Methods

Randomised controlled trial
Number of dropouts pre‐randomisation: Not stated
Stratified by: Number of positive nodes (4 ‐ 9 or 10+)
Number of women randomised: 605 (307 high dose, 298 standard dose)
Number of women analysed: 603
Number of women not analysed: 2 in high‐dose arm lost to follow‐up
Number of breaches of protocol/ failure to receive prescribed treatment: 39 (27 in high‐dose arm did not receive HDC; 12 in conventional‐dose arm did not complete treatment ‐ of these, 5 received high‐dose treatment elsewhere)
Intention‐to‐treat analysis: Yes
Number of centres: 34
Source of funding: NHS executive (West Midlands); Biotechnology company (AMGEN)
Years: 2/95 ‐ 6/99
Countries: UK, Ireland, Belgium, New Zealand

Participants

INCLUDED:
Women aged > 18 with operable Stage II or IIIa breast cancer with 4+ involved lymph nodes, ECOG performance status 0/1, normal haematological and biochemical parameters and no other malignant disease. Adequate surgery mandatory

Interventions

After randomisation all women received 4 standard cycles of doxorubicin (75 mg/m²) then HDC or CDC. HDC group received PBPC mobilisation (cyclophosphamide 4.0 gm/m² + filgrastim) followed by a single cycle of PBPC‐supported HDC (cyclophosphamide 6.0 gm/m², thiotepa 800 mg/m² + filgrastim). CDC group received conventional course of CMF (cyclophosphamide, methotrexate and fluorouracil)
All women had radiotherapy on completion of radiotherapy and tamoxifen for 5 years if oestrogen receptor status positive or unknown. Otherwise at discretion of treating physician

Outcomes

Overall survival
Event‐free survival
Quality of Life (EORTC Quality of Life Questionnaire)
Cost effectiveness

Notes

Power calculation: 300 participants in total would give power to detect a 12% survival difference at 5 years, assuming a survival with conventional chemotherapy (A‐CMF) of 50% at 10 years. Rapid accrual enabled inclusion of 600 women.
Data are immature as in the most recent trial publication not all participants have completed 5‐year follow‐up. 5‐year survival data presented in the tables of comparison have been calculated from 5‐year percentages reported by trialists at median of 6 years' follow‐up

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐based randomisation programme used

Allocation concealment (selection bias)

Low risk

"Patients were randomly assigned to their treatment by telephone from the trial management office."

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Blinding not mentioned; however this appears unlikely to influence primary review outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

603/605 (over 99%) of randomised women included in analysis

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

No other potential bias identified

Methods

Randomised controlled trial
Stratified by: Participating institution, disease stage, hormone receptor status, menopausal status
Number entered: 874
Number of dropouts pre‐randomisation: 100 (reasons: 26 had recurrent breast cancer, 2 died from chemo toxicity, 10 never received treatment, 25 were denied insurance cover for transplant, 15 withdrew, 5 were ineligible, 3 other reasons, 14 were removed for medical reasons)
Number of women randomised: 785 (394 high dose, 391 controls)
Number of women analysed: 785
Number of women not analysed: None
Number of breaches of protocol/failure to receive prescribed treatment: 112 minor protocol violations (54 in HDC, 58 in CDC) and 2 major protocol violations (2 women in HDC arm received CDC) included in analysis. 94% of HDC arm and 95% of CDC arm received prescribed treatment
Intention‐to‐treat analysis: Yes
Number of centres: 40
Source of funding: Public Health Service Grants
Years: 1/91 ‐ 5/98
Countries: Canada and USA

Participants

INCLUDED:
Women with operable Stage II or IIIa breast cancer with 10+ involved axillary lymph nodes, within 8 weeks of definitive surgery
No evidence of metastasis: Negative CTs, bone scans, bone marrow biopsies, chemistry panel. > 18 years and "physiologically" < 55 years of age. performance status of CALGB 0 or 1 or Karnofsky 80% ‐ 100%. Normal bone marrow, cardiac, pulmonary, renal function
No serious medical/psychiatric condition, evidence of adequate financial resources to cover treatments (e.g. insurance coverage)
Radical or modified mastectomy or lumpectomy with level 1/11 axillary dissection required not > 8 weeks prior to CAF initiation
EXCLUDED:
Bilateral, inflammatory or metastatic breast cancer
Prior chemotherapy or radiotherapy

