Download BREAST, adjuvant, AC

BREAST, adjuvant,
Evaluator Review
AC
(doxorubicin
and
cyclophosphamide)
Other Relevant Regimens
This protocol can be used alone.
The AC + Paclitaxel combined protocol (or the Paclitaxel 3 weekly protocol for information
regarding the paclitaxel component of the regimen) and the TAC (docetaxel, doxorubicin and
cyclophosphamide) protocol are useful for considering the added benefits/toxicities of adding a
taxane (during/after) AC therapy.
Clinical considerations:
•
•
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Effects of antitumour drugs on fertility and options for preservation of fertility.
G-CSF: drugs, doses and links to Section 100 indications. Some patients may be eligible for
G-CSF.
Anthracyclines and mitozantrone - cumulative dose cardiac toxicity.
Evidentiary basis:
Key evidence
A number of trials have investigated the use of doxorubicin and cyclophosphamide in differing
regimens. The most relevant are listed below, together with a meta-analysis of anthracycline use;
AC vs CMF
• NSABP B15 randomised trial of women with primary operable breast cancer and at least one
positive axillary node (n= 2194); AC vs CMF vs AC-CMF. Found convenience advantages for
AC, but no survival-related advantages.1
• Bang et al; Randomised trial of pre-menopausal women with node positive, stage II breast
cancer (n=124). Compared AC vs CMF and found no significant difference at 5 years.2
AC vs AC plus paclitaxel
• CALBG 9344(n= 3170); AC vs AC-P (at 2 different doses of paclitaxel)3 and
• NSABP B28 (n=3060); AC vs AC-P.4 Both trials show additional benefits of adding paclitaxel.
Meta-analysis of anthracycline use vs no anthracycline use.
• EBCTCG Meta-analysis; anthracycline containing regimens, vs no-anthracycline and taxane
containing regimens, vs anthracycline with no taxane, etc. 5
Summary
The NSABP B15 trial compared 4 cycles of doxorubicin (Adriamycin) and cyclophosphamide; AC , at
three weekly intervals (overall treatment duration 63 days), with six cycles of conventional
cyclophosphamide, methotrexate and fluorouracil (CMF) treatment, at four weekly intervals
(overall treatment duration 154 days). The study also compared the sequential use of both AC and
CMF treatment to AC treatment alone. While there was no difference found between the groups in
the primary endpoints of the study (disease-free survival and overall survival at 3 years, AC;62%
and 83%, respectively and CMF; 63% AND 82%, respectively), AC was found to be preferable as it
was completed more quickly, with many less visits to health professionals, less days of
chemotherapy administration (4 vs 84) and required use of less anti- emetic medications (12 days vs
84 days).
A smaller trial (Bang et al, 2000) showed no difference between AC and CMF, however this was a
trial of only 134 patients and used lower doses of doxorubicin.2
More recently, trials of AC alone versus AC followed by paclitaxel in similar patients show
improved results. At five years, disease free survival for AC alone ranged from 65% (CALGB 9344)
to 72% (NSABP B28) and overall survival 77% (CALGB 9344) to 85% (NSABP B28). (Disease free
survival at five years with additional paclitaxel was 70% (CALGB 9344) to 76% (NSABP B28) and
overall survival 80% (CALGB 9344) to 85% (NSABP B28). It is possible survival benefits of adding
paclitaxel may become more apparent after 5 years.3,4 There is also evidence for the use of
docetaxel with AC, where similar rates of disease free-survival have been found in similar patients.
(Martin et al. 2005)6
A meta-analysis by the 2005 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) found an
improved efficacy of chemotherapy regimens containing anthracyclines (eg doxorubicin), over those
without. This benefit was greatest in women less than 50 years old, however was also significant in
women older than 50 years.5 The meta-analysis combined results from numerous different
anthracycline regimens, and possible differences in effectiveness between these have not been
fully established.
Efficacy:
Therapeutic relativity
“AC is at least as effective as CMF, possibly more effective and has convenience advantages. It is
no worse, in terms of safety, than CMF, although the nature of toxicity is quite different.
However, AC alone is less effective than AC combined with a taxane, but AC alone is associated
with less toxicity than when combined with a taxane.”
