High Dose Chemotherapy and Autologous
Bone Marrow Transplant as Adjuvant
Therapy for Breast Cancer
By David Martin MD
February 6, 2001
Case Presentation
• C.S. is a 27 year old white female with no
significant past medical history who presented
with a breast mass six weeks after starting a
new birth control pill.
• Lumpectomy revealed ductal carcinoma
• Patient referred to NCBH for High dose
chemotherapy and autologous bone marrow
transplant
Case Presentation
• Past Medical History: None
• Past Surgical History: Right Mastectomy 6/99
• Medications: None
• Family History: Negative for breast/ovarian
cancer
• OB/GYN: No pregnancies. Patient has been on
OCP for five years
Case Presentation
• Physical Exam:
• T 99.1 Pulse 85 BP 123/62
• Chest: Right Mastectomy site clear, Left
Breast no masses
• Nodal Exam: Negative
• Neurology: non-focal
Case Presentation
• Laboratory Data
– CMP, CBC, CXR all Normal
– CT Scan of Chest/Abdomen/Pelvis
negative
– Bone Marrow Biopsy Negative
Case Presentation
• Mastectomy:
– Tumor 7.5 x 5.5 x 5.5 cm
– 15/15 Positive Lymph nodes ER/PR +
– Her-2/Neu Negative
Case Presentation
• Treatment
– Four cycles of conventional dose
chemotherapy with Cytoxan/Adriamycin
– High Dose Chemotherapy Cytoxan,
Thiopeta, and Carboplatin with peripheral
blood stem cell rescue.
– Post-chemotherapy radiation and
tamoxifen.
Case Presentation
• Clinical Question
– Patient told by friend that BMT not
effective in treatment of Breast Cancer
– Patient asked:
– “Does high dose chemotherapy and bone
marrow transplant help women with
breast cancer?”
Overview
• Introduction
• Theory Behind Bone Marrow Transplant
• Political and Social Influences
• Early Phase I/II Trials
• Randomized Controlled Trials
• Clinical Case Revisited
• Conclusion
Introduction
• Breast Cancer develops in 1/8 American
women who live to age 85
• Leading cause of death of women ages 15-54
• Prognosis inversely related to number of
positive lymph nodes
Introduction
• 4-9 Positive Lymph Nodes
– 50-60% Relapse by 10 years
• 10 or more Positive Lymph Nodes
– 55-87% Relapse at 5 years
– 70-90% Relapse at 10 years
Theory Behind Treatment
• “More is Better”
• Dose Response Curves
• Tumor Growth Models
• Cytoreduction followed by high dose
chemotherapy
Political and Social Influences
• 1990 HDCT and ABMT
• Insurance companies reluctant to cover
• 1991, 60 Minutes interview
• 1993 Neline Fox case
Political and Social Influences
• 1994 New England Journal study
• 1994 and 1995 many state legislatures
mandated coverage
• Results:
– Large increase in number of HDCT as
treatment
– Difficult to perform randomized controlled
trials
Early Phase I/II Trials
Peters et. al
• 85 Patients with 10 or more axillary nodes
• CAF adjuvant Therapy
• High dose chemotherapy
Cyclophosphamide, cisplatin, carmustine
• Median age: 38
• Median Number of Lymph nodes: 14
• Follow up: 5 years
Early Phase I/II Trials
Peters et. al
80
70
60
50 Peters et al
40 CALGB 8541
CALGB 8082
30
CALGB 7581
20
10
0
Event Free Survival Overall Survival
Early Phase I/II Trials
Peters et. al
• Limitations
– Not RCT
– Selection Bias
– Different Therapies for Treatment and
Control Groups
– Treatment Related Mortality 12%
Early Phase I/II Trials
Selection Bias
• Garcia-Carbonero et. al examined DFS and OS in
Patients who meet Criteria for HDCT
• 171 Patients with met Criteria
– > 10 Lymph nodes
– age 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
Randomized Controlled Trials
• M.D. Anderson Trial by Hortobagyi et. al
• Netherlands Trial by Rodenhuis et. al
• South African Trial by Bezwoda et. al
• CALGB Trial by Peters et. al
Randomized Controlled Trials
M.D. Anderson Trial by Hortobagyi et. al
M.D. Anderson Study Design
All Patients Recieved
6 Cycles of Chemotherapy
With CAF
1/2 Randomized to 1/2 Randomized to
2 Cycles of HDCT with 2 Additional Cycles of
CVP CAF
Patients then recieved Patients then recieved
radiotherapy/Tamoxifen radiotherapy/Tamoxifen
Randomized Controlled Trials
M.D. Anderson Trial by Hortobagyi et. al
• Eligibility Criteria
– Resectable tumor
– >10 Lymph nodes after primary surgery
– >4 Lymph nodes after 4 cycles of
neoadjuvant therapy
Randomized Controlled Trials
M.D. Anderson Trial by Hortobagyi et. al
• Patients Matched
– Age
– Race
– Stage
– Estrogen receptor status
– # of positive nodes
Randomized Controlled Trials
M.D. Anderson Trial by Hortobagyi et. al
• 78 patients randomized
• 6 patient in HDCT did not receive treatment
(3 Refused, 1 Insurance denial, 2 other
illness)
• 3 patients in SDC received HDCT off
protocol elsewhere
• Median follow-up 53 months
Randomized Controlled Trials
