An analysis of chemotherapy dose and dose-intensity in small-cell lung cancer: lessons to be drawn.
BACKGROUND
The survival in untreated small-cell lung cancer (SCLC) is <3 months. Prognosis has improved with chemotherapy, but remains poor. One of the issues concerning current chemotherapy is whether there is any benefit of increasing chemotherapy dose or dose intensity (DI).


METHODS
In the present review, 20 randomised studies, published in the period 1980-2001, in which dose or DI of chemotherapy in SCLC were the only variables tested, are analysed. The studies were categorised as follows: (i) number of cycles (treatment duration); (ii) dose per cycle; (iii) interval between cycles (dose densification); and (iv) a combination of these variables.


RESULTS
(i) With treatment duration reduced to three to six cycles, median survival time (MST) was 2 months shorter, most evident in patients showing a (complete) response to initial chemotherapy. (ii) An improved survival was observed in two out of five high-dose studies. (iii) Survival was increased by 0.6 to 6.2 months in all four densification studies. (iv) Survival was not improved in studies that used dose-escalation and/or -densification in combination with a reduced number of cycles. The sample sizes were too small to be conclusive in most of the individual trials. The median of the MSTs in the 20 trials taken together was 9.8 months for the standard arms and 11.5 months for the intensified arms (i.e. more cycles, higher dose per cycle and/or shorter intervals). After omitting the two trials with reduced number of cycles in the so-called 'high-dose' arm, the median of MSTs was 8.7 and 11.5 months, respectively. There was only a slight improvement (1%) in 2-year survival for all trials taken together. However, when only taking high-dose and dose-densified chemotherapy trials into account, the difference in median 2-year survival became 19% (12% versus 31%).


CONCLUSIONS
The above classification facilitates our understanding about doses of chemotherapy and it makes us appreciate the relevance of the individual determinants. It appears that the number of cycles, dose level, dose density, cumulative dose and DI are all important factors for improving survival. Intensification of chemotherapy still deserves further research in SCLC.
Tjan-Heijnen
V C G
VC
University Medical Center Nijmegen, Department of Medical Oncology, The Netherlands. V.Tjan@onco.azn.nl
Wagener
D J T
DJ
Postmus
P E
PE
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000627:therapeutic use*; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D013534:Survival; D016896:Treatment Outcome