The PROSPECT was a randomized phase III trial that included patients with resectable rectal cancer (clinical stage cT2-3N+ or cT3N0). The trial aimed to test the hypothesis that pre-operative chemotherapy consisting of 6 cycles of FOLFOX given over a 12-week period, followed by total mesorectal excision (TME) surgery, was non-inferior to pre-operative long-course chemoradiotherapy (CRT). The primary endpoint of the study was disease-free survival (DFS), and patients were also monitored for other relevant oncological outcomes such and health-related quality of life (HRQoL) using patient-reported outcome (PRO) tools [1, 2]

Adams, Richard

Fokas, Emmanouil

Hawkins, Maria A

Marijnen, Corrie AM

O'Cathail, Sean M

Sebag-Montefiore, David

English

UCL Discovery

Clinical and Translational Radiation Oncology 43 (2023) 100672Available online 30 August 20232405-6308/© 2023 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology. This is an open access article under theCC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Patient-reported outcomes in PROSPECT trial (Alliance N1048) – FOLFOX is not a panacea  A R T I C L E  I N F O   Keywords Rectal cancer Trials PROSPECT QoL Radiotherapy Chemotherapy Overtreatment Guidelines       The PROSPECT was a randomized phase III trial that included pa-tients with resectable rectal cancer (clinical stage cT2-3N+ or cT3N0). The trial aimed to test the hypothesis that pre-operative chemotherapy consisting of 6 cycles of FOLFOX given over a 12-week period, followed by total mesorectal excision (TME) surgery, was non-inferior to pre- operative long-course chemoradiotherapy (CRT). The primary endpoint of the study was disease-free survival (DFS), and patients were also monitored for other relevant oncological outcomes such and health- related quality of life (HRQoL) using patient-reported outcome (PRO) tools [1,2]. We congratulate the investigators for their success in enrolling 1194 patients into a non-inferiority designed trial and applaud their use of PRO-CTCAE tools. However, we have a number of concerns regarding the interpretation of the data and how they pertain to toxicity in this patient group, which are important to clarify in the academic literature. Firstly, we would like to stress that this trial does not represent a patient population with truly locally advanced disease by international standards. Notably, the trial excluded any patients with cT4 or cN2, or disease within 3 mm of the mesorectal fascia. The cT3 and nodal sub-groups were not reported in line with international consensus, and it is concerning that just over 15% of patients were not staged with MRI. According to the ESMO rectal cancer guidelines, widely used interna-tionally, this population would constitute early and intermediate disease in most cases [3]. Whilst circa 90% of both arms had patients with cT3 disease only 14.2% of the FOLFOX arm and 16.6% of the CRT had tu-mors within 5 cm of anal verge. This suggests that many of these patients could have been managed with total mesorectal excision (TME) and a preserved sphincter. Within this disease spectrum, PROSPECT supports FOLFOX as non-inferior to CRT in preventing local recurrence, but given the very low local recurrence risk, neither may be necessary and thus be considered as overtreatment with accompanying toxicity. The FOLFOX arm was also non-inferior to CRT for both DFS and OS at 5 years, underlining that neoadjuvant chemotherapy did not improve disease relapse (distant or local) [1], but the question whether neo-adjuvant FOLFOX could replace adjuvant chemotherapy cannot be answered, given that there was a high level of postoperative chemo-therapy in both arms. Postoperative FOLFOX was associated with higher toxicity when patients had neoadjuvant CRT (32.6%) than neoadjuvant FOLFOX (25.6%). The use of adjuvant chemotherapy after CRT is in itself questionable with established poor compliance, increased toxicity and importantly, no Level 1 data that it increases survival [4]. The more pertinent question is whether neoadjuvant FOLFOX has a role in a risk stratified group. The ongoing ACO/ARO/AIO-18.2 phase III trial (ClinicalTrials.gov Identifier: NCT04495088) is comparing primary TME followed by stage-based adjuvant chemotherapy (only in pT4 or pN + ) vs neoadjuvant FOLFOX/CapOx chemotherapy over 3 months followed by TME with inclusion criteria that are largely overlapping with those of the PROSPECT. The primary objective of this study is to demonstrate superiority for DFS. It is questionable whether PROSPECT can really be viewed as a de- escalation strategy. Severe (≥grade 3) acute toxicity with FOLFOX was double (41%) that of CRT (22.8%). Across 14 PRO domains, CRT was significantly superior to FOLFOX in 12 and worse in only one, diarrhoea [2]. Therefore, both clinicians and patients reported that CRT is the better tolerated neoadjuvant treatment choice. Despite the median follow-up of 58 months, data on long-term toxicity and quality of life are still awaited. Furthermore, PRO