Long-Term Outcome of Oxaliplatin and Capecitabine (XELOX) Concomitant with Neoadjuvant Radiotherapy and Extended to the Resting Period in High Risk Locally Advanced Rectal Cancer

Introduction

Substantial progress has been made in the management of locally advanced rectal cancer (LARC) during the past decades. With combined-modality therapy consisting of preoperative chemoradiotherapy (CRT), total mesorectal excision surgery (TME) and postoperative chemotherapy, local recurrence rate has been dramatically reduced ^1-5. However, few of the published randomized trials have demonstrated a survival benefit after a long term follow-up ^{5, 6}. Despite the local recurrence rates having been reduced to less than 5%, distant metastasis still occur in about 25% of patients. Given that better control of systemic disease becomes the major challenge for the management of LARC, there is a strong clinical rationale for upfront use of intensified systemic therapy to prevent or eradicate micrometastases. Adding oxaliplatin to the regimen of fluorouracil based adjuvant chemotherapy has improved disease free survival and overall survival in colon cancer ^7-9. Therefore, several large randomized phases III trials tested the efficacy of adding oxaliplatin to the multimodal neoadjuvant treatment for LARC. However, except the German CAO/ARO/AIO-04 study showing an improved disease free survival, integrating oxaliplatin into the combined modality strategies failed to show a survival benefit ^10-13. As a result, the strategy of simply adding oxaliplatin concomitant to conventional CRT remains unsatisfactory.

Previously, to enhance systemic control, we used an intensified chemotherapy with oxaliplatin and capecitabine (XELOX) administered concomitantly to preoperative radiotherapy and extended to the resting period between complication of CRT and surgery for high-risk LARC patients. Preliminary results suggest this alternative strategy was well tolerated and associated with high rates of pathological complete response (pCR) and major regression rates ¹⁴. In the present study, we aimed to report the long-term outcomes of the patients treated according to this protocol.

Patients and methods

Results

Discussion

The intensified strategy with XELOX regimen administered concurrently with preoperative radiation and extended to the resting period after CRT before surgery and as postoperative adjuvant chemotherapy resulted in excellent disease control and long-term survival, with well-tolerated toxicity and good compliance. After a median follow-up of 51 moths, the cumulative incidence of local recurrence and distant metastasis is 4.4% and 24.4%, respectively.

With preoperative CRT/RT and optimized TME, local recurrence rates have been markedly reduced to below 5% in locally advanced rectal cancer ^{2, 4, 5, 17}. In present study, the cumulative incidence of local recurrence was 4.4% which was comparable to the published studies. Hence, distant metastases are now the predominant causes for failure and better control of systemic disease becomes the major challenge for the management of LARC.

Several studies have investigated integrating combination chemotherapy into the combined modality aiming to improve local and systemic control. The strategy of adding oxaliplatin weekly to fluoropyrimidine-based chemotherapy was well studied. Except the CAO/ARO/AIO-04 trail, results from randomized phase III trials: STAR-01, ACCORD 12, NASPBR-04, and PETACC-6 showed that adding oxaliplatin to 5-FU/capecitabine-based preoperative CRT increased acute toxicity, but failed to improve the pCR rate and disease free or overall survival ^{10-13, 17}. The CAO/ARO/AIO-04 trail with more than 1250 patients recruited reported a significant improvement of pCR rate (13% vs. 17%, P=0.04) and 3-years DFS (71.2% vs. 75.9%, P=0.03). The current study reported a feasible pCR rate (37.8%) and 3-years DFS 75.5% (95% CI, 63.0%-88.0%) which was comparable to that of the CAO/ARO/AIO-04 trial. Of note, except the CAO/ARO/AIO-04 trial, most of the above mentioned studies did not change the schedule of fluoropyrimidine delivery with oxaliplatin weekly added to the conventional CRT, which might increase toxicities and result in more dose reduction or treatment interruptions. In the STAR-01, only 66% patients received initially planned oxaliplatin infusions with or without radiation dose reduction ¹⁰. In the ACCORD-12, only 41% patients received full dose of oxaliplatin ¹¹. The current study using the XELOX regimen as the concurrent chemotherapy scheduled 1 week free of chemotherapy in the middle of radiation, which was similar to the CAO/ARO/AIO-04 trail. The alternative schedule was well tolerated and 85% patients received full dose of neoadjuvant oxaliplatin. In our study, all patients received the planned full dose of radiation and concurrent chemotherapy. Less dose reduction and treatment interruption might account for favorable outcome.

Lengthening the interval between CRT and surgery was associated with improved tumor response ¹⁸. With the longer chemotherapy-free interval, there are also concerns about the possibility of increasing the risk of metastasis. Several small trails have tested the utility of consolidation chemotherapy into the resting period between the CRT and the surgery. Habr-Gama et al. first reported an impressive sustained complete response (65%), with 3 additional cycles of fluoropyrimidine-based chemotherapy during the resting period ¹⁹. Garcia-Aguilar et al. reported a prospective phase 2 trial consisting of 4 sequential study groups ²⁰. All patients received fluoropyrimidine-based chemoradiation. Study group 1 had surgery 6-8 weeks after CRT. Study group 2-4 received two, four, six cycles of mFOLFOX6, respectively, during the waiting period before surgery. The pCR rate was 18%, 25%, 30%, and 38% in study group 1-4, respectively. Although promising, long-term follow up to measure the oncological outcome remains pending. Soo Jung Lee et al. recently reported a pilot study adding one cycle of fluoropyrimidine-based chemotherapy during the resting period between CRT and surgery. Despite more N2 disease and higher carcinoembryonic antigen level in the historical control group, the estimated 3 years DFS in the study was better than the control group (79.5% vs. 67.5%, P=0.04)²¹.

Adjuvant chemotherapy after preoperative chemoradiotherapy and surgery for patients with rectal cancer was still controversial ^22-25. Although with insufficient strong evidence, current practices recommend a full course of adjuvant chemotherapy for all patients with rectal cancer receiving CRT and surgery, irrespective of the final pathology. The ADORE trail indicated that adjuvant FOLFOX improves DFS compared with fluorouracil plus leucovorin in patients with postoperative pathological stage II or III rectal cancer after preoperative chemoradiotherapy (71.6% vs. 62.9%, P=0.047) )²⁶. In the present study, a benefit of adjuvant chemotherapy with XELOX regimen was observed in exploratory subgroup analysis (HR 0.24, 95% CI 0.08-0.74; P=0.01). Since these subgroup analyses are exploratory, it is hard to draw any conclusion.

The limitations of the present study are obvious. The inherent retrospective nature, relatively small numbers of patients, and single-arm design might limit the power to interpret data. Because of the absence of a control group, our results are merely hypothesis rather than confirmatory.

Conclusion

The intensified strategy with a XELOX regimen administered concurrently with radiation and extended to the resting period after CRT before surgery and as postoperative adjuvant chemotherapy was well tolerated and resulted in excellent long-term survival. These promising results warrant further investigation in future prospective randomized trials.