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The Oncologist, Vol. 3, No. 5, 365-368, October 1998
© 1998 AlphaMed Press

Physician Education

The Importance of Planned Dose of Chemotherapy on Time: Do We Need to Change Our Clinical Practice?

MaryAnn Foote

Amgen Inc., Thousand Oaks, California, USA

Correspondence: MaryAnn Foote, Ph.D., Medical Writing Department, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA. Telephone: 805-447-4925; Fax: 805-498-5593; e-mail: mfoote{at}amgen.com


   Introduction
Top
 Introduction
The Concept of Dose...
 The Effect of Dose...
 References
 
Dose-limiting hematological toxicity is encountered with many chemotherapy regimens; it is common clinical practice to reduce the dosage or delay the administration of the next cycle of chemotherapy in response to toxicity [1, 2]. Reducing or delaying the dose, however, will reduce the dose intensity of treatment. This practice may achieve some reduction in toxicity, but may also decrease the therapeutic effect of the treatment. This review will examine the evidence for a relationship between reductions in dose intensity of treatment and suboptimal outcome, as distinct from studies seeking to improve survival by using dose-intensified chemotherapy regimens.


   The Concept of Dose Intensity
Top
 Introduction
 The Concept of Dose...
The Effect of Dose...
 References
 
Curative treatment of most tumor types is based on the administration of multiple cycles of intensively dosed chemotherapy. These principles are derived from in vitro studies in experimental tumor cell lines, animal xenograft models, and mathematical modeling of the tumor response. The classic experiments of Skipper's group with tumor models demonstrated two important findings: first, that some cytotoxic agents have a steep dose-response curve; and second, that there is a logarithmic relationship between drug dose and tumor cell kill, which equates to increased potential for cure of smaller tumor burdens [3]. The logarithmic cell-kill relationship is based on the exponential tumor cell growth of animal models, but most human tumors do not share these first-order kinetics. The growth of human tumors is better modeled by "Gompertzian" kinetics. In simple terms, this means that the proportion of cells killed is greater when the number of cells present is low, but also that the tumor regrowth is more rapid when cell numbers decrease. Mathematical modeling of tumor cell kill and regrowth based on Gompertzian kinetics and validated by clinical data has been elegantly proposed by Norton to show the effect of varying the dose and intensity of cytoreductive agents (Fig. 1Go) [4]. The model can also be viewed as an illustration of the consequences of chemotherapy dose reduction and delay. A further important observation from animal tumor models illustrates an effect of dosage reduction that is potentially relevant to the clinical effects of suboptimal dose intensity. In the Ridgeway osteosarcoma model in rodents [5], a reduction in dose intensity of cyclophosphamide and melphalan decreased the cure rate without affecting the rate of complete remission. An approximately 25% reduction in dose intensity had no effect on the 100% remission rate, but the cure rate fell from 60% to 10%. While animals can never model perfectly the human situation, the clinical message from this would be that apparently satisfactory results in the short term after ad hoc dosage adjustment may be obscuring a loss of long-term survival for the patient.



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  		Figure 1. Effect of chemotherapy dose intensity and density on tumor cell kill and regrowth between cycles. Used with permission from [4].

 
Dose intensity is a function of dose and frequency of administration. Hryniuk and colleagues defined dose intensity as the amount of drug delivered per unit of time (mg/m2/week), and applied it retrospectively to show a clear relationship between dose intensity and outcome in patients with breast cancer, from various clinical data using differing doses, schedules, and cycles of chemotherapy in both adjuvant and metastatic settings [6, 7]. They also proposed the concept of relative dose intensity (RDI), in which the amount of drug administered per unit of time is expressed as the fraction of that used in the standard regimen [8].

Hryniuk's demonstration of the steep dose-response relationship in breast cancer provided the impetus for many subsequent clinical studies, particularly with dose-intensified chemotherapy regimens for breast cancer. This work, however, has been criticized for its several limitations, including the equal weighting of different drugs in the chemotherapy regimen, failure to take into account the importance of schedule effects, and the assumption that doses of drugs with different mechanisms of action combine to give linear increases in drug kill [9]. More recently, Hryniuk has described a single scale for comparing dose intensity of all breast cancer chemotherapy regimens, known as summation dose intensity (SDI). This is based on unit dose intensity ([UDI]; the dose of each drug required to achieve a 30% complete or partial remission rate). Within each treatment regimen, the dose intensity of each drug is divided by its UDI and these fractions are summed to derive the SDI of a particular treatment arm. Using historical data, a significant correlation between SDI and survival was demonstrated in the adjuvant and metastatic breast cancer settings. In the adjuvant studies, for example, relapse-free survival rates were significantly increased when the SDI increases >=0.65 units [10].

