Elsevier

Clinical Oncology

Volume 33, Issue 12, December 2021, Pages 788-794
Clinical Oncology

Original Article
Intensified Total Neoadjuvant Therapy in Patients With Locally Advanced Rectal Cancer: A Phase II Trial

https://doi.org/10.1016/j.clon.2021.06.006Get rights and content

Abstract

Aims

We assessed the efficacy and safety of total neoadjuvant therapy, including targeted agent plus FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) induction chemotherapy followed by intensified chemoradiotherapy (CRT) and surgical resection, in patients with locally advanced rectal cancer.

Materials and methods

This was a single-arm, single-centre phase II trial. Eligible patients had non-metastatic locally advanced rectal adenocarcinoma. Based on Ras-BRAF status, patients were treated with bevacizumab (mutated Ras-BRAF) or panitumumab/cetuximab (wild-type Ras-BRAF) plus FOLFOXIRI regimen followed by oxaliplatin–5-fluorouracil-based CRT and surgery. The primary end point was pathological complete response rate. Secondary end points were toxicity, compliance, tumour downstaging, complete resection, surgical complications, local and distant failures and overall survival. The sample size was planned to expect an absolute 20% improvement in pathological complete response rate over historical literature data with an α error of 0.05 and a power of 80%.

Results

Between October 2015 and September 2019, 28 patients (median age 66 years) were enrolled. All patients had regional lymph node involvement at diagnosis. FOLFOXIRI plus bevacizumab was administered in 11 mutated Ras-BRAF patients, whereas the 17 wild-type Ras-BRAF patients received FOLFOXIRI plus panitumumab/cetuximab. Overall, total neoadjuvant therapy was well tolerated and 26 patients (92.9%) completed the programmed strategy. A complete response was achieved in nine cases (32.1%) and a nearly pathological complete response (ypT1 ypN0) in two patients (7.2%). There was no evidence of febrile neutropenia and no grade 4 adverse events were recorded. Radical resection was achieved in all cases.

Conclusion

FOLFOXIRI plus targeted agent-based induction chemotherapy and intensified CRT before surgery showed promising clinical activity and was well tolerated in locally advanced rectal cancer patients. This phase II trial provides a strong rationale for phase III studies.

Introduction

Currently, total neoadjuvant therapy, including induction FOLFOX (5-fluorouracil [5-FU], leucovorin and oxaliplatin) or FOLFOXIRI (5-FU, leucovorin, oxaliplatin and irinotecan) chemotherapy followed by chemoradiotherapy (CRT) and surgical resection, represents a valid treatment option in locally advanced rectal cancer (LARC) management [1]. This approach results in favourable treatment compliance, a better toxicity profile and seems to assure superior control of distant metastasis compared with the traditional sequence: neoadjuvant CRT – surgical resection – adjuvant FOLFOX [[2], [3], [4]].

In attempts to improve the clinical and survival outcomes achieved with standard treatment in LARC patients, we addressed the addition of targeted agents (such as bevacizumab, panitumumab or cetuximab) to the induction chemotherapy regimen and the addition of oxaliplatin to the neoadjuvant 5-FU-based CRT. Here we present the results for the primary end point (patients with a pathological complete response; pCR) and the early secondary end points (toxicity and compliance with the regimen, tumour downstaging, R0 resection rate and surgical complications) of the trial.

Section snippets

Materials and Methods

This was a single-centre, single-arm, phase II study. The trial protocol was approved by the “Sapienza” University of Rome (ethical committee number 88569-140/5638) and written informed consent was obtained from all patients prior to participation in the study. The design of the trial and the preliminary results were reported previously [5].

Patient and Tumour Characteristics

Between October 2015 and September 2019, 28 patients were enrolled. Demographic and tumour characteristics are listed in Table 1. All patients had positive lymph nodes at diagnosis and in 12 cases (42.9%) the primary lesion was located in the low rectum. In total, 11 patients (39.3%) had Ras-BRAF mutations.

Induction Chemotherapy

Twenty-seven patients (96.4%) completed the planned cycles of induction chemotherapy. During the induction period, 14 patients (50%) showed a toxicity ≥ grade 3. Details are listed in Table 2

Discussion

This phase II study suggests that LARC patients may benefit from the integration of a triplet chemotherapy and a targeted agent in induction chemotherapy and intensification of CRT before surgery. Our results confirmed that induction chemotherapy plus CRT is associated with an improved complete response, an acceptable and easily manageable toxicity profile, good patient compliance, high rates of tumour response/downstaging and optimal radical resection. A complete/nearly complete response rate

Conclusion

This phase II trial supports the possible role of adding a targeted agent to the FOLFOXIRI regimen and the oxaliplatin to the standard CRT during the neoadjuvant phase to increase the complete response rate, without compromising the trimodality approach in LARC management. Further evaluation in a phase III trial is necessary.

Conflicts of Interest

All authors have nothing to disclose.

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