Sledge et al. (2003)

Sledge et al. (2003)
Design: Randomized controlled trial (therapy) evidence level: 1−
Country: United States
Inclusion criteria:
Histologically confirmed breast cancer with progressing regional or metastatic disease
Prior (> 6 months previously) non-anthracycline or non-taxane adjuvant therapy was acceptable
Prior endocrine therapy in any setting was acceptable
Measurable or evaluable disease (defined by ECOG) including pleural or peritoneal effusions
Adequate renal, haematological and hepatocellular function
ECOG status of 0,1 or 2
Life expectancy > 3 months
Exclusion criteria:
History of congestive heart failure
Myocardial infarction within 6 months
Ischemic heart disease requiring medication
Cardiac conduction abnormalities
Receipt of drugs known to affect cardiac conductions
History of deep vein thrombophlebitis
Any other thromboembolic conditions
Prior malignancy < 5 years except CIS cervix or non-melanoma skin cancer
No RT except to breast, chest wall or to < 25% bone marrow
Population:
Number of patients = 731
Interventions:
Therapy was administered every three weeks as follows:

Arm A (n = 245):
Started on doxorubicin (60 mg per m2) i.v. for a maximum of 8 cycles or until progression then crossed over to paclitaxel

Arm T (n = 242):
Started on paclitaxel (175 mg per m2) over 24 hours until progression then crossed over to doxorubicin

Arm A+T (n = 244):
Combined doxorubicin (50 mg per m2) followed after 3 hours by paclitaxel (150 mg per m2) over 24 hours
Outcomes:
Tumour response (ORR = CR + PR) compete response (CR) partial response (PR) overall survival (OS) stable disease (SD) progressive disease (PD) time to treatment failure (TTF) adverse events Quality of life (assessed by FACT-B questionnaire) Adverse events.
Follow up:
33 patients were excluded from the analysis:
Concurrent tamoxifen (n = 2)
No evaluable disease (n = 7)
Adjuvant chemotherapy within 6 months (n = 1)
No histological proof of MBC (n = 1)
Endocrine therapy within 2 weeks (n = 8)
Prior metastatic breast cancer (n = 4)
Major surgery < 4 weeks prior (n = 1)
Laboratory values > 2 weeks old (n = 2)
Cardiac history (n = 1)
Consent signed after randomisation (n = 1)
Inadequate history taking (n = 4)
Extensive prior RT (n = 1)

The number of patients included in the analysis (683) differs from the total number of patients assigned (731) by 48, of which only 33 are accounted for, as above.
Results:
Median age:
Arm A (n = 224) = 58 years (range: 25 – 79 years)
Arm T (n = 230) = 56 years (range: 25 – 76 years)
Arm A+T (n = 229) = 56 years (range: 27 – 78 years)

ORR:
Arm A = 36% (6% CR)
Arm T = 34% (3% CR)
Arm A+T = 47% (9% CR)
Arm A versus Arm T (NSD)
Arm A versus Arm A+T (P = 0.017)
Arm T versus Arm A+T (P = 0.006)

Median TTF:
Arm A = 6 months
Arm T = 6.3 months
Arm A + T = 8.2 months
Arm A versus Arm T (NSD)
Arm A versus Arm A+T (P = 0.0022)
Arm T versus Arm A+T (P = 0.0567) NB. this is not significant

Median OS:
Arm A = 19.1 months
Arm T = 22.5 months
Arm A + T = 22.4 months
Arm A versus Arm T (NSD)
Arm A versus Arm A+T (NSD)
Arm T versus Arm A+T (NSD)

Adverse events:
% of patients with grade 3/4 events (Arm A)(Arm T)(Arm A+T):
Leukopenia (49.6)(59.9)(54.9)
Thrombocytopenia (5.4)(2.1)(16.0)
Anemia (6.2)(9.5)(17.2)
Infection (4.1)(8.3)(12.7)
Cardiac complications (8.7)(3.7)(8.6)
Neurologic complications (1.6)(3.7)(10.7)
Vomiting (6.6)(2.5)(4.5)
Diarrhoea (1.6)(1.6)(4.5)
Stomatitis (7.8)(2.9)(4.5)
Lethal toxicity (2.5)(1.6)(1.6)

Prognostic factors for impaired OS (Relative risk):
ER −ve (RR = 1.7, P = 0.0001)
Visceral dominant disease (RR = 1.4, P = 0.004)
>3 sites of disease (RR = 1.4, P = 0.005)
Short disease-free interval (1–24 months) (RR = 1.3, P = 0.03)
Prior systemic therapy (RR = 1.1, P = 0.03)
Treatment regime was NSD

Crossover responses:
Tumour response from Arm A to Arm B = 28/129 patients (22%)
Tumour response from Arm B to Arm A = 25/128 patients (20%)
Median TTF from Arm A to Arm B = 4.5 months
Median TTF from Arm B to Arm A = 4.2 months
Median OS from Arm A to Arm B = 14.9 months
Median OS from Arm B to Arm A = 12.7 months
All results are NSD

Quality of life (n = 451 patients completing questionnaires at both baseline and follow-up in week 16): There were no significant differences between any arms for any subscale.
General comments:
This three-arm RCT compares single agents versus the same agents in combination. Patients on either of the single agent arms crossed over to the other agent on disease progression. The 731 study participants are assumed to be women - it is not stated otherwise in the text. They were recruited between February 1993 and September 1995.

Statistical power calculations determined the number needed to detect a 15% improvement in ORR and a 50% improvement in TTF between any two arms. Doxorubicin as a single agent was assumed to have an ORR of 30–35% and a median TTF of 6–8 months. With 220 patients on each arm the actual power would have been 0.84 for the ORR and 0.95 for TTF.

The three arms were said by the authors to have been well matched in respect of patient characteristics but there is no statistical evidence to exclude heterogeneity. Appropriate statistics were used to compare tumour response rates, TTF and OS and to examine potential prognostic factors on both.

There are no details of randomisation or allocation. This means that it would be impossible to rule out the possibility of bias in the observed results. Some patients are missing from the outcomes analysis and data are poorly presented. There is no mention of an ITT analysis.

The authors concluded that:
  • Combination therapy resulted in superior ORR and TTF but failed to improve OS or quality of life.
  • The percentage of patients who may have responded only to one or other of the two drugs may have been the same as the number who responded to the combination anyway.
  • The OS may relate more to biology of the disease since the prognostic factors point towards these indicators rather than the chemotherapy regime.
  • Combination therapy often involves a reduction in the dosage of individual drugs which might compromise the likelihood of synergy between them.
  • Combination therapy may impair the quality of life if the adverse events are disproportionate to the response.

From: Chapter 4, Systemic disease-modifying therapy

Cover of Advanced Breast Cancer
Advanced Breast Cancer: Diagnosis and Treatment.
NICE Clinical Guidelines, No. 81.
National Collaborating Centre for Cancer (UK).
Copyright © 2009, National Collaborating Centre for Cancer.

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