Major progress for a less common cancer.

Uterine corpus malignancies represent the fourth most common malignancy and eighth most common cause of cancer death in US women in 2005. 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. 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. 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. 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. 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 wholeabdominal 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 advancedand 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. 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. 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. 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 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 1 JANUARY 1 2006