Dose-dense chemotherapy for breast cancer: the story so far
This issue of the British Journal of Cance r contains two related papers addressing the feasibility of increasing the intensity adjuvant chemotherapy by increasing the frequency of adminis tion. This approach, called ‘dose-dense’ treatment, is predic on several related observations and hypotheses. First, fract cell kill has been observed in selected experimental tum models, suggesting that while a single cycle of e ffective cytotoxic chemotherapy may not be curative, multiple cycles should be if cells are drug-sensitive and the duration is adequate (Skip r, 1971). Secondl y, the dose-to-response relationship for some of most active drugs against breast cancer may not rise contin but instead appears to reach a plateau in the higher end o normal dose range (Fisher et al, 1997, 1999; Henderson e 1998). Thirdl y, prior adjuvant treatment with some drugs does preclude the possibility of a response upon retreatment, sugge that we are not eliminating all sensitive cells when we u currently available standard agents and regimens ( Valagussa et al, 1986). Fourthl y, tumour regrowth may be particularly rapid whe the number of viable cells is at its lowest because of Gompertzian shape of the growth curve (Norton et al, 197 Hence, cell cycle-specific agents might be most useful if app quickly after a prior treatment when the cells are dividing m rapidly. In addition, this growth pattern is consistent with t observed results of adjuvant therapy trials in terms of their mo impact on outcome and also with the possibility that conventio chemotherapy renders patients much closer to complete cure it might otherwise seem. Dose-density is a relative concept. A regimen standing al cannot really be said to be dose-dense except in compariso another treatment plan. Treatment with a fixed dose of drug ‘D every 2 weeks is therefore more dose-dense than the same dose given for the same number of cycles at 3-week interval contrast, ‘dose-intensity’ is a mathematic transformation wh takes into account not only dose size but also the relative valu individual drugs and the total duration of treatment. Howeve r, it specifically does not account for frequency of administration a assumes, for example, that drug ‘D’ given at dose ‘X’ once eve weeks has the same e ffect as when it is given at 1/4X weekly fo four weeks doses. In both cases the dose-intensity calculate 1/4X per week but the real biological e ffect could be quite different, particularly if 1/4X is as cytotoxic as X. Indeed, t observations and hypotheses described above predict that ev dose X is four times more e ff ctive than 1/4X, it may have a lesse