Again, Oxaliplatin Is Toxic and No Benefit in Rectal Cancer

Kate Johnson

April 07, 2014

VIENNA, Austria — Yet another rectal cancer study has found that the addition of oxaliplatin to capecitabine chemoradiation in locally advanced disease gives no short-term postoperative benefit and increases toxicity.

The finding comes from new data from the PETACC-6 trial, reported here at the European Society for Radiotherapy and Oncology (ESTRO) 33 annual conference.

"The addition of oxaliplatin to preoperative capecitabine chemoradiation led to increased toxicity and decreased treatment compliance and did not improve the R0 resection rate, the pathological complete remission rate, and the sphincter preservation rate," reported researcher Karin Haustermans, MD, PhD, professor of medicine and head of the Department of Laboratory of Experimental Radiotherapy at University Hospital Gasthuisberg in Leuven, Belgium.

However, only secondary results from PETACC were released, and long-term results on disease-free survival are not yet known, she told Medscape Medical News.

"Whether pathological complete response (pCR, one of the secondary endpoints) is a surrogate of disease-free survival (primary endpoint) is not that clear," she said, "… although we have many data showing that pCR patients tend to have a better prognosis."

The new data from the trial are in agreement with most previous short-term results of the oxaliplatin regimen, said Dr. Haustermans.

To date, 4 trials have investigated the potential of adding oxaliplatin to bolus or infusional fluorouracil (5-FU) or capecitabine in the preoperative chemoradiation (CRT) setting. As reported previously by Medscape Medical News, the ACCORD 12/0405-Prodige 2 trial had findings similar to those of the current study, as did STAR, ARO/AIO/CAO 04, and, most recently NASBP RO4.

PETACC 6 is the fifth trial to investigate oxaliplatin in the preoperative CRT setting, and the first, along with the German ARO/AIO/CAO 04 trial, to also include oxaliplatin in the adjuvant setting, said Dr. Haustermans.

In the preoperative setting, the trial assessed oxaliplatin's effect on local complete response and local relapse, while long-term results will be used to assess its adjuvant role on the rate of distant metastases and 3-year disease-free survival.

Commenting on the findings, session chair David Sebag-Montefiore, MD, professor of clinical oncology and health research at Leeds Institute of Cancer & Pathology, United Kingdom, told Medscape Medical News, "although the results are disappointing that the trial has not shown improved early outcomes for the addition of oxaliplatin, it's very important that we wait for the long-term results in terms of cancer endpoints before we form a firm conclusion about the role of oxaliplatin."

However, Karyn A. Goodman, MD, from the Department of Radiation Oncology at Memorial Sloan-Kettering Cancer Center in New York, had a more definitive reaction.

"Clearly, with the results of the PETACC-6 trial in combination with the 3 other large randomized trials, there is no role for oxaliplatin in combination with neoadjuvant 5-FU based chemoradiation," she told Medscape Medical News. "It appears to only increase toxicity without improving pCR rates, sphincter preservation, or local control."

Details of the Study Findings

The trial enrolled 1094 patients, median age 62 years, with histologically proven adenocarcinoma of the rectum and tumors a maximum of 12 cm from the anal verge. Patients had T3/4 or node-positive disease, with no evidence of metastasis, and their disease was considered to be resectable at the time of entry or expected to become resectable after preoperative CRT, said Dr. Haustermans.

All patients received 5 weeks of preoperative CRT (45 Gy in 25 fractions, with an optional boost to a total dose of 50.4 Gy) with capecitabine (825 mg/m2 twice daily), followed by 6 cycles of adjuvant capecitabine (1000 mg/m2 twice daily for days 1 to 15 every 3 weeks).

They were then randomly assigned (n = 547 in each group) to receive no additional therapy or the addition of oxaliplatin before surgery (50 mg/m2 on days 1, 8, 15, 22, and 29) and after surgery (130 mg/m2 on day 1 every 3 weeks).

The primary endpoints of distant metastases and 3-year disease-free survival are not yet available, but secondary endpoints of pathologic downstaging, complete remission, sphincter preservation, and R0 resection were reported.

Adherence to preoperative radiation was similar in both groups, with more than 90% of patients receiving more than 45 Gy. In terms of preoperative chemotherapy adherence, most patients in both groups started; 24% of those in the oxaliplatin group received less than 90% of the prescribed dose of capecitabine compared with 7.5% of patients in the nonoxaliplatin group.

More grade 3 and 4 toxic events occurred in the oxaliplatin group (32.5% and 5.1%, respectively) than in the nonoxaliplatin group (14.7% and 0.6%); most such events were grade 3 diarrhea (18.3% in the oxaliplatin group vs 6.1% in the nonoxaliplatin group).

Postoperative complications did not differ between the groups.

For cancer outcomes, the R0 resection rate was 89.8% in the oxaliplatin group and 94.9% in the nonoxaliplatin group (P = .31), and anal sphincter preservation was also similar (67.1% vs 70.6%, respectively; P = .26).

Dr. Haustermans and Dr. Sebag-Montefiore have disclosed no relevant financial relationships.

European Society for Radiotherapy and Oncology (ESTRO) 33. Abstract OC-0250. Presented April 6, 2014.

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