Chemoradiotherapy Widens Options in Rectal Cancer

Liam Davenport

July 13, 2015

Patients with distal rectal cancer could safely undergo intensive chemoradiotherapy and watchful waiting as an alternative to abdominoperineal resection, potentially avoiding undesirable outcomes, Danish researchers suggest.

Their study, which involved patients with primary, resectable adenocarcinoma of the lower rectum, revealed that the vast majority of the patients had a complete response, with acceptable rates of acute and late toxicity.

If these findings are borne out in further studies, chemoradiotherapy regimens could offer an alternative treatment for patients unwilling or unable to undergo surgery, the authors suggest. "This is clearly a realistic treatment option for low rectal cancer that should be prospectively explored in a multicentre setting to see whether the results can be reliably reproduced outside of individual groups," they comment.

The research was published online July 5 in the Lancet Oncology.

Lead researcher Ane L. Appelt, PhD, from the Danish Colorectal Cancer Centre South at Vejle Hospital in Denmark, explained that the majority of patients with low rectal cancer undergo major surgery, which will often result in a permanent stoma or a very low anastomosis. As this does not result in a good functional outcome, Dr Appelt told Medscape Medical News, "there's a lot of research going into exploring alternative treatment options."

Another motivation for the current study is the dearth of prospective investigations into chemoradiotherapy as a primary treatment for patients with low rectal cancer.

"Additionally, people have generally been...treating these patients with standard preoperative chemoradiotherapy, which is meant to control subclinical lymph node disease and what's not removed by the surgeons, in order to prevent recurrence around the anastomosis," Dr Appelt noted.

"So people have not been optimizing the chemoradiotherapy in order to try and use it as a primary treatment," she added.

For the study, 55 patients with primary, resectable adenocarcinoma (T2 or T3, N0 - N1) in the lower 6 cm of the rectum were given chemoradiotherapy consisting of 60 Gy in 30 fractions to the tumor, 50 Gy in 30 fractions to elective lymph node volumes, and a 5 Gy endorectal brachytherapy boost, as well as oral tegafur-uracil 300 mg/m2 every weekday for 6 weeks.

Endoscopies were performed and biopsies taken from the tumor at baseline, during treatment, and 6 weeks after treatment.

Patients were assigned to watchful waiting if they had a complete clinical tumor regression, negative tumor site biopsies, and no nodal or distant metastases on computed tomography and magnetic resonance imaging (MRI) 6 weeks after treatment.

A complete response was observed in 40 of the 55 patients, and these 40 patients were followed by watchful waiting. Local recurrence occurred at a median of 23.9 months, with 15.5% of patients experiencing recurrence at 1 year

The remaining 3 patients underwent surgery.

Diarrhea was the most common acute grade 3 adverse event during treatment, seen in four of 51 patients. Sphincter function was deemed excellent: After 1 year, 18 of 25 patients reported no fecal incontinence at all, and after 2 years, 11 of 16 patients remained free of these problems.

Grade 3 late rectal bleeding was reported in two of 30 patients at 1 year and one of 17 patients at 2 years. The team reported no unexpected serious adverse reactions or treatment-related deaths.

Discussing the findings, Dr Appelt commented that the team became "more confident about foregoing surgery" as the study progressed, noting: "There was very much a learning curve."

She continued: "We were more reluctant in the beginning to let people undergo observation, and we got more and more confident that this was actually doable."

Dr Appelt feels that in previous studies, the criteria for identifying complete responders "have been quite strict," with criteria such as no ulcerations, just a small scar, and a demonstrably complete response.

"You could say we were more lax about it," she said. "As long as we couldn't biopsy a tumor, we were happy."

She continued, "It was a bit of a learning experience getting the confidence that this was okay, and we could treat them without surgery."

Dr Appelt believes that, in the future, the treatment and follow-up regimens could be further optimized to minimize the effect on patients and improve monitoring of local recurrences.

She said: "We used a brachytherapy boost for these patients to boost the tumor at the end of the external beam radiotherapy, and we found that a large proportion of patients came back with bleeding from the rectal mucosa."

