cancer cases and 2.1% of cancer-related deaths. Despite advances in cytoreductive surgery, peritonectomy, hyperthermic intraperitoneal chemotherapy (HIPEC), and systemic maintenance therapies, strategies for prolonged intraperitoneal (IP) chemotherapy remain underexplored.

Objectives

The aim of the study was to evaluate the feasibility, safety, and tolerability of extended IP cisplatin chemotherapy as a maintenance strategy following cytoreductive surgery in advanced ovarian cancer.

Materials and Methods

This retrospective study included stage III epithelial ovarian cancer patients treated between June 2021 and December 2022. A chemoport was placed intraoperatively, and patients received IP cisplatin (50 mg in 1 L normal saline) every 3 weeks for up to 1 year. Exclusion criteria included patients with incomplete medical records, those who did not undergo definitive cytoreductive surgery, and those with nonepithelial ovarian cancers. Data were collected from electronic medical records, including toxicity profile, compliance, and quality of life. Statistical analysis was performed using SPSS version 20, with descriptive statistics reported as frequencies, percentages, medians, and ranges.

Results

Twenty-five patients received IP chemotherapy. Median age was 54 years; 22 (88%) had high-grade serous carcinoma. Neoadjuvant chemotherapy (NACT) was administered in 23 (92%) patients, with a good response in 21 (93%) patients. Peritonectomy was performed in 20 (80%) patients, and HIPEC in 18 (72%) patients. Median peritoneal carcinomatosis index was 14, and cytoreduction was complete (CC-0) in 18 (90%) cases. Median infusion time was 35 minutes, and median number of sessions was nine. Treatment interruptions occurred in 3 (12%) patients due to port blockage or infection. Common side effects included grade I/II nausea (40%) and mild abdominal pain (8%). No grade III/IV toxicities, neutropenia, or hospital admissions were observed. The average cost per session was ∼6000 INR.

Conclusion

Extended-duration IP cisplatin chemotherapy is feasible, well tolerated, and cost-effective. It can be safely combined with NACT, peritonectomy, and HIPEC without increasing morbidity. Further randomized studies are warranted to assess incremental survival benefits.

Keywords

intraperitoneal chemotherapy - advanced ovarian cancer - maintenance therapy - HIPEC - peritonectomy

Introduction

Ovarian cancer causes the maximum number of deaths among all gynecological cancers.[1] According to GLOBOCAN 2020, it constitutes 1.6% of all new cancer cases and is responsible for 2.1% of all cancer-related deaths. Among women, ovarian cancer is known to be the eighth leading cause of death.[2] The majority of patients present in stage III/IV. Peritoneal dissemination at presentation and its affinity for serosal linings during recurrences are hallmarks of the biological behavior of this disease. Studies have shown that predominantly peritoneal dissemination has poorer outcomes than predominantly lymphatic dissemination.[3] As our understanding of disease pathophysiology has improved over a period of time, various treatment strategies have evolved centered around controlling peritoneal disease. Aggressive cytoreductions, peritonectomies, hyperthermic intraperitoneal chemotherapy (HIPEC), and intraperitoneal (IP) chemotherapy have been postulated to give incremental survival benefit after primary treatment. IP chemotherapy has been shown to have a peculiar impact on disease outcomes in various studies.[4] [5] [6] Although some systemic strategies of maintenance therapy also have evolved, such as Poly (ADP-ribose) polymerase (PARP) inhibitors, bevacizumab, etc.,[7] similar maintenance strategies for IP treatment are lacking. IP chemotherapy has shown promising results in a short duration for perioperative ovarian cancer patients. Here, we retrospectively assessed ovarian cancer patients who had undergone IP chemotherapy at our institution for a longer duration (up to 1 year). We have described our short-term experience and analysis of feasibility and tolerance parameters in this article.

