Recently presented results suggest that a subset of patients with early stage rectal cancer could skip pre-operative radiotherapy, thus raising some questions about the standard of care
Earlier this year, findings presented from the US-based multicentre, phase II/III randomised PROSPECT trial generated controversies in the gastrointestinal cancers community on whether we are currently overtreating our patients.
The trial showed that pre-operative FOLFOX chemotherapy – with chemoradiotherapy given only in the case of primary tumour size decrease of <20% or if FOLFOX was discontinued because of side effects – was non-inferior to pre-operative chemoradiotherapy in terms of disease-free survival, the study’s primary endpoint (N Engl J Med. 2023;389:322–334). The study included 1,128 treated patients who had rectal cancer staged clinically as T2 node-positive, T3 node-negative, or T3 node-positive and who were candidates for sphincter-sparing surgery.
Some may interpret these data as supporting a change in clinical practice to avoid pre-operative chemoradiotherapy, but further considerations are paramount to translate research into better cancer management.
Observations in the experimental setting are relevant for clinical practice in the treatment of patients, but only when they have the same characteristics as those enrolled in the trial – in this case, a very specific subgroup of patients.
Not all patients who are described as having advanced rectal cancer are the same. Actually, in the context of non-metastatic rectal cancer, it is very important to be precise about detailed disease features. According to ESMO clinical practice guidelines, the recommended standard of care in patients accounting for the majority of those enrolled in the PROSPECT trial is not pre-operative chemoradiotherapy. Locally advanced disease refers to patients with stage cT3c or greater and/or extramural vascular invasion and/or extra-nodal involvement. In the very advanced (ugly) risk group, we may have cT4 or cT3 with involvement of the mesorectal fascia, circumferential resection margin, levators threatened and positive lateral nodes. All these features are used to identify locally or more advanced rectal cancer, and pre-operative chemoradiotherapy, as in the control arm of PROSPECT, is an option for these patients. However, using the definitions in the current ESMO guidelines, most patients enrolled in the study would be considered to have early or intermediate advanced rectal cancer, as opposed to locally advanced or ugly advanced disease, so they generally have a better prognosis and more positive outcomes than those with locally or more advanced rectal cancer and pre-operative treatment can be avoided in most. This interpretation is confirmed by the outcomes of the control arm of the trial, in which results such as a low local recurrence rate (1.6%) were better than in the control arms of other trials addressing other chemoradiotherapy strategies in rectal cancer, such as those investigating total neoadjuvant strategies like PRODIGE 23 (Lancet Oncol. 2021;22:702–715) and RAPIDO trials (Lancet Oncol. 2021;22:29–42), but also others avoiding pre-operative radiotherapy, such as the FOWARC trial (J Clin Oncol. 2019;37:3223–3233).
The PROSPECT data suggest that for patients with early or intermediate advanced rectal cancer who have a low probability of local recurrence – i.e., not patients with poor outcomes or ugly advanced disease – a valid option is to omit pre-operative chemoradiotherapy. The benefits of omitting radiotherapy are clear in terms of the avoidance of serious, long-term side effects, which have a detrimental impact on quality of life: radiotherapy is associated with urinary incontinence, sexual dysfunction and infertility.
However, if we omit the radiotherapy part of the treatment pathway in this subgroup of patients, we must intensify the chemotherapy component, which brings its own problems, particularly from oxaliplatin and its associated adverse events. In fact, the clinical results of the PROSPECT trial are supported by the patient-reported outcomes data, which show a greater burden of oxaliplatin-associated adverse events, such as neuropathy, nausea and vomiting, in the chemoradiotherapy-avoiding arm than in the control arm (J Clin Oncol. 2023;41:3724–3734).
The rectal cancer setting is a rapidly evolving field with several high-quality clinical trials that in recent years yielded to a shift from the paradigm of neoadjuvant chemoradiotherapy for all our patients to more individualised approaches. To this intent, in the near future, an essential contribution is awaited from the integration into the therapeutic pathway of molecular determinants including dynamic markers of disease evolution.