Advances in the Treatment of Gynecologic Malignancies
Advances in the Treatment of Gynecologic Malignancies
In their excellent summary of randomized trials examining the management of cancers of the uterus and ovary, Kim and coauthors highlight a significant and worrisome difference that has developed between the two gynecologic malignancies over the past decade, with regard to the direction of clinical research involving chemotherapy. Although it is recognized that cytotoxic chemotherapy is employed in the majority of women with ovarian cancer at initial diagnosis, whereas such treatment is fortunately only required in a minority of individuals with endometrial cancer, it is unclear why there has been such a major divergence in the drugs and combination regimens currently being evaluated in clinical trials.Chemotherapeutic Substitutions
In the case of ovarian cancer, studies in the 1980s explored the use of carboplatin (Paraplatin) as a substitute for cisplatin. This approach was designed to reduce the toxicity of treatment while preserving efficacy. Moreover, cyclophosphamide (Cytoxan, Neosar), rather than doxorubicin, was generally employed in this malignancy (along with a platinum agent) in phase III trials and in standard clinical practice. That decision was based on considerations of toxicity (eg, doxorubicin-induced emesis and cardiac dysfunction), rather than on any evidence of superior efficacy associated with the alkylating agent.
Subsequently, when paclitaxel was shown to be active in platinum-resistant ovarian cancer, it was quickly tested as a front-line treatment of ovarian cancer in a two-drug combination with cisplatin. Despite the favorable survival impact associated with the use of cisplatin/paclitaxel compared with cisplatin/cyclophosphamide, clinicians had legitimate concerns about the toxicity of this new combination (eg, cisplatin caused more emesis), which led to trials comparing the combination of carboplatin/paclitaxel to cisplatin/paclitaxel. Several studies have confirmed the more favorable side-effect profile of the carboplatin-based program, without a loss of efficacy, and most investigators and clinicians now consider this combination to be the standard of care for this malignancy.
Thus, randomized trials exploring the optimal management of advanced ovarian cancer have progressed along highly logical pathways, focusing on both the efficacy and toxicity of the individual drugs in the two-drug regimen. The selection of agents to be examined in these definitive trials has been based on data obtained in phase II studies in well-characterized patient populations (eg, the activity of cisplatin in alkylating-resistant disease, or of paclitaxel in platinum-resistant disease).Different Story for Endometrial Cancer
In contrast, it is difficult to draw such conclusions regarding clinical research in the chemotherapeutic management of recurrent or metastatic endometrial cancer. Despite the recognized more favorable toxicity profile of carboplatin compared to cisplatin, and the absence of any data from controlled trials demonstrating the superiority of the more toxic platinum agent, cisplatin remains the key platinum drug examined in randomized trials conducted by the Gynecologic Oncology Group (GOG) in metastatic endometrial cancer.
Based on the successful investigative strategy in ovarian cancerand the fact that a phase II trial showed paclitaxel to be among the most active single agents ever examined in metastatic endometrial cancerone might have anticipated that the less toxic paclitaxel would have been substituted for doxorubicin and evaluated in a randomized trial (ie, cisplatin/doxorubicin vs either cisplatin/paclitaxel or single-agent paclitaxel). Unfortunately, such a trial was never conducted. Instead, the GOG elected to add paclitaxel to the combination of doxorubicin and cisplatin, comparing this more toxic regimen to the GOG "gold standard" of cisplatin plus doxorubicin.
One might speculate that this peculiar clinical research direction evolved because it is not possible to safely deliver the combination of carboplatin/paclitaxel in endometrial cancer, due to patient age or prior radiation. However, this is certainly not the case, as several published phase II studies have documented both the safety and activity of the combination in this setting.[7,8]Conclusions
In general, it is reasonable to conclude that a chemotherapy regimen should be tested in a randomized trial before it is declared to be the standard of care for any malignancy. However, in the absence of definitive trials comparing a regimen of carboplatin/paclitaxel to the so-called "gold standard" of cisplatin/doxorubicin in the treatment of metastatic endometrial cancer, it may be necessary for clinicians to rely on published phase II data in the peer-reviewed literature to select an optimal management approach.
Currently, the realistic goals of chemotherapy for metastatic endometrial cancer are to attempt to palliate cancer-induced symptoms, minimize the toxicity of treatment, optimize overall quality of life, and possibly prolong survival to a limited extent. Any chemotherapy program considered for randomized trials or standard clinical practice should be critically evaluated as to how it satisfies these reasonable clinical requirements.
1. 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.
2. 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.
3. 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.
4. Moore TD, Phillips PH, Nerenstone SR, et al: Systemic treatment of advanced and recurrent endometrial carcinoma: Current status and future directions. J Clin Oncol 9:1071-1088, 1991.
5. Ball HG, Blessing JA, Lentz SS, et al: A phase II trial of paclitaxel in patients with advanced or recurrent adenocarcinoma of the endometrium: A Gynecologic Oncology Group study. Gynecol Oncol 62:278-281, 1996.
6. Fleming GF, Fowler JM, Waggoner SE, et al: Phase I trial of escalating doses of paclitaxel combined with fixed doses of cisplatin and doxorubicin in advanced endometrial cancer and other gynecologic malignancies: A Gynecologic Oncology Group study. J Clin Oncol 19:1021-1029, 2001.
7. Zanotti KM, Belinson JL, Kennedy AW, et al: The use of paclitaxel and platinum-based chemotherapy in uterine papillary serous carcinoma. Gynecol Oncol 74:272-277, 1999.
8. Hoskins PJ, Swenerton KD, Pike JA, et al: Paclitaxel and carboplatin, alone or with irradiation, in advanced or recurrent endometrial cancer: A phase II study. J Clin Oncol 19:4048-4053, 2001.