Identify non-responders quickly to pave way for total mesorectal excision

Patients with locally advanced rectal cancers who do not respond well to chemoradiotherapy should be identified quickly after completing chemoradiation and undergo total mesorectal excision (TME) without delay, according to a recent study published in JAMA Surgery.

Researchers led by Angelo Restivo, MD, of the University of Cagliari, Italy, found that a longer interval before surgery upon completion of neoadjuvant chemoradiotherapy (nCRT) was associated with worse survival in patients whose tumors demonstrated a poor pathological response to nCRT.

“Neoadjuvant CRT followed by TME is the standard approach for locally advanced rectal cancer, resulting in better locoregional control and disease-free survival (DFS),” wrote Restivo and colleagues.

But, they noted, differences in treatment responses to CRT are prevalent, with roughly 15% to 20% of patients achieving pathologic complete response (pCR).

Previous studies have also shown that longer wait times before surgery are becoming de rigueur.

“In recent years, as shown in the paper, there has been a consistent trend toward increasing the waiting period after neoadjuvant therapy for rectal cancer before proceeding to surgical resection. This has been driven by the willing of increasing the rates of pathological complete responses that are known to be very time dependent. The more we wait, the more complete responses we see,” Restivo told BreakingMED.

“Although this might seem as ’just a good thing,’ we did never really check on the overall oncological results of expanding this strategy to almost every patient. As easy as it looks, we wanted to check if everything was fine in the long term, especially in those patients who at last will not achieve a complete or almost complete tumor response,” he added.

For this multicenter, retrospective study, Restivo and colleagues analyzed data from 1,064 patients (median age: 64 years; 61.5% male) with rectal cancer who exhibited minor or null tumor response stage greater than 0 to neoadjuvant CRT treated at 12 referral centers in Italy for colorectal surgery. They divided patients into two groups based on their wait times between neoadjuvant therapy and surgery and assessed differences in oncological and surgical outcomes. Primary outcomes included overall and disease-free survival.

In all, 54.4% (n=579) patients had a shorter wait time of ≤8 weeks, while 45.6% (n=485) had longer wait times (>8 weeks).

Ultimately, longer wait times before surgery were associated with worse 5-year survival compared with shorter wait times (67.6% vs 80.3%, respectively), as well as worse 10-year overall survival (4.1% vs 57.8%; P<0.001). Longer wait times were also associated with worse 5-year DFS compared with shorter wait times (59.6% vs 72.0%, respectively), and 10-year DFS survival (36.3% vs 53.9%; P<0.001).

Upon multivariable analysis, longer wait times were also found to be associated with an increased risk of death (HR: 1.84; 95% CI: 1.50-2.26; P<0.001) and death or cancer recurrence (HR: 1.69; 95% CI: 1.39-2.04; P<0.001).

“Postponing surgical resection over a certain period might be dangerous for many patients. As a result, tumor response to neo-adjuvant therapies should be checked early and, especially if a clear major response is not achieved, surgery shouldn’t be postponed beyond 8 weeks from neo-adjuvant treatment ends,” Restivo said.

In an accompanying editorial, Ranim Alsaad, MD, and Sandy Hwang Fang, MD, both of The Johns Hopkins Hospital, Baltimore, noted the lack of data on optimal treatment timelines.

“At the turn of the century, prospective randomized clinical trials supported the use of nCRT prior to TME of locally advanced rectal cancers (LARC). Few studies have determined the optimal time interval between nCRT and surgery, which is traditionally 6 to 12 weeks with the fundamental intent that extending the time interval to TME achieves further tumor regression or a pathologic complete response,” they wrote.

As for the tendency to wait to surgically intervene, Alsaad and Fang wrote: “As pointed out by the authors, limitations of this study include its retrospective design, as it is difficult to determine factors that delayed surgery beyond 8 weeks, eg, surgeon or patient preference. Were the surgeons delaying surgery to allow more time for tumor regression in patients with more advanced pathology?”

The question of short versus long intervals between nCRT and TME remains unanswered, they continued, citing results from the GRECCAR-6 study, which showed no differences in DFS and local recurrence between the two approaches, but also showed that 3-year DFS was better in patients with good tumor responses compared with poor, “confirming that tumor biology factors into oncologic prognosis,” they noted.

“As we move toward individualized multimodal rectal cancer treatment, it will be essential to identify better diagnostic cancer biomarkers and functional imaging (magnetic resonance imaging, positron emission tomography, computed tomography) in order to further elucidate tumor biology,” concluded Alsaad and Fang.

Restivo also urged more study.

“Our data are not conclusive at all, and more studies are needed in order to find the best time for every single patient. There might be some patients [who] can still wait longer and others [who] should proceed very early to surgery. The point is that, while we work to better fit the therapeutic strategy to every single patient, the 8-week limit to proceed to rectal resection should be respected,” he told BreakingMED.

Limitations of the study include its retrospective design and the failure to assess the quality of TMEs.

  1. Patients with locally advanced rectal cancer who do not respond well to chemoradiotherapy should be identified early after the end of chemoradiation and undergo surgery without delay.

  2. Findings from this study challenge the overuse of pCR as the primary therapeutic endpoint in treating these patients.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

Restivo reported no disclosures.

Alsaad and Fang reported no disclosures.

Cat ID: 120

Topic ID: 78,120,580,730,16,120,23,935,192,925,482,96,159