Interventions

2 ‐ 8 weeks after primary surgery all women received 3 cycles of standard dose CAF chemotherapy (cyclophosphamide 600 mg/m²; doxorubicin 60 mg/m²; fluorouracil 1200 mg/m²). Women were then re‐evaluated and if disease‐free were randomised to HDC or CDC. HDC group had bone marrow harvest before or after a 4th cycle of standard‐dose CAF and GCSF‐primed PBPC harvest after the 4th cycle. They then received a course of HDC (cyclophosphamide 5625 mg/m², cisplatin 165 mg/m², carmustine 600 mg/m²) with both bone marrow and PBPC support, plus GCSF. The CDC group completed the 4th cycle of CAF then received an intermediate level dose of cyclophosphamide (900 mg/m²), cisplatin (90 m/m²) and carmustine (90 mg/m²), plus GCSF
All women received local‐regional radiation therapy and those with positive or unknown hormone receptor status received tamoxifen for 5 years following completion of chemotherapy

Outcomes

Disease‐free survival
Treatment toxicity (including death, infections, thrombocytopaenia, pulmonary drug toxicity, renal dysfunction, hepatic dysfunction) within 60 days of therapy
Quality of life (companion study CALGB 9066). Used the Functional Living Index‐Cancer (FLIC) scale and the McCorkle Symptom Distress Scale
Overall survival

Notes

Power calculation: 380 participants per arm give 90% power to detect 15% absolute difference in disease‐free survival at 5 years (P = 0.05)

Participants relapsing on CDC eligible for HDC, but post‐relapse transplant not part of protocol

Data are immature. 3‐year survival data in our tables of comparison have been calculated from percentages reported by trialists at median of 37 months' follow‐up, and 5‐year data have been calculated from 5‐year percentage survivals quoted by trialists at median of 7.3 years' follow‐up

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Methods not reported

Allocation concealment (selection bias)

Unclear risk

Methods not reported

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Blinding not mentioned; however this appears unlikely to influence primary review outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All randomised women included in analysis

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Unclear risk

112 women initially declared ineligible (with minor protocol violations) but subsequently randomised

Methods

Randomised controlled trial
Stratification: According to nodal status (4 ‐ 9 or > 9), age, menopausal status, and tumour size
Number of dropouts pre‐randomisation: Not stated
Number of women randomised: 885 (442 high dose, 443 standard dose)
Number of women analysed: 885
Number of women not analysed: None
Number of breaches of protocol/failure to complete prescribed treatment: 37 women found to be ineligible (4 had prior radiation, 2 had evidence of distant metastases, 1 had prior cervical cancer, 30 had abnormalities in lab tests); all stayed in the study. 2 women declined chemotherapy after randomisation (1 in each group). 45 women in the high‐dose group did not receive high‐dose chemotherapy (15 refused, 5 had psychological problems, 9 had medical complications, 6 had disease progression, 1 had venous access problems, 1 had insufficient progenitor cells harvested, 1 had early death, 7 for unknown reasons). Of 397 women who received high dose treatment, 6 did not receive the full dose due to complications: high fever (4), cardiac arrhythmia (1), possible heart failure (1).
Control arm: 1 refused any chemotherapy
Intention‐to‐treat analysis: Yes
Number of centres: 10
Source of funding: Health Care Insurers' Council
Years: 8/93 ‐ 7/99
Country: The Netherlands

Participants

INCLUDED:
Mastectomy or breast‐conserving surgery, < 6 weeks post‐op
Women < 56 years, WHO functional status 0 or 1
No prior chemotherapy or radiotherapy
Post‐mastectomy or breast‐conserving surgery for Stage II or III breast cancer
No distant metastases (assessed by chest X‐Ray, isotope bone scan, liver ultrasound)
Adequate organ function
At least 4 positive axillary lymph nodes

Interventions

Women randomised to the HDC group received 4 cycles of FEC (fluorouracil 500 mg/m², epirubicin 90 mg/m², cyclophosphamide 500 mg/m²) and 1 cycle of CTC (cyclophosphamide 6 g/m², thiotepa 480 mg/m², carboplatin 1600 mg/m²) with PBPC support
Women randomised to the CDC group received 5 courses of FEC
All women received radiation therapy and all received tamoxifen for 2 years post‐surgery, subsequently increased to 5 years for hormone receptor‐positive women

Outcomes

Relapse‐free survival
Overall survival
Toxicity
Quality of life (unpublished data)
Cost effectiveness

Notes

Power calculation: 880 participants give 90% power to detect a reduction in hazard of 24% after 571 events (progression‐free survival 30% to 40%)

3‐year data are mature: 3‐year survival results in our tables estimated from graphs published at median 57 month follow‐up
5‐year data immature: 5‐year event‐free survival results in our tables based on 5‐year actuarial rates reported as percentages by trialists at median follow‐up of 57 months. 5‐year overall survival results in our tables estimated from graphs published at median 57 month follow‐up

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated

Allocation concealment (selection bias)

Low risk

Treatment allocation by phone call to centralised trial office

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

A centralised review of pathological specimens was carried out in a blinded fashion. Otherwise blinding was not mentioned; however this appears unlikely to influence primary review outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All randomised women included in analysis

Selective reporting (reporting bias)

Low risk

Quote: "In two patients data were lacking on infectious complications and in three patients data were lacking on bacterial cultures. In 99% of patients (437 patients) sufficient data could be retrieved from the medical records and case record forms. Ultimately, 392 patients actually received high‐dose chemotherapy. Reasons not to proceed with the high‐dose regimen were an infected central venous catheter prior to high‐dose chemotherapy in three patients, venous access problems in one patient and catheter‐unrelated in the remaining patients."

