Adjuvant Therapy of Breast Cancer: Dose-Intensification of Cyclophosphamide is Not Warranted

ABSTRACT & COMMENTARY

Synopsis: Doubling the dose-intensity and total dose of cyclophosphamide did not significantly improve disease-free or overall survival in women undergoing adjuvant chemotherapy for node-positive breast cancer.

Source: Fisher B, et al. J Clin Oncol 1997;15: 1858-1869.

The need to improve the success of adjuvant therapy of breast cancer has been recognized for the past 10 years. While previous manipulations of doses, schedules, and drug combinations appeared to have reached a plateau in benefit, the work of Hryniuk and Bush, and other retrospective studies, suggest that a greater dose-intensity (i.e. the amount of drug given per unit of time) might improve the response rate in women with advanced breast cancer and improve results in the adjuvant setting. Hryniuk and Bush tabulated results from several clinical trials that seemed to show a correlation of benefit with dose-intensity. Other considerations also added to the rationale for the study of dose intensity. For example, many tumors exhibit a substantial dose-response curve in regard to their sensitivity to drugs in vitro, and higher doses of drugs may circumvent resistance mechanisms. (Hryniuk and Bush. J. Clin. Oncol. 1994;2:1282-1289)

The National Surgical Adjuvant Breast Project (NSABP) set out to perform a clinical trial to test this hypothesis. The study was designed to control the doses of a recognized beneficial regimen to ensure an adequate test of the hypothesis. The trial included three arms. Arm One was a conventional regimen of four cycles of doxorubicin and cyclophosphamide at 60 mg/m2 and 600 mg/m2, respectively. Arm Two gave the identical regimen of the doxorubicin, but cyclophosphamide was intensified to 1200 mg/m2 for two cycles while holding the total dose constant. The third arm again held the doxorubicin the same, but the cyclophosphamide was intensified by giving 1200 mg/m2 and increased in total dose by giving it for four cycles. All patients 50 years old or older received 20 mg of tamoxifen a day for five years.

The randomized trial, which began in 1989 and ended in 1991, enrolled 2305 women. Only 2% of the patients were found to have been ineligible. All patients had primary operable breast cancer with at least one positive axillary node. Stratification according to the number of positive nodes (1-3, 4-9 £ 10); age (³ 49 vs ³ 50); ER level (0-9, 10-49, 50-99, and ³ 100 fmoles); and type of surgery (breast conserving vs mastectomy) was balanced in each institution. Approximately 45% of patients had tumors 2.0 cm or larger; 55% had 1-3 positive nodes, and 14% had 10 or more positive nodes; 35% had ER/PR negative tumors. A lumpectomy was performed in 25%.

No dose reductions were allowed for asymptomatic cytopenias, but there was a 25% dose reduction for an episode of granulocytopenic sepsis, and patients with a second episode went off study. Treatment was generally given per protocol, and less than 10% of the patients had any treatment delay. Overall, patients received around 90% of the stipulated doses.

The trial had sufficient power to detect a 7.6% difference in disease-free survival (DFS) and a 6.0% difference in overall survival after five years of follow-up. There was no significant difference in DFS (P = 0.30) among the three groups at five years of follow-up. The DFS was 62% in the standard arm, 60% in the intensified arm, and 64% in the intensified and increased arm. There was no difference in outcome in any of the lymph node subsets or age subsets. ER positive patients did better than ER negative patients, but in no ER category was there a significant difference in annual events among the three treatment groups. The findings for overall survival were even more concordant. Five-year overall survival for patients on the three arms were 78%, 77%, and 77%, respectively. The failure to detect a difference between the treatment groups was observed regardless of whether the analyses were performed using either the protocol-stipulated doses of drugs, or using the doses of drug that were actually received. Interestingly, the five-year overall survival of patients with 10 or more involved lymph nodes was 54-59% in the three groups.