Materials and Methods

Stage III epithelial ovarian cancer patients receiving IP chemotherapy during a curative course of treatment from June 1, 2021, to December 31, 2022, were included retrospectively in the study. Exclusion criteria included patients with incomplete medical records, those who did not undergo definitive cytoreductive surgery, and those with nonepithelial ovarian cancers. During curative surgery for this patient, before abdominal closure, a 9.6-Fr open-ended chemoport was placed by the operating surgeon, which was later used for the IP chemotherapy. In most of the patients, the catheter was placed in the right iliac fossa, and the chemoport dial was fixed onto the costal margin as per the operative notes. At our institution, the first infusion through the port was administered on day 5 postoperatively, which included 1,000 mL of normal saline (NS) with 500 mg of 5-FU and 2,000 units of heparin as a fibrinolytic agent and antiadhesive measure to ensure chemoport patency for subsequent use. Later, the first dose of IP chemotherapy was started 2 weeks postsurgery after ensuring wound healing and functional recovery. Inj. cisplatin (50 mg) (diluted in 1 L of NS) was used as the anticancer drug. All the patients received IP infusions three times weekly on an OPD basis in day care. Postinfusion, patients were asked to turn in various positions for half an hour to ensure even distribution of the solution within the peritoneal lining. No specific dietary precautions or routine monitoring of blood investigations were practiced in these patients. In case of port block, infection, or after treatment completion, it was removed under local anesthesia. We assessed the disease status of patients retrospectively through electronic medical records (EMRs) and assessed clinical examination findings, ultrasonography of the abdomen, and serum CA 125 levels at follow-up visits. Clinical parameters were recorded from clinical case files and institutional EMRs. Toxicity was assessed with the help of the Common Toxicity Criteria for Adverse Events. SPSS software (equivalent to version 20 and above) was used for statistical analysis of the data. Data were analyzed using SPSS version 20. Descriptive statistics were used to summarize patient demographics, treatment characteristics, and toxicity profiles. Categorical variables were expressed as frequencies and percentages, while continuous variables were reported as medians with ranges.

Ethical Approval

This is a retrospective study. The authors declare that they have adhered to the Declaration of Helsinki. No patient identities were disclosed.

Results

A total of 25 patients with stage III ovarian cancer underwent IP chemotherapy after initial surgery. Two patients had peritoneum-limited recurrent disease. The median age of the cohort was 54 years. High-grade serous carcinoma constituted 22 (88%) of all patients. Twenty-three (92%) patients received neoadjuvant chemotherapy (NACT). The median number of cycles of NACT was four. A good response to NACT was observed in 21 (93%) patients.

Bidirectional chemotherapy (intravenous [IV] and IP, both given simultaneously) was administered to four patients. All these patients received IP chemotherapy within 4 hours of the standard IV chemotherapy regimen (paclitaxel 175 mg/m² + carboplatin area under the curve 6). None of these patients needed a dose reduction of IV chemotherapy due to the addition of IP chemotherapy. There were no events of grade III or IV toxicity among these patients.

All patients underwent definitive surgery with curative intent. Involved peritonectomy was performed in 20 (80%) patients. HIPEC was administered in 18 (72%) patients. The median peritoneal carcinomatosis index of the cohort was 14. Completeness of cytoreduction score (CC score) was CC-0 in 18 (out of 20, 90%) cases and CC-1 in 2 cases.

The median time required for the IP chemotherapy infusion was 35 minutes (range: 25–60 minutes). Common side effects were grade I/II nausea for 12 hours post IP (10/25 patients) and mild abdominal pain (2/25 patients). The median number of IP chemotherapy sessions administered was 9 (range: 2–14). Treatment interruption was needed in 3/25 (12%) patients. Two patients had chemoport blockage without infection after completion of two and eight IP chemotherapy sessions, respectively. One patient had a chemoport infection after two IP chemotherapy sessions. None of the patients had clinically detectable neutropenia or grade III/IV chemotherapy-related toxicity. None of the patients needed admission for chemotherapy-related side effects. The average cost per IP chemotherapy session was approximately 6,000 INR.

