Watch-and-Wait Approach Again Proven Safe in Rectal Cancer

Pam Harrison

December 28, 2015

A "watch-and-wait" approach in the treatment of rectal cancer has again been shown to be as oncologically safe as radical surgery among patients who achieve a clinical complete response to chemoradiotherapy. It also allows many patients to avoid a permanent colostomy, conclude researchers reporting on the Oncological Outcomes after Clinical Complete Response in Patients With Rectal Cancer (OnCoRe) project.

The study was published online December 16 in the Lancet Oncology.

"When we started this study 4 to 5 years ago, oncologists were concerned that by not operating on patients with rectal cancer, they would be leaving residual disease that could spread and disseminate and have adverse consequences," lead author Andrew Renehan, PhD, from the Institute of Cancer Sciences, Manchester Academic Health Science Centre, United Kingdom, told Medscape Medical News.

"But we've now had follow-up of over 3 years, and we've convincingly shown that patients treated with the watch-and-wait approach don't do worse than those who had their tumors operated on when compared stage for stage, and in fact, they do marginally better," he said.

In an accompanying comment, Rodrigo Oliva Perez, MD, from the University of Sao Paulo School of Medicine in Brazil, says, "these findings might contribute to increasing widespread implementation of watch and wait into clinical practice."

Analysis From Real-World Clinical Practice

OnCoRe was a propensity-score-matched, observational analysis of real-world clinical practice across cancer treatment centers in four neighboring regions in the United Kingdom. Patients of all ages with a new diagnosis of histologically confirmed rectal adenocarcinoma without distant metastases were included in the analysis.

All patients received preoperative chemoradiotherapy given at the standard dose of 45 Gy in 25 daily fractions, together with concurrent fluoropyrimidine-based chemotherapy for 34 days. Patients who had an incomplete clinical response to chemoradiotherapy were managed by surgical resection.

Patients managed by the watch-and-wait strategy received a digital rectal examination and a magnetic resonance imaging scan every 4 to 6 months in the first 2 years, as well as an examination under anesthesia or endoscopy; computed tomography scans of the chest, abdomen, and pelvis; and at least two carcinoembryonic antigen measurements in the first 2 years as well.

A total of 259 patients were included in the Manchester tertiary cancer center cohort, 228 of whom underwent surgical resection and 31 of whom achieved a clinical complete response to chemoradiotherapy and were managed with the watch-and-wait strategy.

An additional 98 patients were added to the watch-and-wait group via the OnCoRe registry, so the total number of patients followed by observation was 129.

Among these 129 patients with primary nonmetastatic rectal cancer managed by the watch-and-wait strategy, 34% had local growths at a median follow-up of 33 months. This percentage corresponded to a 3-year actuarial rate of 38%.

Of the subgroup with local growths at 3 years, 88% of those with nonmetastatic local regrowths were salvaged.

"This meant that more than 60% [of the watch-and-wait group] avoided major surgery (ie, organ preservation was maintained), and a quarter could avoid permanent colostomy, without loss of oncological safety in these first 3 years," Dr Renehan and colleagues point out.

In a propensity-score-matched analysis of 109 patients in the watch-and-wait group and the same number of patients undergoing surgical resection, there was no statistically significant difference in 3-year non-regrowth: The disease-free survival rates were 88% among the watch-and-wait group compared with 78% for surgical controls.

There was also no significant difference in overall survival at 3 years, with 96% of patients in the watch-and-wait group and 87% in the surgical resection group being alive at follow-up.

Importantly, and in favor of the watch-and-wait group, 74% of patients in the watch-and-wait group were colostomy-free at 3 years compared with 47% of those who underwent surgical resection. The authors emphasize that this was a 26% absolute difference in patients who avoided needing a permanent colostomy between the two groups (P < .0001).

Watch-and-wait was also associated with an absolute difference in patients who avoided a permanent colostomy over time, with an absolute difference of 36% between the two groups at 1 year and 28% between the two groups at 2 years.

"Thought to be a Potential Disaster"

"Local disease regrowth was initially thought to be a potential disaster and one of the main drawbacks of the watch-and-wait strategy because it was thought to frequently result in uncontrolled incurable local disease," Dr Perez writes in the accompanying comment. "Instead, results [from the OnCoRe project] show that most regrowths are present within the rectal lumen and are amenable to salvage resection," he adds.

"[W]atch-and-wait for patients who develop a clinical complete response [to chemoradiotherapy] seems to be oncologically safe, possibly more so than surgery, provides an opportunity for salvage in the event of local regrowth...and avoids the terrible consequences of radical surgery, including definitive stoma," he writes.

The proportion of patients who achieve a clinical complete response after widely used radiotherapy regimens of 45 Gy is 10% to 15%, the investigators note.

However, as Dr Renehan noted, in certain prospective studies where doses have been increased to the order of 60 Gy, "they get far better response rates of up to 50%, although the downside is there can be considerable toxicity," he said.

In contrast, a permanent colostomy is needed in up to 50% of patients with locally advanced rectal cancer who undergo surgical resection.

In his comment, Dr Perez also noted that patients with a clinical complete response to chemoradiotherapy and who are subsequently managed by the watch-and-wait strategy also seem to maintain excellent anorectal function.

"[A] lower risk of having a definitive stoma, combined with the benefits of an intact rectum and preserved function, will definitely be decisive factors when selecting strategies to manage [these] patients," he writes.

Dr Perez also supported greater uptake of the watch-wait strategy despite the absence of evidence from a randomized clinical trial supporting this approach over radical surgery.

Indeed, given results from the current study, Dr Perez felt it would be unlikely that many patients would be willing to participate in a clinical trial where the risk of receiving a colostomy would be much higher with the standard approach compared with the experimental strategy.

"Ultimately, it comes down to whether patients would be willing to undergo radical surgery and a definitive stoma after a clinical complete response in the absence of evidence suggesting any benefit for radical surgery," Dr Perez writes.

The study was funded by the Bowel Disease Research Foundation. Dr Renehan reported receiving grants and personal fees from Sanofi Pasteur MPS. Dr Perez has disclosed no relevant financial relationships.

Lancet Oncol. Published online December 16, 2015. Article abstract, Comment extract

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