Other bias

Low risk

No other potential bias identified

Methods

Randomised controlled trial
Stratification: Yes, according to a) whether clinically complete response to initial chemotherapy and b) postmenopausal status
Number of women who had upfront 3 cycles chemotherapy: 97
Number of dropouts pre‐randomisation: 16 (11 reluctant to undergo high‐dose therapy; 5 unresponsive to FEC)
Number of women randomised: 81
Number of women analysed: 81 (41 high dose, 40 standard dose)
Number of women not analysed: None
Number of breaches of protocol/failure to receive prescribed treatment: 6 (5 HDC arm refused HDC; 1 HDC arm failed to mobilise PBPCs so unsuitable for HDC)
Intention‐to‐treat analysis: Yes
Number of centres: 2 institutions, Phase II study
Source of funding: Schumaker‐Kramer Foundation
Years: 4/91 ‐ 12/95

Country: The Netherlands

Participants

INCLUDED:
Women < 60 years with operable breast cancer
Extensive involvement of level III axillary lymph notes as evidenced by positive axillary apex node on infraclavicular lymph node biopsy
No distant metastases: normal CXR, liver U/S, bone scan
Normal bone marrow, renal and hepatic functions
WHO performance status of 0 or 1.
Initial criterion: Evidence of at least a minimal clinical or subjective response to upfront 3 cycles FEC chemo
Later criteria: No evident progression of disease during upfront 3 cycles of FEC chemo
EXCLUDED:
Evidence of disease progression during initial chemotherapy (but before randomisation), defined as increase in tumour size of 25% or more, or appearance of new lesion

Interventions

Women were assessed for appropriate breast surgery.
All women received 3 courses of FEC (5 fluorouracil 500 mg/m², epirubicin 120 mg/m², cyclophosphamide 500 mg/m²)
At this stage women were clinically assessed to exclude those with no response to initial chemo. As this evaluation proved poorly reproducible, it was decided to exclude only those women with signs of disease progression
After surgery, women were randomised to receive HDC or CDC. The HDC arm received a 4th cycle of GCSF‐primed FEC followed by PBPC harvest. They then received HDC (cyclophosphamide 6 g/m², thiotepa 480 mg/m², carboplatin 1600 mg/m²) with PBPC support. The control group received a 4th cycle of FEC if they were judged to have chemosensitive disease
All women received radiation therapy and tamoxifen for 2 years.

Outcomes

Disease‐free survival
Overall survival
Toxicity

Notes

Power calculation: designed to provide 80% power to predict 30% increase in progression‐free survival at 4 years (30% ‐ 60%)
5‐year survival rates based on percentages reported in text. Follow‐up complete to 5 years. 7‐year survival rates based on median follow‐up of 6.9 years

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computerised randomisation

Allocation concealment (selection bias)

Low risk

Treatment allocation by phone call to centralised trial office

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Blinding not mentioned; however this appears unlikely to influence primary review outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All randomised women included in analysis

Selective reporting (reporting bias)

Low risk

Seems to be free of selective reporting

Other bias

Low risk

No other potential bias identified

Methods

Randomised controlled trial
Stratification: By institution, oestrogen receptor status, age, menopausal status
Number of women randomised: 540 (270 high dose, 270 standard dose)
Number of women analysed: 511
Number of women not analysed: 29 (28 due to major protocol violations: No bone scan (1), positive resected margins (5), no bone marrow biopsy (6), inflammatory carcinoma or peau d'orange (5), suspected metastasis (1), prior invasive Ca breast (1), diabetes (1), prior therapeutic oophorectomy (2), no documented LVE (1) or no documented pulmonary function test (3) at baseline, residual axillary disease (1), < 10 positive nodes (1); 1 due to having no data submitted)
Number of breaches of protocol: 28 major protocol violations as above, 94 minor protocol violations (e.g. documentation failures) but still included in analysis: 45 in high‐dose arm, 49 in control arm
Number who failed to receive prescribed treatment: 14% of high‐dose group did not receive a transplant and 7% underwent transplantation outside the study. 7% of control group received some form of transplantation therapy
Intention‐to‐treat analysis: 29 women not included in primary analysis due to major protocol violations or lack of data, as above.
Number of centres: Not stated
Source of funding: supported in part by grants from the Public Health Service, the National Cancer Institute, National Institutes of Health, and the Department
of Health and Human Services.
Years: 1991 ‐ 1998

