For Advanced Colorectal Cancer Sequential Chemotherapy Equals Combined Drugs

NIJMEGIN, The Netherlands, July 13 -- In advanced colorectal cancer, combination chemotherapy did not significantly improve overall survival over the sequential use of the same drugs, according to two randomized trials.

Median survival (about 14 to 17 months) was similar for patients given sequential and combination treatment in both studies, according to two reports in the July 14 issue of The Lancet.

In one of the trials, an open-label, randomized phase III study known as capecitabine, ironotecan, and oxaliplatin (CAIRO), patients were enrolled from 74 centers in Holland from 2003 to 2004, reported Cornelis J.A. Punt, M.D., of Nijmegen Medical Center here, and colleagues.

Of 820 patients with advanced colorectal cancer, 410 were randomly assigned to sequential treatment with either first-line capecitabine (Xeloda), second-line irinotecan (Camptosar), and third-line capecitabine plus oxaliplatin (Eloxatin).

In the combination therapy group, 410 patients were given first-line treatment with capecitabine plus irinotecan, and second-line capecitabine plus oxaliplatin.

Seventeen patients (nine in the sequential treatment group, eight in the combination group) were found to be ineligible and were excluded from the analysis.

Of the remaining patients, 675 (84%) died during the study, including 336 in the sequential group and 339 in the combination group, the researchers reported.

Median overall survival was 16.3 (95% CI 14.3-18.1) months for sequential treatment and 17.4 (15.2-19.2) months for combination treatment (P=0.3281). The median follow-up for the 128 patients still alive was 31.5 months.

The hazard ratio for combination versus sequential treatment was 0.92 (CI 0.79-1.08; P=0.3281).

The frequency of grade 3-4 toxicity over all lines of treatment did not differ significantly between the groups, except for grade 3 hand-foot syndrome, which was more common with sequential treatment. The higher dose of capecitabine when given as a single agent may have been the cause.

Treatment related deaths occurred in 11 patients, eight after sequential and three after combination treatment (P=0.13). However, most of these deaths involved protocol violations.

With the availability of targeted agents such as Bevacizumab (Avastin) and cetuximab (Erbitux), the treatment options and outcomes for patients with advanced colorectal cancer have changed considerably. But chemotherapy remains the backbone of systemic treatment, and these results indicate that sequential treatment remains a valid treatment option, said Dr. Punt..

The second study, the FOCUS trial (Fluorouracil, Oxaliplatin, and CPT11 [irinotecan]-Use and Sequencing), also challenged the assumption that in this non-curative setting, maximum tolerable treatment must necessarily be used first-line, said Matthew T. Seynour, M.D., of Cookridge Hospital in Leeds, England.

From May 1, 2000 to Dec. 31, 2003, 2,135 patients were randomly recruited from 59 centers in the United Kingdom and one in Cyprus and assigned to one of five groups.

These included a control group given single-agent fluorouracil (with levofolinate over 48 hours every two weeks) until failure, then single-agent irinotecan.

Two groups received initial fluorouracil until failure, then a combination of fluorouracil with either irinotecan or oxaliplatin.

Two other groups received initial combinations of fluorouracil with either irinotecan or oxaliplatin from the outset.

The investigators found:

• Median survival of the control patients given single agent drug courses was 13.9 months, shorter than the other groups;
• Median survival for those given fluorouracil followed by either irinotecan or oxiliplatin was 15.0 and 15.2 respectively;
• Median survival for initial combinations of fluorouracil plus either irinotecan or oxaliplatin was 16.7 and 15.4 months respectively.

However, log-rank comparison of each group against the control group showed that only the first-line combination therapy including irinotecan satisfied the statistical test for superiority (P=0.01).

Overall, a comparison of fluorouracil followed by combination therapy versus initial combined chemotherapy was within the predetermined noninferiority boundary of HR=1.18 or less (HR=1.06, 90% CI 0.97-1.17).

These data, Dr. Seymour said, challenge the assumption that, in this non-curative setting, maximum tolerable treatment must necessarily be used first-line. The staged approach of initial single-agent treatment upgraded to combination when required is not worse than first-line combination, and is an alternative option for discussion with patients.

In an accompanying comment, Hans-Joachim Schmoll, M.D., of Martin-Luther University in Halle, Germany, and Daniel Sargent, M.D., of the Mayo Clinic in Rochester, Minn., expressed reservations about the findings, stating that the "evidence continues to support initial combination chemotherapy as the backbone of treatment for metastatic colorectal cancer, as least for most patients."

Recent trials of initial triple therapy even for only six months, followed by a break, resulted in a median overall survival of about 23 months, better than that seen in FOCUS or CAIRO, Drs. Schmoll and Sargent said.

The writers noted that certain patients-those not having potentially resectable metastases and those not needing immediate treatment with high response--can be well treated with initial single-agent fluorouracil as indicated by FOCUS and CAIRO.

They also pointed out that "patients with metastases limited to lung or liver, who are potential candidates for secondary surgery after response to chemotherapy, were not included in FOCUS and under-represented in CAIRO, therefore the findings of the trials cannot be applied to these patients."

Dr. Punt, of the CAIRO trial, reported receiving research grants and honoraria from Sanofi-Aventis, Roche, and Pfizer. The DCCG received grant support from the Commissie Klinisch Toegepast Onderzoek of the Dutch Cancer Foundation, and unrestricted scientific grants from Roche, Aventis, Sanofi, and Pfizer. Logistic support was provided by Schmidt Consultancy

The FOCUS trial researchers declared no conflict of interest. During and subsequent to the conduct of the trial, Dr. Seymour and others participated in other trials funded or part-funded by the manufacturers of irinotecan and oxaliplatin, and receive educational support in the form of travel bursaries or departmental research support.