The results of the PROSPECT trial (ALLIANCE N1048) have been presented at the 2023 ASCO meeting, but their interpretation in public newspapers and social media causes significant concern amongst health care professionals, patients and the public.
PROSPECT was a randomized phase III trial, enrolling patients with resectable rectal cancer (clinical stage cT2-3N+ or cT3N0) and testing the hypothesis that multiagent pre-operative chemotherapy (6 cycles over a 12 week-period) with the FOLFOX regimen followed by total mesorectal excision (TME) surgery could be non-inferior compared to pre-operative long-course radio-chemotherapy. The primary endpoint of the study was disease-free survival, but patients were followed up for other relevant oncological outcomes (overall survival, local recurrence, pathological complete response rate, free-margin resection), together with treatment-related toxicity profile and health-related quality of life.
The trial demonstrated that pre-operative chemotherapy can be considered non-inferior compared to chemoradiation in this clinical setting with respect to oncological outcomes. But rather than showing that radiation should be omitted in these patients, as incorrectly pointed out in several news reports, the trial in fact adds a new option to the therapeutic portfolio for managing rectal cancer, with specific advantages and disadvantages of both the chemotherapy and radio-chemotherapy strategies.
The non-inferiority of pre-operative chemotherapy does not come at zero cost. The toxicity rate was almost double in the chemotherapy-only arm (41% vs 23%) compared to radio-chemotherapy. Overall health-related quality of life was very similar with both treatment approaches at any timepoint, only significantly worse in few domains at 18 months after radio-chemotherapy. However, despite the long median follow-up of 58 months, data on long-term toxicity and quality of life are not yet reported.
Another consideration is that some of the side effects experienced by patients in the radio-chemotherapy arm are not exclusively due to radiation but depend on the combination of radiotherapy with surgery. Also, several prospective studies have shown that deteriorations in bowel and urogenital function can occur in patients treated with surgery alone. Therefore, the management of rectal cancer has already shifted towards organ preservation, as reflected by international guidelines, and commonly employed in clinical practice. Radiotherapy, either with dose escalation using endorectal brachytherapy or as part of the so-called total neoadjuvant therapy, constitutes an essential and valuable component of rectal cancer management that leads to high rates of organ preservation in both early stage (up to 80%) and advanced stage (up to 50%) disease, sparing patients from surgical and combined radiation-surgery side effects, and improving their quality-of-life.
Importantly, patients enrolled in PROSPECT had small tumours and may have been overtreated in both arms, e.g., cT3a-T3bN0 tumour of the middle- and upper rectal third that may otherwise have been treatable with surgery alone as per European guidelines. In contrast to international consensus radiological protocols, the cT3-subgroups were not reported in the PROSPECT trial, whereas approximately 20% of patients did not undergo baseline MRI for accurate disease staging.
The PROSPECT trial team is to be congratulated for successful completion of this important study, which broadens therapeutic options for future patients with rectal cancer. Public media can contribute to successful implementation of clinical trial data into real-world practice by translating complex medical science into approachable, neutral, and balanced language, informing patients and the public of scientific advances.
Unfortunately, several newspapers reported the PROSPECT trial using provocative and misleading headlines, describing the effects of radiation as “brutal”. Such inflammatory use of language not only goes beyond the evidence generated by the PROSPECT trial but also risks unnecessarily alarming a large group of patients with rectal cancer for whom radiation therapy will still form an important part of their cancer treatment with proven beneficial effects on survival and quality-of-life.
On behalf of the European radiation oncology community and our patients, ESTRO therefore urges a return to responsible communication presenting scientific facts in a balanced manner with headlines that inform rather than alarm.
Pierfrancesco Franco, Chair, ESTRO Lower GI Focus Group
Emmanouil Fokas, Course Director, ESTRO Lower GI Course
Anna Kirby, ESTRO President
Matthias Guckenberger, ESTRO President-Elect
Ben Slotman, ESTRO Past-President