Original ArticleIntensified Total Neoadjuvant Therapy in Patients With Locally Advanced Rectal Cancer: A Phase II Trial
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.
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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.
References (19)
- et al.
Induction chemotherapy reduces patient-reported toxicities during neoadjuvant chemoradiation with intensity modulated radiotherapy for rectal cancer
Clin Colorectal Cancer
(2019) - et al.
Chemoradiation, surgery and adjuvant chemotherapy versus induction chemotherapy followed by chemoradiation and surgery: long-term results of the Spanish GCR-3 phase II randomized trial
Ann Oncol
(2015) - et al.
Disease control, survival, and toxicity outcome after intensified neoadjuvant chemoradiotherapy for locally advanced rectal cancer: a single-institution experience
Clin Colorectal Cancer
(2016) - et al.
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
Eur J Cancer
(2009) - et al.
Chemoradiation, surgery and adjuvant chemotherapy versus induction chemotherapy followed by chemoradiation and surgery: long-term results of the Spanish GCR-3 phase II randomized trial
Ann Oncol
(2015) - et al.
Total neoadjuvant approach with FOLFOXIRI plus bevacizumab followed by chemoradiotherapy plus bevacizumab in locally advanced rectal cancer: the TRUST trial
Eur J Cancer
(2019) National comprehensive cancer network clinical practice guidelines in oncology (NCCN Guidelines®), rectal cancer
(2020)- et al.
Adoption of total neoadjuvant therapy for locally advanced rectal cancer
JAMA Oncol
(2018) - et al.
Induction chemotherapy followed by neoadjuvant chemoradiotherapy and surgery in locally advanced rectal cancer: preliminary results of a phase II study
Oncotarget
(2018)
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