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.
In a 1981 review article published in the Annals of Internal Medicine discussing "current strategies" in the management of ovarian cancer, the authors noted the controversies regarding the role of a single agent vs combination chemotherapy, and single-agent chemotherapy vs radiation therapy in stage III disease, as well as the lack of a clearly established role for the "new" cytotoxic drug cisplatin. This paper further noted that the "age-adjusted death rate from ovarian cancer has remained unchanged over the past 20 years despite attempts at earlier diagnosis and more aggressive treatment." In commenting on the data regarding the risk of secondary alkylating agent-associated acute leukemia, the authors stated,[2,3] "clearly, the benefits of adjuvant chemotherapy and prolonged chemotherapy in ovarian cancer patients need closer scrutiny." Finally, although the article described the "significant" toxicities of chemotherapy (including cisplatin)—which "may include troublesome nausea and vomiting, renal impairment, ototoxicity, and peripheral sensorimotor neuropathy, and unusual side effects such as anaphylactic reactions and clinical tetany from hypomagnesemia"—there was no discussion regarding the impact of these effects on either overall short-term or long-term quality of life.
It is important to understand the state of affairs regarding the treatment of ovarian cancer in the early 1980s to truly appreciate the enormous changes in disease management since that time, and evidence for substantial improvement in both the duration of survival and quality of life for patients with the disease. This paper will briefly discuss the increasingly favorable impact of evolving treatment paradigms in improving these critical parameters, and note future directions for clinical research in this complex disease process.
Primary Treatment of Ovarian Cancer
Central Role of Platinum Agents
Multiple randomized trials and several meta-analyses have clearly established the role of platinum agents (cisplatin and carboplatin) in the primary chemotherapeutic management of ovarian cancer.[4-7] The most recent 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.
Based on this extensive experience revealing the critical role of platinum agents in ovarian cancer,[4-7] it is difficult to see a justification for future front-line chemotherapy trials in this malignancy to attempt to find substitutes for this class of cytotoxic drugs. Rather, research efforts should be focused on discovering agents that can add to the activity of platinum agents. (Of course, if a well conceived and conducted prospective phase III randomized trial demonstrates that a pretherapy "in vitro diagnostic test" can reliably determine that the ovarian cancer in a particular patient is highly resistant to platinum drugs, it would be appropriate to consider treatment with alternative strategies.)
Studies have now convincingly shown that carboplatin is equivalent to cisplatin when combined with either cyclophosphamide[10,11] or paclitaxel in the primary treatment of advanced ovarian cancer, with the carboplatin-based regimen generally being preferred by most oncologists (and patients) due to its more favorable toxicity profile (eg, less emesis, neuropathy, nephrotoxicity). However, it remains uncertain whether this same statement can be made for the equivalence of cisplatin and carboplatin when delivered by the intraperitoneal route as primary treatment of small-volume residual advanced ovarian cancer.
Based on the results of a series of excellent phase III clinical trials, it is appropriate to conclude there are three intravenous platinum-based primary chemotherapy regimens acceptable for use outside the setting of a clinical trial (Table 1).[12-15] As previously noted, the carboplatin-based programs are more likely to be employed in routine practice, not because of superior efficacy, but due to less toxicity and ease of administration (eg, when given with cisplatin, a 24-hour paclitaxel infusion is required to reduce the risk of severe neurotoxicity).
Clinical Research Efforts in Advanced Disease
For more than a decade investigators have explored methods to improve the primary treatment of advanced ovarian cancer. The substitution of paclitaxel for an alternative second agent (eg, cyclophosphamide), when combined with cisplatin, has been shown to substantially (and statistically significantly) improve both progression-free and overall survival in the malignancy.[13,16]
When combined with carboplatin, docetaxel has been demonstrated to be equivalent to paclitaxel in the treatment of advanced ovarian cancer (Table 1), but the two taxanes have different toxicity profiles. The docetaxel-containing regimen is associated with a greater risk of potentially clinically relevant neutropenia compared to paclitaxel, while the paclitaxel program is more likely to produce a sensory peripheral neuropathy. The decision regarding which taxane to employ as a component of primary chemotherapy in ovarian cancer should be based on the experience of the oncologist with the agents, unique clinical characteristics (eg, preexisting neuropathy from diabetes, elderly patient with a concern for bone marrow suppression), and patient choice.
