Elsevier

Gynecologic Oncology

Volume 91, Issue 1, October 2003, Pages 123-129
Gynecologic Oncology

Regular article
Platinum retreatment of platinum-resistant ovarian cancer after nonplatinum therapy

https://doi.org/10.1016/S0090-8258(03)00464-5Get rights and content

Abstract

Objective

The objective was to determine the response rate to platinum retreatment of “platinum-resistant” ovarian cancer after intervening nonplatinum therapy.

Methods

We retrospectively identified 30 patients with platinum-resistant ovarian cancer who received nonplatinum chemotherapy for recurrent epithelial ovarian cancer prior to additional platinum therapy. All patients were treated between July 1, 1997, and June 30, 2001. Platinum resistance was defined as less than a partial response to platinum therapy or progression within 6 months of the last platinum therapy.

Results

Overall, 7 of 30 patients experienced an objective response to platinum therapy (partial response, 23%; complete response, 0%) based on CT scan (2/21) and/or CA-125 (5/9) criteria. The median time to progression for the group was 17 weeks (range, 4–59 weeks). Several predictive factors were identified. The interval since the last platinum treatment did not appear to be predictive in this group. Only 1 of 16 patients who did not have an objective response to the most recent platinum-based therapy responded to platinum rechallenge. Similarly, no patient who received more than three intervening nonplatinum treatments responded to additional platinum therapy (0/10).

Conclusions

Our small retrospective series suggest that the platinum-resistant category is heterogenous and includes patients who may respond to retreatment with platinum-based agents. This group includes the patients with prior platinum responses and early progression. However, patients without an objective response to the last prior platinum therapy or more than three intervening treatments are unlikely to respond to subsequent platinum therapy.

Introduction

The combination of platinum and taxane therapy after cytoreductive surgery has been the standard therapy for newly diagnosed advanced ovarian cancer since 1995 [1]. Responses are seen in 70–80% of cases with nearly half of all patients achieving a complete clinical remission [2], [3]. Yet, most ovarian cancer patients die of their disease, with cure rates of only 20–30% in advanced disease [2], [3]. Since many women will relapse and are not considered curative, the goals of therapy should be to control the disease without significantly diminishing quality of life. The optimal choice of therapy for recurrent disease remains controversial [4]. The decision regarding which agent to use is often based on disease- and treatment-free intervals, as well as prior response to therapy, especially platinum therapy.

Retreatment with platinum has been retrospectively demonstrated to result in responses of up to 77% depending on the platinum-free interval (PtFI) and overall treatment-free interval [5]. Patients with a longer PtFI seem to have a greater chance of responding to retreatment. This has led some authors to suggest a prolongation of the PtFI by using intervening nonplatinum agents [6]. This remains an unproven hypothesis that has been questioned by other authorities [4], [7]. In addition, some authors have suggested that the treatment-free interval is not an independent predictor of subsequent response. In a retrospective review of 700 patients treated in trials for recurrent ovarian cancer, time from last treatment was not a significant predictor of response on multivariate analysis but response was correlated with tumor size at the time of retreatment [7]. Responses to salvage therapies are often stratified based on the presumed sensitivity to platinum therapy into “platinum-sensitive” and “platinum-resistant” groups based on prior response and PtFI. Patients who do not have a response to platinum therapy or who relapse within 6 months after completion of therapy are thought to be platinum-resistant and felt to have a worse prognosis [1], [8]. Patients with a PtFI of more than 6 months are generally considered platinum-sensitive [5].

Many agents have been investigated for the treatment of platinum-resistant recurrent ovarian cancer. These include topotecan [9], liposomal doxorubicin [10], [11], oral etoposide [12], vinorelbine [13], docetaxel [14], ifosfamide [15], [16], paclitaxel [17], and gemcitabine [18]. Complete response for this group is rare (5%) and the overall response rates have been low, ranging from 9 to 33%.

The two most frequently used treatments, topotecan and liposomal doxorubicin, have reported response rates of 6–15% in the platinum-resistant group [9], [10], [11], [19]. Median response durations and time to disease progression are generally less than 6–8 months with median survivals of less than 1 year. The goals of therapy in this poor prognostic group should be tailored to disease control, symptom relief, and limitation of therapy-related toxicities.

Single-agent platinum therapy is well tolerated with a high response rate in platinum-sensitive patients. No other agent produces a greater response in this group [5], [20]. The definition of platinum sensitivity is somewhat arbitrary and is dependent on the timing of diagnosis of recurrent disease. Retreatment with platinum is often not considered for patients who are thought to be platinum-resistant, regardless of the pattern of resistance. That is, patients with progression on platinum treatment, partial responders, and early relapse patients are all grouped together as platinum-resistant. Still, there are clearly patients who do respond to platinum rechallenge. For example, Kavanagh et al.[21] reported a 21% response to platinum retreatment in platinum-resistant patients after progression on taxane therapy. However, this was not the central point of the report and the PtFI was difficult to ascertain. His observations have led to the proposition that “extending the platinum-free interval” with nonplatinum therapy may improve platinum responsiveness. We were interested in evaluating the response and outcomes in a cohort of patients with presumed platinum resistance who were subsequently retreated with platinum after receiving at least one intervening nonplatinum agent for recurrent ovarian cancer.

Section snippets

Patients and methods

Using the institutional database at Memorial Sloan–Kettering Cancer Center (MSKCC), we retrospectively identified 30 patients with platinum-resistant ovarian cancer who received nonplatinum chemotherapy for recurrent epithelial ovarian cancer (EOC) and then received additional platinum therapy (either single agent (n = 20) or platinum containing combination (n = 10)) between July 1, 1997, and June 30, 2001. Platinum resistance has been defined as one of the following during either initial or

Results

The clinical characteristics of the patient cohort at the time of initial diagnosis are listed in Table 1. The median age at initial diagnosis was 51 years (range, 26–73 years). Twenty-six patients (87%) were initially stage III or greater with 18 (60%) having undergone an optimal cytoreduction. Twenty-four patients (80%) were clinically without evidence of disease (NED) at the completion of their initial platinum therapy. In all, 9 patients (30%) were platinum-resistant within 6 months of

Discussion

Markman and Hoskins [5], [8] have defined several different prognostic groups among the recurrent ovarian cancer population. Patients in the platinum-resistant group have a worse prognosis than those who are in the platinum-sensitive group [1]. Phase II trials in platinum-resistant patients generally show relatively low response rates and short response durations (Table 6). For the platinum-resistant group, the vast majority of responses to retreatment are partial responses, with median time to

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    1

    Supported by an ASCO Clinical Development Award and the Byrne Institutional Grant from Memorial Sloan–Kettering Cancer Center.

    2

    Supported by Grant POI CA52477.

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