Paradigm Buster in Locally Advanced Rectal Cancer

Nick Mulcahy

January 13, 2015

Currently, every curative treatment plan for locally advanced rectal cancer involves surgery.

But that does not need to be the case for a substantial number of patients, according to Philip Paty, MD, a surgical oncologist at the Memorial Sloan Kettering Cancer Center in New York City.

"Many people can be cured without surgery," he told reporters during a presscast held in advance of the 2015 Gastrointestinal Cancers Symposium in San Francisco.

"Carefully selected" patients with low rectal cancers (within a finger's reach at digital exam) whose tumors disappear after chemoradiation and systemic chemotherapy can forgo surgery and be followed with "watch and wait" surveillance, he said.

Many people can be cured without surgery.

Dr Paty believes that patients should be informed of this approach, and cites world-renowned colorectal cancer surgeon Bill Heald, CBE, MChir, from the Pelican Cancer Foundation in Basingstoke, United Kingdom, as a leading proponent of the idea.

"He feels we have an obligation to let patients know that this is an option," Dr Paty told Medscape Medical News.

The quality-of-life benefits of avoiding rectal surgery — and therefore the risks for impaired bowel and sexual function — are potentially great, he said.

Since 2006, Memorial Sloan Kettering has been using "nonoperative management" in patients who have a clinical complete response to upfront chemoradiation and systemic chemotherapy for locally advanced rectal cancer (stage I to III disease).

Dr Paty presented data from a nonrandomized retrospective outcomes study. Of the 145 patients, 73 were treated with a watch and wait strategy after having achieved a complete response to neoadjuvant therapy (confirmed with clinical examination) and 72 underwent surgical resection of the rectum and were found to have achieved a complete response to neoadjuvant therapy (confirmed with pathology review after surgery).

In other words, the study compared two groups of patients who had a complete response to upfront therapy but were subsequently managed differently (surveillance vs surgery).

The 4-year overall survival rate was 91% in the surveillance group and 95% in the surgery group (P = .47). The number of distant recurrences was not significantly different between the surveillance and surgery groups (9 vs 5; P = .23)

Median follow-up was 3.5 years.

These are "important results," said Smitha S. Krishnamurthi, MD, from the Case Western Reserve University School of Medicine in Cleveland, who moderated the presscast. "Avoiding surgery has the potential to significantly improve quality of life for patients, for example, by avoiding a colostomy," she said in an American Society of Clinical Oncology (ASCO) press statement.

However, "longer-term" follow-up is needed to further assess recurrence rates, Dr Krishnamurthi said.

Dr Paty pointed out that the risk for local regrowth is greatest in the first 18 months after neoadjuvant therapy — a period covered by this study.

In the surveillance group, 54 of the 73 patients (72%) sustained their complete response at 4 years. There were 19 local tumor regrowths; 2 were treated with local excision and 17 required total resection. At 4 years, more patients in the surveillance group than in the surgery group had their organ preserved (77% vs 0%).

Rectal cancer patients managed with surveillance at Memorial Sloan Kettering are monitored at 3- to 4-month intervals with digital rectal and endoscopic exams and at 6-month intervals with cross-sectional imaging.

Growing Evidence

Dr Paty acknowledged that the new data reflect "cherry picking" of patients in the surveillance group, but said that the data are "very compelling" nonetheless.

He explained that the surveillance approach is "more difficult for the surgeon." Foremost, "you have to follow patients longer," he said.

Also, according to Dr Paty, clinical judgment is required to determine if the cancer is gone. In this study, "most" of the rectal cancers were low. It takes 8 to 12 weeks after chemoradiation and systemic chemotherapy to determine if the cancer is completely gone. Even then, there is the specter of legal liability if the cancer recurs. The surgeon and patient must enter into a "mutual agreement" and acknowledge that there is a risk for recurrence and for salvage surgery.

Memorial Sloan Kettering is now spearheading a multicenter prospective randomized phase 2 clinical trial of the nonoperative management of rectal cancer in the United States.

The trial will compare, in locally advanced disease, chemoradiation (with sensitizing capecitabine or 5-fluorouracil) plus systemic chemotherapy (8 cycles of FOLFOX) with the same treatments in reverse order to determine which results in the maximal downsizing of tumors.

The nonoperative approach to rectal cancer was pioneered in the 1990s in Brazil by Angelita Habr-Gama, MD, and now has a modest but growing body of evidence to support it, said Dr Paty.

Some Brazilian patients have been followed for up to 20 years, but in the most recent publication of data, median follow-up was 5 years (J Gastrointest Surg. 2006;10:1319-1328).

There is also a cohort of Dutch patients being followed at the University Hospital Maastricht. Median follow-up in the most recent data reported was 25 months (Lancet Oncol. 2010;11:835-844).

"Nonoperative management is being accepted more and more around the world," said Dr Paty.

A substantial proportion of patients with locally advanced rectal cancer are eligible for nonoperative management.

Dr Paty stated that 40% to 50% of patients with stage I rectal cancer and 30% to 40% of patients with stage II or III disease will have their tumors disappear clinically after initial treatment with chemoradiation and systemic chemotherapy, according to an ASCO press statement.

"From my experience, most patients are willing to accept some risk to defer rectal surgery in hope of avoiding major surgery and preserving rectal function," he added.

Since initiating nonoperative management in 2006, only two of his patients with a complete response to upfront therapy have declined the offer to be managed with surveillance, he told Medscape Medical News.

This study was supported in part by funding from the Berezuk Colorectal Cancer Fund. Some of the study authors report financial relationships with industry. Dr Krishnamurthi has disclosed no relevant financial relationships.

2015 Gastrointestinal Cancers Symposium (GICS): Abstract 509. To be presented January 17, 2015.


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