INTENSIFICATION OF CHEMOTHERAPY FOR THE TREATMENT OF SOLID TUMORS - FEASIBILITY OF A 3-FOLD INCREASE IN DOSE INTENSITY WITH PERIPHERAL-BLOOD PROGENITOR CELLS AND GRANULOCYTE-COLONY-STIMULATING FACTOR

Dose intensity may be an important determinant of the outcome in cance r chemotherapy, but is often limited by cumulative haematological toxi city. The availability of haematopoietic growth factors such as granul ocyte colony-stimulating factor (G-CSF) and of peripheral blood progen itor cell (PBPC) transplantation has allowed the development of a new treatment strategy in which several courses of high-dose combination c hemotherapy are administered for the treatment of solid tumours. PBPCs were mobilised before chemotherapy using 12 or 30 mu g kg(-1) day(-1) G-CSF (Filgrastim) for 10 days, and were collected by 2-5 leucapheres es. The yields of mononuclear cells, colony-forming units and CD34-pos itive cells were similar at the two dose levels of Filgrastim, and the numbers of PBPCs were sufficient for rescue following multiple cycles of chemotherapy. High-dose chemotherapy (cyclophosphamide 2.5 g m(-2) for 2 days, etoposide 300 mg m(-2) for 3 days and cisplatin 50 mg m(- 2) for 3 days) was administered sequentially for a median of three cyc les (range 1-4) to ten patients. Following the 30 evaluable cycles, th e median duration of leucopenia less than or equal to 0.5 x 10(9) l(-1 ) and less than or equal to 1.0 x 10(9) l(-1) was 7 and 8 days respect ively. The median time of thrombopenia less than or equal to 20 x 10(9 ) l(-1) was 6 days. There was no cumulative haematological toxicity. T he duration of leucopenia, but not of thrombopenia, was inversely rela ted to the number of reinfused CFU-GM (granulocyte-macrophage colony-f orming units). In the majority of patients, neurotoxicity and ototoxic ity became dose limiting after three cycles of therapy. However, the a verage dose intensity delivered was about three times higher than in a standard regimen. The complete response rate in patients with small-c ell lung cancers was 66% (95% CI 30-92%) and the median progression-fr ee survival and overall survival were 13 months and 17 months respecti vely. These results are encouraging and should be compared, in a rando mised fashion, with standard dose chemotherapy.