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Originally published as JCO Early Release 10.1200/JCO.2005.03.8836 on December 5 2005 © 2006 American Society of Clinical Oncology.
Major Progress for a Less Common CancerSection of Medical Oncology, University of Chicago, Chicago, IL Uterine corpus malignancies represent the fourth most common malignancy and eighth most common cause of cancer death in US women in 2005.1 However, the majority of incident cases are endometrial cancers of good prognosis—those diagnosed in surgical stage I (72%), of endometrioid histology (88%), and with a grade of 1 or 2 (88%). Women with surgical stage I tumors have an 88% 5-year overall survival, all grades combined.2 Tumors with high grade, unfavorable histology, or advanced stage, which do have a high propensity to recur, are less common, and treatment recommendations have been quite varied. To date, no randomized data have demonstrated a survival benefit to any systemic adjuvant therapy in these higher risk groups, and administration of some form of radiotherapy has been the usual practice. Three negative randomized trials of adjuvant progestins for endometrial carcinoma were reported in the 1980s.3-5 As cytotoxic chemotherapy began showing promising response rates in women with measurable metastatic or recurrent disease, the Gynecologic Oncology Group (GOG) designed GOG 122 for women with stage III and low-volume (< 2 cm residual disease after abdominal resection) stage IV disease. This trial compared whole-abdominal radiotherapy (with a boost to the pelvis or pelvis and para-aortic node area) versus cisplatin plus doxorubicin chemotherapy. The mature results of this trial are published in this issue of the Journal of Clinical Oncology.6 They show a significant survival benefit for chemotherapy (hazard for death, 0.68; 95% CI, 0.52 to 0.89; P < .01) and represent a milestone in the treatment of endometrial cancer. Supportive evidence comes from a report at the 2005 American Society of Clinical Oncology meeting on a Japanese trial comparing pelvic radiotherapy versus chemotherapy in a group of "intermediate-risk" (> 50% myometrial invasion) patients. There was no survival difference between modalities overall, but the subgroup analysis of women who were stage IIIa by virtue of positive cytology had significant benefit from chemotherapy.7 Like any good experiment, GOG 122 raises more questions than it answers. The trial started to accrue in 1992. Available chemotherapy regimens, radiation techniques, and supportive care options have all changed since then. Some of the most important clinical issues include the following questions. Should chemotherapy and radiotherapy be combined? For GOG 122, patients randomly assigned to whole-abdominal radiotherapy received no chemotherapy, and those randomly assigned to chemotherapy received no radiotherapy. Randomized data have not yet shown a survival benefit to the use of radiotherapy in any stage of endometrial cancer, but it clearly reduces the rate of local relapse in early-stage disease. Combinations of chemotherapy and whole-abdominal radiotherapy are potentially toxic, and pilot and phase I studies suggest that such regimens are feasible only with significant reductions in chemotherapy dosage. Sequential use of more limited radiotherapy and full-dose chemotherapy is feasible, and seems intuitively reasonable; 35% of recurrences in the chemotherapy arm of GOG 122 were localized initially to the pelvis. The successor trial to GOG 122, GOG 184, administered involved-field radiation (ie, to either pelvis or pelvis plus para-aortic nodes), followed by six cycles of chemotherapy. The randomization, unfortunately, was not to chemotherapy alone or radiotherapy followed by chemotherapy, but to different chemotherapy regimens (doxorubicin plus cisplatin compared with doxorubicin, cisplatin, and paclitaxel, based on results demonstrating a survival benefit to the addition of paclitaxel to doxorubicin plus cisplatin in the advanced- and recurrent-disease setting). However, GOG 184 should at least give a reliable estimate of the adverse effects of such sequential therapy, including secondary leukemias and chronic bowel toxicity. It should be noted that growth factor was required for both chemotherapy arms. The trial has completed accrual, and results should be available in the next several years. Other sequences of treatment, more limited radiation fields, such as vaginal brachytherapy only, and algorithms including concomitant chemoradiotherapy are areas of active interest. Should earlier stage disease also be treated? Stage III, as included in GOG 122, includes a number of different situations (Table 1). All of the substages appeared to benefit from chemotherapy versus radiotherapy. Earlier stage high-risk groups have been identified. For example, the Postoperative Radiation Therapy in Endometrial Carcinoma trial reported that women with grade 3 deeply invasive tumors treated with postoperative pelvic radiotherapy had only a 58% 5-year overall survival.8 Given that women from the Postoperative Radiation Therapy in Endometrial Carcinoma trial did not have pelvic lymph node dissections, some of those with grade 3 deeply invasive tumors were certainly stage III rather than stage IC. However, International Federation of Gynecology and Obstetrics data suggest that even women whose grade 3 deeply invasive tumors are node negative (surgical stage IC; most received some form of radiotherapy) have only a 66% 5-year overall survival.2
