Temozolomide is a rapidly absorbed chemotherapeutic agent, achieving significant central nervous system penetration. Previous clinical trials suggested that temozolomide in sequence with low-dose recombinant human interleukin-2 might be an efficacious and relatively non-toxic chemo-immunotherapeutic treatment, which may synergistically eliminate tumours. The primary objective was to determine the safety and tolerance of temozolomide administered orally 200 mg/m2 days 1–5, in sequential combination with subcutaneous injections of 4.5×106 IU recombinant human interleukin-2 on days 8–11, 15–18 and 22–25 in patients with measurable, progressive metastatic malignant melanoma without radiological signs of central nervous system metastases. The secondary objectives were to determine tumour response and time to progression. Twenty-seven patients were included, of which four were non-evaluable for response. Twenty-three patients tolerated the regimen with side effects below grade 3 according to the World Health Organization (WHO) scale. Three patients suspended the treatment because of WHO grade 3 side effects already during the first 3 days of the first course of temozolomide. Seven patients showed no tumour progression during the first four treatment cycles. Two patients had complete responses, three partial responses and two stable disease at the end of the four cycles defined by the protocol and they continued the treatment until signs of relapse or a maximum of 21 courses. Five of these patients are still alive. Thrombocytopenia was significantly more pronounced in patients with objective response and stable disease than in non-responders to therapy. The median time to progression for all patients was 3.1 months and for responding and stable disease patients was 15 months. Five of 23 treated patients (22%) developed brain metastases during follow-up. Temozolomide in combination with recombinant human interleukin-2 is a well-tolerated regimen for outpatient treatment and the bio-chemotherapy combination induced durable clinical responses. Thrombocytopenia might be a positive predictive factor for response to therapy.
aDepartment of Oncology–Pathology, Karolinska Institute and Karolinska University Hospital, Stockholm
bDepartment of Oncology, Uppsala University Hospital, Uppsala, Sweden
Correspondence and requests for reprints to Giuseppe Valentino Masucci, MD, Karolinska Institute, Radiumhemmet, Rum no. P301-057, Karolinska University Hospital, Stockholm SE-17176, Sweden
Tel: +46851776010; e-mail: firstname.lastname@example.org
Sponsorship: This trial was academically initiated and was partly supported by grants from the Cancer Society in Stockholm and the King Gustaf V Jubilee Fund. This study was also supported by grants from the Swedish Cancer Society.
Conflict of interest statement: All authors disclose no financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work.
Received 12 December 2005 Accepted 22 February 2006