PORTEC-3: Do we need a deeper insight into the appropriateness of chemoradiotherapy?

Mukherjee-Anindya

The PORTEC-3 study was based on the RTOG 9708 phase 2 study which showed that combination of radiotherapy and chemotherapy produces commendable loco-regional control and survival in elevated risk post-operative endometrial cancer cases [1]. The benefit of 'additive effects' of these modalities was tested with chemotherapy given in both adjuvant and concurrent settings. Barring the GOG 122 study [2] which used whole abdominal radiotherapy (a procedure seldom used nowadays due to increased risks of toxicity) the other predecessors of PORTEC 3, namely the Japanese [3] and Italian studies [4] have also included chemotherapy in both the settings. However, the EORTC-55991 and ManGoIliade[5] studies tested sequential chemotherapy after radiotherapy but not concurrent chemoradiotherapy. The reason for giving concurrent chemotherapy with radiotherapy needs a critical appraisal considering the PORTEC-3 study results.

The multicentric PORTEC-3 trial enrolled endometroid-type endometrial cancers of high-risk stage I (Grade 3 with deep myometrial invasion or lymphovacular invasion), stage II and III and also stage I to III of serous or clear cell variety. Patients were randomized into two groups in 1: 1 ratio- the radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) group and the chemoradiotherapy group. It needs special mention here that the second arm included both concurrent (two cycles of cisplatin 50 mg/m² given during radiotherapy) and sequential chemotherapy (four cycles of carboplatin AUC5 and paclitaxel 175 mg/m² following radiotherapy).

With a median follow-up of 60.2 months, 660 eligible patients were analyzed for survival outcomes and toxicities suffered. 5-year overall survival was 81·8% (95% CI 77·5–86·2) with chemoradiotherapy versus 76·7% (72·1–81·6) with radiotherapy (adjusted hazard ratio [HR] 0·76, 95% CI 0·54–1·06; p=0·11); 5-year failure-free survival was 75·5% (95% CI 70·3–79·9) versus 68·6% (63·1–73·4; HR 0·71, 95% CI 0·53–0·95; p=0·022). Grade 3 or worse toxicities were significantly higher in the chemoradiotherapy arm than radiotherapy alone arm(60% vs 12%, p<0.0001). Similar results were with persistent grade 2 or worse neuropathy (8% vs 1% at 3 years, p < 0.0001). The authors have concluded that chemotherapy (given concurrently and sequentially) has contributed to better failure-free survival in chemoradiotherapy arm, but it confers no overall survival advantage over radiotherapy alone. The authors have argued that in view of increased pelvic relapse with the use of adjuvant chemotherapy alone, the combination of chemotherapy and radiotherapy merited exploration. However, it is well known that chemotherapy is mainly responsible for distant control and radiotherapy for local control. Therefore, it is obvious that adjuvant chemotherapy alone can never be expected to provide adequate local control in absence of radiotherapy. A better rationality would have been the necessity of combing these therapies in the light of poor failure free survival with radiotherapy alone since these high-risk cases quite often failed distally.

Coming to the methodologies, the concurrent schedule of 50mg/m2 CDDP in first and fourth weeks of radiotherapy is inadequate as a radio sensitizing dose, if it has been intended for this purpose. Usually concurrent CDDP is given in weekly schedules. Such a schedule of CDDP is unlikely to potentiate the effects of radiotherapy in ensuring local control but may have toxicity implications. The radiobiological reason for such a schedule merits explanation.

The results show that mostly recurrences were distal pointing to the fact that high-risk endometrial cancer cases fail distally rather than locally. The extremely low and nearly same local recurrence rates in both the arms (isolated vaginal recurrences in one patient of either arm and isolated pelvic recurrences in three and five patients of chemoradiotherapy and radiotherapy alone arms respectively) reiterate the fact that chemotherapy has not contributed significantly to the local control due to radiotherapy. On the contrary, chemotherapy has indeed contributed to better distal control than radiotherapy alone arm (76 vs. 93 events).

Coming to the representations of survival estimates, Kaplan-Meier curves for local and distant failure free survivals would have better been presented separately to clearly differentiate between the two. Separate toxicity assessments post concurrent radiotherapy could have been presented to weigh the risks vs. benefits of the concurrent schedule.

The PORTEC- 3 has attempted to investigate the outcomes of high-risk endometrial cancers treated with postoperative radiotherapy with or without combined chemotherapy. The study was well powered with a sufficient median follow-up to give mature survival and toxicity data. However, the study arms could have been constructed better. A two arm (radiotherapy alone vs. radiotherapy followed by chemotherapy) study would have brought forth the results more unambiguously. If concurrent chemotherapy had to be included, its role could have been better understood in a 1: 1 subdivision (i.e., with and without concurrent chemotherapy) within the chemoradiotherapy arm.

References

  1. Greven K, Winter K, Underhill K et al. Final analysis of RTOG 9708: adjuvant postoperative irradiation combined with cisplatin/paclitaxel chemotherapy following surgery for patients with high-risk endometrial cancer. Gynaecol Oncol. 2006 Oct; 103(1):155-9.
  2. Homesley HD, FiliaciV, Gibbons SK, et al. A Randomized Phase III Trial in Advanced Endometrial Carcinoma of Surgery and Volume Directed Radiation Followed by Cisplatin and Doxorubicin with or without Paclitaxel: A Gynaecologic Oncology Group Study. Gynaecologic oncology. 2009;112(3):543-552. 
  3. Susumu N, Sagae S, Udagawa Y, et al. Randomized phase III trial of pelvic radiotherapy versus cisplatin-based combined chemotherapy in patients with intermediate- and high-risk endometrial cancer: a Japanese Gynaecologic Oncology Group study. Gynaecol Oncol 2008; 108: 226-33.
  4. Maggi R, Lissoni A, Spina F, et al. Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial. British Journal of Cancer. 2006; 95(3):266-271.
  5.  Hogberg T, Signorelli M, de Oliveira CF, et al. Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer - results from two randomised studies. European journal of cancer (Oxford, England: 1990). 2010;46(13):2422-2431.

Discussion question

To conclude, the role of concurrent chemotherapy needs clarification from the authors. What is the justification of following a concurrent chemotherapy regime of a precursor study when it neither contributes to local control nor distant control? Should we just continue the existing practice of sequential radiotherapy and chemotherapy in high-risk post-operative cases?

Anindya Mukherjee has no actual, potential, real or apparent interest to declare. I have no involvement that might raise the question of bias in the work reported or in the conclusions, implications, or opinions stated