Like grade 3 deeply invasive tumors, stage I tumors of aggressive histology, such as serous carcinomas, have a 20% to 30% relapse rate even when carefully surgically staged.9 It has become common practice in many centers to treat even stage I endometrial tumors of serous histology with adjuvant chemotherapy. Interestingly, the hazard ratios for benefit for chemotherapy compared with radiotherapy for the 20% of women with tumors of serous histology enrolled onto GOG 122 were 0.9 for progression-free survival and 1.025 for overall survival. However, the CIs for benefit by histologic subtype are overlapping, and it is unlikely that women with serous carcinomas have no benefit from chemotherapy. A recent overview demonstrated that the response rate of advanced-stage endometrial serous tumors to doxorubicin plus cisplatin-based chemotherapy is identical to that of endometrioid tumors10; the apparent lower benefit from chemotherapy in GOG 122 may be due to chance or, possibly, greater effect of abdominal radiotherapy. The relative rarity of early-stage serous disease (2.6% of surgically staged stage I/II cancers)2 makes randomized trials limited to that histology not feasible. The ability to complete trials in earlier stage high-risk endometrial cancer in general has been hampered by inconsistent algorithms for defining risk and varying practices with regard to lymph node dissection; unfortunately, a recent randomized trial mounted by the Radiation Therapy Oncology Group to evaluate chemoradiotherapy in high-risk stage I to II patients failed to accrue. Is cisplatin plus doxorubicin the only appropriate adjuvant regimen? The authors note that chemotherapy produced "more frequent and severe toxicity" than whole-abdominal radiotherapy, and only about two thirds of patients completed the prescribed eight cycles of chemotherapy. Much of the neutropenia was asymptomatic, and could be alleviated by growth factors, and it is likely that some of the grade 3/4 GI toxicity noted could be alleviated by the use of modern antiemetic regimens. Nonetheless, carboplatin plus paclitaxel, a regimen in common use for other solid tumors, has become widely used in the setting of both adjuvant and metastatic endometrial cancer. Multiple phase II studies have suggested efficacy and tolerability of carboplatin plus paclitaxel in advanced and recurrent disease,11 and the GOG is currently conducting a large, randomized, noninferiority trial in women with advanced and recurrent endometrial cancer to compare carboplatin plus paclitaxel versus the previous most effective regimen of paclitaxel, doxorubicin, and cisplatin (GOG 209). The comparison of this triplet to doxorubicin plus cisplatin from GOG 184 should be available in the next several years, and the results of these two trials should help guide the direction of future adjuvant chemotherapy regimens. A major step in the therapy of women with high-risk endometrial carcinoma has been made. Adjuvant systemic chemotherapy improves survival. Future trials need to address the treatment of earlier stage disease, optimization of chemotherapy regimen, integration of radiotherapy, and application of newer targeted agents. However, although in common tumors, such as breast cancer, multiple, large, randomized trials can be mounted to answer and confirm answers to a large variety of questions about choice and sequencing of adjuvant regimen and modality, the limited number of patients available for adjuvant endometrial cancer trials dictates that the questions to be answered in a randomized setting must be carefully prioritized, and the answers will not come quickly. As molecular markers stratify tumor types into ever smaller subgroups, this is becoming an issue in all tumor types. Perhaps in the future, trials using molecular profiling will allow cross–tumor-type treatment selection for clinical trials: for example, a certain group of markers may predict a high risk of recurrence, a different group will predict sensitivity to taxanes, and yet others will predict sensitivity to radiotherapy, all independent of site of origin of the cancer. Then progress in less common tumors can keep pace with progress in more common tumors. Until then, attempts should be made to standardize reporting of outcomes according to the risk factors we recognize, which should allow greater cooperation in large-scale clinical trials. Every effort should be made to enroll patients in randomized trials (such as GOG 122) when they are available; this remains the only way we ultimately will be able to make informed treatment recommendations to our patients. Author’s Disclosures of Potential Conflicts of Interest
The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed discription of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000–99,000 (C)
Author Contributions
REFERENCES
1. Jemal A, Murray T, Ward E, et al: Cancer Sstatistics, 2005. CA Cancer J Clin 55:10-30, 2005 2. Creasman WT, Odicino F, Maisonneuve P, et al: Carcinoma of the corpus uteri. Int J Gynaecol Obstet 83:79-118, 2003 (suppl 1)[CrossRef][Medline] 3. Macdonald RR, Thorogood J, Mason MK: A randomized trial of progestogen in the primary treatment of endometrial carcinoma. Br J Obstet Gynaecol 95:166-174, 1988[Medline] 4. Kauppila A: Progestin therapy of endometrial, breast and ovarian carcinoma: A review of clinical observations. Acta Obstet Gynecol Scand 63:441-450, 1984[Medline] 5. De Palo G, Mangioni C, Periti P, et al: Treatment of FIGO (1971) stage I endometrial carcinoma with intensive surgery, radiotherapy and hormonotherapy according to pathological prognostic groups: Long-term results of a randomized multicenter study. Eur J Cancer 29:1133-1140, 1993[CrossRef] 6. Randall ME, Filiaci VL, Muss H, 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 24:36-44, 2006 7. Sagae S, Udagawa Y, Susumu N, et al: Randomized phase III trial of whole pelvic radiotherapy vs cisplatin-based chemotherapy in patients with intermediate risk endometrial carcinoma. J Clin Oncol 23:455, 2005 (suppl; abstr 5002) 8. Creutzberg CL, van Putten WL, Warlam-Rodenhuis CC, et al: Outcome of high-risk stage IC, grade 3, compared with stage I endometrial carcinoma patients: The Postoperative Radiation Therapy in Endometrial Carcinoma Trial. J Clin Oncol 22:1234-1241, 2004 9. Creasman WT, Kohler MF, Odincion F, et al: Prognosis of papillary serous, clear cell, and grade 3 stage I carcinoma of the endometrium. Gynecol Oncol 95:593-596, 2004[CrossRef][Medline] 10. McMeekin DS, Filiaci VL, Thigpen T, et al: Importance of histology in advanced and recurrent endometrial cancer patients participating in 1st line chemotherapy trials: A Gynecologic Oncology Group (GOG) Trial. Gynecol Oncol 96:940, 2005 (abstr 69) 11. Muggia FM: Recent updates in the clinical use of platinum compounds for the treatment of gynecologic cancers. Semin Oncol 31:17-24, 2004 (suppl 14)[Medline]
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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