Country: USA

Participants

INCLUDED: Women aged 15 ‐ 60 years with stage II or III epithelial breast cancer, within 12 weeks of breast surgery, with histologically free surgical margins and at least 10 positive ipsilateral lymph nodes
Negative bone marrow biopsy and bone scan or received 1 ‐ 2 cycles of doxorubicin based chemotherapy prior to trial entry
Normal LVE and FEV
ECOG performance status 0 or 1

EXCLUDED:
Any evidence of metastatic disease, serious organ dysfunction, pregnancy or breast feeding, prior malignancy
Any prior therapy for breast cancer except tamoxifen for up to 21 days and/or 1 or 2 cycles of doxorubicin‐based chemotherapy
Currently taking HRT

Interventions

All women had 6 cycles of cyclophosphamide 100 mg/m² orally for 14 days, and doxorubicin 30 mg/m² I/V and fluorouracil 500 mg/m² I/V on days 1 and 8 in 28‐day cycles. Women randomised to the HDC group then received 1 cycle of high‐dose CTM (cyclophosphamide 6 gm/m² and thiotepa 800 mg/m², continuously for 4 days with autologous stem cell support.
All women had a course of radiotherapy to the chest wall and regional lymphatics, plus tamoxifen for 5 years if hormone receptor positive

Outcomes

Event‐free survival, overall survival, time to recurrence, toxicity

Notes

Data immature: 6‐year results in our tables based on percentage survival figures at median follow‐up 6.1 years

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of randomisation not stated

Allocation concealment (selection bias)

Unclear risk

Method of allocation concealment not stated

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Blinding not mentioned; however this appears unlikely to influence primary review outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

511/540 (95%) randomised women included in analysis

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Unclear risk

"The primary analysis was originally planned to include the subgroup of eligible patients. However, owing to the high rates of ineligibility, this policy was reviewed in July 1999, whereupon we decided to divide protocol violations into major and minor categories and to include patients with minor violations in the primary analysis."

Methods

Randomised controlled trial
Stratified by clinical centre
Number of dropouts pre‐randomisation: None mentioned
Number of women randomised: 307 (150 high dose, 152 standard dose, 5 (who were subsequently excluded) not stated)
Number of women analysed: 302, including 18 who breached entry criteria (5 in high‐dose arm, 13 in control arm)
Number of women not analysed: 5 (excluded from analysis because of lack of co‐operation after randomisation)
Number of breaches of protocol/ failure to receive prescribed treatment: 20/150 (13%) of HDC arm did not complete treatment (11 refused, 8 had recurrence or died, 1 reason unknown); 16/152 CDC arm did not complete treatment (8 refused, 3 had recurrence or died, 2 due to side effects, 3 unknown)
Intention‐to‐treat analysis: No
Number of centres: 33 (plus 3 centres which were excluded because the 5 women they enrolled did not co‐operate)
Source of funding: the Dr Mildred Scheel Stiftung der Deutschen Krebshilfe, the Hamburger Krebsgesellschaft and the Erich and Gertrud Roggenbuck Foundation.
Years: 1993 ‐ 2000

Country: Germany

Participants

INCLUDED:
Women with > 10 positive axillary lymph nodes found at mastectomy or breast‐conserving surgery, aged not more than 60, Karnofsky index of at least 70
EXCLUDED:
Women with distant metastases, heart disease or reduced lung function

Interventions

All women had 4 cycles of EC (epirubicin 90 mg/m², cyclophosphamide 600 mg/m²). Women randomised to the HDC group then received 1 cycle of high‐dose CTM (cyclophosphamide 6 gm/m² , thiotepa 600 mg/m², mitoxanthrone 40 mg/m²) with PBPC support
Women randomised to the CDC group then received 3 cycles of CMF (cyclophosphamide 1000 mg/m², methotrexate 80 mg/m², 5‐fluorouracil 1200 mg/m²)
Both groups had tamoxifen for 5 years if their hormone receptor status was oestrogen‐ or progesterone‐positive

Application of radiotherapy not specified in protocol until 1998: from then on, radiotherapy recommended after both mastectomy and breast ‐conserving surgery, to start within 3 ‐ 6 weeks postoperatively

Outcomes

Event‐free survival
Absolute survival
Second cancer

Toxicity

Notes

Power calculation: 320 participants would give 80% power to detect an improvement in the 5‐year event‐free survival rate from 25% to 40% (P = 0.05)
Randomisation stopped at 307 in 2000 due to low recruitment

Data are immature: 4‐year data in our tables based on results at median 3.8 year follow‐up

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The randomization code was produced by the statistical center using a computerized random‐number generator. The clinical center was used as a stratification criterion, and within each center block, randomization with varying block size was performed."

