Despite a recent decline in incidence and mortality, breast cancer currently develops in one of eight North American women who live to 85 years of age, and remains the major cause of death in American women between the ages of 15 and 54.[1,2] Data from historical series and the results of cooperative group adjuvant trials from the 1970s and 80s indicate that mortality at 10 years in women who have 10 or more involved lymph nodes or a large primary tumor at presentation exceeds 60%. Virtually all patients who initially present with or later develop metastatic breast cancer ultimately die of their disease.[3,4]
In a large series using standard fluorouracil(Drug information on fluorouracil), Adriamycin, and cyclophosphamide(Drug information on cyclophosphamide) (FAC), 17% of women with metastatic breast cancer responded completely, but only 3% were still in remission at 5 years (and only 1.3% at the time of publication). Only complete responders remained free of disease. Thus, complete response, necessary but not sufficient for long-term disease-free survival, is an important surrogate end point. Curative therapy for this group of patients is urgently needed.
Higher chemotherapy doses correlate with response and cure in laboratory models of breast and other cancers. The observation of responses after marrow-ablative chemotherapy doses in patients with disease refractory to conventional chemotherapy led to further clinical trials of high doses in metastatic disease. A recent analysis from the American Blood and Marrow Transplant Registry (ABMTR) showed a 32% progression-free survival rate at 3 years in 640 patients treated in these trials. In addition, pilot data from several centers and the ABMTR showed a 4-year progression-free survival rate ranging from 60% to 65% in patients with high-risk primary breast cancer undergoing transplantation.
Based on these promising data with high-dose therapy (compared with conventional treatment), several centers and cooperative groups began phase III trials comparing high-dose chemotherapy to best available conventional therapy. Of the nine reports of randomized trials of high-dose therapy in patients with high-risk primary or metastatic breast cancer, seven are published only in abstract form, including five trials presented at the American Society of Clinical Oncology (ASCO) meeting in May 1999.
The randomized trials of high-dose therapy used in the adjuvant setting are summarized in Table 1.
CALGB Intergroup Study
The Cancer and Leukemia Group B (CALGB) intergroup adjuvant study by Peters et al compared high- vs intermediate-dose CBP (cyclophosphamide, BCNU, and Platinol) after induction therapy with CAF (cyclophosphamide, Adriamycin, and fluorouracil) in women with 10 or more involved lymph nodes and no evidence of metastatic disease (as measured by computed tomographic [CT] scans and bilateral bone marrow aspirates and biopsies). Patients underwent primary excision of their breast tumors and an axillary lymph node dissection prior to the initiation of chemotherapy. Chest wall, supraclavicular, and internal mammary node irradiation followed 6 weeks after chemotherapy. Patients with estrogen-receptor (ER) positive tumors also received hormonal therapy with tamoxifen(Drug information on tamoxifen) (Nolvadex) for 5 years.
Among the 884 patients accrued to the trial from 1991 to 1998, the median age of eligible patients was 44 years (range, 22 to 66 years), and the median number of involved lymph nodes was 14. Of the 91 patients who were not randomized, 22 had relapsed and 26 had no insurance coverage. A total of 394 patients were randomized to receive high-dose therapy plus stem-cell transplantation and 391 were assigned to intermediate-dose therapy.
The primary end point of this study is event-free survival. The protocol stipulated an initial analysis after all patients had been followed for at least 3 years. Thus, the data presented at the ASCO meeting are preliminary, and 2 more years of follow-up are needed to assess this primary end point.
Overall, the mortality of transplantation was 7.4% but varied with the experience of the transplant center and increased with patient age. Nonfatal pulmonary and hepatic toxicity of this first-generation BCNU-containing regimen was also substantial. At the median follow-up of 37 months, event-free survival was 68% for the transplant group and 64% for the chemotherapy group.
Discussion of ResultsScientifically, this trial represents a pure comparison between high- and intermediate-dose CBP (since intermediate-dose CBP is not a standard regimen).
The number of relapses was 126 (32%) in the control arm vs 85 (22%) in the transplant group. Patients on both arms of the study had a better progression-free survival than expected for similar historical controls who received conventiona-dose chemotherapy. Eligibility criteria included bilateral marrow biopsies and head CT scans, which are not routinely required for studies of conventional-dose therapies. All patients received consolidative radiotherapy, and patients in both treatment arms received dose-intensive CBP (either at an intermediate dose with growth factor support or at a high dose with stem-cell support).
Survival rates in the two arms were similar at 5 years (71% vs 68% for the transplant and control arms). The lack of a difference in survival is not surprising given the following factors: the expected median time to relapse (months to years) and then to death after relapse (approximately 18 to 24 months); the studys short median follow-up of 3.6 years; and the potential confounding effect of transplant at relapse. (At the time of study presentation, at least 20 patients on the control arm had already undergone a transplant at relapse.) Because of early mortality, transplant studies often do not initially demonstrate any significant differences in disease-free and overall survival.
Companion QOL StudyA total of 210 consecutive patients in the CALGB intergroup study (about 30% of the study patients) also participated in the companion quality-of-life (QOL) study presented at ASCO 1999. Quality of life was assessed by telephone interviews at baseline and at 3, 12, 24, and 36 months after treatment. The instruments used were the Functional Living IndexCancer (FLIC), the Symptom Distress Scale, and the Psychosocial Adjustment to Illness Scale (PAIS).
At baseline, QOL scores were similar in women in the two treatment arms. Scores for women in the higher-dose arm were significantly worse on the FLIC and symptom distress scales, and on one subset of the PAIS scale at 3 months, but were equivalent by 1 year and thereafter. Thus, high-dose chemotherapy was associated with worse QOL in the short term only.
South African Study
The South African adjuvant study compared conventional CAF with two high-dose cycles of cyclophosphamide, 4.4 g/m², mitoxantrone(Drug information on mitoxantrone) (Novantrone), 45 mg/m², and etoposide(Drug information on etoposide), 1.5 g/m², plus peripheral blood stem-cell transplantation. This adjuvant trial had no induction phase.
Eligible patients were < 55 years of age, and had a T1 to T3a primary lesion with > 10 involved nodes, a > 5-cm primary tumor with 7 to 9 involved nodes plus one additional poor prognostic factor (such as ER negative disease), or > 7 involved nodes plus two or more first-degree relatives with breast cancer. Eligibility criteria using family history is unusual, but the number of such patients was small, and they were equally distributed among the treatment arms.
Clinical metastases were excluded by bone scan, abdominal ultrasound, and chest x-ray. Chest wall with or without axillary irradiation was given to 11% of the bone marrow transplant (BMT) group and 17% of the CAF group.
Of the 154 patients entered, 1 patient died of toxicity in each arm before day 150. At a median follow-up of 5.3 years, 76 patients had relapsed (21 in the transplant arm and 55 in the control arm; P < .01). The overall survival durations were 400+ weeks for the transplant group and 320 weeks for the control group (P < .01).
Discussion of ResultsThis unequivocally positive study differs from the other studies in several important ways. First, the duration of follow-up was longer. Second, the experimental arm consisted of two cycles of anthracycline-based high-dose chemotherapy, which differs from the single cycle of alkylator-based therapy used in most other studies. Third, the control arm was conventional CAF rather than the escalated intermediate-dose CBP used in the American intergroup study. Fourth, the patient population had particularly poor prognostic factors, with a low rate of ER and progesterone(Drug information on progesterone) receptor (PR) positivity. Finally, no conventional-dose induction therapy was administered.