Loading ...

Neoadjuvant radiotherapy followed by surgery can improve overall survival compared with surgery alone in certain patients with locally advanced rectal cancers, most notably in those with lower rectal cancers, new research found.

However, patients can experience a trade-off: An increased risk for permanent diverting stomas.

This risk may become especially concerning in patients with upper rectal cancers. The study revealed that patients with upper rectal cancers did not experience a survival benefit from neoadjuvant radiotherapy and had the highest risk for permanent diverting stomas.

“The trade-off between [neoadjuvant radiotherapy] use and diverting stoma nonreversal may not be justified for upper rectal cancer, emphasizing the importance of considering tumor height when treating resectable [locally advanced rectal cancer],” wrote senior author Chao-Han Lai, MD, PhD, from National Cheng Kung University Hospital and College of Medicine, Tainan, Taiwan, and colleagues.

The Trade-Off

The standard of care for resectable locally advanced rectal cancer has been neoadjuvant radiation and chemotherapy followed by surgery for resectable locally advanced rectal cancers.

However, some recent studies have called that standard into question. For instance, the recent PROSPECT trial indicated that many patients without high-risk features could forgo radiation before surgery and just receive neoadjuvant chemotherapy.

To better understand the optimal approach for these patients, Lai and colleagues analyzed data from 3792 individuals undergoing curative resection for locally advanced rectal cancer between January 1, 2014, and December 31, 2017, with follow-up until December 31, 2020.

Patients were registered on the Taiwan Cancer Registry Database and the Taiwan National Health Insurance Database.

A target trial emulation framework was applied to simulate randomization of 1308 who underwent neoadjuvant radiotherapy followed by surgery (median age, 62 years) and 2484 who underwent upfront surgery (median age, 65 years). Among patients in the neoadjuvant radiotherapy group, 82.3% received long-course radiotherapy, and 78.6% received concurrent 5-fluorouracil–based chemotherapy.

Patients were followed from the date of treatment until death or December 31, 2020, whichever came first. Primary outcomes were overall survival and local recurrence, and a secondary outcome was intraoperative diverting stoma that remained permanent 3 years after surgery.

The researchers found that 3-year overall rates were significantly higher in the radiotherapy group than in the upfront surgery group (88.5% vs 85.2%; hazard ratio [HR], 0.74; 95% CI, 0.59-0.92), though local recurrence rates were not significantly different (5.7% vs 6.6%; HR, 0.78; 95% CI, 0.55-1.11).

However, the trade-off in the neoadjuvant radiotherapy group was a higher rate of both intraoperative stoma creation and nonreversal of those stomas.

Overall, 49.4% of patients underwent intraoperative diverting stoma creation — 65.5% in the neoadjuvant radiotherapy group and 41.0% in the upfront surgery group (relative risk [RR], 1.6).

While 71.6% of all stomas were closed within 1 year of treatment, patients in the radiotherapy group had a nearly twofold higher rate of permanent diverting stoma at 3 years in the radiotherapy group (20.6% vs 11.1% in the surgery group; RR, 1.91).

Tumor Height Matters

A subgroup analysis revealed that the 3-year overall survival benefit of neoadjuvant radiotherapy was greatest in patients with lower rectal cancers (HR, 0.66). While 3-year overall survival was better among those with middle rectal cancers (90.3% vs 84.5%), the difference was not statistically significant (HR, 0.70; 95% CI, 0.48-1.02). And for those with upper rectal disease, neoadjuvant radiotherapy offered no survival benefit (HR, 1.54; 95% CI, 0.82-2.90).

Similarly, for 3-year local recurrence, neoadjuvant radiotherapy led to a statistically significant benefit for lower rectal cancers (HR, 0.53), but not middle (HR, 1.13; 95% CI, 0.60-2.14) or upper (HR, 1.08; 95% CI, 0.23-5.00).

Likewise, while the risk of diverting stoma creation and permanent diverting stomas was higher with the neoadjuvant radiotherapy group than in the upfront surgery group overall, the risks were highest for upper rectal cancer (RR, 3.61 and RR, 3.54, respectively) and lowest for lower rectal cancer (RR, 1.31 and RR, 1.62, respectively).

“Thus, for upper rectal cancer, the trade-off between using [neoadjuvant radiotherapy] to pursue better oncological outcomes and creating diverting stomas to lower the risk of symptomatic leak may not be justified,” the authors concluded. “These findings raise concerns about the potential overtreatment and harm of neoadjuvant radiotherapy.”

The Findings in Context

George Chang, MD, who wasn’t involved in the research, noted that no prior randomized studies have demonstrated an overall survival benefit with radiation.

“The primary reason we give radiation is to decrease local recurrence risk,” explained Chang, chair of Colon and Rectal Surgery at The University of Texas MD Anderson Cancer Center in Houston.

But, Chang noted, in North America and other parts of the world, the use of neoadjuvant radiotherapy is already based on factors such as tumor location, microsatellite instability status, and patient preferences.

Still, “we are likely overtreating some rectal cancer patients with radiotherapy in the US if we broadly apply a recommendation for radiotherapy for all patients without risk stratification,” he said. “Indeed, the greatest benefit of radiotherapy is for those patients with low rectal cancers or those with locally advanced cancers with high-risk features such as at-risk circumferential margins. Those with proximal rectal cancers, especially above the pelvic reflection, are least likely to benefit.”

Deborah Schrag, MD, chair of the Department of Medicine at Memorial Sloan Kettering Cancer Center in New York City, agreed. “When proximal tumors are in the upper rectum and lymph nodes appear to be uninvolved, US practice guidelines continue to endorse surgical resection as a treatment option,” she said.

“The risk is that if surgical pathology identifies more extensive involvement, postoperative radiation could be indicated — and we know that postoperative radiation is less well tolerated than preoperative treatment,” Schrag added.

The bottom line, according to Schrag, is “when it comes to rectal cancer, one size does not fit all.”

No disclosures were reported. This study was supported by grants from the Taiwan Ministry of Science and Technology and the National Cheng Kung University Hospital.

Kate Johnson is a Montreal-based freelance medical journalist who has been writing for more than 30 years about all areas of medicine.