Allocation concealment (selection bias)

Low risk

Quote: "The randomised treatment was communicated centrally by phone after registration of the patient, guaranteeing concealment of the randomised treatment."

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Quote: "Obviously, blinding was not possible, and the statistician was also aware of the treatment." This appears unlikely to influence primary review outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

302/307 (98%) randomised women included in analysis

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Unclear risk

More women in the high‐dose arm than in the control arm had in excess of 16 positive lymph nodes (52% compared to 38% in the control arm)

Methods

Randomised controlled trial
Stratified by menopausal status, hormone receptor status, institution
Number of dropouts pre‐randomisation: None mentioned
Number of women randomised: 344 (173 high dose, 171 standard dose)
Number of women analysed: 344
Number of women not analysed: None
Number of breaches of protocol/failure to receive prescribed treatment: None stated
Intention‐to‐treat analysis: Yes
Number of centres: 17
Source of funding: Grants plus industry support
Years: 1995 ‐ 2000

Countries: Australia, New Zealand, Italy, Switzerland, Hong Kong, Slovenia

Participants

INCLUDED:
Women with stage 2 or stage 3 breast cancer, having at least 10 positive nodes OR at least 5 positive nodes and oestrogen receptor‐negative OR at least 5 positive nodes and an operable T3 tumour

Interventions

HDC arm had 3 cycles of epirubicin 200 mg/m² and cyclophosphamide 4 gm/m² with PBPC support
CDC arm had 3 cycles of doxorubicin 60 mg/m² or epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² then 3 cycles of cyclophosphamide 100 mg/m², fluorouracil 600 mg/m² and methotrexate 40 mg/m²
After completing chemotherapy all women had tamoxifen 20 mg daily for 5 years

Outcomes

Event‐free survival
Overall survival
Treatment‐related death
Toxicity

Notes

Data immature: 8‐year data in our tables based on 8‐year estimates reported by trialists at median follow‐up 8.3 years

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomization was conducted centrally (at the coordinating centres in Bern, Switzerland, and Sydney, Australia). A permuted blocks randomization schedule was produced by use of pseudorandom numbers generated by a congruence method."

Allocation concealment (selection bias)

Low risk

Carried out by central data centre

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Blinding not mentioned; however this appears unlikely to influence primary review outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All randomised women analysed

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

No other potential bias identified

Methods

Randomised controlled trial
Number of women randomised: 281 (143 high dose, 138 standard dose)
Number of women analysed: 279
Number of women not analysed: 2 (lost to follow‐up)
Number of breaches of protocol/failure to receive prescribed treatment: 68 (30 in high‐dose arm, due to toxicity (5), centre error (1), refusal of treatment (10), recurrence (2), death (2), other reasons (10); 38 in control arm, due to toxicity (13), intercurrent illness (2), centre error (2), refusal of treatment (2), recurrence (3), death (2), other reasons (14))
Intention‐to‐treat analysis: 279 women analysed by intention‐to‐treat
Number of centres: 8
Source of funding: Cancer Research UK, Pharmacia, Amgen
Years: 1993 ‐ 2001

Countries: UK, Italy, Spain, Australia

Participants

INCLUDED: Women with primary breast cancer, T1 ‐ T4, aged 60 or less, with at least 4 positive axillary nodes after complete surgical resection and no metastatic disease on bone scan
EXCLUDED: Women with overt metastatic disease or abnormal bone marrow, hepatic or renal function or WHO performance status > 1

Interventions

All women had 1 3‐week cycle of FEC (cyclophosphamide 600 mg/m², epirubicin 50 mg/m², fluorouracil 600 mg/m²) followed by 2 4‐week cycles of FEC (as above but 2 doses per cycle)
Women randomised to the HDC arm then received cyclophosphamide 6 gm/m², epirubicin 50 mg/m² and carboplatin 800 mg/m² with PBSC support
Women randomised to the control arm had a further 3 4‐week cycles of FEC as above
Women who had had conservative surgery and some who had had a mastectomy received radiotherapy. All received tamoxifen for 5 years

Outcomes

Disease‐free survival
Overall survival
Toxicity

Notes

Power calculation: 300 participants would show an improvement from 30% ‐ 45% in 5‐year survival with 80% power (α = 0.05) Accrual failed following early reports from other trials

Data immature: 5‐year data in our tables based on 5‐year estimates by trialists at median 50 months follow‐up

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Centres randomised their patients by telephoning the ICCG Data Centre. The randomisation method used was adapted minimisation, where the weighted probabilities ensure a random component to the allocation. Stratification factors were centre, menopausal status and number of axillary nodes involved (4–9, 10+)".

