Regular articlePlatinum retreatment of platinum-resistant ovarian cancer after nonplatinum 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.
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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
References (28)
- et al.
Phase 2 trial of liposomal doxorubicin (40 mg/m2) in platinum/paclitaxel-refractory ovarian and fallopian tube cancers and primary carcinoma of the peritoneum
Gynecol Oncol
(2000) - et al.
Phase 2 trial of single agent ifosfamide/mesna in patients with platinum/paclitaxel refractory ovarian cancer who have not previously been treated with an alkylating agent
Gynecol Oncol
(1998) - et al.
Treatment of relapsed carcinoma of the ovary with single-agent paclitaxel following exposure to paclitaxel and platinum employed as initial therapy
Gynecol Oncol
(2000) - et al.
Activity of gemcitabine in patients with advanced ovarian cancerresponses seen following platinum and paclitaxel
Gynecol Oncol
(1996) - et al.
Carboplatin alone vs carboplatin plus epidoxorubicin as second-line therapy for cisplatin- or carboplatin-sensitive ovarian cancer
Gynecol Oncol
(2001) - et al.
Gemcitabine reverses cisplatin resistancedemonstration of activity in platinum- and multidrug-resistant ovarian and peritoneal carcinoma
Gynecol Oncol
(2003) - et al.
Analysis of patients with epithelial ovarian cancer or fallopian tube carcinoma retreated with cisplatin after the development of a carboplatin allergy
Gynecol Oncol
(2002) - et al.
Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds
Gynecol Oncol
(1990) “Recurrence within 6 months of platinum therapy:”an adequate definition of “platinum-refractory” ovarian cancer?
Gynecol Oncol
(1998)- et al.
Chemotherapy of advanced ovarian cancer
Semin Oncol
(1998)
Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer
N Engl J Med
Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancerthree-year results
J Natl Cancer Inst
Is there a “best” choice of second-line agent in the treatment of recurrent, potentially platinum-sensitive ovarian cancer?
J Clin Oncol
Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin
J Clin Oncol
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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.