High Dose Chemotherapy and Autologous Bone Marrow Transplant as
Adjuvant Therapy for Breast Cancer
Case Presentation
HPI:
C.S. is a 27 year old white female with no significant past medical history who presented
in June 1999 with a breast mass. The patient stated that six weeks prior to this
presentation she had a normal physical exam, including a breast exam. Because of painful
intercourse, her birth control pill was switched to a higher estrogen-containing pill. Soon
after starting this medication she noticed the mass and states that it grew rapidly. She
underwent fine needle aspiration of the mass that was non-diagnostic. She subsequently
had lumpectomy with revealed a 7.5 x 5.5 x 5.5-cm mass that was positive for ductal
carcinoma. The patient was treated with a mastectomy and axillary node dissection. She
was found to have 15/15 positive lymph nodes (ER positive). She underwent CT scan of
the chest and abdomen that were negative for metastatic disease. She also had negative
bone scan, chest x-ray, CMP, and bone marrow biopsies. The patient was referred to
North Carolina Baptist Hospital for evaluation for high dose chemotherapy and
autologous bone marrow transplant.
Past Medical History: None
Past Surgical History: None
Medications: None
Family History: She denied any history of breast cancer, ovarian cancer, or colon cancer.
GYN History: Menarche at age 12. She has never been pregnant. She had taken birth
control pills for past five years. She never had any breast disease or breast biopsies prior
to recent cancer diagnosis. She never had any mammograms.
Review of Systems: Negative
Physical Exam:
VS 99.1 Pulse 85 BP 123/62
Gen: Young white female in no acute distress
HEENT: PERRLA, EOMI, oropharynx clear
Chest: Right mastectomy site clear without nodules/discharge
Left Breast: No masses
CV: RRR no M/G/R
Lungs: CTAB
Ab: Soft NTND No hepatosplenomegaly
Nodal Exam: No cervical, supraclavicular, axillary, inguinal lymphadenopathy
Extremities: No c/c/e
Neuro: Non-focal
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Pathology:
Tumor Size 7.5 x 5.5 x 5.5 cm. 15/15 positive lymph nodes. ER positive in more than
90%. PR positive in more than 20%. Her-2/neu negative. DNA index 2.0 Tetraploid S-
Phase 19%.
The patient received four cycles of conventional dose chemotherapy with
Cytoxan/Adriamycin followed by high dose chemotherapy with Cytoxan (6000 mg/m2),
Thiopeta (500mg/m2), and Carboplatin (800mg/m2) followed by peripheral blood stem
cell rescue. She was subsequently treated with radiotherapy and tamoxifen. She is
currently 12 months post bone marrow transplant and is disease free.
Clinical Question:
The patient received the high dose chemotherapy on January 20, 2000. On the day before
she was to have her peripheral blood stem cells reinfused, the patient was found to be
tearful. She stated that she spoke to a friend of hers who read on the Internet that Bone
Marrow Transplants don’t work for breast cancer and that in a month, insurance
companies are going to stop covering this procedure. The patient asked, “Does high dose
chemotherapy and autologous bone marrow transplants help women with breast cancer?”
Theory behind the Treatment
Despite a recent decrease in the incidence and mortality, breast cancer currently develops
in one of eight American women who live to the age of 85, and remains the leading cause
of death in American women ages 15 to 54. Virtually all patients who initially present
with or later develop metastatic breast cancer will ultimately die of their disease.
Adjuvant therapy has consistently demonstrated a modest improvement in long-term
disease-free and overall survival in breast cancer patients. The prognosis of patients with
primary breast cancer is inversely related to the number of involved axillary lymph nodes
at surgery. Analysis of treatment outcomes in patients with four to nine positive lymph
nodes indicates that 50-60% will relapse by 10 years. The outcome of patients with 10 or
more positive lymph nodes is even worse: at 5 years 55-87% and at 10 years 70-90%
have relapsed, respectively. Twenty-year follow-up data suggests that even at that time,
no plateau has been reached (1). Only complete responders to therapy have a chance at
prolonged disease-free and overall survival. Thus curative therapy for this group is
desperately needed.
