Post-Op Chemo No Help in Adequately Pretreated Rectal Cancer

Kate Johnson

April 07, 2014

VIENNA — Postoperative chemotherapy given to stage 2 and 3 rectal cancer patients after surgery and preoperative (chemo)radiotherapy does not improve outcome, according to new results from the multicenter, randomized, controlled PROCTOR/SCRIPT study from the Netherlands.

"We are contraire to the rest of the world in the Netherlands ― we've just rewritten the guidelines, and we still think there's very little evidence to add chemotherapy to the treatment of rectal cancer patients if they have been treated appropriately preoperatively," said Corrie Marijnen, MD, PhD, from Leiden University Medical Center in the Netherlands, who presented the findings at the European Society for Radiotherapy and Oncology (ESTRO) 33.

PROCTOR/SCRIPT "did not demonstrate significant differences between the observation group and the adjuvant chemotherapy group in either overall survival, disease-free survival, or recurrences after a median follow-up of 5 years," lead researcher Anne Breugom, MD, also from Leiden University Medical Center, told Medscape Medical News.

Although the study had recruitment problems and was therefore underpowered, she pointed out that there are now 3 other studies that support these findings: the EORTC 22921 trial ( Lancet Oncol. 2014;15:184-90), an Italian trial (Cionini et al), and the CHRONICLE trial (Glynne-Jones et al).

"We are planning to perform a meta-analysis with these other 3 trials to identify possible subgroups that do benefit from adjuvant chemotherapy and to definitively solve the discussion on the role of adjuvant chemotherapy," she said.

Results Were "Rather Disappointing"

The PROCTOR/SCRIPT study recruited stage 2 and 3 rectal cancer patients during a 13-year period, between 2000 and 2013. A total of 440 were eligible to enter the study, and all received total mesorectal excision (TME) after preoperative radiotherapy or chemoradiotherapy.

Patients were then randomly assigned to observation (n = 222) or adjuvant chemotherapy, consisting of either 5-FU/leucovorin or 8 courses of 1250 mg/m2 oral capecitabine twice daily, given on days 1-14 every 21 days.

The primary endpoint was overall survival, with secondary endpoints of disease-free survival and local and distant tumor control.

After a median follow-up of 5 years, the results were "rather disappointing," said Dr. Marijnen. "We didn't see any difference in the distant recurrence rate, which was around 35%, between the 2 arms (hazard ratio [HR], 0.9; P = .52). Local regional recurrence rates were acceptable at around 7%, but again, no different (HR, 1.19; P = .66), and an overall recurrence rate of 36% to 38% (HR, 0.91, P = .56)."

For disease-free survival, there was a slight difference in favor of the adjuvant chemotherapy arm, but it was not statistically significant (62.3% vs 57.1%; HR, 0.8; P = .15), and overall 5-year survival rates were not different, although "very good," she said, at 80% for both arms (HR, 0.9; P = .62).

"In stage II and III rectal cancer patients treated with appropriate surgery and neoadjuvant radiotherapy or chemoradiotherapy, we had a very good overall 5-year survival rate of 80%, but there was no effect of the adjuvant chemotherapy," she concluded.

"We will try to identify molecular biomarkers in tumor material of patients included in the PROCTOR/SCRIPT trial, which could offer prognostic or predictive information to clinicians," added Dr. Breugom.

Despite the growing evidence showing no benefit to adjuvant chemotherapy in this setting, both the National Comprehensive Cancer Network (United States) and the European Society for Medical Oncology (ESMO) continue to recommend postoperative chemotherapy after preoperative chemoradiotherapy in rectal cancer patients.

Yet, as recently reported by Medscape Medical News, the authors of the recently published EORTC 22921 trial concluded, "our trial does not support the current practice of adjuvant chemotherapy after preoperative radiotherapy with or without chemotherapy."

Asked by Medscape Medical News to comment on the PROCTOR/SCRIPT findings, the lead author of EORTC 22921, Jean-François Bosset, MD, from Besançon University Hospital, France, said, "At this time, we do no know exactly why postop chemotherapy does not work after preop radiotherapy (with or without chemotherapy). Moderate adherence to postop chemo is suspected to be an important parameter. Possibly there are others."

He said he is hopeful that the meta-analysis promised by Dr. Breugom's group will finalize the question and possibly lead to new recommendations from the NCCN and ESMO.

With a North American perspective, Karyn Goodman, MD, from the Department of Radiation Oncology at Memorial Sloan–Kettering Cancer Center in New York City, suggested the question still remains open.

"The questions of the benefit of adjuvant chemotherapy in rectal cancer is a very important one since we routinely give chemotherapy in this setting, but we base this on colon cancer data," she told Medscape Medical News. "The EORTC 22921 looked at this question and found no benefit of adjuvant 5-FU. Unfortunately, the current PROCTOR/SCRIPT study may not be large enough to identify a survival benefit in this population. A larger, well-powered study should be designed to identify which subgroups of rectal cancer patients may benefit from adjuvant chemotherapy. Moreover, induction chemotherapy followed by chemoradiation may become more widely used; however, we may be overtreating many of our patients."

Dr. Marijnen, Dr. Breugom, and Dr. Bosset did not disclose any relevant financial relationships.

European Society for Radiotherapy and Oncology (ESTRO) 33. Abstract OC-0251. Presented April 6, 2014.

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