While it would seem obvious that dose intensity is an important determinant of treatment outcome in aggressive lymphomas, actually there are very few prospective data to support this hypothesis. Circumstantial evidence derived from retrospective analyses suggests that dose intensity is of clinical significance. However, based on available phase II and III data and the one prospective randomized trial to date that has specificially addressed this issue, it remains unclear what impact dose intensity has on treatment outcome.
While it would appear to be intuitively obvious that dose intensity is an important determinant of treatment outcome in aggressive lymphomas, actually very few prospective data support this hypothesis. There is, however, considerable circumstantial evidence that dose intensity may be an important variable in treatment outcome. Unfortunately, this is not adequate to prove the hypothesis.
DeVita et al were among the first investigators to discuss the relationship of dose intensity to lymphoma treatment outcome . These investigators proposed a model to relate the projected relative dose intensities of nine drugs (as defined by a treatment protocol) to the outcome realized by using various other regimens that incorporated some or all of these agents. Using this model, they demonstrated a significant correlation between dose intensity and treatment outcome. Problems inherent in a model such as this, which uses projected dose intensity, include the following:
- Generally, all agents are considered to be equally effective.
- There is no way to take into account possible effects related to drug scheduling.
- The projected dose intensity is usually not fully delivered.
Several authors have attempted to analyze the contribution of dose intensity to outcome in retrospective analyses of completed trials. In a preliminary analysis of results obtained with M-BACOD and m-BACOD (both regimens employing methotrexate [in different doses], bleomycin, Adriamycin, cyclosphophamide, Oncovin, and dexamethasone), Shipp et al reported that delivery of more than 80% of projected doses of doxorubicin, vincristine, and cyclophosphamide (Cytoxan, Neosar) was associated with improvement in remission rates and survival . A subsequent analysis noted, however, that in patients who successfully completed eight cycles of therapy, this relationship of received dose intensity and outcome was no longer observed.
The results obtained with the LNH-84 regimen were reported by Coiffier et al . Received dose intensity data were available for 720 of 737 patients treated. While the authors were unable to show statistically significant differences in outcome, they did demonstrate a trend toward a lower relapse rate in those receiving higher dose-intense therapy. It should also be noted that a trend toward a higher death rate also was seen in this same group of patients.
Epelbaum et al analyzed a series of 78 patients with diffuse large-cell lymphoma treated with the CHOP (cyclophosphamide, doxorubicin HCl, Oncovin, and prednisone) regimen to ascertain the contribution, if any, of dose intensity to outcome . These authors were able to demonstrate a statistically significant association between survival and the received dose intensity of doxorubicin.
Kwak et al reported results of a multivariate analysis of 115 patients with diffuse large-cell lymphoma treated with three different chemotherapy regimens: CHOP, M-BACOD, and MACOP-B (methotrexate, Adriamycin, cyclophosphamide, Oncovin, prednisone, and bleomycin) at different periods of time . Similar survival curves were noted for each of the three regimens. However, the authors did observe a correlation between average relative dose intensity and the received dose intensities of doxorubicin and cyclophosphamide and survival. Using the statistical technique of recursive partitioning, the authors found that after pretreatment hemoglobin, the dose intensity of doxorubicin proved to be the most discriminating prognostic variable.
The technique of meta-analysis also has been employed in an attempt to define the relationship between dose intensity and treatment outcome. Meyer et al performed a meta-analysis on pooled data from 22 studies, of which 14 were randomized trials . High- and low-intensity treatment groups within the 14 trials, which included 2,366 patients, were pooled and compared.
The results of the analysis demonstrated that the relative probability of achieving a complete response was 1.34 in favor of the pooled arm of high dose intensity. Unfortunately, because of the variable length of follow-up, long-term disease-free survival, which is a more meaningful measure of treatment outcome than is complete remission rate, could not be compared in the analysis. The authors correctly point out that any conclusions drawn from this analysis must be accepted with caution because the groups are heterogeneous, the treatments are varied, and considerable assumptions are made at the outset in the performance of such an analysis.