Unfortunately, other attempted modifications of the "established" 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 (1) "doubling" platinum dose intensity (eg, cisplatin, from 50 to 100 mg/m2; carboplatin, from AUC 4 to AUC 8; or AUC 6 to AUC 12)[17-19]; (2) extending the paclitaxel infusion schedule from 24 to 96 hours; and (3) adding a third drug to a platinum/taxane program (eg, topotecan [Hycamtin], epirubicin [Ellence]). Of note, the preliminary results of a large (4,000-patient) international phase III ovarian cancer primary chemotherapy trial directly comparing several three-drug combination regimens to a carboplatin/paclitaxel program should be available within the next year.
Duration of Primary Chemotherapy in Advanced Disease
Several research groups have explored the concept of extending the duration of primary cisplatin-based chemotherapy regimen, from a standard 5 or 6 treatment cycles, to as many as 10 to 12 courses.[20-22] Unfortunately, prospective phase III trials have failed to reveal any additional benefits from this approach, but toxicity was clearly increased.
Despite this outcome with extended platinum-based primary chemotherapy in advanced ovarian cancer, interest was generated for examining a consolidation, or maintenance, strategy using paclitaxel, a cycle-specific agent that had previously been shown to exhibit a relatively acceptable toxicity profile when delivered for prolonged time periods (> 1-2 years) in the second-line treatment of the malignancy.[23-26] 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 study was discontinued by its Data Safety and Monitoring Committee when approximately one-half of the intended patient population had been entered, because of a highly statistically significant difference in progression-free survival in favor of the 12-cycle arm (28 vs 21 months; P = .002). Although the monitoring committee has the absolute prerogative to independently assess the ethical justification for continuing any randomized study, the decision to close the trial has been criticized, as it essentially eliminated any possibility that the trial would reveal an overall survival benefit associated with this novel strategy, if one truly exists.
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 (eg, normal physical exam and computed tomography scan of the abdomen and pelvis, normal serum CA-125 antigen level) 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). In this discussion, the possible benefits (ie, extended time to disease relapse, improvement in overall survival) will need to be balanced against the potential harms (eg, development of treatment-related peripheral neuropathy).
Cisplatin-Based Intraperitoneal Chemotherapy of Small-Volume Residual Advanced Disease
For more than 50 years, researchers have been interested in the intraperitoneal delivery of cytotoxic agents in the management of ovarian cancer, largely based on the anatomic location of the malignancy and its propensity for malignant ascites formation. In the late 1970s, a solid pharmacokinetic rationale for this strategy was presented by Dedrick and his colleagues at the National Cancer Institute (NCI), which led a number of research groups to systematically explore the approach.
These efforts culminated in three multicenter NCI cooperative group-based randomized phase III trials (Table 2),[30-32] which have unequivocally demonstrated the superiority of intraperitoneal cisplatin compared to intravenous cisplatin, when employed as primary chemotherapy of small-volume residual advanced ovarian cancer (variously defined as the largest residual tumor nodule being < 1-2 cm in maximal diameter following initial cytoreductive surgery).
The randomized trials have revealed that cisplatin-based intraperitoneal chemotherapy programs are associated with somewhat greater acute toxic effects compared to an "all-intravenous" regimen, but the studies also showed no increase in treatment-related mortality. 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: While there was a greater decline in formally assessed quality of life during treatment with the regional strategy, when examined at 12 months' follow-up, there was no difference between the two study arms. Thus, it is reasonable to conclude that all women with small-volume residual advanced ovarian cancer who do not have contraindications to intraperitoneal drug delivery (eg, extensive abdominal adhesions, infectious peritonitis) should be considered for management by this approach.
