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Over the past 2 decades, we have seen major progress in the management of women with ovarian cancer, with improvements in both overall survival and quality of life. To truly appreciate this progress, it is important to understand the state of affairs regarding the treatment of ovarian cancer in the early 1980s. This paper will discuss that historical background, describe the increasingly favorable impact of evolving treatment paradigms in ovarian cancer, and note future directions for clinical research in this complex disease process.
As part of the celebration of the 20th year of publication of ONCOLOGY, Dr. Maurie Markman has written a thoughtful, fair, and balanced review of some of the major issues in treating epithelial ovarian cancer over the past quarter of a century. Having treated my first patient with epithelial ovarian cancer in 1968, I hope to add my "balanced" view to four of the major topics discussed by Dr. Markman: (1) the central role of platinum agents, (2) the clinical research efforts in advanced disease, (3) duration of primary chemotherapy in advanced disease, and (4) intraperitoneal cisplatin chemotherapy for small-volume residual advanced disease.
Central Role of Platinum Agents
Dr. Markman states that "the most recent published phase III study, which directly compared single-agent cisplatin to single-agent paclitaxel as front-line treatment of advanced ovarian cancer, demonstrated that cisplatin produced a substantially higher objective response rate, compared to what many consider to be the 'second-most-active drug' in the malignancy." What he does not mention, however, is that this was a three-arm trial in suboptimally debulked patients, that the single-agent cisplatin arm (100 mg/m2) was as effective as the cisplatin/paclitaxel doublet arm, and that both were superior to single-agent paclitaxel (200 mg/m2) in terms of response rate and progression-free survival. Median survival in all three arms of the study was similar: for cisplatin, 30.2 months; for paclitaxel, 25.9 months; and for cisplatin plus paclitaxel, 26.3 months.
With the carboplatin/paclitaxel doublet having become "standard" therapy in almost all centers, the controversy over this issue continues. I think we still need to ask, what is the benefit of adding paclitaxel to cisplatin or carboplatin in advanced ovarian cancer?
Clinical Research Efforts in Advanced Disease
Dr. Markman states that "unfortunately, other attempted modifications of the 'established' [by which he means platinum plus taxane] ovarian cancer treatment program, examined in prospective phase III randomized trials, have not been shown to favorably affect outcome in the disease. These changes include...adding a third drug to platinum/taxane (eg, topetecan (Hycamtin), epirubicin (Ellence)." He cites no reference here, but on balance he is correct. The authors of a recently published phase III randomized trial comparing carboplatin/paclitaxel (TC) to TC plus epirubicin concluded that "the addition of epirubicin to TC did not improve survival or time to treatment failure in patients with advanced epithelial ovarian cancer."
Many of us who have been treating ovarian cancer for a long time have come to the 21st century realization that more (three drugs vs two drugs) is not necessarily better. Instead, what we need are novel agents to act against molecular targets that dictate malignant growth-for example, trastuzumab (Herceptin), targeting the ErbB growth factor receptor; gefitnib (Iressa), targeting the epidermal growth factor receptor; and bevacizumab (Avastin), a vascular endothelial growth factor inhibitor added to cytotoxic chemotherapy. More phase III trials of doublets and triplets, I believe, will not improve survival for women with epithelial advanced ovarian cancer.
Duration of Primary Chemotherapy in Advanced Disease
Dr. Markman writes "in a somewhat controversial phase III trial, the Southwest Oncology Group (SWOG) and the Gynecologic Oncology Group (GOG) randomized women with advanced ovarian cancer who had achieved a clinically defined complete response to primary platinum/paclitaxel chemotherapy to receive either 3 or 12 additional cycles of single-agent paclitaxel (175 mg/m2) delivered on an every-28-day schedule. . . [The investigators found] a highly statistically significant difference in progression-free survival in favor of the 12-cycle arm (28 vs 21 months; P = .02)."
