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)."
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.
1. Muggia FM, Braly PS, Brady MF, et al: Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 18:106-115, 2000.
2. duBois A, Weber B, Rochon F, et al: Addition of epirubicin as a third drug to carboplatinum-paclitaxel in first line treatment of advanced ovarian cancer: A prospective randomized gynecologic cancer intergroup trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study group and the Groupe d' Investigateurs Nationaux poor l'etude des Cancers Ovariens. J Clin Oncol 24:1127-1135, 2006.
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.
4. Eltabbakh GH, Hempling R, Piver MS, et al: Prolonged disease-free survival by maintenance chemotherapy among patients with recurrent platinum-sensitive ovarian cancer. Gynecol Oncol 71:190-195, 1998.
5. Piver MS, Lele SB, Marchett DL, et al: Surgically documented response to intraperitoneal cisplatin, cytarabine and bleomycin after intravenous cisplatin-based chemotherapy in advanced ovarian adenocarcinoma. J Clin Oncol 16:1679-1684, 1988.
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.