The New England journal of medicine 2019-06-13
Adjuvant Chemotherapy plus Radiation for Locally Advanced Endometrial Cancer.
Abstract
Background
Stage III or IVA endometrial cancer carries a significant risk of systemic and locoregional recurrence.
Methods
In this randomized phase 3 trial, we tested whether 6 months of platinum-based chemotherapy plus radiation therapy (chemoradiotherapy) is associated with longer relapse-free survival (primary end point) than six cycles of combination chemotherapy alone in patients with stage III or IVA endometrial carcinoma. Secondary end points included overall survival, acute and chronic toxic effects, and quality of life.
Results
Of the 813 patients enrolled, 736 were eligible and were included in the analysis of relapse-free survival; of those patients, 707 received the randomly assigned intervention (346 received chemoradiotherapy and 361 received chemotherapy only). The median follow-up period was 47 months. At 60 months, the Kaplan-Meier estimate of the percentage of patients alive and relapse-free was 59% (95% confidence interval [CI], 53 to 65) in the chemoradiotherapy group and 58% (95% CI, 53 to 64) in the chemotherapy-only group (hazard ratio, 0.90; 90% CI, 0.74 to 1.10). Chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs. 7%; hazard ratio, 0.36; 95% CI, 0.16 to 0.82) and pelvic and paraaortic lymph-node recurrence (11% vs. 20%; hazard ratio, 0.43; 95% CI, 0.28 to 0.66) than chemotherapy alone, but distant recurrence was more common in association with chemoradiotherapy (27% vs. 21%; hazard ratio, 1.36; 95% CI, 1.00 to 1.86). Grade 3, 4, or 5 adverse events were reported in 202 patients (58%) in the chemoradiotherapy group and 227 patients (63%) in the chemotherapy-only group.
Conclusions
Chemotherapy plus radiation was not associated with longer relapse-free survival than chemotherapy alone in patients with stage III or IVA endometrial carcinoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00942357.).
Related Questions
What adjuvant treatment would you recommend for a patient with FIGO 2023 IIIB2 endometrioid endometrial adenocarcinoma (Grade 3, p53mut, MMR proficient), metastatic to the uterine serosa, bilateral ovaries, and anterior peritoneal reflection?
Chemotherapy followed by pelvic RT
For a patient with IIIC1 (micromets), MSI-high, Grade 2 endometrial adenocarcinoma who has undergone full surgical staging, do you recommend adding immunotherapy to adjuvant chemotherapy + radiation?
Short answer: No, I do not recommend adjuvant CT/IO + RT for this patient based on the patient's risk factors in the prompt, and the data below. Should the patient have recurrent/metastatic disease following adjuvant CT + RT/VCBT, then I/O + CT is a good option. Ongoing trials hope to answer this qu...
In light of new NCCN guidelines that state combination chemotherapy + pelvic RT should be reserved for endometrial cancer of at least stage IIIB, will you recommend EBRT in addition to chemotherapy for stage IIIA endometrial cancers?
Well, this is a little hard.I think it is pretty clear that chemotherapy is really the foundation for treatment of advanced disease. PORTEC-3 looked at women with high risk stage I, stage II, or stage III, or tumors with serous or clear cell histology (very diverse group!) and noted a survival benef...
Despite the paucity of strong data showing benefit of chemotherapy + radiotherapy in patients with stage I-II high risk histology endometrial cancer, if you recommend treatment with both modalities, how do you determine treatment schedule?
For the purpose of this answer, I'll define high risk as serous, carcinosarcoma, undifferentiated, and dedifferentiated. Clear cell carcinoma can be considered and likely treated more by its molecular profile. As you indicate, there is little data to support the routine use of chemotherapy for FIGO ...
In light of findings from GOG 258, is the benefit of adjuvant RT in IIIC endometrial cancer worth the potential acute and late risks of RT in the setting of significant autoimmune disease?
I agree with the thoughtful answers of others in terms of tailoring therapy and balancing risk/benefit. In this case, however, GOG 258 answered the value of doing radiation on top of chemotherapy for any patient that met its criteria. And in this case, it included 75% that indeed had stage IIIC dise...
How do you approach adjuvant chemotherapy for high risk/advanced endometrial cancer patients?
For patients with high risk/advanced endometrial cancer where adjuvant therapy is advised, I recommend paclitaxel (175 mg/m2) + carboplatin (AUC 6) (TC) every 3 weeks for 6 cycles. Data from GOG #209 strongly support this recommendation. In this large prospective study, TC demonstrated noninferiorit...
How do you select the concurrent cisplatin dose and schedule when treating locally advanced endometrial cancer with chemoradiation?