He continues, "For the present, it is reasonable to conclude that women with advanced ovarian cancer who achieve a clinically defined complete response to primary platinum/taxane-based chemotherapy. . . should be informed of the results of this trial and be given the option of receiving this therapy, in the absence of clear treatment-related contraindications (eg, prior chemotherapy-induced neuropathy)."
Before an oncologist even considers this therapy, he or she should bear in mind that the trial, which was discontinued early, showed no difference in overall survival, and that patients in the 12-cycle arm experienced significantly more neurotoxicity. Moreover, progression-free interval may but not necessarily translate into prolonged survival. Because the trial was discontinued early and patients who received the 3 cycles of paclitaxel were allowed to cross over to the 12 cycles, we will never know if 12 cycles of paclitaxel improves overall survival compared to 3 cycles.
Finally, the gold standard for accepting a new treatment is a confirmatory trial, but such a study may never be conducted with paclitaxel.
Although I do not believe we have evidence supporting the use of maintenance chemotherapy in patients in a well-defined complete clinical remission after first-line platinum-based chemotherapy, I do believe there is a role for maintenance chemotherapy in women who achieve a complete clinical remission after chemotherapy for recurrent ovarian cancer. After the encouraging 1970s, when we witnessed responses to the newly developed platinum-based chemotherapy-which were unheard of in the alkylating agent monotherapy era-a new approach became clear to me: For the small number of patients who achieved a complete clinical response to second-line platinum-based chemotherapy, our goal should be to try to convert recurrent ovarian cancer into a "chronic illness." In 1982, we started using continuous maintenance chemotherapy for almost all patients who were fortunate enough to achieve a second remission after recurrent ovarian cancer. We reported our small but encouraging findings in 1998, asserting that these results could only be verified by a large randomized phase III trial.
Cisplatinum Intraperitoneal Chemotherapy of Small-Volume Residual Advanced Disease
Dr. Markman states, "further, a finding of great importance emerged from the most recently reported phase III trial, which compared a regimen of intravenous cisplatin/paclitaxel to a program of intraperitoneal cisplatin plus both intravenous and intraperitoneal paclitaxel... Thus, it is reasonable to conclude that all women with small-volume residual advanced ovarian cancer who do not have contraindications to intraperitoneal delivery (eg, extensive abdominal adhesions, infectious peritonitis) should be considered for management by this approach."
Fair, but I am not certain these remarks are balanced. After we reported our first trial of intraperitoneal cisplatin-based chemotherapy as second-line treatment in advanced epithelial ovarian cancer in 1988, I was convinced that for very small (< 5 mm) disease, this is an effective therapy. However, I am not convinced that the National Cancer Institute Alert encouraging doctors to use intraperitoneal chemotherapy as first-line treatment in small-volume residual stage III epithelial ovarian cancer is warranted.
First, intraperitoneal chemotherapy can be difficult to deliver and can be very toxic (compared to intravenous chemotherapy), as evidenced in the phase III trial cited by Dr. Markman. This study was done in academic centers, where 58% of patients did not complete the planned six cycles of therapy. It demonstrated a median progression-free survival of 5.5 months and a 15.9-month improvement in overall survival in the intraperitoneal arm. With the vast majority of patients in the intraperitoneal arm not completing the planned treatment, I have to wonder what factors other than intraperitoneal chemotherapy might have contributed to the increased overall survival.
While this strategy may become standard therapy, discussing the option with a terrified women preoperatively before a diagnosis of ovarian cancer is made-and before knowing whether she will even be a candidate for this therapy-seems problematic at best.
-M. Steven Piver, MD, LLD (HC)
The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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3. Markman M, Liu PY, Wilczynski S, et al: Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: A Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol 21:2460-2465, 2003.
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6. Armstrong DK, Bundy B, Wenzel L, et al: Phase III randomized trial of intravenous cisplatin and paclitaxel versus an intensive regimen of intravenous paclitaxel, intraperitoneal cisplatin and intraperitoneal paclitaxel in stage III ovarian cancer: A Gynecologic Oncology Group study. N Engl J Med 354:34-43, 2006.