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The most easily understood rationale for the use of high-dose chemotherapy is “more is
better.” The scientific basis for this hypothesis assumes that for some drugs, doses above
certain levels will successfully overcome drug resistance. The demonstration that
increased drug exposure increases cell kill is termed “dose-response” and high-dose
chemotherapy is the translation of this laboratory observation to the clinical setting.
Clinically relevant drugs for which a steep dose-response relationship has been seen in
the laboratory include most alkylating agents and anthracyclines which, given their
proven efficacy, makes them excellent candidates for study (2).
The method of applying high-dose therapy is also based on laboratory studies. Some
experiments suggest that the application of high-dose alkylating agents following optimal
cytoreduction can eradicate viable tumor, even when the same treatment is not curative if
applied earlier (i.e. prior to an initial cytoreductive therapy). This concept is also
supported by the Gompertzian model of tumor growth which predicts that a smaller
volume of tumor cells will have relatively increased growth fraction and therefore greater
sensitivity to cell-cycle specific agents (3). These studies provide the basis for the most
common regimens used in high dose chemotherapy in which patients are first treated with
multiple (usually two to six) rounds of “induction” chemotherapy prior to the
administration of a single or multiple rounds of high-dose chemotherapy.
Political and Social Influences make High-Dose Chemotherapy Standard of Care
By 1990, patients with advanced breast cancer, with the support of some clinicians, began
to seek coverage for the experimental use of autologous bone marrow transplant from
managed care organizations. Analogues to this treatment had proven effective for some
lymphatic cancers, and there was some scientific rationale for extending the treatment to
solid tumors. Despite the enthusiasm of the clinicians and the desperate belief of the
breast cancer patients, there was no hard clinical evidence to support this therapy.
Specifically, there were no randomized trials that showed a benefit from this expensive
and risky treatment over standard treatments. (It should be remembered that at this time
the mortality associated with bone marrow transplant was reported to be from 10-25%.)
Because of the lack of data, many insurance companies refused to cover these treatments.
When some managed care organizations insisted the therapy was still “investigational”
and “unproven” and might even prove worse than standard therapies, patients pursued
both litigation and legislation, and the media “exposed” the denials. In 1991, 60 Minutes
featured a story about Aetna declining coverage for ABMT in breast cancer. In
California in 1993, the estate of Neline Fox won $89 million suit against Healthnet,
which had originally denied coverage, then provided it. The suit charged that the delay
cost Fox her life (4).
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Throughout the 1990’s many insurers were providing coverage for patients participating
in approved clinical trials. Unfortunately, according to a study in the New England
Journal of Medicine, this coverage did not correlate with pretreatment clinical
characteristics, or the response to induction therapy. This study showed that as many as
three out of four patients seeking coverage for participation in a trial were granted it, and
another half of those who threatened legal action when initially denied also received
coverage (5).
In addition, many state legislatures mandated coverage as early as 1994 and 1995 despite
protests that these mandates would make it virtually impossible to continue proper
clinical trials aimed at assessing efficacy. Thus through legislative mandates and
lawsuits, high-dose chemotherapy soon became the standard of care for women with
metastatic and "high-risk" breast cancer patients. As a result, the number of bone marrow
transplants for breast cancer dramatically increased from 310 in 1989 to over 3000 in
1996 (6). Also, because bone marrow transplant was seen as standard of care, most the
early data regarding high-dose chemotherapy for breast cancer consisted of small, non-
randomized phase I/II studies.