Allocation concealment (selection bias)

Low risk

By telephone to central data centre

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Blinding not mentioned; however this appears unlikely to influence primary review outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

279/281 (99%) randomised women included in analysis

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

No other potential bias identified

Methods

Randomised controlled trial
Stratified by: Number of axillary nodes positive, menopausal status, institution
Number of women randomised: 97 (49 high dose, 47 standard dose)
Number of women analysed: 95
Number of women not analysed: 2 (ineligible: 1 was stage IV, 1 enrolled too late)
Number of breaches of protocol/failure to receive prescribed treatment: 17 (2 on standard arm: 1 wanted high‐dose chemotherapy, 1 refused any chemotherapy; 15 on high‐dose arm: 7 had recurrent breast cancer, 7 no reason stated, 1 was ineligible)
Intention‐to‐treat analysis: 95/97 participants analysed by intention‐to‐treat
Number of centres: 8
Source of funding: Grants‐in‐Aid from the Ministry of Health, Labor and Welfare of Japan, and the Science and Technology Agency
Years: 1993 ‐ 99

Country: Japan

Participants

INCLUDED:
Women with stage I to IIIB breast cancer, postoperatively (all had radical mastectomy)
≥ 10 positive axillary nodes (median 16; range 10 ‐ 49)
Age 15 ‐ 55
Grade 0 or 1 performance status
Negative bone marrow aspiration or biopsy, adequate bone marrow, hepatic, renal, cardiac and respiratory function
EXCLUDED:
Previous chemotherapy, radiotherapy or endocrine therapy
Median age was 46
72 (of 95) were premenopausal

Interventions

After randomisation, all women had 6 cycles of CAF (cyclophosphamide 500 mg/m², adriamycin 40 mg/m², fluorouracil 500 mg/m²)
HDC arm then had cyclophosphamide 6 gm/m² and thiotepa 600 mg/m²
Both arms: tamoxifen for at least 2 years

Outcomes

Relapse‐free survival
Overall survival
Treatment toxicity

Notes

1. Power calculation: 90% power to detect 30% increase in relapse‐free survival at 5 years of a 60% power to detect a 20% increase (P = 0.05) (1‐sided logrank)
2. Large number of withdrawals: Over 17% withdrew before treatment
3. 2 ineligible women were randomised and then excluded from event‐free survival analysis

Data immature ‐ median follow‐up 5.25 years

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "eligible patients were randomly assigned to the STD or HDC arm at the time of enrolment by
minimization method to balance the numbers of positive axillary nodes (10–19 or 20–), menopausal status (pre or post) and institution between the arms."

Allocation concealment (selection bias)

Low risk

Allocation by phone call to centralised trial office

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Blinding not mentioned; however this appears unlikely to influence primary review outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

95/97 (98%) randomised women included in analysis

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

No other potential bias identified

Methods

Randomised controlled trial
Number of dropouts pre‐randomisation: Not stated
Number randomised: 398 (196 high dose, 202 standard dose)
Stratified by number of nodes: 4 ‐ 9 or > 9
Number analysed: 382
Number of women not analysed: 16 (ineligible)
Number of breaches of protocol/failure to receive prescribed treatment: 16 refused treatment (5 in standard‐dose arm and 11 in high‐dose arm)
Intention‐to‐treat analysis: The 382 eligible participants were analysed by intention‐to‐treat
Number of centres: Multicentre
Source of funding: Italian Association for Cancer Research and pharmaceutical companies
Years: 1993 ‐ 98

Country: Italy

Participants

INCLUDED:
Post‐operative women with breast cancer with at least 4 positive axillary lymph nodes
Aged < 60

Interventions

Women randomised to the high‐dose arm received 1 cycle of cyclophosphamide 7 gm/m², then 1 cycle of methotrexate 8 gm/m², then 2 cycles of epirubicin 120 mg/m², then 1 cycle of thiotepa 600 mg/m² plus melphalan 160 ‐ 180 mg/m² plus PBPC transplant
Women in the control arm received 3 cycles of epirubicin 120 mg/m² then 6 cycles of CMF (cyclophosphamide 600 mg/m², methotrexate 40 mg/m² and fluorouracil 600 mg/m²)
Both arms: tamoxifen for 5 years
Women who had had conservative surgery received locoregional radiotherapy

Outcomes

Progression‐free survival
Overall survival
Treatment‐related mortality

Toxicity

Notes

Power calculation: 80% power to detect a 15% increase in progression‐free survival at 5 years

Progression‐free survival not defined; this outcome is reported as event‐free survival in this review