Despite the fact that chemotherapy dose reduction and delay feature routinely in clinical trial protocols, it is only in recent years that RDIs or received dose intensities have begun to be commonly reported as part of clinical trials. When assessing the effectiveness of a particular protocol, it is essential to know the influence of dose reductions and delays by using a variable such as RDI, to judge if the trial is a valid comparison of the specified regimens or if suboptimal doses have been administered.


   The Effect of Dose Intensity on Outcome
Top
 Introduction
 The Concept of Dose...
 The Effect of Dose...
References
 
Dose intensity has been shown to correlate with outcome in prospective clinical studies in various tumor types, including breast cancer [11, 12], ovarian cancer [13], and adult acute myeloid leukemia [14]. The dose intensity-response relationship has also been observed in retrospective analyses, for example, in breast cancer [15], small cell lung cancer [16], ovarian cancer [17], and lymphomas [18].

Breast Cancer
One of the most striking examples of the effect of suboptimal doses on outcome was demonstrated in Bonadonna's study in patients with breast cancer receiving 12 cycles of adjuvant CMF (cyclophosphamide, methotrexate, 5-fluorouracil [5-FU]) chemotherapy [15, 19, 20]. Adjuvant chemotherapy was compared with surgery alone, and dose reduction was used routinely in the case of toxicity or for older patients. Over a 20-year follow-up, patients receiving <85% of the intended dose had a markedly poorer survival (Fig. 2Go) [20]. The effect in clinical practice may be more pronounced; it has been estimated that the CMF regimen is used in the community at about half the dose intensity originally shown to be effective [2]. Since the publication of the Bonadonna study in 1976, many attempts have been made to modify the classical dosage and schedule of the CMF regimen using a variety of strategies which result in a lower dose intensity. In a recent review of this subject, Goldhirsch observed that such strategies had provided inferior results in both the adjuvant setting and in metastatic breast cancer, and concluded with a recommendation for adherence to the classical dose and schedule [21].



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  		Figure 2. Adjuvant CMF in node-positive breast cancer: suboptimal doses were associated with poorer outcome. Used with permission from [20].

 
Bonadonna's observations of reduced survival with suboptimal dosing of adjuvant chemotherapy in breast cancer have been confirmed in a randomized controlled trial. Wood et al. [12] reported on a large study (CALGB 8541) that prospectively examined the effect on outcome of three different dose intensities of adjuvant chemotherapy with CAF (cyclophosphamide, doxorubicin, and 5-FU) in 1,572 women with breast cancer. Both disease-free and overall survival were longer in women receiving a higher dose of CAF at high or moderate intensities than in women treated with a lower dose at a low intensity (Fig. 3Go). Reducing dose by 50% resulted in an 11% decrease in three-year disease-free survival. Although this study has been widely cited in support of escalating dose intensities, the doses evaluated were within the conventional range and it is probably more appropriate as a comparison of standard and "suboptimal" dose intensities, with clear evidence of a reduced benefit if chemotherapy doses are reduced from those that have been shown to improve outcome in large clinical trials in breast cancer.



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  		Figure 3. Improved survival with moderate and high-intensity adjuvant CAF (cyclophosphamide, doxorubicin, fluorouracil) in 1,572 women with node-positive, stage II breast cancer. Used with permission from [12].

 
Lymphomas
Lepage [18] observed a statistically significant difference in survival of patients with non-Hodgkin's lymphoma (NHL) according to received RDI of an ACVB (doxorubicin, cyclophosphamide, vindesine, bleomycin, methylprednisolone, methotrexate) induction chemotherapy regimen, using 70% RDI as the threshold value. In this study, the reduction in RDI was accounted for by treatment delays due to toxicity, as specified by the protocol, rather than dose reductions. This clear-cut effect of dose intensity was not observed in the SWOG/ECOG study that failed to show any advantage for three intensive chemotherapy regimens (m-BACOD [methotrexate with leucovorin rescue, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone], ProMACE-CytaBOM [prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, and methotrexate with leucovorin rescue], and MACOP-B [methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin]) over conventional CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) [22] in patients with advanced NHL. It is possible that these "intensive" regimens, by incorporating more drugs, actually resulted in reduced dose intensity of the two most important agents, doxorubicin and cyclophosphamide [23, 24]. However, as in breast cancer, where intensified chemotherapy has not always provided the expected benefit [25, 26], it appears easier to demonstrate that "less is worse," while more is sometimes (but not always) better.

In summary, when chemotherapy is being given with curative intent, we believe that it is important to avoid reductions and delays in chemotherapy if the best possible outcome is to be achieved, although this is not possible for all patients.


   References
Top
 Introduction
 The Concept of Dose...
 The Effect of Dose...
 References
 

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