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, Adriamycin, and
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 (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
(Novantrone), 45 mg/m², and 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
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 receptor (PR) positivity. Finally, no conventional-dose
induction therapy was administered.
1. Landis SH, Murray T, Bolden S, et al: Cancer statistics, 1999. CA
Cancer J Clin 49:8-11, 1999.
2. Wingo PA, Reies LAG, Rosenberg HM, et al: Cancer incidence and
mortality, 1973-1995: A report card for the United States. Cancer
3. Clark G, Sledge GW, Osborne CK, et al: Survival from first
recurrence: Relative importance of prognostic factors in 1,015 breast
cancer patients. J Clin Oncol 5:55-61, 1987.
4. Mick R, Begg CB, Antman K, et al: Diverse prognosis in metastatic
breast cancer: Who should be offered alternative initial therapies?
Breast Cancer Res Treat 13:33-38, 1989.
5. Greenberg P, Hortobagyi G, Smith T, et al: Long-term follow-up of
patients with complete remission following combination chemotherapy
for metastatic breast cancer. J Clin Oncol 14:2197-2205, 1996.
6. Frei III E, Canellos GP: Dose, a critical factor in cancer
chemotherapy. Am J Med 69:585-594, 1980.
7. Antman K, Rowlings P, Vaughn W, et al: High-dose chemotherapy with
autologous hematopoietic stem cell support for breast cancer in North
America. J Clin Oncol 15:1870-1879, 1997.
8. Rowlings P, Antman K, Fay J, et al: Prognostic factors for outcome
of autotransplants in women with high-risk primary breast cancer
(abstract). Proc Am Soc Clin Oncol 16:117a, 1997.
9. Peters WP, Rosner G, Vredenburgh J, et al: A prospective,
randomized comparison of two doses of combination alkyating agents as
consolidation after CAF in high-risk primary breast cancer involving
ten or more axillary lymph nodes: Preliminary results of CALGB
9082/SWOG 9114/NCIC MA-13 (abstract). Proc Am Soc Clin Oncol 18:1a, 1999.
10. Winer EP, Herndon J, Peters WP, et al: Quality of life in
patients with breast cancer randomized to high-dose chemotherapy with
bone marrow support vs intermediate-dose chemotherapy: CALGB 9066
(companion protocol toCALGB 9082) (abstract). Proc Am Soc Clin Oncol
11. Bezwoda WR: Randomized, controlled trial of high-dose
chemotherapy vs standard dose chemotherapy for high-risk, surgically
treated, primary breast cancer (abstract). Proc Am Soc Clin Oncol
12. Rodenhuis S, Richel KJ, van der Wall E, et al: Randomized trial
of high-dose chemotherapy and hematopoietic progenitor-cell support
in operable breast cancer with extensive axillary lymph-node
involvement. Lancet 352:515-521, 1998.
13. Hortobagyi GN, Buzdar AU, Champlin R, et al: Lack of efficacy of
adjuvant high-dose tandem combination chemotherapy for high-risk
primary breast cancer: A randomized trial (abstract). Proc Am Soc
Clin Oncol 17:12, 1998.
14. Bergh J: Results from a randomized adjuvant breast cancer study
with high-dose chemotherapy with CTCb supported by autologous bone
marrow stem cells vs dose escalated and tailored FEC therapy
(abstract). Proc Am Soc Clin Oncol 18:2a, 1999.
15. Stadtmauer EA, ONeill A, Goldstein LJ, et al: Phase III
randomized trial of high-dose chemotherapy and stem cell support
shows no difference in overall survival or severe toxicity compared
to maintenance chemotherapy with cyclophosphamide, methotrexate, and
5-fluorouracil for women with metastatic breast cancer who are
responding to conventional induction chemotherapy: The Philadelphia
intergroup study (abstract). Proc Am Soc Clin Oncol 18:1a, 1999.
16. Bezwoda W, Seymour L, Dansey R: High-dose chemotherapy with
hematopoietic rescue as primary treatment for metastatic breast
cancer: A randomized trial. J Clin Oncol 13:2483-2489, 1995.
17. Bezwoda WR: Primary high-dose chemotherapy for metastatic breast
cancer: Update and analysis of prognostic factors (abstract). Proc Am
Soc Clin Oncol 17:115a, 1998.
18. Peters W, Jones R, Vredenburgh J, et al: A large prospective
randomized trial of high-dose combination alkylating agents (CPB)
with autologous cellular support as consolidation for patients with
metastatic breast cancer achieving complete remission after intensive
doxorubicin-based induction therapy (AFM) (abstract). Proc Am Soc
Clin Oncol 15:121, 1996.
19. Lotz JP, Cure H, Janvier M, et al: High-dose chemotherapy with
hematopoietic stem cells transplantation for metastatic breast
cancer: Results of the French protocol Pegase 04 (abstract). Proc Am
Soc Clin Oncol 18:43a, 1999.