What is the role of chemotherapy following surgery in women diagnosed with endometrial cancer?

It was unanimously agreed by all members of the working group that the NCCN guidelines version 2.2015, regarding the use of adjuvant chemotherapy in endometrial (uterine) carcinoma (EC), were sufficiently comprehensive and evidence-based for it to be adopted in Singapore.

In the specific context of endometrioid EC, all members agreed that all FIGO (International Federation of Gynecology and Obstetrics) stage II (although rare), III and IV patients who have had their disease resected should be offered adjuvant chemotherapy. This is based on the results from the pooled analysis of 2 randomized clinical trials (NSGOEC-9501/EORTC-55991 and MaNGO ILIADE-III) that were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival (PFS) in high-risk endometrial cancer.1In the NSGO/EORTC study, combined modality treatment was associated with a 36% reduction in the risk for relapse or death (HR 0.64, 95% CI 0.41-0.99; p=0.04). The result from the MaNGO-study pointed in the same direction (HR 0.61), but was not significant. In combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44-0.89; p=0.009). Neither study showed significant differences in overall survival (OS). However, in combined analysis, OS approached statistical significance (HR 0.69, CI 0.46-1.03; p=0.07) and cancer-specific survival was significant (HR 0.55, CI 0.35-0.88; p=0.01). The results of these 2 studies suggest that addition of adjuvant chemotherapy to radiation improves PFS in endometrial cancer patients following surgical resection with no residual tumour and a high risk profile. However, it remains unclear if the addition of radiotherapy to chemotherapy improves the results.

There was, however, initially a difference in opinion regarding the role of adjuvant chemotherapy for patients with stage IA and IB fully staged uterine endometrioid cancer with grade 3 disease. 3 workgroup members were not in favour of routinely offering chemotherapy to patients with stage 1A/1B grade 3 endometrioid uterine carcinoma while 3 other members were of the opinion that these patients (especially those who are younger and/or who have additional risk factors for distant and/or vaginal recurrence e.g. lymphovascular and myometrial invasion) should be offered adjuvant chemotherapy together with a detailed discussion on the lack of high quality clinical data regarding its risks and potential benefit or lack thereof for PFS and OS in this context. One member had no comments on the issue and two members were absent from the discussion. Two members quoted the results of a retrospective data analysis of patient outcomes with endometrioid uterine cancer from KKWCH showing that patients with 1C (i.e. new FIGO 2009 stage 1B) grade III uterine cancers without adjuvant chemotherapy had a 5-year OS of 89% (unpublished data), hence suggesting that there is likely to be minimal OS benefit for the addition of chemotherapy. One member proffered the opinion that the KKWCH data was not a randomized controlled study of adjuvant chemotherapy in early stage uterine cancer and it would therefore be inappropriate to infer too much from this single retrospective unpublished study of a small number of patients as a basis to define guidelines for practice in Singapore. Furthermore, 64% of patients in the NSGOEC-9501/EORTC-55991 and MaNGO ILIADE-III pooled analysis who showed benefit for adjuvant chemotherapy had stage I disease (IC n=190 [36%], IB n=109 [20%], IA n=44 [8.2%])1, which would support the use of adjuvant chemotherapy in this subgroup of patients. Additionally, while the local data from KKWCH would suggest that OS outcomes for local patients with stage 1B grade III are generally very good even without adjuvant chemotherapy, published data from other groups have also demonstrated improved disease free survival and OS outcomes following adjuvant chemotherapy in early stage high risk endometrial cancer (i.e. grade 2-3, stage IB or II cancers with more than 50% myometrial invasion).2In view of published data suggesting that the addition of chemotherapy may improve outcomes for women considered to be at the highest risk of distant and/or vaginal recurrence (i.e., outer one-third myometrial invasion, grade 2-3, and the presence of lymphovascular invasion LVSI), one member felt cautious about adopting the practice of not offering chemotherapy to stage 1B uterine cancers as a standard of care on the basis of this single retrospective study. In reply, a member mentioned further data collection would be performed to update this series and to further delineate the effect of adjuvant treatment in patients with stage 1B uterine cancer in Singapore. Until then, the group endorses the NCCN version 2.2015 guidelines in its entirety, including the use of adjuvant chemotherapy in combination with radiotherapy in patients with stage 1B disease with high risk features, which have been defined in the NCCN guidelines as age, positive lymphovascular invasion, tumour size, and lower uterine segment or surface cervical glandular involvement. For patients with high risk stage 1A disease, 3 members were not in favour of routinely offering chemotherapy to patients with high risk features, while 4 were of the opinion that these patients (especially those who are younger and/or who have additional risk factors for distant and/or vaginal recurrence e.g. lymphovascular and myometrial invasion) should be offered adjuvant chemotherapy together with a detailed discussion on the lack of high quality clinical data regarding its risks and potential benefit or lack thereof for PFS and OS in this context.

In terms of the choice of adjuvant chemotherapy regimen, the working group would suggest four to six cycles of 3-weekly carboplatin and paclitaxel to be used as the regimen of choice in this setting. Our preference for carboplatin plus paclitaxel in the adjuvant setting is based on the results of GOG 209 (currently unpublished), which was presented at the 2012 Society of Gynecologic Oncology Annual Meeting.3This trial compared carboplatin plus paclitaxel to the three drug regimen of paclitaxel, doxorubcin and cisplatin (TAP) in 1300 women with chemotherapy nave advanced uterine cancer, including women with stage III disease, and demonstrated that carboplatin and paclitaxel results in an equivalent overall response rate and similar PFS, but is also less toxic.3

There are currently no cost-benefit/cost-effectiveness analyses available with regard to the NCCN guidelines/ recommendations on adjuvant chemotherapy of uterine cancer.