Reduced-dose combo treatment helps some with metastatic colorectal cancer

By Will Boggs MD

NEW YORK (Reuters Health) - 26/3/2019

Reduced-dose combination chemotherapy improves progression-free survival, compared with full-dose monotherapy, in older vulnerable patients with metastatic colorectal cancer (CRC), according to results from the phase II NORDIC9 trial.

"Dose-reduced combination chemotherapy is a good option for patients who are not candidates for standard combination chemotherapy," Dr. Stine Braendegaard Winther from Odense University Hospital and the University of Southern Denmark told Reuters Health by email. "In the NORDIC9 trial we used S-1, a prodrug of 5-fluorouracil, which is not accessible in all parts of the world, but we do believe that the strategy is very interesting to these patients."

Older patients are under-represented in cancer clinical trials, and only the fittest are included in trials that don't exclude older patients. As a result, evidence to support their treatment is sparse.

Dr. Winther and colleagues evaluated whether dose-reduced combination therapy with S-1 and oxaliplatin was more effective, and as tolerable, as full-dose S-1 monotherapy in 160 patients age 70 or older with colorectal adenocarcinoma, nonresectable metastases and low World Health Organization performance status (0-2).

After a median follow-up of nearly 24 months, 98% (81/83) of patients on monotherapy and 92% (71/77) of patients on the combination had progressed or died.

Median progression-free survival, the primary endpoint, was significantly longer in the combination group (6.2 months) than in the monotherapy group (5.3 months), the researchers report in The Lancet Gastroenterology & Hepatology, online March 6.

However, median overall survival did not differ significantly between the combination group (14.5 months) and the monotherapy group (11.5 months).

The proportion of patients with at least one grade-3-4 adverse event was significantly higher in the monotherapy group (62%) than in the reduced-dose combination group (43%).

In post-hoc analyses, patients who also received bevacizumab had significantly longer median progression-free survival (8.2 months vs. 4.7 months for those without bevacizumab) and nonsignificantly longer overall survival (20.5 months vs. 12.6 months).

"With the results of the trial, we hope that physicians are provided with arguments that support treatment with dose-reduced combination therapy in relation to both efficacy and toxicity," Dr. Winther said.

"How to select patients who will benefit from treatment is still not clear," she said. "The geriatric screening tools used in the NORDIC9 trial did not provide clinically meaningful additional information in this patient group."

Dr. Winther added, "We plan to evaluate quality of life and analyses on biomarkers from the NORDIC9 trial."

"Given the results of NORDIC9, reduced-dose S-1 plus oxaliplatin has become an attractive option for older patients with metastatic colorectal cancer," writes Dr. Julien Taieb of Sorbonne Paris Cite/Universite Paris Descartes, in Paris, in a linked editorial.

"However," he adds, "S-1 is not available in many countries, especially in Europe, which could limit the impact of these results in the future.

Moreover, the superiority of S-1 over standard infusional fluorouracil has not been proven in patients with metastatic colorectal cancer in western countries. And the idea of using reduced-dose infusional fluorouracil combined with oxaliplatin or even irinotecan should also be explored."

"The good outcomes observed with the addition of oxaliplatin and bevacizumab to a fluoropyrimidine-based chemotherapeutic regimen in older patients with metastatic colorectal cancer should now motivate academic groups to design an ambitious, international, and sufficiently powered randomized controlled trial in patients older than 75 years of age with documented vulnerability as an inclusion criterion, with a view to improving the poor overall survival constantly reported in this patient population," the editorial concludes.

Dr. Jung Han Kim from Hallym University College of Medicine in Seoul, who was not involved in the research, has reviewed the use of targeted therapies in older patients with metastatic CRC. He told Reuters Health by email, "Reduced dose intensity can be considered in old and fragile patients. The decision should depend on the individual's features and the physician's experience."

Taiho Pharmaceuticals and Nordic Group partially funded the study and had various relationships with five of the 13 authors.


Lancet Gastroenterol Hepatol 2019.

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