AREAS OF CONFUSION IN ONCOLOGY
The Role of Adjuvant Radiation in Endometrial Cancer
By Virginia Diavolitsis, MD1, John Boyle, BA2, Diljeet K. Singh, MD, DrPH3, William Small, Jr, MD4 |
April 10, 2009
1Radiation Oncology Resident, Robert H. Lurie Comprehensive Cancer Center of Northwestern University
2Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Feinberg School of Medicine
3Assistant Professor, Gynecologic Oncology, Robert H. Lurie Comprehensive Cancer Center of Northwestern University
4Professor and Vice Chairman, Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois
|Our group recommends:
||Vaginal brachytherapy for most intermediate-risk patients
||Radiation therapy combined with chemotherapy for patients with stage III disease
For patients who have endometrial cancer with a high risk of recurrence, adjuvant therapy should be considered. Patients in this group include those with stage IIB disease, evidence of cancer spread to the lymph nodes, pelvic disease outside of the uterus (ovaries or parametria), high-risk stage I disease (ie, grade 3 disease with deep myometrial invasion), and high-risk cell types such as papillary serous or clear cell histologies.
The data on patterns of recurrence with no additional therapy after surgery in patients with high-risk disease are scarce. In the study by Aalders et al, patients with stage IC, grade 3 tumors had a death rate of 27.5%. Ayhan et al noted a 41% recurrence rate in a group of 68 surgically staged IIIA/IIIC patients who received no additional therapy. Nine patients (13%) had a local recurrence only, 13 (19%) had a distant recurrence only, and 6 (9%) had both local and distant recurrence. The total recurrence rate in the pelvis was 22%.
Risk of Locoregional Recurrence in Patients With Stage III Endometrial Cancer Treated With Chemotherapy Alone
More information is available regarding the recurrence risk with chemotherapy alone. In a study of 43 patients with high-risk or advanced endometrial cancer who received chemotherapy alone, 29 patients (67%) relapsed, with 17 (39.5%) relapses in the pelvis and 23 (55.5%) outside of the pelvis. The 3-year actuarial pelvic relapse rate was 46.5%. The authors concluded that adjuvant radiation therapy should be used even in patients receiving postoperative chemotherapy.[ 43] The GOG-122 study randomized 396 stage III/IV patients treated with surgery (with maximal resection of disease to ≤ 2 cm) to postoperative chemotherapy or whole-abdominal radiation therapy. Among patients who received postoperative chemotherapy, the initial recurrence site was in the pelvis alone in 18%, in the abdomen in 14%, and included extra-abdominal or liver metastases in 18%. Table 2 summarizes the data on locoregional recurrence in stage III patients treated with chemotherapy alone.
• Radiotherapy Options—Several studies of patients with uterine-confined disease but higher risk of recurrence show a benefit of radiation therapy. In the Norwegian study, when examining the subset of patients with stage IC, grade 3 tumors, the addition of radiation therapy decreased the incidence of cancer-related death from 27.5% to 18.2%. In the GOG-99 trial, the subset of patients in the high-intermediate risk group who received postoperative pelvic irradiation had a 19% decrease in recurrence and a 0.73 relative hazard of death.
Patients who have disease outside of the uterus may also benefit from adjuvant radiation therapy, which has been given using whole-pelvis radiation therapy, extended-field radiation therapy, and whole-abdomen radiation therapy. In a study of 121 patients with stage III disease, the addition of pelvic radiation therapy improved 5-year survival from 50.3% to 68% (P = .029). Extended-field irradiation—ie, extending the radiation therapy fields to include the common iliac and paraaortic lymph nodes—is used most often in patients with para-aortic metastasis.
One series in a group of 40 surgically staged patients with para-aortic lymph node metastases reported a 47% 5-year survival with adjuvant extended-field radiation therapy. Only one severe complication was noted. A previous series showed a 5-year survival of 10% in similar patients who did not receive extendedfield radiation.
Rose and colleagues reported the Massachusetts General Hospital experience of patients found to have para-aortic node metastases on lymph node dissection. A total of 26 patients were identified, of whom 17 received extended-field irradiation and 9 did not. Median survival time in the group that received extended-field radiation therapy was 27 months, compared to 13 months in the group given no adjuvant therapy (P = .004). There was one treatment-related death in the extended-field irradiation group.
Whole-abdominal irradiation has previously been used as a treatment option in patients with upper abdominal disease that has been completely excised or in those who are at a very high risk for intra-abdominal recurrence, such as those with papillary serous histology. The Stanford experience of whole-abdominal radiation in stage III/IV patients showed 3-year disease-free and overall survival rates of 79% and 89%, respectively. Our institution’s experience showed a 5-year relapse-free survival rate of 70%, with a 5-year actuarial overall survival of 86%.
The GOG-122 trial, as noted above, compared adjuvant whole-abdominal radiation therapy to adjuvant chemotherapy. With adjustment for stage, 5-year disease-free survival was predicted at 50% for the chemotherapy group compared to 38% in the whole-abdominal radiation therapy group. Overall survival also favored chemotherapy (hazard ratio = 0.68, P < .01). The 5-year actuarial pelvic control rate was 49% with adjuvant chemotherapy, but 7 4% with adjuvant radiation therapy (P = .011). The combined locoregional and distant metastasis rate was not reported. However, the authors note that whole-abdominal radiation therapy “may not be the most effective RT approach.”
• Combined Chemoradiotherapy— Given the improvement in disease-free survival seen with chemotherapy alone, but acknowledging the incidence of locoregional failures, the combination of chemotherapy and radiation therapy may be optimal.
Radiation Therapy Oncology Group (RTOG) 9708, a phase II study, was designed to assess the feasibility, toxicity, safety, recurrence patterns, and survival for high-risk patients receiving chemotherapy combined with adjuvant radiation therapy. Chemotherapy consisted of cisplatin(Drug information on cisplatin) at 50 mg/m2 on days 1 and 28 of radiation treatment followed by four additional courses of cisplatin at 50 mg/m2 and paclitaxel(Drug information on paclitaxel) (175 mg/m2). Radiation therapy consisted of 45 Gy in 25 fractions to the whole pelvis, followed by vaginal brachytherapy. A total of 46 patients were enrolled, and the median follow-up was 4.3 years. Four-year overall and disease-free survival rates for stage III patients were 77% and 72%. The investigators observed no recurrences for patients with stage IC, IIA, or IIB disease. The incidence of grade 3 toxicity was 16%, and of grade 4 toxicity, 5%.
A phase III study conducted by the Nordic Society of Gynecologic Oncology–European Commission and European Organisation for Research and Treatment of Cancer (NSGOEC- 9501/EORTC 55991), randomized high-risk early-stage patients to adjuvant external- beam radiation therapy with a brachytherapy boost vs adjuvant chemoradiation therapy. The investigators found an estimated 7% absolute difference in progressionfree survival favoring the combined-modality arm. Table 2 shows outcome data for selected trials in patients with stage III disease.
Endometrial cancer is the most common gynecologic cancer in the United States. Early-stage disease, in a large percentage of patients, is highly curable with surgery alone. Patients with uterine-confined disease and an intermediate risk of recurrence clearly benefit—in terms of local control— from the addition of radiotherapy. Ongoing evaluation of risk factors not included in staging is needed to clarify treatment recommendations. Until additional data are available, individual risk factors and competing morbidities should be considered when recommending adjuvant treatment. A combination of chemotherapy and radiotherapy may prove to be the preferred treatment algorithm in patients with a high risk of recurrence.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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