As expected, toxicity tended to increase with dose. While diarrhea, thrombophlebitis, and cardiac disturbances occurred with similar frequency in all groups, severe infection and vomiting were increased in the intensified group and were greater yet in the intensified and increased group. There were four deaths during treatment: one in group 2, and three in group 3.

COMMENTARY

Fisher and colleagues were challenged to design a trial in breast cancer that would address one of the many questions regarding dose-intensity and adjuvant therapy. No single clinical trial can test every hypothesis related to the dose-intensity concept, so Fisher et al had to focus on a single question that could be answered in a standard clinical trial. Fisher et al selected the "60/600" dose level of doxorubicin and cyclophosphamide as the control arm, because the efficacy of the combination has been established in two large clinical trials (NSABP B-15 and B-16). The B-15 study shows that this regimen is as good, or possibly better, than CMF. The investigators chose to intensify the cyclophosphamide dose because it exhibited the steepest dose-response curve in the laboratory.

The current study (NSABP B-22) shows us that moderate increases in the intensity and total dose of CTX do not improve outcomes. In fact, there is nothing in the current study that can be construed as promoting increased dose intensity of cyclophosphamide in the adjuvant treatment of breast cancer. All of the patients in B-22 had positive nodes, and there were no differences between the treatment arms when number of nodes was used to stratify patients. This suggests that higher doses were not superior in higher risk patients, particularly patients with more than 10 positive lymph nodes. There is certainly nothing to suggest that there would be a differential effect in node-negative patients.

There are two other studies that shed light on the impact of dose-intensity on adjuvant therapy of breast cancer. The CALGB has reported a randomized trial of four cycles of CAF (cyclophosphamide 600 mg/m2, doxorubicin 60 mg/m2, and 5-FU 600 [´ 2] mg/m2) vs. the same total doses given over 50% more time (i.e. 6 cycles) vs. half the dose in the same time. The CALGB observed no significant differences between the first two arms and inferior results in the half dose arm. They properly conclude that doses of chemotherapy should not be reduced below limits known to be effective.

One potential criticism of B22 is that Fisher et al did not escalate the dose of cyclophosphamide enough. To address this, the NSABP has conducted another trial (B-25) using the intensified and increased dose arm of B-22 (arm 3) as the standard treatment, and comparing it with two other regimens in which cyclophosphamide dose has been further intensified and increased. This trial required administration of G-CSF and accrued 2580 patients when it was closed in January 1994. Until further information becomes available, we agree with the authors’ conclusions that increasing the total dose of cyclophosphamide is not appropriate in the treatment of women with primary breast cancer.

However, the issue of whether the dose of drugs needs to be pushed further still lingers. Based on the hypothesis-generated graphs of Hryniuk and Bush, one would have expected to see some impact on survival at these dose levels. The results of the B-25 study that pushes cyclophosphamide to maximal levels short of stem cell support will be of interest. In addition, clinical trials boosting the dose of doxorubicin, and others adding paclitaxel and docetaxel to adjuvant treatment regimens, have been activated by NSABP and SWOG, and we await their results.

Further dose escalation will require stem cell support, and this approach is being used in many centers. The same issue of the Journal of Clinical Oncology also contained a report from the North American Bone Marrow Transplant registry, which registered 5886 patients, 1747 of whom had stage II or III disease. The estimated DFS at three years for these women was 60-65%. The DFS for women with 10 nodes or more in the B-22 trial was 33-41% at five years. Doses requiring stem cell support do not have a prima facie advantage over the standard "60/600." Unfortunately, only 11% of the patients who received high-dose therapy requiring stem cell support were treated in randomized clinical trials.

No one is satisfied by a 30% relapse rate in these patients, but this report does not show us an improvement in outcome. However, this excellent clinical trial shows how these improvements can be detected. It starts with a clearly stated hypothesis. Then, we are shown an adequate test of the hypothesis with enrollment of large numbers of patients, followed by a clear presentation of the data and a dispassionate discussion of the results. We hear neither the moaning of tortured data nor the pleading of ex post facto subset analysis. Real progress will come with continued application of this method.