Discussion

Peritoneal dissemination is very frequent in ovarian cancer. Roze et al[3] showed that nearly 70% of recurrences of ovarian cancer are predominantly peritoneal. The study also observed that the most common cause of death after getting a recurrence of ovarian cancer was bowel obstruction secondary to peritoneal disease (nearly 80%). Survival of patients with predominantly peritoneal recurrences was very poor compared with those with mainly lymphatic recurrences. This underlines the background need to develop better treatment strategies to control the peritoneal dissemination of ovarian cancer.

The high rate of recurrences in the peritoneal lining after primary treatment and dose-limiting toxicity of IV chemotherapy has made researchers explore various modalities of administering chemotherapy intraperitoneally. There is a theoretical advantage with IP drug delivery, allowing higher concentrations of chemotherapeutic agents within peritoneal fluid as compared with the bloodstream, leading to a favorable pharmacokinetic profile requiring lower absolute doses within the peritoneal lining. It also leads to better penetration of the drug into residual tumor nodules.

Initially, three large randomized trials have shown the benefit of adjuvant postoperative IP cisplatin in improving disease-free and overall survival (OS)[4] [5] [6] in patients with stage III ovarian cancer. Long-term follow-up data from the Gynecologic Oncology Group (GOG)-172 trial also showed that the survival benefit of IP chemotherapy lasts for more than 8 years.[8]

The Cochrane review of IP chemotherapy in women undergoing treatment of stage III ovarian cancer also demonstrated a 21% decrease in the risk of death (hazard ratio: 0.79, 95% confidence interval: 0.70–0.90) in the patients undergoing combined IV/IP therapy versus those undergoing IV therapy alone.[9]

However, the postoperative adjuvant IP chemotherapy completion rate was as low as 42% in GOG-172.[4] Catheter-related complications were the primary reason for discontinuation in 34% of patients.[10] Aletti et al,[11] in their single-institution study, encountered challenges similar to those present in GOG-172, namely, the poor tolerability of IP chemotherapy that resulted only in 36% of patients completing the planned treatment when high-dose paclitaxel and cisplatin were used in the IP arm. The reasons for discontinuing treatment included catheter-related complications (38%), nephrotoxicity (14%), and sepsis (14%).

This suggested that the choice of catheter, insertion technique, IP regimen, and choice of IP drug needed further investigation. Also noteworthy is the fact that survival benefits were still achieved despite low rates of treatment completion. This highlights that adjuvant IP chemotherapy still has a significant impact on the outcome of these patients. Thus, the inability to complete the stipulated number of cycles and associated morbidity within the abdomen has discouraged clinicians from using IP chemotherapy routinely in the treatment of ovarian cancer despite its showing survival benefit. The present study has only a 12% interruption rate; this is probably due to the lower doses of cisplatin used.

The latest GOG trial, GOG-252[12] (vs. GOG-172),[4] has shown that extended duration of anticancer treatment (up to 2 years vs. 3 months as standard duration) leads to improvement in progression-free survival (PFS) (24.9–27.1 vs. 18.3–23.8 months) and OS (74.1–78.2 vs. 49.7 and 65.6 months). This demonstrates a need to develop robust treatment strategies as a maintenance schedule for better survival outcomes. GOG-252 has also shown us that patients with no gross residual disease at the end of cytoreduction have better PFS and OS than those with optimal cytoreduction (< 1 cm residual disease). Grade III or worse infections were higher in the IP arm (17 vs. 11%). Forty percent of patients needed discontinuation of paclitaxel by cycle 4. There was no difference in intra-abdominal complications between the IP and IV arms. GOG-252 also has shown us that a reduction in IP cisplatin dose from 100 mg/m² (in GOG-172) to 75 mg/m² resulted in better tolerance of IP chemotherapy and improved completion rate (84 vs. 42%).

In this study, none of the patients received IP paclitaxel, probably due to concerns over its higher complication rate and catheter blockages as observed in GOG-252.[12] Since cisplatin has maximum evidence for efficacy, it probably was the drug of choice at our institution. The dose of cisplatin 50 mg/m² was concorded with the study by Gadducci et al[13] involving 113 International Federation of Gynecology and Obstetrics (FIGO) stages II to IV ovarian cancer patients from 1989 to 1996 who were randomly allocated to receive 50 mg/m² IP cisplatin found that IP chemotherapy, slightly improved PFS and OV of optimally cytoreduced advanced ovarian cancer patients, despite poor compliance in community hospitals.

