Elsevier

Gynecologic Oncology

Volume 102, Issue 3, September 2006, Pages 432-439
Gynecologic Oncology

Randomized phase III trial of three versus six cycles of adjuvant carboplatin and paclitaxel in early stage epithelial ovarian carcinoma: A Gynecologic Oncology Group study

https://doi.org/10.1016/j.ygyno.2006.06.013Get rights and content

Abstract

Objective.

Compared to 3 cycles, to determine if 6 cycles of adjuvant carboplatin (C) and paclitaxel (P) significantly lower the rate of recurrence in surgically staged patients with stage IA grade 3, IB grade 3, clear cell, IC, and completely resected stage II epithelial ovarian cancer (EOC); and to compare toxicities.

Methods.

Postoperatively, randomization was to either 3 or 6 cycles of chemotherapy consisting of P (175 mg/m2 over 3 h) and C (7.5 AUC over 30 min) every 21 days. Recurrence was any clinical or radiological evidence of new tumor.

Results.

Of 457 patients, 427 (93%) were histologically and medically eligible. While thorough surgical staging was required, it was incomplete or inadequately documented in 29% of otherwise eligible patients. Median age was 55.5 years; 69% of patients had stage I disease. Median follow-up is 6.8 years for 344 women alive at last contact. Grade 3 or 4 neurotoxicity occurred in 4/211 (2%) and 24/212 (11%) treated patients on the 3- and 6-cycle regimens, respectively (p < 0.01); 6 cycles also caused significantly more severe anemia and granulocytopenia. The recurrence rate for 6 cycles was 24% lower (hazard ratio [HR]: 0.761; 95% confidence interval [CI]: 0.51–1.13, p = 0.18), and the estimated probability of recurrence within 5 years was 20.1% (6 cycles) versus 25.4% (3 cycles). The overall death rate was similar for these regimens (HR: 1.02; 95% CI: 0.662–1.57).

Conclusions.

Compared to 3 cycles, 6 cycles of C and P do not significantly alter the recurrence rate in high risk early stage EOC but are associated with more toxicity.

Introduction

Approximately 30% of ovarian carcinomas are localized and amenable to complete surgical resection at the time of their initial presentation. The need for adjuvant therapy for patients with early stage epithelial ovarian cancer (EOC) has been the basis for numerous clinical trials conducted over the past two decades. For patients with stage IA or IB disease and favorable histology, survival after thorough surgical staging alone is excellent (> 90% disease-free survival at 6 years). In these cases, adjuvant therapy is considered unnecessary when thorough surgical staging and histological confirmation have been performed [1].

In contrast, other patients with early stage EOC (stage IA or IB and unfavorable histology including grade 3 or clear cell, stage IC, or stage II) are candidates for adjuvant treatment based upon significant 5-year recurrence rates of approximately 25–45%. The optimal adjuvant treatment for this group of high risk early stage EOC patients is unknown. Early experience in the Gynecologic Oncology Group (GOG) showed that such patients treated with either intraperitoneal phosphorus-32 or oral melphalan had similar survival rates of approximately 80% at 6 years [1]. A subsequent study of patients with the same disease stages compared intraperitoneal phosphorus-32 to 3 cycles of cisplatin plus cyclophosphamide. Although not statistically significant, the recurrence rate on the cisplatin regimen was 31% lower than the phosphorus-32 regimen [2]. A multicenter Italian trial also comparing cisplatin to intraperitoneal phosphorus-32 in stage IC EOC found that cisplatin significantly reduced the relapse rate by 61% [3]. This series of studies led the GOG to select platinum-based chemotherapy as the standard treatment for high risk early stage ovarian cancer.

Carboplatin plus paclitaxel has become the standard adjuvant chemotherapy for advanced ovarian cancer based upon data demonstrating that the combination of cisplatin plus paclitaxel is superior to that of cisplatin plus cyclophosphamide [4] and that carboplatin's activity is equivalent to that of cisplatin [5]. Based on these data, the GOG chose the combination of carboplatin plus paclitaxel for this trial in early stage ovarian cancer.

The optimal duration of adjuvant chemotherapy in ovarian carcinoma is unclear. Three randomized trials in primarily advanced ovarian cancer comparing 5–6 cycles versus 8–12 cycles of cisplatin-based chemotherapy failed to show a benefit from chemotherapy beyond 6 cycles [6]. In early stage disease, the GOG has historically used 3 cycles of chemotherapy as the standard treatment. The objective of this study was to compare recurrence rates following randomization to either a standard regimen of 3 cycles of C plus P or 6 cycles of the same agents.

Section snippets

Methods

All eligible patients had a histological diagnosis of epithelial ovarian cancer including serous, mucinous, endometrioid, mixed, undifferentiated, Brenner, clear cell, and transitional types. Borderline or low malignant potential tumors were ineligible. Participating institutions' institutional review boards approved the study prior to enrolling any patient; and all patients provided written informed consent consistent with federal, state and local regulations before randomization. After a

Results

Between March of 1995 and May of 1998, 457 patients were enrolled in this study, of whom 427 (93%) were considered eligible following centralized pathologic and medical review (Table 1). In a subsequent centralized review of all the surgical reports, 126 of the 427 (29%) had surgical procedures that were considered inadequately documented or less thorough than specified by the protocol. Of the 427 patients deemed pathologically and medically eligible, 293 (69%) were surgical stage I and 134

Discussion

This multi-institutional study demonstrates that adding 3 cycles of carboplatin plus paclitaxel to the standard 3 cycles does not significantly reduce the cancer recurrence rates for patients with high risk, early stage EOC. On the other hand, the additional cycles of chemotherapy did significantly increase toxicity. Not surprisingly, fewer patients completed the 6-cycle regimen. Whereas 95% of patients (pooling both treatment groups) completed 3 cycles, only 83% completed 6 cycles of therapy,

Acknowledgments

This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical and Data Center (CA 37517). The following GOG member institutions participated in this study: University of Alabama at Birmingham, Duke University Medical Center, Abington Memorial Hospital, Walter Reed Army Medical Center, Wayne State University, University of Minnesota Medical School, University of Mississippi Medical

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