Dose and Dose-Intensity Influence Outcome of Adjuvant Breast Cancer Treatment

ABSTRACT & COMMENTARY

Synopsis: Cancer and Leukemia Group B study 8541 examined the influence of total dose and dose intensity of adjuvant chemotherapy in 1550 women with stage II breast cancer after primary surgical treatment. Patients were randomly assigned to a high-dose, moderate-dose, and low-dose of chemotherapy; the high-dose arm had twice the total dose of drugs and twice the dose-intensity of the low-dose arm, and the moderate-dose arm had two-thirds the dose-intensity and the same total dose as the high-dose arm. The disease-free and overall survival were similar on the moderate- and high-dose arms and were significantly better than that seen on the low-dose arm. Thus, total dose of adjuvant therapy influences treatment outcome. Higher dose intensities of therapy are more toxic but not necessarily more effective.

Source: Budman DR, et al. Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. J Natl Cancer Inst 1998;90:1205-1211.

Adjuvant chemotherapy improves the survival of women with operable breast cancer. Controlled studies have demonstrated that six months of therapy is as effective as twelve months of therapy. However, the role of the dose-intensity of the therapy has not been demonstrated consistently. The International (Ludwig) Breast Cancer Study Group Trial I demonstrated no significant differences in disease-free or overall survival in patients treated with cyclophosphamide, methotrexate, 5-fluorouracil (CMF), or CMF plus prednisone (CMFP), even though the CMFP arm patients received a higher dose intensity.1 Similarly, National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-22 employed a higher dose of cyclophosphamide together with doxorubicin and found no improvement over patients receiving standard dose cyclophosphamide plus doxorubicin.2 On the other hand, Cancer and Leukemia Group B study 8541 seemed to show some benefit from higher dose or higher dose-intensity therapy.3 However, the study was criticized for being reported early (median follow-up 3.4 years). CALGB has recently updated the results of this study with a median follow-up of nine years.

CALGB 8541 enrolled 1550 analyzable patients with stage II breast cancer. Patients were randomly assigned to one of three adjuvant therapy arms: a low-dose arm (518 patients), a moderate-dose arm (513), and a high-dose arm (519). (See Table.) The moderate- and high-dose arms involved delivery of the same total dose of the agents but with different dose-intensities. The low-dose arm delivered half the dose and dose intensity of the high-dose arm. No dose modifications were made for hematologic toxicity. Post-menopausal patients with estrogen receptor-positive tumors received estrogen for five years following the adjuvant chemotherapy.

Table

Doses of agents on CALGB 8541

Low-dose
Moderate-dose
High-dose
Cyclophosphamide (mg/m2 day 1)
300
400
600
Doxorubicin (mg/m2 day 1)
30
40
60
5-Fluorouracil (mg/m2 days 1,8)
300
400
600
4 cycles
6 cycles
4 cycles

Grade 3 or 4 hematologic toxicity was noted in 4% of the patients on the low-dose arm, 17% of patients on the moderate-dose arm, and 66% of patients on the high-dose arm. Two toxic deaths were noted, one on the low-dose arm and one on the high-dose arm. Overall survival and disease-free survival were similar on the moderate- and high-dose arms, and both were superior to those on the low-dose arm (P = 0.0034 for survival, P < 0.001 for disease-free survival). Overall, five-year survival on the three arms was 72% for low-dose, 77% for moderate-dose, and 78% for high-dose. Disease-free survival at five years was 56% for low-dose, 61% for moderate-dose, and 66% for high-dose. Those patients who relapsed had a median survival of 22 months regardless of which arm of adjuvant therapy they received. Patients with four or more positive nodes had a greater reduction in relapse on the high- and moderate-dose arms than did patients with 1-3 positive nodes, but both groups benefited from treatment. The benefit was mainly observed in the first five years after diagnosis. After five years, the relapse rates appear similar in all three arms of the study.

In multivariate analysis, in addition to known prognostic factors such as the number of positive nodes, tumor size, menopausal status, and estrogen receptor status, the chemotherapy dose was a significant prognostic factor.

COMMENTARY

The major benefits of adjuvant therapy are related to a reduction in the recurrence rate within the first five years after diagnosis. After five years, recurrence rates are significantly lower and are roughly comparable for the various risk groups. In other words, if one can get a patient with high-risk disease through the first five years without relapsing, her subsequent relapse risk is comparable to women who had a low risk of recurrence at diagnosis.

Furthermore, it appears that the total dose and/or the dose-intensity of the adjuvant therapy matters. Given that the moderate- and high-dose arms on this study were similar in tumor-related outcomes and the moderate-dose arm was less toxic, it would appear that the moderate-dose arm would get the nod as the best arm. As adjuvant regimens are altered to include new more active agents, such as paclitaxel, it is clear that questions related to total dose will need to be revisited. However, low-dose therapy is not as effective and should be avoided.

References

    1. Castiglione-Gertsch M, et al. Ann Oncol 1994;5: 717-724.

    2. Dimitrov N, et al. Proc Am Soc Clin Oncol 1994;13: A58.