This probably resulted in fewer systemic and abdominal toxicities and also fewer treatment interruptions due to catheter-related complications, and more patients continued for a greater number of cycles (median 9 cycles).

Recently, usage of NACT for stage III ovarian carcinoma has gathered momentum due to its noninferiority and lesser perioperative morbidity as compared with adjuvant chemotherapy.[14] [15] [16] [17] HIPEC has also been shown to improve relapse-free survival after NACT. In a landmark trial, van Driel et al[18] showed that aggressive cytoreduction along with HIPEC improves relapse-free survival in a post-NACT setting (14 vs. 10 months, p = 0.001). They also noted a reduction in deaths at the 5-year follow-up (51 vs. 62%, p = 0.001). The adoption of both postoperative adjuvant IP chemotherapy and HIPEC into routine practice is potentially limited by concerns over tolerability and morbidity. However, mortality rates of cytoreductive surgery and HIPEC for advanced (0–5%) and recurrent (0–10%) ovarian cancer are similar to mortality rates of other major gastrointestinal surgeries ([Table 1]).[19]

The majority of our patients were operated on after NACT. The primary purpose for the same probably was to reduce disease burden before surgery, to improve functional fitness of the patient preoperatively, and also to make gross total resection of the disease more feasible. Most of the patients in the present study underwent HIPEC (18/25 patients) at the time of definitive surgery. This was followed by IP chemotherapy for nearly 1 year without significant complications. This highlights the fact that usage of NACT, HIPEC, and subsequently IP chemotherapy in maintenance format is well tolerated by patients without significant toxicity. Probably, this study is the first attempt in the available world literature focusing on combining all these modalities together to maximize the impact on survival of stage III ovarian cancer patients.

Table 1 Summary of results

Parameter	Findings
Total patients	25
Median age	54 y
Histology	22 (88%) high-grade serous carcinoma
NACT	23 (92%) patients; median 4 cycles
Response to NACT	21 (93%) good response
Peritonectomy performed	20 (80%)
HIPEC administered	18 (72%)
Median PCI	14
CC score	CC-0: 18 (90%); CC-1: 2 (10%)
Median IP infusion time	35 min (range: 25–60)
Median IP sessions	9 (range: 2–14)
Treatment interruptions	3 (12%)—2 port blockage, 1 infection
Common side effects	Grade I/II nausea (10 patients), mild abdominal pain (2 patients)
Severe toxicity	None (no grade III/IV events)
Hospital admissions	None
Cost per session	∼6,000 INR

Abbreviations: CC score, completeness of cytoreduction score; HIPEC, hyperthermic intraperitoneal chemotherapy; IP, intraperitoneal; NACT, neoadjuvant chemotherapy; PCI, peritoneal carcinomatosis index.

Conclusion

IP chemotherapy for an extended time period is well tolerated by ovarian cancer patients. It has a favorable side effect profile and is cost-effective as well. IP chemotherapy can be easily combined with existing treatment strategies such as NACT, peritonectomy, and HIPEC without increasing morbidity substantially. IP chemotherapy can potentially also be explored as an option for bidirectional chemotherapy without increasing toxicity substantially. Further randomized studies are needed to explore the incremental survival benefit of extended-duration IP chemotherapy in addition to currently available treatment strategies.

Conflict of Interest

None declared.

Acknowledgment

The authors acknowledge the support extended by the Department of Medical Oncology for their invaluable support in managing these patients.

Authors' Contributions

A.T. contributed to conceptualization, execution, data collection, analysis, and manuscript preparation. T.T. and M.J. contributed to data collection, analysis, and manuscript preparation.

Patients' Consent

Patient consent: Written informed consent for publication of clinical details was obtained from the patient.

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Publication History

Article published online:
03 February 2026