1. Carlson, Robert H.

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BARCELONA, Spain-Preoperative chemoradiotherapy followed by total mesorectal excision has become the standard in locally advanced rectal carcinoma treatment. But the ability to predict which patients will or will not benefit from preoperative chemoradiotherapy may result in a better oncologic prognosis with a lower rate of post-therapeutic functional disorders.

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The goal of the phase II GRECCAR 4 trial was to tailor treatment by first measuring the response to preoperative chemotherapy and then omitting chemoradiotherapy for very chemo-sensitive patients, escalating the dose of radiotherapy for chemo-resistant patients, while still achieving at least R0 (less than 1mm) resection in 90 percent of patients or more.


Preoperative Chemoradiotherapy

Preliminary results indicate an early tumoral response to a short and intensive induction chemotherapy regimen can identify a subset of patients not likely to achieve curative resection and who would potentially benefit from preoperative chemoradiotherapy. The study was presented at the recent European Society of Medical Oncology 18th World Congress on Gastrointestinal Cancer (Abstract O-021).


Lead investigator Philippe Rouanet, MD, PhD, Professor of Surgery in the Department of Surgical Oncology, Institut Regional du Cancer de Montpellier, France, reported that, among 194 patients evaluable after induction therapy, 30 (15%) were good responders (chemo-sensitive) and 164 (85%) showed an unfavorable response (chemo-resistant). The best surgical outcomes, with no residual tumor (ypT0), were among favorable responders assigned to standard chemoradiotherapy, 57.9 percent (11/19).


"Early evaluation after neoadjuvant chemotherapy can discriminate between good and bad responders without adverse effects to the curative resection rate," Rouanet said.


Tumor response after induction FOLFIRINOX was evaluated using magnetic resonance imaging. Good response was defined as having a 75 percent or greater reduction of tumor volume. Poor response was measured by a predictive circumferential resection margin or a volumetric response of less than 75 percent.


Good responders were randomly assigned to either immediate surgery (Arm A, 16 patients) or to standard chemoradiotherapy comprising 50 Gy in 25 fractions plus capecitabine 800 mg/m2 twice daily 5 days per week (Cap 50) followed by surgery (Arm B, 14 patients).


Poor responders were randomly assigned to either chemoradiotherapy (Cap50) in Arm C (113 patients) or intensive chemoradiotherapy (Cap 60; 60 Gy) in Arm D (51 patients). Patients in Arms C and D then underwent surgery.


The surgical procedure was similar among the four groups regarding hospitalization length, conversion rate, abdominoperineal resection rate, postoperative morbidity, and re-intervention.


Rouanet said the required number of unfavorable responders for statistically significant results was reached, but the failed to accrue the required number of favorable responders.


Rouanet reported on 130 patients analyzed according to the treatment received and the planned number in the favorable stratum: 10 in Arm A, 19 in Arm B, 52 in Arm C, and 49 in Arm D.


None of the good responders achieved a circumferential resection margin of 1mm or less, compared with 11.8 percent (six patients) in the unfavorable responder group who received CAP 50 and 4.5 percent (two patients) in the CAP 60 arm.


"Early response to induction chemotherapy with four cycles of FOLFIRINOX enabled us to adapt preoperative radiotherapy for locally advanced rectal carcinoma," Rouanet said. "A tailored strategy seems feasible in terms of safety and pathologic results for bad responders."


Despite a poor accrual, this strategy also seems promising for good responders. "Long-term clinical results are needed to confirm the efficacy of such a tailored strategy," he said.


Small Trial Numbers

The discussant for this paper, Rob Glynne-Jones, Lead Clinician in Gastrointestinal Cancer, Mount Vernon Cancer Centre, Northwood, Middlesex, U.K., said the hypothesis of the GRECCAR 4 trial is intriguing, "but the trial has very small numbers and it's not going to change my practice next week."


Even so, he said, "the notion of virtually a 60 percent complete pathological response rate in a very small group of patients who respond very well to chemotherapy is a very exciting prospect."


He said the trial overall was very satisfactory in that the vast majority of patients had a curative resection.


"Early response to a relatively short amount of chemotherapy-6 weeks-does allow you to individualize therapy," he said.


Robert H. Carlson is a contributing writer.