There isn’t enough evidence to justify the risks of always giving chemoradiotherapy before surgery in this group of patients, researchers say.
Evidence around the use of chemotherapy and radiotherapy before rectal cancer surgery should be critically evaluated to consider the potential harms of overtreatment, according to researchers.
Dutch authors have questioned using total neoadjuvant therapy (TNT) for patients with locally advanced rectal cancer (LARC), arguing that the risks do not justify a blanket approach and that there is not enough evidence of improved survival.
“We raise the question whether the addition of chemotherapy is worth the benefit of TNT in the long run because it is accompanied by potential long-term toxicity,” they said in JCO Oncology Practice.
Incorporating TNT as the standard of care for patients with LARC means intensifying treatment compared with chemoradiotherapy (CRT) alone with its associated toxicity, “without conclusive evidence of improved response rates or overall survival (OS)”.
“Therefore, we feel that CRT should remain the standard of care for patients with LARC.
“Future research should focus on novel biomarkers, enabling identification of patients who will substantially benefit from a TNT regimen to justify the added toxicity.”
The Dutch authors said there were four main randomised trials with long-term oncological outcomes – the RAPIDO trial, PRODIGE-23 trial, POLISH II trial and STELLAR trial – but these trials did not show a benefit in disease-free survival, and absolute differences in recurrence rates were small.
Australian medical oncologist Professor Jeanne Tie said the commentary piece was well written and the authors made a valid point.
“It’s disappointing that results haven’t been better by moving the chemotherapy from after surgery to before surgery,” said Professor Tie, medical oncology lead for the Lower GI tumour stream at Peter MacCallum Cancer Centre and a senior research fellow within the division of personalised oncology at the Walter and Eliza Hall Institute.
Professor Tie said that while many clinicians have adopted pre-operative chemotherapy in an attempt to improve outcomes, the authors raised valid and timely questions about the magnitude of benefit.
“There’s often an understandable desire to intensify treatment in the hope of achieving better results,” she told Oncology Republic. “But it’s important to critically examine whether that additional treatment meaningfully benefits patients.”
“The data to date is not particularly strong, and [the authors] make a reasonable case that long-course radiation should remain the standard approach rather than routinely adding chemotherapy before surgery.
“At Peter Mac, we take a selective approach. Chemotherapy before surgery is generally reserved for patients with high-risk features rather than given to everyone.
“We’ve reviewed the data closely, and share the view that applying intensive pre-operative chemotherapy across the board risks overtreatment.”
Professor Tie said most cancer treatment centres in Australia now use some form of chemotherapy before surgery, but said it was crucial to balance potential benefits against toxicity.
“If chemotherapy hasn’t been clearly shown to improve patient outcomes, we need to weigh the risks carefully – including treatment side effects, rare but serious complications, and system impacts such as delaying surgery or prolonging recovery,” she said.
“For many patients, that additional four to five months of chemotherapy may not ultimately change the long-term outcome.”
Professor Tie said the PRODIGE-23 trial showed some survival benefit when using the intensive FOLFIRINOX regimen but acknowledged the debate around its interpretation.
“There may be a signal of benefit, but the treatment is highly toxic and can be difficult to tolerate. It’s reasonable to question whether modest gains justify exposing all patients to that level of intensity.”
Related
The authors said there was a general belief that lowering the risk of distant metastases through perioperative chemotherapy would improve overall survival.
However, they said, there are several colorectal cancer studies showing that disease-free survival does not translate into overall survival.
“This observation is likely multifactorial.
“One explanation is related to competing risks, in which death because of non–cancer-related causes reduces the ultimate benefits of intensified oncologic treatment. Another explanation is related to salvage therapy of recurrences.”
The RAPIDO trial showed no differences in quality of life between the two treatment arms at 36 months, they said, “but significant and clinically relevant differences regarding neurotoxicity were present”.
“Moreover, it is questionable whether general quality of life is even a sufficient measure for assessing differences in the impact of toxicity between treatment arms of an interventional study.
“Intensification of treatment is a logical reflex to evaluate whether this might translate into improved complete response rates and survival outcomes, but it also results in substantial long-term treatment-related toxicity. To prevent overtreatment, the focus should be on selecting patients in need of a more aggressive approach.”
A post-hoc analysis of the RAPIDO trial showed that total neoadjuvant therapy reduced liver-only distant metastases, but otherwise metastatic patterns were similar among the study arms, they said.
“Treatment of these liver-only metastases in the control arm included surgery in 70% of the patients. Therefore, preventing salvageable recurrences with chemotherapy might limit the effect on survival.”
That analysis also showed that patients who developed distant metastases after total neoadjuvant therapy had worse survival compared with chemoradiotherapy, they said.
“Chemotherapy can lead to changes in tumour biology (new mutations) and might induce chemotherapy resistance with limited response to systemic treatment once metastases develop.”
The authors said that several clinical trials have not shown conclusive evidence on the benefit of adjuvant chemotherapy in LARC, but it has been recommended for high-risk stage II and stage III rectal cancer in the past two decades by US, Japanese and European guidelines.
“Adjuvant chemotherapy is not considered standard in all countries for stage III rectal carcinoma, because of the lack of a clear benefit in terms of overall survival.
“In such countries, the TNT strategy would mean intensification of treatment together with the introduction of its related toxicity instead of simply a change in treatment order.
“Therefore, a critical evaluation of the current literature about TNT is needed with careful consideration of the harm/benefit ratio as compared with chemoradiotherapy alone.”
