Elsevier

Gynecologic Oncology

Volume 114, Issue 2, August 2009, Pages 206-209
Gynecologic Oncology

Southwest Oncology Group Trial S9912: Intraperitoneal cisplatin and paclitaxel plus intravenous paclitaxel and pegylated liposomal doxorubicin as primary chemotherapy of small-volume residual stage III ovarian cancer

https://doi.org/10.1016/j.ygyno.2009.04.023Get rights and content

Abstract

Objective

While primary cisplatin-based intraperitoneal chemotherapy has been shown to favorably impact survival in small-volume residual advanced ovarian cancer, there is a need to develop strategies that improve the effectiveness of this approach.

Methods

A multi-center phase 2 trial was conducted that added intravenous pegylated liposomal doxorubicin (day 8; 30–40 mg/m2) to a regimen of intraperitoneal cisplatin (day 2; 75 mg/m2) and intravenous (day 1; 135 mg/m2) plus intraperitoneal (day 8; 60 mg/m2) paclitaxel. Treatment was initially delivered on an every 3-week schedule, but was modified to an every 4-week program due to excessive toxicity. Patients were to receive 6 cycles of this regimen.

Results

Of 68 patients entering this trial, 63 patients were eligible and evaluable, of whom 39 (62%) completed 6 cycles. Overall, 32 (51%) experienced at least 1 grade 4 or worse toxicity (most commonly hematologic) including 5 treatment-related deaths. Median progression-free survival (PFS) was 25 months (2-year PFS: 52%) and median overall survival 51 months, an outcome similar to previous reports of cisplatin-based intraperitoneal chemotherapy in comparable patient populations. Seventeen patients (27% of all eligible patients) were without evidence of disease recurrence > 4 years following entry into the trial.

Conclusion

Both the overall trial outcome, and specifically the excessively severe systemic toxicity of this regimen would prevent its future development in this exact form. The provocative PFS in a subset of individuals should encourage the development of alternative strategies designed to optimize the delivery of regional therapy in ovarian cancer management.

Introduction

The results of several phase 3 randomized trials have revealed the favorable impact on survival associated with the intraperitoneal, compared to the systemic administration of cisplatin when employed as primary chemotherapy of small-volume residual advanced epithelial ovarian cancer [1], [2], [3], [4]. This outcome led to a decision by the National Cancer Institute to issue a “Clinical Announcement” regarding primary regional therapy in the management of this malignancy [5].

In the most recently reported phase 3 study, which demonstrated a median 16 month improvement in overall survival, paclitaxel was delivered by both the intravenous and intraperitoneal routes [3]. The results of this particular trial stimulated interest in the development of investigative strategies that build upon the foundation of an intraperitoneal cisplatin plus intravenous and intraperitoneal paclitaxel regimen.

Pegylated liposomal doxorubicin has been shown to be biologically active and of clinical utility in platinum and paclitaxel resistant ovarian cancer [6], [7]. An attraction associated with adding this specific agent to a cisplatin/paclitaxel combination is its lack of neurotoxicity [6], [7]. Further, treatment with pegylated liposomal doxorubicin results in a relatively modest degree of bone marrow suppression, certainly compared to other cytotoxic agents commonly employed in this clinical setting [7], [8], [9], [10].

This paper reports the results of a phase 2 front-line ovarian cancer chemotherapy trial conducted by the Gynecology Committee of the Southwest Oncology Group that added systemically-delivered pegylated liposomal doxorubicin to a cisplatin-based intraperitoneal program that also included the administration of both intravenous and intraperitoneal paclitaxel.

Section snippets

Eligibility criteria

Patients considered eligible to enter this multi-center cooperative group phase 2 trial had to satisfy the following criteria: (a) histologically confirmed diagnosis of epithelial ovarian or primary peritoneal carcinoma; (b) previously undergone a staging exploratory laparotomy with an attempt at maximal surgical cytoreduction within 56 days prior to study entry and have optimal residual FIGO stage III disease (largest residual tumor nodule remaining within the peritoneal cavity ≤ 1 cm in

Results

Sixty-eight patients were enrolled on this phase 2 study, of which 5 individuals were subsequently determined to be ineligible. The median age of the treated population was 59 (range 34–80).

Sixty-three patients were evaluable for adverse events (Tables 2A, 2B). There were 5 treatment-related deaths, 4 of which occurred in patients treated with the modified paclitaxel and liposomal doxorubicin regimen after the previously described temporary closure of the study. These deaths resulted from:

Discussion

Several reasonable conclusions can be drawn from the results of this relatively large phase 2 multi-center cooperative group trial that explored the addition of systemically-administered pegylated liposomal doxorubicin to a cisplatin-based intraperitoneal program employed as primary treatment of small-volume residual advanced epithelial ovarian cancer.

First, while the study demonstrated the ability to add pegylated liposomal doxorubicin to a cisplatin-based intraperitoneal chemotherapy program,

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgments

This investigation was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA32102, CA38926, CA22433, CA46368, CA35431, CA67575, CA12213, CA86780, CA58861, CA13612, CA46113, CA12644, CA35119, CA46441, CA105409 and in part by Alza Corporation (now part of Johnson and Johnson).

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Current location: Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA.

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