12‐year data in our tables based on percentages for survival reported by trialists at median follow‐up 136 months

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random‐number table

Allocation concealment (selection bias)

Low risk

Allocation by fax to centralised trial office

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Blinding not mentioned; however this appears unlikely to influence primary review outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

382/398 (96%) randomised women included in analysis

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

No other potential bias identified

Methods

Randomised controlled trial
Stratified by: Stage
Number randomised: 78 (39 high dose, 39 standard dose)
Number analysed: 78
Number of women not analysed: None
Number of breaches of protocol/failure to receive prescribed treatment: High‐dose arm: 10 (of 39) did not proceed to high‐dose chemotherapy: (1 was denied insurance cover, 3 refused the treatment, 1 developed hepatitis B, 1 was ineligible, 4 relapsed before high‐dose treatment). Of the women who proceeded to high‐dose therapy, 4 received only 1 of the 2 scheduled cycles (3 for toxicity and 1 refused) and 2 received different high‐dose regimens from those dictated by the protocol
Control arm: 3 (of 39) withdrew, electing to receive high‐dose treatment at other institutions
Intention‐to‐treat analysis: Yes
Number of centres: Not stated
Financed by: Supported in part by Public Health Service grant from the National Cancer Institute, National Institutes of Health, Department of Health
and Human Services, the Nylene Eckles Professorship in Breast Cancer Research, and the Nellie B. Connally Chair in Breast Cancer.
Years: 1/90 ‐ 11/97

Country: USA

Participants

INCLUDED:
1. Women with operable Stage II or III breast and 10+ positive axillary lymph nodes, having had no preoperative chemotherapy OR
2. Women with stage III or locally‐advanced breast cancer who had had 4 cycles of preoperative chemotherapy and at least 4 positive axillary lymph nodes found at surgery
Aged < 65
Adequate liver function, renal function, cardiac function, pulmonary function
EXCLUDED:
Comorbid condition that excludes possibility of high‐dose chemotherapy
Prior chemotherapy or radiation
HIV positive
Evidence of distant metastasis

Interventions

Women entered the trial in 2 ways:
a) Postoperative women were randomised before receiving any chemotherapy
b) Women who had chemotherapy preceding surgical resection were randomised before commencing postoperative chemotherapy
All women received a total of 8 cycles of FAC (5‐fluorouracil 1000 mg/m², doxorubicin 50 mg/m², cyclophosphamide 500 mg/m²)
Women randomised to high‐dose chemotherapy went on to receive 2 cycles of CEP (cyclophosphamide 5250 mg/m², cisplatin 165 mg/m², etoposide 1200 mg/m²) with autologous stem cell/bone marrow support. The control group did not receive any further chemotherapy. All women received radiotherapy. Those who were aged > 50 with oestrogen receptor‐positive tumours received tamoxifen for 5 years

Outcomes

Time to relapse
Overall survival
Treatment toxicity

Notes

Power calculation: Needed 40 participants in each arm to 80% power to detect 30% improvement in 3‐year relapse‐free survival (P = 0.05)
OR Needed observation of 24 participants who failed to respond to treatment (the latter was achieved)
Text of trial publication differs from flow chart with respect to number of women who withdrew from treatment in high‐dose group Figures given here are derived from the text
Results in our tables based on percentage estimates reported for 3‐year survival. Data are mature: median follow‐up 6.5 years

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote:"Randomization was performed by remote computer access; blocks of four patients (1122, 1221, 1212, 2121, etc.) were used in random order to ensure balance between the two treatment arms."

Allocation concealment (selection bias)

Low risk

Remote allocation. "Access to the computerized randomization program was restricted to research nurses and was not available to treating physicians."

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Blinding not mentioned; however this appears unlikely to influence primary review outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All randomised women included in analysis

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Unclear risk

10/39 women randomised to high‐dose arm did not receive high‐dose chemo

Methods

Randomised control trial

Number of dropouts pre‐randomisation: Not stated
Number randomised: 536 (265 high dose, 271 standard dose)
Stratified by: Primary therapy i.e. mastectomy without radiotherapy, mastectomy with radiotherapy after chemotherapy, or breast‐conserving therapy with radiotherapy after chemotherapy
Number analysed: 536
Number of women not analysed: None
Number of breaches of protocol/failure to receive prescribed treatment: None stated
Intention‐to‐treat analysis: Yes
Number of centres: Multicentre
Source of funding: National Cancer Institute, Department of Health and Human Services
Years: 1996 ‐ 2001

Country: USA

Participants

Women with breast cancer who had completed modified radical mastectomy or breast‐conserving surgery with axillary dissection within 12 weeks of registration. Initially, the study included patients with four to nine involved lymph nodes. In March 2000, the study was amended to include patients with 10 or more involved lymph
nodes. Patients with ipsilateral internal mammary or supraclavicular lymph node involvement and patients with T4 tumours were excluded.

