The anti-tumour effect of cisplatin and ifosfamide on xenografted squamous cell carcinoma of the head and neck is schedule-dependent

The role of chemotherapy (CHX) in squamous cell carcinoma of the head and neck (SCCHN) has been expanding. Although combination chemotherapy regimens regularly produce significantly high response rates, meta-analyses show little benefit regarding final outcome. One way to improve induction CHX is to improve drug combinations and schedules for CHX. Cisplatin (CDDP) is one of the most active drugs in the treatment of patients with SCCHN, and it is used in most combinations. Ifosfamide (IFO) is another agent that has shown activity in the treatment of patients with SCCHN. A poorly differentiated squamous cell carcinoma xenografted to nude mice was used. CDDP (2.5 mg/kg) and IFO (100 mg/kg) as single bolus doses induced significant retardation of tumour growth. Single drug administration was compared with CDDP given before IFO and IFO given before CDDP. Mean specific growth delay (SGD) for untreated controls was 0. For CDDP as single drug it was 1.50, for IFO as single drug it was 0.79, for CDDP given 4 h before IFO it was 1.79, and for IFO given 4 h before CDDP it was 2.90. Maximum toxicity, calculated as change in median weight at day 7, was less than 10%. The efficacy and toxicity of CDDP and IFO is schedule-dependent, with IFO given before CDDP being more effective than CDDP given before IFO. This is in contrast to most schedules used clinically. The toxicities were comparable. The number of combinations of drugs with respect to order and time interval is of a magnitude that would not be possible to test clinically. In the pursuit of more efficient combinations, the importance of order and schedule of drugs and also the potential of xenografted SSCHN are underestimated.