Comment on Fokas E et al. Randomized Phase II Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: CAO/ARO/AIO-12. J. Clin. Oncol. 2019 May 31:JCO1900308. doi: 10.1200/JCO.19.003081by Prof. Dr. R.-D. Hofheinz, Head of Outpatient Treatment at the Interdisciplinary Tumor Center, University Hospital Mannheim, University of Heidelberg, Germany.
The treatment landscape of locally advanced rectal cancer is changing and the strategy of offering chemoradiotherapy for all patients with cT3/4 or cN+ tumours is increasingly abandoned. While patients with a low risk for local and systemic failure may be treated with immediate surgery, patients with a high risk for local and/or systemic failure may benefit from total neoadjuvant therapy (TNT), i.e. neoadjuvant chemotherapy before (induction chemotherapy) or after chemoradiotherapy (consolidation). Both strategies have been shown to be feasible and have demonstrated promising data in phase II trials.2,3 Compliance with induction chemotherapy as compared to postoperative chemotherapy has been reported to be improved without compromising surgical morbidity and mortality.4 Moreover, using an increasing cycle number of FOLFOX as consolidation chemotherapy in sequential cohorts of patients with rectal cancer resulted in increased rates of pathological complete response (pCR) and – notably – improved disease-free survival in patients with locally advanced rectal cancer. Thus, TNT may have benefits beyond increasing pCR rate and improving adherence to perioperative chemotherapy.
Recently, Fokas and co-workers published the first randomized phase II trial comparing induction and consolidation chemotherapy. Patients received three cycles of FOLFOX either before or after chemoradiotherapy using 50.4Gy and infusional 5-FU as well as four administrations of oxaliplatin in weeks 1, 2, 4 and 5 of radiotherapy. The primary end point was the pCR rate, deﬁned as ypT0N0 after surgery. Using a pick-the-winner design, this randomized phase II trial aimed to identify and select the more promising TNT sequence against standard preoperative chemoradiotherapy. The authors hypothesized that TNT could increase pCR rate up to 25%. Of note, the trial was not powered to demonstrate differences between the TNT sequences. Rather, each treatment arm was compared to a historical pCR rate of 15%. A total of 306 patients were evaluable. Compliance with chemoradiotherapy (CRT) was better in the consolidation arm and CRT toxicities were lower (grade 3-4: 27 versus 37%). The percentage of patients completing all scheduled chemotherapy cycles, however, was somewhat higher in the induction chemotherapy arm (92% versus 85%). In terms of surgical morbidity and mortality no differences were noticed between both arms, i.e. the longer interval between the end of CRT and the timing of surgery had no adverse impact on surgical outcomes. Regarding the primary end point, only the arm using consolidation chemotherapy fulfilled the statistical hypothesis: pCR was achieved in 17% using induction but 25% using consolidation chemotherapy. Data on disease-free and overall survival have not been reported thus far.
This large randomized trial adds to a growing body of data indicating that TNT may be used safely in patients with locally advanced rectal cancer. Advantages of using TNT over standard CRT followed by resection and adjuvant chemotherapy are (i) better compliance with chemotherapy; (ii) use of systemically effective chemotherapy doses at an early time point during cancer treatment, i.e. preoperatively; (iii) increased pCR rates offering the option of organ preservation (i.e. watch-and-wait or local excision strategies).
Nevertheless, several questions remain, e.g. What is the optimal cycle number of FOLFOX? And what is the optimal chemoradiotherapy regimen? Moreover, it is crucial to ensure that high-quality magnetic resonance tomography is used to select patients for the most adequate perioperative treatment. Only using optimized imaging methods will allow us to tailor treatment for patients with locally advanced rectal cancer. Ultimately, phase III trials using strict MRI-based inclusion criteria are required to compare TNT against standard CRT using patient relevant end points such as disease-free and overall survival.