Dr. Komatsu indicated that the current first-time chemotherapy regimen for inoperable CRC is multiple drug therapy that includes the use of CPT-11 or the cytotoxic platinum derivative oxaliplatin. However, as he detailed for the new oral fluorinated pyrimidine anticancer agent that they used, "S-1 has been shown to be effective for gastric cancer in Japan, and last year S-1 was reported to be effective against colon cancer." Indeed, S-1 has shown considerable efficacy in patients with CRC, achieving a single agent response rate of 39.5%.

Therefore, Dr. Komatsu and colleagues conducted a study to determine the effectiveness, safety and adverse effects of a regimen combining CPT-11 and S-1. The eligibility criteria for entrance included histologically confirmed CRC with no previous chemotherapy or radiotherapy, age 75 years or older, adequate bone marrow, heart, liver and renal function, and no other active malignancies or severe medical problems.

The 19 men and 13 women had a median age of 62 years.

The combination treatment schedule included S-1 at fixed daily doses for 14 days; the doses were determined by patient body surface area: <1.25 m², 2x 40 mg/day; 1.25-1.50 m², 2x 50 mg/day; 150 or more m², 2x 60 mg/day. Patients then had 14 days off S-1. CPT-11 was given at 100 mg/m² as 90 min DIV on days 1 and 15. This combination cycle was administered every 4 weeks for a total of 173 cycles across the full patient group, with a median number of cycles per patient of 4 (range, 1-17).

Supportive therapy during these 173 cycles included granulocyte colony-stimulating factor in 4.6% of cycles. Dose reduction was necessary in 13.9% of cycles, arose primarily from the CPT-1 therapy (23/24 patients) and were mainly related to neutropaenia (in 15 cycles), diarrhea (3) and liver dysfunction (2).

There was a range of adverse events seen across all of the 173 cycles administered, which mainly involved nausea (24 patients), alopecia (24), neutropaenia (22), leukocytopaenia (20), anaemia (19) and diarrhea (19), although Dr. Komatsu stressed that this combination therapy demonstrated manageable toxicity.

The resulting 50% overall response rate included no complete responses; all were partial responses (15 patients); a further 13 patients showed stable disease. With this therapy still ongoing in 13 patients, the median survival and progression-free survival have not yet been reached, which demonstrates the high activity of this combination therapy.

Dr. Komatsu stressed that in addition to proving both convenient and highly active for these patients with inoperable advanced CRC, the oral nature of the S-1 administration indicated the potential for outpatient use, thus reducing treatment costs over the more standard catheter-based therapies.


[Study title: Phase 2 Clinical Study of Combination Therapy with CPT-11 and S-1 for Inoperable Recurrent Advanced Colorectal Cancer. Abstract WED-G-134]

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