Dose intensity in cancer chemotherapy

Abstract

There is substantial evidence that, for the majority of antitumour agents including alkylating agents, anthracycline antibiotics and anti-metabolites, there is a steep dose response curve when these agents are studied in in vitro and in vivo models (Griswold et al., 1963;Bruce et al., 1966;Schabel et al., 1984). It is this dose-response relationship which is often cited in support of high dose chemotherapy with autologous bone marrow rescue as a promising avenue for the treatment of solid tumours. The purpose of this review is to assess the evidence that dose and dose intensity are important determinants of outcome in the treatment of human cancer with cytotoxic chemotherapy. We will review retrospective and prospective studies of dose and dose intensity in a variety of tumour types, and discuss how future clinical studies may be planned and presented to provide a more informed therapeutic rationale for exposing patients to greater doses of cytotoxic drugs in an attempt to improve outcome. Retrospective dose intensity analysis Breast cancerIn 1984 Hryniuk and Bush analysed the complete and partial remission rates and median survival times of 26 published studies using CMF-type regimens in the treatment of advanced breast cancer. For each regimen they also calculated the average relative dose intensity in the following way.The doses of cyclophosphamide, methotrexate and 5-fluorouracil were converted to a standard form of mg m2 per week. The dose intensities of each agent were compared to the dose intensity of a regimen used by Cooper (1969). The dose intensities of the test regimen were expressed as a fraction of the intensities of each drug in the Cooper protocol. The relative dose intensities for each drug in an individual CMF regimen were then averaged to give the average relative dose intensity (ARDI) of CMF-containing therapy for that particular 'test' regimen. They found a linear relationship between response rate and ARDI (Figure 1). The relationship was even more clearcut when doses actually delivered to patients, rather than planned protocol doses, were used to calculate ARDI (Figure 1).When the ARDI of a variety of CAF (cyclophosphamide, doxorubicin and 5-fluorouracil) regimens were calculated in the same way and expressed as a fraction of the ARDI of a dose intensive 'reference' regimen used by Bull and Tormey (1978) again there was a clear positive correlation between ARDI and response rate and again the relationship was clearer when delivered, rather than planned, doses were used. Hryniuk and Bush also extended their observations to median survival time. The median survival time (MST) (of all patients) and the remission rates in these studies (CMF and CAF)

Chemotherapy-induced neutropenia as a prognostic factor in patients with unresectable pancreatic cancer

“…Factors involving blood tests were examined immediately prior to chemotherapy. The relative dose intensity (RDI) of GEM was calculated according to the method described by Dodwell et al [24].…”

A phase II study of weekly high-dose cisplatin combined with oral etoposide in advanced non-small-cell lung cancer

“…Studies analyzing the results obtained in locally advanced disease separately report even higher response rates of up to 69% in this subset of patients [39]. Retrospective analyses of several tumor types have suggested that the dose intensity of chemotherapy may be important [8,20]. However, the results of prospective randomized studies addressing cisplatin dose intensity in NSCLC are inconclusive.…”

Dose Intensity Phase l/lI Trial with Carboplatin, Ifosfamide, Etoposide and Vincristine Combined with Filgrastim in Patients with Small-Cell Lung Cancer

“…It is tempting to speculate that the increase in dose intensity has contrib uted to the conversion of partial into complete remis sions. A number of retrospective studies of different types of tumor and SCLC has demonstrated that dose intensity is significantly correlated with the clinical outcome [33,41], Also, accelerated weekly chemotherapy may result in a prolongation of survival as recently described by Miles et al [42] and Murray et al [18], In a recent prospective randomized trial by Woll et al [43] patients received VICE chemotherapy with or without G-CSF support. No treatment intervals were defined and retreatment was based on WBC and platelet recovery.…”

“…Although no optimal regimen has been identified combinations containing cisplatin, carboplatin, etoposide, doxorubicin, or ifosfamide have been demon- (18)(19)(20)(21)(22)(23)(24)(25)(26)(27) 20 All cycles 28 (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41) 23 (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37) 21 (20)(21)(22)(23)(24)(25)(26)(27)…”