Nick Mulcahy

October 14, 2011

October 14, 2011 (Miami Beach) — Oxaliplatin is not a good choice for the neoadjuvant treatment of locally advanced rectal cancer, according to the lead author of a phase 3 randomized trial that was presented during the plenary session here at the American Society for Radiation Oncology (ASTRO) 53rd Annual Meeting.

The investigators of the trial, conducted at 50 hospitals in France, had hoped that oxaliplatin, a radiosensitizer, would increase the local control of these T3–4 M0 rectal cancers by priming the tumor tissue that is subsequently irradiated, explained lead author Jean-Pierre Gérard, MD, a radiation oncologist at Centre Antoine-Lacassagne in Nice, France.

However, the study, which followed 598 patients for 3 years, showed that oxaliplatin increased early toxicity, especially diarrhea, with no significant improvement in the rate of pathologic complete response (ypCR) or local recurrence, Dr. Gerald reported.

"There is no role for oxaliplatin in combination with neoadjuvant 5-FU [fluorouracil]-based chemoradiation" in this setting, summarized Karyn Goodman, MD, from the Memorial Sloan-Kettering Cancer Center in New York City. She served as discussant of the study at the plenary session.

The standard of care remains 5-FU-based chemoradiation (50.0 to 50.4 Gy) for neoadjuvant treatment, she asserted.

One clinician pointed out that not all rectal cancer patients in the United States receive such extensive treatment. Neoadjuvant chemoradiation is "not considered standard around the country," said Tim Williams, MD, a radiation oncologist at the Lynn Cancer Institute at Boca Raton, Florida, and a past chair of ASTRO. He moderated a press conference at which Dr. Gérard spoke.

Surgery (total mesorectal excision) is the cornerstone of treatment for locally advanced rectal cancer everywhere, said Dr. Gérard.

The main end point of the study, know as ACCORD 12/0405-Prodige 2, was the rate of ypCR or "sterilization," which refers to the surgically removed tissue without cancer after neoadjuvant chemoradiation. However, as Dr. Goodman observed, ypCR "has not been validated as a surrogate for overall survival" in this setting, and this study was not powered to assess overall or disease-free survival. In short, it is a phase 3 study with considerable limitations.

More Studies to Consider

In this study, the investigators compared radiotherapy 45 Gy plus capecitabine (the Cap45 regimen; n = 299) with radiotherapy 50 Gy plus capecitabine plus oxaliplatin (the Capox50 regimen; n = 299) in patients with resectable T3–4 M0 rectal cancer. Patients in France were enrolled from 2005 to 2008.

Radiotherapy (45 or 50 Gy in 25 fractions of 1.8 or 2.0 Gy, respectively) was administered 5 times per week for 5 weeks. This dose was delivered, using a 3-or 4-field technique, to a restricted posterior pelvic volume that included the mesorectal and medial rectal nodes but excluded the external and common iliac nodes. In the Capox50 group, the target volume was restricted to the gross tumor with shrinking field after a dose of 44 Gy was reached.

There is now a median follow-up of 36.8 months, and Dr. Gérard reported 3-year results.

In terms of quality-of-life measures (bowel function, erectile dysfunction, and social life), the 2 treatment regimens did not differ significantly in terms of outcomes at 3 years, he said.

There were also no statistically significant differences between the 2 regimens in distant metastases, disease-free survival, overall survival, or toxicities of grade 3 or higher at 3 years, he said. The Capox50 regimen did have a lower rate of local recurrence (4.4% vs 6.1%) than the Cap45 regimen but again, the difference was not significant. Capox50 provided a better rate of ypCR (19% vs 13%), but the result was not significant.

However, in an earlier report, Dr. Gérard and colleagues noted that the Capox50 regimen had significantly more early adverse events.

More preoperative grade 3 to 4 toxicity (including diarrhea) occurred in the Capox50 group (25% vs 11%; < .001) at 1 year, they reported last year (J Clin Oncol. 2010;28:1638-1644).

In comparing the clinical value of Capox50 and Cap45, the investigators had to do some detective work of sorts, because the 2 regimens differed in 2 ways: radiation dose and chemotherapies.

To tease out whether it was the higher dose of radiation or the oxaliplatin that was responsible for the increased early toxicities seen with Capox50, Dr. Gérard and colleagues looked at results from other trials.

The Studio Terapia Adiuvante Retto (STAR) trial involved 747 patients with T3–4 M0 rectal tumors, and had selection criteria similar to the ACCORD 12/0405-Prodige 2 trial. STAR compared neoadjuvant radiotherapy 50.4 Gy (1.8 Gy per fraction) with concurrent 5-FU with the same regimen plus the addition of weekly oxaliplatin. This trial showed the same significant increase in grade 3 to 4 early toxicities with oxaliplatin (24%) as ACCORD 12/0405-Prodige 2, but no real difference in the rate of ypCR (16%).

These findings suggest that in ACCORD 12/0405-Prodige 2, the early toxicity might be mainly attributable to oxaliplatin and to the improved efficacy outcomes related to radiotherapy dose intensification, Dr. Gérard said in an interview with Medscape Medical News.

Other evidence endorses Cap50 — that is, 50 Gy of radiation and capecitabine as the chemotherapy — as the neoadjuvant regimen of choice in locally advanced rectal cancer, said Dr. Gérard.

"The results of [the ACCORD] trial, when analyzed together with the Italian STAR01 and the American NSABP R04 randomized trials, bring solid scientific evidence that a Cap50 regimen should be the standard treatment for locally advanced rectal cancer. Using capecitabine avoids the intravenous injection of fluorouracil, while a radiation dose of 50 Gy in 25 fractions over 5 weeks increases the chance of tumor sterilization and limits the risk of local recurrence to 5% or less," he said in an ASTRO press statement.

The authors have disclosed no relevant financial relationships.

American Society for Radiation Oncology (ASTRO) 53rd Annual Meeting: Abstract 3. October 3, 2011.

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