on sex-ual function 1 year after TME in the CRT arm were based on 34/173 patients (20%) and 97/370 patients (26%), respectively, which should be considered when interpreting these data. We do not underestimate the late effects of pelvic CRT, and its potential for severe consequences in some patients. At 18 months, patients receiving CRT reported higher rates of fatigue, neuropathy and sexual dysfunction without a difference in HRQoL [2]. These are important data for practising oncologists where patients are managed with multimodal treatment. Advances in radiation delivery using intensity modulated radiotherapy (IMRT) can minimise doses to organs at risk and spare some long-term late effects [5,6]. More importantly, the management of rectal cancer has now shifted towards organ preservation for selected patients with clinical complete response that can limit some of the side effects from multimodal treatment [7,8]. Contents lists available at ScienceDirect Clinical and Translational Radiation Oncology journal homepage: www.sciencedirect.com/journal/clinical-and-translational-radiation-oncology https://doi.org/10.1016/j.ctro.2023.100672 Received 11 July 2023; Accepted 29 August 2023   Clinical and Translational Radiation Oncology 43 (2023) 1006722The true value of PROSPECT is that it adds to, rather than replaces, the therapeutic options for rectal cancer. These data will inform a multidisciplinary, patient centred discussion of evidence-based options, some of whom will undoubtedly benefit from this approach, but not everyone. We urge caution not to extrapolate these findings to patients with high-risk or low-lying rectal cancer. The colorectal research com-munity needs to better understand the biology and derive predictive biomarkers [9] that will optimise individualised treatment solutions. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References [1] Schrag D, Shi Q, Weiser MR, Gollub MJ, Saltz LB, Musher BL, et al. Preoperative treatment of locally advanced rectal cancer. N Engl J Med 2023;389(4):322–34. [2] Basch E, Dueck AC, Mitchell SA, Mamon H, Weiser M, Saltz L, et al. Patient-reported outcomes during and after treatment for locally advanced rectal cancer in the PROSPECT trial (Alliance N1048). J Clin Oncol 2023;41(21):3724–34. [3] Glynne-Jones R, Wyrwicz L, Tiret E, Brown G, Rödel C, Cervantes A, et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28:iv22–40. [4] Carvalho C, Glynne-Jones R. Challenges behind proving efficacy of adjuvant chemotherapy after preoperative chemoradiation for rectal cancer. Lancet Oncol 2017;18(6):e354–63. [5] Hanna CR, Slevin F, Appelt A, Beavon M, Adams R, Arthur C, et al. Intensity- modulated Radiotherapy for Rectal Cancer in the UK in 2020. Clin Oncol (R Coll Radiol) 2021;33(4):214–23. [6] Appelt AL, Sebag-Montefiore D. Technological advances in radiotherapy of rectal cancer: opportunities and challenges. Curr Opin Oncol 2016;28:353–8. [7] Fokas E, Appelt A, Glynne-Jones R, Beets G, Perez R, Garcia-Aguilar J, et al. Inter-national consensus recommendations on key outcome measures for organ preser-vation after (chemo)radiotherapy in patients with rectal cancer. Nat Rev Clin Oncol 2021;18(12):805–16. [8] Fokas E, Glynne-Jones R, Appelt A, Beets-Tan R, Beets G, Haustermans K, et al. Outcome measures in multimodal rectal cancer trials. Lancet Oncol 2020;21(5): e252–64. [9] Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med 2022;386(25):2363–76. Sean M. O’Cathail School of Cancer Sciences, University of Glasgow & Beatson Cancer Centre, Glasgow, UK Richard Adams Velindre Cancer Centre, Cardiff, UK Maria A. Hawkins Department of Medical Physics and Bioengineering, University College London, UK David Sebag-Montefiore Leeds Institute of Medical Research, University of Leeds, UK Corrie A.M. Marijnen Dept of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, NL, Netherlands Dept of Radiation Oncology, Leiden University Medical Center, Leiden, NL, Leiden University Medical Center, Netherlands Emmanouil Fokas* Department of Radiotherapy of Oncology, University of Frankfurt, Germany German Cancer Research Center (DKFZ), Heidelberg, Germany German Cancer Consortium (DKTK), Partner Site: Frankfurt, Germany Frankfurt Cancer Institute (FCI), Germany * Address: Department of Radiotherapy and Oncology, University of Frankfurt Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. E-mail address: emmanouil.fokas@kgu.de (E. Fokas). S.M. O’Cathail et al.                                                                                                                                                                                                                           

Patient-reported outcomes in PROSPECT trial (Alliance N1048) – FOLFOX is not a panacea

https://discovery.ucl.ac.uk/10177185/1/Hawkins_Patient-reported%20outcomes%20in%20PROSPECT%20trial_VoR.pdf

Patient-reported outcomes in PROSPECT trial (Alliance N1048) – FOLFOX is not a panacea

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