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Evidence for sequential PACLItaxel following breast adjuvant AC (DOXOrubicin and CYCLOPHOSPHamide)

This document is a quick and concise evidence-based summary to provide additional information, instruction, or guidance to complement a treatment protocol or clinical resource document. 

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The evidence for adding paclitaxel sequentially to AC (doxorubicin, cyclophosphamide) comes from the results of 2 randomised controlled trials:

1. CALGB (Cancer and Leukaemia Group B) 9344 trial r

This trial was designed to see whether the benefits from 4 cycles of AC could be increased either by doxorubicin dose escalation or by adding paclitaxel. Between May 1994 and April 1999, a total of 3121 patients were randomly assigned to 3 treatment arms, each receiving cyclophosphamide 600 mg/m2 with doxorubicin in doses of either 60 mg/m2, 75 mg/m2 or 90 mg/m2. After completion of 4 cycles of AC, patients were then randomised to either receiving 4 cycles of paclitaxel 175 mg/m2 or no further treatment.

All patients had operable breast cancer and metastases to axillary nodes.

The primary end point of this trial was disease free survival (DFS) and the secondary end points were overall survival (OS) and toxicity.

2. NSABP (National Surgical Adjuvant Breast and Bowel Project) B-28 trial r

The results of this trial confirm the benefit of incorporating paclitaxel to an AC regimen in the adjuvant setting.

Between August 1995 and May 1998, 3060 patients were randomly assigned to AC alone (n=1529) or AC followed by PTX (n=1531). All patients had resected operable breast cancer and histologically positive axillary nodes.

The primary end points were disease free survival (DFS) and overall survival (OS).

Efficacy

1. CALGB (Cancer and Leukaemia Group B) 9344 trial r

After a median follow-up of 69 months, there was no significant reduction in either the hazard of recurrence or death related to doxorubicin dose.

Disease-free survival and overall survival at 5 years with different doxorubicin doses r

  Arm 1 (%) Arm 2 (%) Arm 3 (%)
Disease-free survival (DFS) 69 66 67
Overall survival (OS) 79 79 77

Arm 1, 2, 3 : Doxorubicin 60 mg/m2, 75 mg/m2, 90 mg/m2 respectively

Adding paclitaxel to AC however led to a significant decrease in DFS and OS.

Disease free survival and overall survival of AC alone or with paclitaxel r

  AC (%) AC-paclitaxel (%)
1-year probability of recurrence 7.9 4.6
Disease-free survival (DFS) at 5 years 65 70
Overall survival (OS) at 5 years 77 80

Hazard ratios for recurrence and deathr

© Journal of Clinical Oncology 2003

Analysis of (A) Disease-free survival and (B) Overall survival, of patients assigned to AC alone or with paclitaxel r

© Journal of Clinical Oncology 2003

2. NSABP B-28 (National Surgical Adjuvant Breast and Bowel Project) trial r

After a median follow-up of 64.6 months, the addition of PTX demonstrated a significant increase in DFS but not in OS. However, it is possible that survival benefits of paclitaxel may be more apparent after 5 years.

Analysis of (A) Disease-free survival and (B) Overall survival, of patients assigned to AC alone or with paclitaxel r

© Journal of Clinical Oncology 2005

Toxicity

CALGB (Cancer and Leukaemia Group B) 9344 trial

In the CALGB trial, doxorubicin dose escalation substantially increased haematologic toxicity and stomatitis. There was also a significant increase in long-term cardiotoxicity by doxorubicin dose.

Paclitaxel treatment, on the other hand, resulted in less haematologic and non-haematologic toxicity than AC.r

Toxicity r AC* (%) Paclitaxel (%)
Neutropenia (grade 4) 62 16
Infection 17 11
Hospitalisation for toxicity 10 3
Nausea 32 3
Vomiting 27 1
Stomatitis 10 1
Hypersensitivity reaction NR 6
Paraesthesias NR 15
Sensory neuropathy NR 3

*at doxorubicin dose of 60 mg/m2 
NR: not reported

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Version 3

Date Summary of changes
31/05/2017

Transferred to new eviQ website.

This additional evidence is part of protocol ID 128 Breast adjuvant AC (doxorubicin and cyclophosphamide). Refer to this protocol for history information.

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https://www.eviq.org.au/p/3283

20 Apr 2024