Personalised neoadjuvant therapy, based on tumour characteristics and patient choice, is the best way forward in rectal cancer

Total neoadjuvant therapy (TNT) is increasingly recognised as a primary treatment option for patients with locally advanced rectal cancer (LARC), with demonstrable and clinically meaningful improvements in disease-free survival (DFS), overall survival (OS), clinical (cCR) and pathological complete response (pCR) rates, and organ preservation (OP) (1-3). These benefits are largely derived from front loading the chemotherapy component of treatment, thus improving compliance and efficacy of systemic treatment, and improving primary tumour response. This has led several centres and authors to ask: if much of the survival benefit is attributed to chemotherapy, is the radiotherapy component of TNT still required, or can treatment be de-escalated to omit radiotherapy entirely? Furthermore, what is the risk-benefit profile of omitting radiotherapy and which patients would be most suited to this de-escalated approach?

A recent publication in the Journal of Clinical Oncology by Zhang et al. attempts to answer some of these questions (4). This paper presents the 10-year follow-up results of the phase III FOWARC trial, which was a randomised controlled trial evaluating the efficacy of modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) with or without radiation compared with fluorouracil with radiation in patients with LARC. The trial had 3 arms: (I) 5 cycles of 5-fluorouracil (5-FU) with concurrent radiotherapy, and postoperative chemotherapy with seven cycles of 5-FU; (II) the same treatment as group 1 with the addition of oxaliplatin; (III) 4 to 6 cycles of mFOLFOX6 and postoperative chemotherapy with six to eight cycles of mFOLFOX6, with the addition of radiation before or after surgery at the physicians’ discretion. A total of 495 adult patients with stage II–III rectal cancer were randomised from 15 hospitals in China with a median follow-up of just over 10 years. There were no statistically significant differences in 10-year OS rates (65.9%, 72.3%, and 73.4%; P=0.90), DFS rates (52.5%, 62.6%, and 60.5%, respectively; P=0.56), or local recurrence rates (10.8%, 8.0%, and 9.6%; P=0.57). Subgroup analysis identified pathological staging (and thus treatment response) as a significant prognostic factor (4).

The FOWARC trial is a seminal paper in this field, with a robust 3-arm, randomised, multicentre design, and high-quality long-term follow-up data. Similarly, the PROSPECT trial is a multicentre, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX versus long course chemoradiotherapy, which enrolled 1128 adults with rectal cancer (T3N0, T3N1, T2N1) who were candidates for sphincter-sparing surgery (5). Patients in both groups underwent surgery, but patients in the chemotherapy alone group were given radiotherapy prior to surgery if tumour regression was <20% by imaging criteria. This study demonstrated that this FOLFOX first strategy was oncologically noninferior to standard long course chemoradiotherapy in patients with intermediate- or low-risk LARC. Furthermore, patients in the FOLFOX group had fewer permanent stomas, a reduced rate of low anterior resection syndrome (LARS), and better sexual function compared with those receiving radiotherapy (5).

Based on the results of these two studies, the authors of the FOWARC trials conclude that neoadjuvant chemotherapy appears to be a safe and feasible primary treatment for LARC, and that radiotherapy could be added based on treatment response after reassessment, offering advantages such as reducing risk of overtreatment and improving quality of life (4).

There are two major points of contention with these results and conclusions, and they both pertain to oncological outcomes with TNT versus Chemotherapy alone. Both the FOWARC and PROSPECT trials demonstrated that survival was non-inferior using de-escalated chemotherapy only versus standard neoadjuvant radiotherapy and were powered for this. However, neither trial included a TNT group. For many included patients, TNT with either induction or consolidation chemotherapy would currently be considered standard of care and it is entirely conceivable that TNT could have improved both DFS and OS in this patient subset as has been demonstrated in other randomized controlled trials (RCTs) comparing TNT with standard chemoradiotherapy (6). While a counter-argument could be made that groups 1 and 2 in the FOWARC trial gave patients both chemotherapy and radiotherapy, this was in fact concurrent treatment (not sequential as would be expected with standard TNT) and most of the chemotherapy was given in the adjuvant, not neoadjuvant setting, meaning that these groups have more in common with standard long course than TNT schemas. A second major concern, and perhaps even more important in the modern era, is the relative lack of emphasis on rates of complete clinical response and OP. Based on the rates of pathological downstaging presented, it would appear that rates of cCR would have been much lower than would be expected with standard TNT paradigms (3). This is crucial when one considers that non-operative management is associated with much improved quality of life metrics than operative management in the setting of TNT (7).

Taking into account the results of FOWARC, PROSPECT and the multiple now mature TNT trials (RAPIDO, OPRA, PRODIGE23), one can begin to form a broader schema of personalised sequencing of chemotherapy, radiotherapy, and surgery with escalation and de-escalation based on clinical tumour staging, tumour height/sphincter preservation, and patient choice. This approach maximises the risks and benefits of the multiple treatment options for LARC to better tailor these to patient and tumour requirements (8). While some patients may be safe to have radiotherapy omitted, this probably applies more to patients with higher tumours and those who do not wish to pursue OP as a strategy. Figure 1 summarises our current thinking, but no doubt this will evolve as more trials are published and existing trials mature, adding further information and complexity to the already extensive menu of options for the treatment of LARC (9). For example, there is emerging data from 3 trials supporting the addition of immunotherapy to TNT to maximise response (TORCH, UNION, STELLAR II) (10-12). Furthermore, more robust data on patient subsets excluded from the current studies, such as those with T4 tumours, limited/resectable stage IV disease, microsatellite instability-high (MSI-H) tumours eligible for immunotherapy, and early-stage rectal cancer patients who decline surgery in favour of OP are urgently needed.

Figure 1 Summary of neoadjuvant therapy options in LARC. adj., adjuvant; APR, abdominoperineal resection; Chemo, chemotherapy; CRT, chemoradiotherapy; cTNT, consolidation TNT; EMVI, extramural venous invasion; iTNT, induction TNT; LARC, locally advanced rectal cancer; MRF, mesorectal fascia; NOM, non-operative management; TME, total mesorectal excision; TNT, total neoadjuvant therapy.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article has undergone external peer review.

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