Early Phase I/II Trials
Table 1. Phase I/II Trials of High-Dose Chemotherapy as Adjuvant Therapy
Stage Author Design No. of Overall Event-Free Mortality
Patients Survival Survival
High Risk Peters et al. CCrP 85 5yr 5yr 12%
>10 LN 7 78% 71%
4-9 LN Bearman et CTCb 54 4yr 4yr 2%
II/III al. 8 84% 71%
High Risk Somlo et al. CAVP or 114 3.5 yr 3yr
II/III 9 CCVP >10 ax. LN >10 ax. LN
82% 71%
IIIA 79% IIIA 57%
IIIB 72% IIIB 50%
High Risk Ayash et al. CTCb 47 30 month 30 month
IIIB 10 89% 64%
High Risk Viens et al. CMA 17 36 months 36 months
IIIB 11 70% 65%
High Risk Lalisang et BuC 19 1490 days 1490 days 10%
II >7LN al. 1 45% 42%
Abbreviations C, cyclophosphamide, V, etoposide, Cb, carboplatin, T, thiopeta, P, cisplatin, Bu busulfan,
M, Mitoxantrone and Melphalan A, doxorubricin, F 5-Fluorouracil, Cr carmustin LN lympn Nodes
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As mentioned, most of the early data consisted of Phase I/II trials. A few of these trials
are shown in Table 1.
One of the most sited trials in the literature is from Duke University (Peters et al. Table
1). In this study, 85 patients with 10 or more axillary lymph nodes were treated with
high-dose cyclophosphamide, cisplatin and camustine (CPB) and ABMT after CAF
adjuvant chemotherapy. The median age was 38 years, and the median number of lymph
nodes was 14. Therapy related mortality was 12%. At the time the abstract was
published, the median follow up was 5 years. The data (shown in Table 2) was compared
to historical CALGB series selected for age 10 lymph axillary
lymph nodes.
Table 2. Results of Duke Pilot Study
Study No. of Patients 5 yr. Event-Free Survival 5 yr. Overall
assessable (95% CI) Survival
(95% CI)
CAF-> CPB + 85 71% 78%
ABMT (53%-84%) (56%-88%)
CAF 37 34% 37%
(CALGB 8541) (18%-54%) (28%-54%)
CMFVP/VATH 116 31% 48%
(CALGB 8082) (23%-40%) (39%-57%)
CMFVP 104 28% 45%
(CALFG 7581) (20%-37%) (36%-54%)
The author concluded that this evidence showed high-dose chemotherapy to be feasible.
He states that the results must be confirmed with a randomized trial.
Although these data seem to be impressive, many factors must be taken into account.
First, this was not a randomized controlled trial. The historical controls used do not
necessarily correlate with those selected for this study. For example, eligibility for this
study included normal contrast-enhanced computed tomography (CT) scan of the head,
chest, abdomen and pelvis along with normal bilateral bone marrow biopsies. The
eligibility for the other studies only indicated normal blood work, chest x-ray and bone
scan. A prospective trial conducted in Toronto showed that intensive screening using CT
scans and bone marrow aspirates and biopsies uncovered distant metastatic disease in an
additional 23% of patients (12).
Selection bias is one of the most frequently used criticisms of these early trials. Garcia-
Carbonero et al. performed a retrospective study to determine the disease-free survival
and overall survival in-patients who met the selection criteria for high dose chemotherapy
but were treated with conventional chemotherapy (13). They found 171 breast cancer
patients with >10 lymph nodes positive from 1975 through 1995. One-hundred twenty-
eight patients met criteria for high dose chemotherapy (> 10 more positive lymph nodes,
age 50),
menopausal status (premenopausal vs. postmenopausal), T stage (T1/T2 vs. T3/T4),
radiotherapy (yes vs. no) chemotherapy (CMF vs. anthracycline- type) number of lymph
nodes (10-15 vs. >15) and HDCT criteria (yes vs. no). Of all of these variables, the only
significant differences were found in those who met HDCT criteria and those who
received radiotherapy (as shown in Table 4). Thus meeting HDCT criteria was found to
be an independent risk factor for prolonged DFS and OS. The data was also presented in
graphical form as shown below in Figures 1-3.
