The Gaining Prominence of Chemotherapy in the Adjuvant Treatment of Advanced Endometrial Cancer
Abstract & Commentary
By Robert L. Coleman, MD, Associate Professor, University of Texas; M.D. Anderson Cancer Center, Houston. Dr. Coleman is on the speaker's bureau for GlaxoSmithKline, Bristol-Myers Squibb, and Ortho Biotech.
Synopsis: Chemotherapy with doxorubicin-cisplatin significantly improved progression-free and overall survival compared with WAI. Nevertheless, further advances in efficacy and reduction in toxicity are clearly needed.
Source: Randall M, et al. Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol. 2006;24:36-44.
Advanced stage endometrial cancer represents a significant therapeutic challenge as it encompasses patients with a diverse spectrum of disease and recurrence risk. Currently, most patients are treated following primary surgical extirpation with a modality either directed at tumor residua or to a high-risk locale of recurrence. Either or both radiation therapy and chemotherapy have been used. Both have been considered to be feasible and effective. Randall and colleagues addressed the question as to which was better in a randomized clinical trial of whole abdominal irradiation (WAI) vs combination chemotherapy with cisplatin and doxorubicin. Nearly 400 patients were entered over 8 years. Patients with stage III or IV (≤ 2 cm post-operative residual) disease were eligible. Both groups were well balanced for known prognostic factors including percent of stage III vs IV disease, nodal status, age, and performance status.
Overall, more patients completed WAI than chemotherapy and experienced less systemic toxicity. Treatment-related deaths, however, were similar on both arms. Progression-free and overall survival were significantly improved with chemotherapy relative to WAI. The reduction in the risk for progression for patients treated with chemotherapy was 33% and for overall survival, 31%; both are highly statistically significant. Subgroup analysis demonstrated that the benefit estimates were similar when evaluated by stage (III vs IV). The authors concluded that cisplatin and doxorubicin chemotherapy significantly improved progression-free and overall survival compared to WAI. However, significant modality-related toxicity should prompt investigation of alternative regimens.
Commentary
Endometrial cancer is the most frequently diagnosed gynecologic malignancy in the United States. Fortunately, most patients have organ-confined disease, which is highly curable with surgery with or without adjuvant therapy. However, patients with more advanced disease comprise the majority of disease-related deaths associated with this condition. Strategies to treat these patients have largely been directed to the known disease (eg, node-bearing tissues) or to the likely patterns of recurrence (eg, vaginal cuff or intra-abdominal locations). This has led to a diverse set of treatment recommendations and a diverse set of reported outcomes in uncontrolled clinical trials.1-3 Another challenge in this setting is the higher representation of high-grade and atypical histologies, such as clear cell and serous, which have a somewhat different natural history. Thus, a review of the literature comprising patients classified as "advanced stage" leaves the reader with a confusing picture of treatment recommendations and expectations.
Traditionally, it has been felt that advanced stage endometrial cancer patients represent a cohort with a significant risk of local and regional disease recurrence. This has been particularly true of patients with known metastatic disease in the abdomen (Stage IV). Those patients with small volume residual disease following surgery have been approached with WAI with significant survival characteristics. Given that patients may recur distantly with similar probabilities, attention has recently turned to the evaluation of systemic chemotherapy. The current trial represents the first such completed trial comparing the modalities head to head. It was somewhat of a surprise that chemotherapy performed as well as it did. Despite being more toxic and less likely to be completed in full, it significantly reduced the risk of disease progression and death by almost one-third. The results held true even in cases where radiation is considered a favored modality given its long track record of success and the oft-considered chemotherapy-sanctuary of the retroperitoneal lymphatics. To be fair, it is likely that WAI is not the best form of radiotherapy to administer in this setting, particularly in patients with stage III disease or in patients with 2 cm macroscopic residual tumors. Better case selection may have offered a more balanced trial. However, these results have ushered in an intensive investigation portfolio of expanded chemotherapy use and novel treatment packages utilizing radiation and chemotherapy for similarly staged patients. The report represents a significant contribution to the literature and is a tribute to the Gynecologic Oncology Group's investigator's tenacity to complete a difficult trial of divergent methodologies.
References
1. Greven KM, et al. Analysis of failure patterns in stage III endometrial carcinoma and therapeutic implications. Int J Radiat Oncol Biol Phys. 1989;17:35-39.
2. Hoskins PJ, et al. Paclitaxel and carboplatin, alone or with irradiation, in advanced or recurrent endometrial cancer: a phase II study. J Clin Oncol. 2001;19:4048-4053.
3. McMeekin DS, et al. Nodal distribution and its significance in FIGO stage IIIc endometrial cancer. Gynecol Oncol. 2001;82:375-379.
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