For locally advanced endometrial cancer treated with pre operative or definitive intent, we use weekly cisplatinum at 40mg/m2. Vargo et al., PMID 25218303
What is your adjuvant therapy for node positive, low grade endometrioid endometrial adenocarcinoma?
Chemotherapy (typically carboplatin/paclitaxel x 6 cycles), restage, and if no progression, whole-pelvic RT. Consider brachytherapy boost if cervical stromal or vaginal involvement and/or presence of other risk factors for vaginal cuff recurrence (e.g. LVSI, deep myometrial invasion, grade 3 [not in...
How would you manage an elderly but otherwise healthy patient with a high grade endometrioid uterine cancer with micro metastasis to a SLN, but otherwise confined to the uterus with superficial myometrial invasion?
With sentinel lymph nodes, pathology can show isolated tumor cells, micro metastasis, or macro metastasis. Our tumor board definitely has debated on how to handle micro metastasis in any patient, but especially those that are elderly, have treatment limited by social determinants, or have to travel ...
What are indications to add WPRT +/- PA field to chemotherapy for uterine serous carcinoma?
There is variation in practice. After adequate surgical staging, our approach: Stage 1A brachytherapy alone. Stage IB and above, EBRT. If node negative, treat pelvic including entire common iliac. If pelvis node positive and PA node dissected same as above, up to common iliac. If pelvis is posit...
How would you deliver/time radiation for a patient with IIIC1 serous endometrial cancer who is HER2+?
Stage III (particularly IIIC) and serous histology are both risk factors for distant failure. In combination, the patient is at an even higher risk. Therefore, I would prioritize getting in all cycles of chemotherapy to maximize distant control; generally, this would comprise 6 cycles of carboplatin...
Would uterine serosal involvement change your adjuvant treatment recommendation for a patient with Stage II grade 2 endometrial cancer?
Would recommend chemotherapy and vaginal brachytherapy. Had the patient had Stage II, Grade 2 disease (ignore the ITC for a moment), we would offer the patient pelvic radiation therapy alone based on GOG 249 and PORTEC 3 results, the latter of which showed a benefit of chemotherapy largely driven by...
Would you offer adjuvant radiation in addition to chemotherapy for a patient with stage IIIC uterine carcinosarcoma with cervical involvement?
This is a hard situation as there is no clear data for the exact treatment plan. For surgically staged patients with stage IIIC uterine cancer our tumor board treatment plans typically include discussion of PORTEC-3 (de Boer et al., PMID 31345626) and GOG-258 (Matei et al., PMID 31189035). Patients ...
How would you sequence chemotherapy and radiotherapy for a patient with stage IIIC1 serous endometrial carcinoma?
Update to Recommendation (3/2025): Clinical trial data supports incorporating immunotherapy with chemotherapy in the adjuvant setting for this group of patients. My recommendation for a patient with Stage IIIC1 serous endometrial cancer depends on the HER2 status as follows: HER2+: Chemotherapy + t...
What adjuvant therapy would you offer a patient with Stage II uterine serous carcinoma without lymph node sampling?
Since the major concern for UPSC is distant mets, these patients typically first receive 6 cycles of carboplatin/taxol after surgery at our institution. If the patient tolerates it without significant toxicity and re-staging scans are clear, we would then offer whole pelvis RT (45 Gy in 25 fractions...
Given the final results of GOG258, what regimen do you recommend use to treat Stage III endometrial cancer?
Full dose chemotherapy is important in stage III+ patients to prevent risk of distant failure. However, patients in GOG 258 who received chemotherapy alone had an unacceptably high risk of developing locoregional recurrence (27% 5-year incidence combining vaginal + pelvic/para-aortic). Despite conc...
Would you recommend EBRT/brachythrapy for any patients with stage III- IV uterine ca in light of GOG-258 data?
GOG-258 will certainly change management approach. The recurrence pattern between the two arms (higher distant mets in chemo RT arm and higher locoregional recurrence in chemo alone arm) suggests that sequencing of treatment may also matter. Our current approach is to have chemotherapy first and con...
How do you sequence chemotherapy with radiotherapy for advanced endometrial cancer?
Unfortunately, we don’t even know for sure if we need RT for stage III disease.GOG 258 showed early concurrent chemo RT is no better than chemotherapy alone (delaying chemo increased distant mets, which probably negated locoregional control benefit of RT). For this reason, chemotherapy has become st...
Do you give vaginal cuff brachytherapy and/or whole pelvis, for patients with Stage III endometrial adenocarcinoma?
Depends on the substage and extent of surgical staging: Stage IIIa serosa: I give pelvic RT alone often following chemotherapy. I would also add vag brachy in cases of cervical stromal invasion. Stage IIIa adnexae. Same as (1). Stage IIIb. I give pelvic RT plus vaginal brachy often following chemot...