Several options for primary intraperitoneal chemotherapy may be considered, including the exact regimen utilized in the most recent GOG trial. However, it is also rational to argue that the tolerability of regional treatment could be enhanced without compromising the major survival advantage of this approach, by reducing the dose of cisplatin from 100 mg/m2, as employed in each of the three randomized trials, to a dose of 75-80 mg/m2.[29-33]
Future research efforts in this area will hopefully build upon current experience and explore other agents for regional delivery. Ongoing studies designed to improve the technology of drug delivery (eg, by optimizing catheter insertion or developing strategies to prevent adhesion formation) have the realistic potential to further enhance the efficacy of this novel management approach.
'High-Risk' Early-Stage Disease
It has been known for more than a decade that the administration of cytotoxic chemotherapy could delay the time to disease progression in women with "high-risk" early-stage (eg, stage IC or II) ovarian cancer, but data were not available to document whether such "adjuvant" treatment would favorably impact overall survival.
This controversy has now been resolved to the satisfaction of most ovarian cancer clinical investigators with the publication of results from a combined analysis of two large randomized phase III trials (N = 1,000), which directly compared adjuvant platinum-based chemotherapy to an observation strategy until disease relapse in women with high-risk early-stage cancer.[34,35] The studies revealed an improvement in both 5-year disease-free survival (76% vs 65%; P = .001) and, most importantly, 5-year overall survival (82% vs 74%; P = .008), associated with the early (adjuvant) treatment approach.[34,35]
The optimal number of platinum-based chemotherapy cycles to be delivered in this setting remains somewhat unsettled. Nevertheless, a strong argument can be made (both on theoretical grounds and considering limited existing data) that the same number of courses routinely employed in advanced disease should be utilized in this patient population, in the absence of excessive toxicity experienced by an individual patient (eg, early development of platinum-induced peripheral neuropathy).
Despite the substantial improvement in the outcome of patients with ovarian cancer, demonstrated both in individual randomized trials and in population-based studies, the majority of women who present with advanced disease ultimately die as a result of complications of progressive cancer. Before discussing the treatment of individuals whose malignancy has "failed to respond completely" to primary chemotherapy, or those in whom this state has been attained but the "cancer has recurred," it is relevant to note an evolving conceptual change in the general management of this population—that of viewing ovarian cancer as a chronic disease process. In this somewhat complex, and unquestionably controversial analysis, it is argued that an increasingly large percentage of patients with persistent/recurrent ovarian cancer can be anticipated to live for extended periods of time (often measured in years), despite the fact that the cancer can only be "controlled" and never eliminated.
Considered in this light, it becomes critically important to focus not only on the short-term side effects of treatment, but also on the longer-term toxicities. These effects may not only substantially interfere with a patient's quality of life, but may also impair her ability to subsequently receive drugs that might further delay the development of symptomatic disease progression. This is far from a trivial matter, as there are an increasing number of antineoplastic agents with documented activity in well-defined "platinum-resistant" ovarian cancer, and it is not uncommon for a patient to receive five or more regimens during the course of her illness.
Thus, for example, if aggressive dosing of a particular treatment program has a reasonably high probability of producing persistent peripheral neuropathy—such that it may be impossible to administer other neurotoxic agents in subsequently delivered regimens—it is difficult (if not impossible) to understand the justification for such an approach, in the absence of evidence-based data (prospective phase III randomized trials) revealing the superiority of an aggressive strategy, compared to more modest dosing programs.
The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Katz ME, Schwartz PE, Kapp DS, et al: Epithelial carcinoma of the ovary: Current strategies. Ann Intern Med 95:98-111, 1981.
2. Greene MH, Boice JD, Greer BE, et al: Acute nonlymphocytic leukemia after therapy with alkylating-agents for ovarian-cancer—a study of five randomized clinical-trials. N Engl J Med 307:1416-1421,1982.
3. Reimer RR, Hoover R, Fraumeni JF, et al: Acute-leukemia following alkylating agent therapy of ovarian cancer. N Engl J Med 297:177-180, 1977.