Table 4. Cox Multivariate Analysis for DFS and OS in High Risk Breast Cancer
Patients
Variable Hazards Risk P Value 95% CI
DFS HDCT Criteria 1.96 0.03 1.06-3.57
XRT 2.00 10 lymph
nodes (LN) after primary surgery or >4 positive LN after four cycles of neoadjuvant
chemotherapy. The two groups were matched for age, race, stage, estrogen receptor
status, # of nodes and histology. Seventy-eight patients were registered and randomized.
Three patients in the standard dose group received high dose chemotherapy off protocol
elsewhere. Six of the patients in the high dose chemotherapy group did not receive
treatment (Refused: 3, Insurance denial 1, Other illness: 2). Median follow up was 53
months. The 4 year disease free survival rates for conventional chemotherapy and high
dose chemotherapy were 55% and 48% respectively with intention-to-treat analysis
(P=0.45) and 52% and 51% by actual treatment (P=0.84). The overall survival figures
were 68% and 60% for the standard dose and high-dose chemotherapy groups,
respectively, by intention-to-treat (P=0.27) or 64% and 63% by actual treatment. Six
treatment related deaths (2 patients developed congestive heart failure, 1 developed acute
leukemia and 1 sepsis) occurred in the high dose treatment group while none occurred in
the conventional group. The author concluded that while this study had limited statistical
power because of the small size, high dose chemotherapy is unlikely to produce major
improvements over conventional chemotherapy. Interestingly, both the control and
treatment groups had much longer disease-free survival and overall survival when
compared to the previously used “historical” controls.
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The next study published was the Netherlands trial by Rodenhuis et al in 1998 (17). This
trial compared high dose versus conventional chemotherapy. In this study, all patients
received three cycles of conventional chemotherapy with and 5-Fluorouracil, epirubricin
and cyclophosphamide, (FEC) (500/120/500mg/m2). The patients were then randomized
to receive either a forth cycle of chemotherapy or a high dose regimen of
cyclophosphamide, thiotepa and carboplatin (6000/480/1600mg/m2). Both groups then
received radiation therapy followed by two years of tamoxifen. This again was a small
study involving only 96 patients. The eligibility criteria was age 10 lymph nodes positive) and has a minimal tumor burden
making her tumor more sensitive to the chemotherapy (theoretically). Finally, because
she is young the most aggressive therapy should be used in the event that a benefit may
be discovered in these patients at longer follow-up times.
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If this were my patient, I would advise her to try to get in a clinical trial using new
chemotherapy for the following reasons. High-dose chemotherapy has not yielded any
significant benefits over conventional therapy. Since this patient has minimal amount of
tumor burden, she probably has about 40-50 month disease-free survival and 60-70
month overall survival. The 4-10% mortality rate associated with the high-dose
chemotherapy is too high to justify its use. Also, studies appear to be showing that many
of the chemotherapy agents do not continue to maintain their dose-response curves above
levels much lower than those used in high-dose treatments. Thus the risk of significant
morbitity and mortality would outweigh the possible benefit that has yet to be shown.
Conclusion
Patients have been treated for over a decade with high dose chemotherapy followed by
autologous bone marrow transplant. For political and social reasons, this became
standard of care for patients viewed at high risk for recurrence or with metastatic disease.
Recently, a number of randomized controlled trails have been published questioning the
efficacy of this treatment. Many of these studies are preliminary with three to five years
of follow-up and most authors of these studies indicate that further follow-up is necessary
before any conclusions can be drawn. While this is true, the fact that no benefit is seen in
patients after this amount of time makes the likelihood of any significant long term
benefit low as the disease-free survival appears to be 40 to 50 months. Finally, recent
studies have been published which question whether a continuous dose-response
relationship exists with the chemotherapy agents used. Thus high doses may only add
significant toxicity without any clinical benefit. In conclusion, high-dose chemotherapy
with bone marrow transplant should only be performed as part of randomized controlled
trials until studies revealing benefits are performed.
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Bibliograpy
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