M.D. Anderson Trial by Hortobagyi et. al
70
60
50
40
30 HDCT
20 SDCT
10
0
OS OS (Actual EFS EFS (Actual
(Intention Treat) (Intention Treat)
to Treat) to Treat)
Randomized Controlled Trials
M.D. Anderson Trial by Hortobagyi et. al
• Results
– No significant EFS or OS between groups
– 4 Treatment Related Deaths in HDCT vs. None
in SDCT
– Author concluded small trial but that HDCT is
“unlikely to produce major improvements over
SDCT”
Randomized Controlled Trials
Netherlands Trial by Rodenhuis et. al
Netherlands Design
All Patients Recieved
3 Cycles of Chemotherapy
With FEC
1/2 Randomized to 1/2 Randomized to
2 Cycles of HDCT with 1 Additional Cycle of
CtCb FEC
Patients then recieved Patients then recieved
radiotherapy/Tamoxifen radiotherapy/Tamoxifen
Randomized Controlled Trials
Netherlands Trial by Rodenhuis et. al
• Eligibility Criteria
– Age 10 Lymph nodes
– No Evidence of Metastatic Disease
• Determined by CT Scan and Bone
Marrow Biopsies
Randomized Controlled Trials
CALGB Study by Peters et. al
• 874 Patients admitted to trial
– 91 not randomized (22 Recurrent disease, 2
death from CAF toxicity, 26 insurance denial,
20 withdrew, 21 ineligible)
• 783 Patients randomized (394 HDCT, 389
IDCT)
• Median Follow Up: 37 months
Randomized Controlled Trials
CALGB Study by Peters et. al
80
70
60
50
40 HDCT
IDCT
30
20
10
0
Overall Survival Event-Free Survival
Randomized Controlled Trials
CALGB Study by Peters et. al
• Results:
– No significant difference between HDCT and
IDCT
– Fewer relapses in HDCT and IDCT (22% vs.
32%) Not significant.
– 29 Therapy Related deaths vs. None in IDCT
Group
• Author notes data is preliminary
Randomized Controlled Trials
Dose-Response Relationship
• Wood et. al examined CAF at different
doses
• 1572 women with Stage II breast cancer
randomized to receive high, intermediate, or
low dose therapy
• Low and intermediate groups received 6
while high dose received 4 cycles q 28 days
• Median Follow up 3 years
Randomized Controlled Trials
Dose Response Relationship
100
90
80
70
60
HDCT
50
IDCT
40 LDCT
30
20
10
0
Overall Survival Event-Free Survival
Randomized Controlled Trials
Dose-Response Relationship
• Results
– Significant differences between low dose and
either high/intermediate doses
– No significant difference between the
intermediate and high dose groups
• Appears to be a plateau at which the
chemotherapy does not provide clinical
benefits
Randomized Controlled Trials
Dose-Response Relationship
• Fisher et. al examined cyclophosphamide at
standard and increased dose intensity in Stage II
Breast Cancer
• 2305 randomized to receive 4 cycles standard dose
(600 mg/m2), 2 cycles of increase dose (1200 mg/
m2) or 4 cycles of increased dose therapy.
• All patients also received Doxorubicin
• Follow up: 5 years
Randomized Controlled Trials
Dose-Response Relationship
80
70
60
50
SDCT
40
HDCT X 2
30 HDCT X 4
20
10
0
Overall Survival Event-Free Survival
Randomized Controlled Trials
Dose-Response Relationship
• Results
– No significant difference between any groups
• Appears that 600 mg/m2 is appropriate dose
for cyclophosphamide
• CALGB 9344 studied Doxorubicin at
60/75/90 mg/m2.
• 18 month follow up: No differences
Clinical Case Revisited
• Healthy young women with Stage IIIB
breast cancer.
• 15/15 Positive nodes make recurrence likely
• Patient should receive radiation therapy and
tamoxifen
Clinical Case Revisited
• Patient should receive adjuvant therapy
– HDCT with BMT
– SDCT
– Clinical Study with new CT regimen
Clinical Case Revisited
• HDCT with BMT
– Pros:
• Patient young, healthy
• May be an advantage that hasn’t been demonstrated
• Patient with minimal tumor burden
– Cons:
• No proven benefit in any trial
• High Mortality (Average 3%)
• Higher incidence of post therapy malignancies
Clinical Case Revisited
• SDCT
– Pros:
• Well tolerated by most
• As good as HDCT
• Patient has better than average prognosis
– Cons:
• Young patient
• Instinctive feeling that more is better
Clinical Case Revisited
• Clinical Study with new CT regimen
– Pros:
• May have benefit over SDCT
• May have lower mortality
• May improve quality of life
– Cons:
• Unproven benefit
• May have more morbidity/mortality
Clinical Case Revisited
• Difficult problem because no effective
treatments
1. Clinical Study with new CT regimen
2. HDCT with BMT
3. SDCT
Conclusion
• HDCT with BMT has been used as treatment for
over 10 years
• No RCT demonstrate benefit of HDCT over
SDCT
• Benefit may occur at longer follow up times
• Significant mortality is associated with HDCT
• At this time, HDCT and BMT should not be used
unless part of Clinical Trial