4. Advanced Ovarian Cancer Trialists Group: Chemotherapy in advanced ovarian cancer: An overview of randomised clinical trials. BMJ 303:884-893, 1991.
5. Aabo K, Adams M, Adnitt P, et al: Chemotherapy in advanced ovarian cancer: Four systematic meta-analyses of individual patient data from 37 randomized trials. Advanced Ovarian Cancer Trialists' Group. Br J Cancer 78:1479-1487, 1998.
6. Neijt JP, Bokkel Huinink WW, van der Burg ME, et al: Randomised trial comparing two combination chemotherapy regimens (Hexa-CAF vs CHAP-5) in advanced ovarian carcinoma. Lancet 2:594-600, 1984.
7. Omura G, Blessing JA, Ehrlich CE, et al: A randomized trial of cyclophosphamide and doxorubicin with or without cisplatin in advanced ovarian carcinoma. A Gynecologic Oncology Group study. Cancer 57:1725-1730, 1986.
8. 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.
9. Samson DJ, Seidenfeld J, Ziegler K, et al: Chemotherapy sensitivity and resistance assays: A systematic review. J Clin Oncol 22:3618-3630, 2004.
10. Alberts DS, Green S, Hannigan EV, et al: Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: Final report by the Southwest Oncology Group of a phase III randomized trial in stages III and IV ovarian cancer. J Clin Oncol 10:706-717, 1992.
11. Swenerton K, Jeffrey J, Stuart G, et al: Cisplatin-cyclophosphamide versus carboplatin-cyclophosphamide in advanced ovarian cancer: A randomized phase III study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 10:718-726, 1992.
12. Ozols RF, Bundy BN, Greer BE, et al: Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 21:3194-3200, 2003.
13. McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1-6, 1996.
14. Vasey PA, Jayson GC, Gordon A, et al: Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst 96:1682-1691, 2004.
15. Markman M, Kennedy A, Webster K, et al: Combination chemotherapy with carboplatin and docetaxel in the treatment of cancers of the ovary and fallopian tube and primary carcinoma of the peritoneum. J Clin Oncol 19:1901-1905, 2001.
16. Piccart MJ, Bertelsen K, James K, et al: Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: Three-year results. J Natl Cancer Inst 92:699-708, 2000.
17. McGuire WP, Hoskins WJ, Brady MF, et al: Assessment of dose-intensive therapy in suboptimally debulked ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 13:1589-1599, 1995.
18. Gore M, Mainwaring P, A'Hern R, et al: Randomized trial of dose-intensity with single-agent carboplatin in patients with epithelial ovarian cancer. London Gynaecological Oncology Group. J Clin Oncol 16:2426-2434, 1998.
19. Jakobsen A, Bertelsen K, Andersen JE, et al: Dose-effect study of carboplatin in ovarian cancer: A Danish Ovarian Cancer Group study. J Clin Oncol 15:193-198, 1997.
20. Lambert HE, Rustin GJ, Gregory WM, et al: A randomized trial of five versus eight courses of cisplatin or carboplatin in advanced epithelial ovarian carcinoma. A North Thames Ovary Group study. Ann Oncol 8:327-333, 1997.
21. Bertelsen K, Jakobsen A, Stroyer J, et al: A prospective randomized comparison of 6 and 12 cycles of cyclophosphamide, adriamycin, and cisplatin in advanced epithelial ovarian cancer: A Danish Ovarian Study Group trial (DACOVA). Gynecol Oncol 49:30-36, 1993.
22. Hakes TB, Chalas E, Hoskins WJ, et al: Randomized prospective trial of 5 versus 10 cycles of cyclophosphamide, doxorubicin, and cisplatin in advanced ovarian carcinoma. Gynecol Oncol 45:284-289, 1992.
23. von Gruenigen VE, Karlen JR, Waggoner SE: A case of chronic paclitaxel administration in ovarian cancer. Gynecol Oncol 89:532-535, 2003.
24. Markman M, Hakes T, Barakat R, et al: Follow-up of Memorial Sloan-Kettering Cancer Center patients treated on National Cancer Institute Treatment Referral Center protocol 9103: Paclitaxel in refractory ovarian cancer. J Clin Oncol 14:796-799, 1996.