She added: "We're pretty sure that bleeding is due to the higher doses from the brachytherapy. For most patients, it's not a problem, but we did have a few grade 2 and grade 3 bleedings."

Dr Appelt continued: "We would probably suggest definitely optimizing the brachytherapy, and we are looking [into] whether we can leave out the brachytherapy altogether."

Regarding optimizing the follow-up regimen, she said: "I think we can optimize the imaging component, especially, of the follow-up."

It's more important that we explore different treatment options than we find one single best treatment for all patients with low rectal cancer. Dr Ane L. Appelt

"There are some really exciting studies coming out, especially from the Dutch groups and from Gina Brown in England, which demonstrate that MRI, especially diffusion-weighted MRI, might be very good for looking at patients during observation and keeping an eye on local recurrences."

Finally, Dr Appelt was keen to emphasize that she does not believe that the optimal treatment for patients with rectal cancer will come down to a "single treatment fits all" scenario.

"It might come down to their very individual preferences, and so I think it's more important that we explore different treatment options than we find one single best treatment for all patients with low rectal cancer," she explained.

Dr Appelt noted that there are potential downsides to chemoradiotherapy, such as if a patient who has experienced toxicity from radiotherapy ends up needing surgery anyway, with its attendant adverse effects.

Some patients may also prefer the kind of definitive treatment offered by surgery and wish to avoid the initial uncertainty that surrounds chemoradiotherapy and whether it has been successful.

In contrast, having a stoma is, for some patients, the most important concern, and they would be willing to accept additional toxicity from the radiotherapy to avoid surgery. Other patients may also be too comorbid and frail to undergo surgery.

"In the end, I think this really comes down to a shared decision-making process between the patients and the physicians, and I'm not quite sure we can pick one," Dr Appelt said.

"It's not like this has to be the new standard of care for all patients, but it is one more treatment option for these patients."

Achievement of Complete Responses is "Remarkable"

In an accompanying comment, Cornelis J. H. van de Velde, MD, PhD, and Anne J. Breugom, MD, from the Department of Surgery, Leiden University Medical Centre, the Netherlands, write: "Despite variation between studies in patient selection and the assessment of a clinical complete response, the high proportion of patients who achieved a complete clinical response in this study in response to chemoradiotherapy is remarkable compared with those from previous studies."

Ascribing the improved response to the intensive chemoradiotherapy regimen used in the study, Dr van de Velde and Dr Breugom say: "The question remains of whether the benefits of intensive chemoradiotherapy followed by observation outweigh the possible long-term adverse effects — especially for patients with clinical T2 rectal cancer, who are not normally given neoadjuvant chemoradiotherapy."

They continue: "Although the study of Appelt and colleagues is a valuable contribution to the evidence base of watchful waiting for patients with low rectal cancer, no consensus has been made on policies for optimum selection of patients, method of imaging, assessment of clinical complete response, follow-up, and chemoradiotherapy regimen. More data and long-term outcomes are needed before this strategy could be safely incorporated into medical practice for suitable patients."

They suggest that it is unlikely that a randomized controlled trial of watchful waiting after chemoradiation in rectal cancer will ever be done.

However, there is a recently launched initiative that will be collecting useful data on this option: the International Watch and Wait Database, set up by the European Registration of Cancer Care and the Champalimaud foundation.

"Uniform prospective registration of all patients with rectal cancer managed with a non-surgical approach in this database will result in a detailed understanding of selection for a watchful waiting strategy and will enable investigators to assess long-term outcomes," the commentators write. "Ultimately, this effort will contribute to core treatment standards for watchful waiting."

This study was supported by the Danish Colorectal Cancer Group, and financially supported by CIRRO–The Lundbeck Foundation Center for Interventional Research in Radiation Oncology and The Danish Council for Strategic Research. The authors and commentators have disclosed no relevant financial relationships.

Lancet Oncol. Published online July 5, 2015. Article abstract, Comment extract


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