Hence, whereas these retrospective analyses have, in some cases, suggested a correlation between dose intensity and outcome, they do have to be interpreted cautiously, in large part, because they are retrospective. Although there is circumstantial evidence that dose intensity may be an important predictor of outcome, there is very little direct evidence available from prospective studies. Four of the regimens in the model proposed by DeVita-m-BACOD, ProMACE/CytaBOM (prednisone, methotrexate, Adriamycin, cyclophosphamide, etoposide, cytarabine, Oncovin, and methotrexate) ProMACE-MOPP (prednisone, methotrexate, Adriamycin, cyclophosphamide, etoposide, mechloroethamine, Oncovin, procarbazine, and prednisone) and MACOP-B-have greater projected dose intensity than CHOP. These regimens have been studied extensively in clinical trials.
In this review, we will focus on results obtained in phase II and III studies employing these regimens. It should be noted that, in many of the earlier phase II studies, received dose intensity data was not reported, and thus, the database is incomplete. It should also be noted that none of the phase III studies we will review that employed these four regimens or CHOP were prospectively stratified by dose intensity. Finally, we will review the single prospective phase III study that has directly tested the question of dose intensity and has been reported in the literature. Key terms that will be used in this article are defined in Table 1.
M-BACOD is a regimen that was developed and piloted at the Dana-Farber Cancer Institute . The regimen employs high-dose methotrexate with leucovorin rescue given at mid-cycle, that is, at the time of maximal bone marrow suppression secondary to the myelotoxic drugs that are given at the beginning of the cycle (see Table 2). Although this regimen proved to be effective and appeared to be a significant improvement over prior chemotherapy regimens, it was also costly and required hospitalization.
The m-BACOD regimen, which employs moderate-dose methotrexate (see Table 2), was therefore piloted by the same group, and results similar to those seen with the high-dose regimen were achieved . Of the 134 patients with diffuse histiocytic or undifferentiated lymphoma who were treated, 75% had either stage III or IV disease. The median age of the treated patients was 49 years. Eighty-two patients (62%) achieved a complete response and 62 (76%) of these remain in complete remission with a median follow-up of 3.6 years. The predicted 1-, 3-, and 5-year survival rates were 80%, 63%, and 60% respectively. The disease-free survival rate at 5 years for patients achieving a complete response was 74%.
As noted above, in a preliminary analysis of the data, Shipp et al noted a correlation between dose intensity and outcome. This correlation, however, was no longer found to be of importance when patients completing eight cycles of therapy were analyzed.
The Southwest Oncology Group (SWOG) conducted a confirmatory phase II trial of the m-BACOD regimen . By study design, patients were stratified at registration as having either normal or impaired bone marrow reserve. Of the 106 eligible patients, 28 were in the impaired category and received decreased doses of cyclophosphamide and doxorubicin. In the study population as a whole, 76% had diffuse large-cell lymphoma, 75% had stage III or IV disease, and 46% had B symptoms.
The overall complete response rate was 56%. There was, however, a marked difference in complete response rates in the normal and marrow-impaired groups. At 3 years, 64% of the normal marrow group who achieved a complete response were disease-free, as compared with 29% in the marrow-impaired group. It should be noted that despite decreased dosages, the marrow-impaired group experienced toxicity similar to those treated with full-dose therapy.
The relative dose intensity on the normal marrow reserve arm was .76 for cyclophosphamide, .75 for doxorubicin, .90 for vincristine, .85 for dexa-methasone, and .55 for methotrexate. On the impaired-marrow reserve arm, as would be expected, the values for all drugs were lower. In addition to being given decreased doses of cyclophosphamide and doxorubicin by study design, patients with marrow impairment also had more dose reductions and treatment delays, as compared to patients with normal marrow reserve.
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