25. Rohl J, Kushner D, Markman M: Chronic administration of single-agent paclitaxel in gynecologic malignancies. Gynecol Oncol. 81:201-205, 2001.
26. Zanotti KM, Belinson JL, Kennedy AW, 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 79:211-215, 2000.
27. 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.
28. Markman M: Intraperitoneal therapy for treatment of malignant disease principally confined to the peritoneal cavity. Crit Rev Oncol Hematol 14:15-28, 1993.
29. Dedrick RL, Myers CE, Bungay PM, et al: Pharmacokinetic rationale for peritoneal drug administration in the treatment of ovarian cancer. Cancer Treat Rep 62:1-11, 1978.
30. Alberts DS, Liu PY, Hannigan EV, et al: Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 335:1950-1955, 1996.
31. Markman M, Bundy BN, Alberts DS, et al: Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: An intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 19:1001-1007, 2001.
32. 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.
33. Markman M, Walker JL: Intraperitoneal chemotherapy of ovarian cancer: A review with a focus on practical aspects of treatment. J Clin Oncol (in press) 2006.
34. Trimbos JB, Parmar M, Vergote I, et al: International Collaborative Ovarian Neoplasm trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm trial: Two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J Natl Cancer Inst 95:105-112, 2003.
35. Elit L, Chambers A, Fyles A, et al: Systematic review of adjuvant care for women with stage I ovarian carcinoma. Cancer 101:1926-1935, 2004.
36. Markman M: Informing patients with cancer of "new findings" that may influence their willingness to participate in research studies. Cancer 98:885-887, 2003.
37. Jemal A, Murray T, Ward E, et al: Cancer statistics, 2005. CA Cancer J Clin 55:10-30, 2005.
38. Markman M: Viewing ovarian cancer as a "chronic disease": What exactly does this mean? Gynecol Oncol 100:229-230, 2006.
39. Markman M, Rothman R, Hakes T, et al: Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol 9:389-393, 1991.
40. Gore ME, Fryatt I, Wiltshaw E, et al: Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds. Gynecol Oncol 36:207-211, 1990.
41. Markman M, Kennedy A, Webster K, et al: Continued chemosensitivity to cisplatin/carboplatin in ovarian carcinoma despite treatment with multiple prior platinum-based regimens. Gynecol Oncol 65:434-436, 1997.
42. Thigpen JT, Blessing JA, Ball H, et al: Phase II trial of paclitaxel in patients with progressive ovarian carcinoma after platinum-based chemotherapy: A Gynecologic Oncology Group study. J Clin Oncol 12:1748-1753, 1994.
43. Parmar MK, Ledermann JA, Colombo N, et al: Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: The ICON4/AGO-OVAR-2.2 trial. Lancet 361:2099-2106, 2003.
44. Sabbatini P, Spriggs D: Salvage therapy for ovarian cancer. Oncology (Williston Park) 12:833-843, 1998.
45. Markman M: Why study third-, fourth-, fifth-, ...line chemotherapy of ovarian cancer? Gynecol Oncol 83:449-450, 2001.
46. Rose PG, Nerenstone S, Brady MF, et al: Secondary surgical cytoreduction for advanced ovarian carcinoma. N Engl J Med 351:2489-2497, 2004.
47. Vergote I, De W, I, Tjalma W, et al: Neoadjuvant chemotherapy or primary debulking surgery in advanced ovarian carcinoma: A retrospective analysis of 285 patients. Gynecol Oncol 71:431-436, 1998.
48. Mazzeo F, Berliere M, Kerger J, et al: Neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy in patients with primarily unresectable, advanced-stage ovarian cancer. Gynecol Oncol 90:163-169, 2003.
49. Davidson SA, Rubin SC, Mychalczak B, et al: Limited-field radiotherapy as salvage treatment of localized persistent or recurrent epithelial ovarian cancer. Gynecol Oncol 51:349-354, 1993.