Summary of Efficacy Results
Outcome
CMF
patients
NSABP B15
AC
patients
63%
62%
Disease Free
Survival (3 yr)
Difference
Difference
NS
Disease Free
Survival (5 yr)
Overall82%
83%
survival (3 yr)
Overall
survival (5 yr)
(Source: Fischer et al1, Mamoumas et al.4)
NSABP-B28
AC-P
patients
AC
patients
72%
76%
ARD = 3%
(RR=0.83;
95%CI
0.72,0.55)
85%
85%
NS
NS
Quality of Life information was not collected in the previously mentioned trials, however, a substudy (NSABP B23-QOL) in another study by the same research group, specifically compares
differences in quality of life between women receiving AC and CMF.7 This study found no overall
difference in quality of life between the two treatment groups, although the two treatments do
produce different symptoms. Side-effects tended to occur more rapidly on AC treatment, however
as it was completed much sooner than CMF, recovery was also more rapid.
Toxicity
The following table lists the toxicities found in patients in the NSABP B-15 trial.
Outcome
AC
Deaths
AC-CMF (iv)
CMF
None during therapy
Patients discontinuing treatment
(Not specifically reported)
Nausea with vomiting
71%
56%
37%
Nausea (without vomiting)
16%
20%
43%
Alpoecia (complete)
70%
6%
15%
Neutropenia (grade 3 or 4)
4%
5%
10%
Diarrhoea (> 4 stools/day))
3%
3%
5%
0.4%
0.2%
0.1%
(grades not specified)
Cardiovascular toxicity (functional)
(Source: Fischer et al.1)
Other toxicities that occurred in less than 1% of patients include; phlebitis, infection, severe
fever. Weight loss or weight gain also occurred in nearly a quarter of patients. (Generally less
than a 10% change.)1 Long-term toxicities associated with doxorubicin (eg cardiac or
myeloproliferative disorders) were not comparable in this study due to the relatively short follow-
up, but are elsewhere reported as less than 1%.8
Refer to the AC-Paclitaxel and TAC protocols to see the additional toxicities that occur when a
taxane is added.
References:
1. Fisher B, Brown AM, Dimitrov NV, et al. Two months of doxorubicin-cyclophosphamide with and
without interval reinduction therapy compared with 6 months of cyclophosphamide,
methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifennonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B15. J Clin Oncol 1990; 8:1483-1496.
2. Bang S, Heo DS, Lee KH, et al. Adjuvant Doxorubicin and Cyclophosphamide versus
Cyclophosphamide, Methotrexate, and 5-Fluorouracil Chemotherapy in Premenopausal Women
with Axillary Lymph Node Positive Breast Carcinoma. Results of a Randomized Controlled Trial.
Cancer 2000; 89: 2521-2526.
3. Henderson IC, Berry DA, Demetri GD, et al. Improved outcomes from adding sequential
paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for
patients with node-positive primary breast cancer. J Clin Oncol 2004; 21: 976-83. (CALGB 9344)
4. Mamounas ERP, Bryant J, Lembersky B, et al. Paclitaxel after doxorubicin plus
cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from
NSABP B-28. J Clin Oncol 2005; 23: 3686-96.
5. Early Breast Cancer Trials Collaborative Group. Effects of chemotherapy and hormonal therapy
for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials.
Lancet 2005; 365: 1687-1717.
6. Martin M, Pienowski T, Mackey J, et al. TAC improves disease free survival and overall survival
over FAC in node-positive early breast cancer patients, BCIRG 001: 55 months follow-up. Breast
Cancer Res Treat 2003; 82(suppl 1): abstr 43.
7. Land SR, Kopec JA, Yothers G, et al. Health-related quality of life in axillary node-negative,
estrogen receptor-negative breast cancer patients undergoing AC versus CMF chemotherapy:
findings from the National Surgical Adjuvant Breast and Bowel Project B-23*. Breast Cancer Res
Treat, 2004; 86: 153–164.
8. Colozza M, de Azambuja E, Cardoso F, et al. Breast Cancer: Achievements in Adjuvant Systemic
Therapies in the Pre-Genomic Era. Oncologist 2006;11:111-125