Interventions

High‐dose arm: doxorubicin and cyclophosphamide X 4 followed by high‐dose STAMP I or STAMP V (depending on centre) with autograft

STAMP I consisted of cyclophosphamide 1.85 g/m²/d and cisplatin 55 mg/m²/d, each for 3 days (days 6, 5, and 4), followed by carmustine 600 mg/m² (day 3).

STAMP V consisted of cyclophosphamide 1.5 g/m²/d, carboplatin 200 mg/m²/d, and thiotepa 125 mg/m²/d for 4 days (days 7 through 4).

Control arm: doxorubicin, paclitaxel and cyclophosphamide X 3 of each in intensive sequential doses supported by GCSF

Outcomes

Disease‐free survival

Overall survival

Toxicity

Notes

Initial plan was to enrol 1000 women as approximately 350 events were required to achieve 90% power to be able to detect 45% improvement in the transplantation arm. The process of enrolment began in July 1996 and was stopped in February 2001 as the data from transplantation trials in breast cancer were not very encouraging

5‐year data immature; median follow‐up 70 months (max 102 months)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computerised randomisation

Allocation concealment (selection bias)

Unclear risk

Method not described

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Blinding not mentioned; however this appears unlikely to influence primary review outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All randomised women included in analysis

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

No other potential bias identified

Methods

Randomised controlled trial
Number of dropouts pre‐randomisation: Not stated
Number of women randomised: 314 (159 high dose, 155 standard dose)
Number of women analysed: 314
Number of women not analysed: None
Number of breaches of protocol/failure to receive prescribed treatment: 15 did not complete high‐dose treatment
Intention‐to‐treat analysis: Yes
Number of centres: Not stated
Source of funding: Ligue Nationale Contre le Cancer, Association pour la Recherche sur le Cancer, Fondation de France
Years: 12/94 ‐ 12/98

Country: France

Participants

INCLUDED:
Postoperative women with breast cancer
< 60 years
> 7 nodes involved
No metastatic disease on clinical examination

Interventions

All women received 4 cycles of FEC (fluorouracil 500 mg/m²; cyclophosphamide 500 mg/m²; epirubicin 100 mg/m²)
Women in the high‐dose arm then received 1 cycle of CMA (cyclophosphamide 120 mg/kg; mitoxantrone 40 mg/m²; alkeran 100 mg/m²) plus PBPC transplant (harvested during 2nd or 3rd FEC cycles with GCSF priming)
Women in the CDC arm had no further chemotherapy
All women had radiotherapy, and postmenopausal hormone receptor‐positive women also had tamoxifen

Outcomes

Event‐free survival
Overall survival
Toxicity
Quality of life
Cost effectiveness

Notes

Power calculation: 90% power to detect a 20% increase in disease‐free survival at 3 years (P = 0.05)
Data are immature. 3‐year survival results in our tables are based on 3‐year percentages reported by the trialists at a median follow‐up of 39 months

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method not reported

Allocation concealment (selection bias)

Unclear risk

Method not reported

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Blinding not mentioned; however this appears unlikely to influence primary review outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All randomised women included in analysis

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

No other potential bias identified

Methods

Randomised controlled trial
Method of randomisation: Remotely generated, "with a random permuted block design and stratification by tumour size (<4 cm or >/=4 cm) and by centre."

Allocation concealment: Done centrally by telephone or fax
Number of dropouts pre‐randomisation: Not stated
Number of women randomised: 403 (201 high dose, 202 standard dose)
Number of women analysed: 403
Number of women not analysed: None
Number of breaches of protocol/failure to receive prescribed treatment: High‐dose arm: 8 received no protocol therapy, 3 crossed to opposite arm, 1 was male (*see Participants), 4 had metastases, 14 had no documented radiotherapy. Control arm: 7 received no protocol treatment, 1 crossed to opposite arm, 2 had metastases, 19 had no documented radiotherapy
Intention‐to‐treat analysis: Yes
Number of centres: 6
Source of funding: Amgen, Pharmacia and Lederle
Years: 6/95 ‐ 6/02

Country: Germany

Participants

INCLUDED:
Women* with breast cancer within 6 weeks of complete resection, No metastases on CXR, liver US, bone scan. Adequate organ function performance status < 2
18 ‐ 60 years
At least 10 axillary nodes involved

* One man was randomised: it is unclear whether this was a breach of protocol

Interventions

All women received 2 cycles of EC (cyclophosphamide 600 mg/m²; epirubicin 90 mg/m²) 2 weeks apart with GCSF priming
Women in the high‐dose arm then received tandem EC‐thiotepa (cyclophosphamide 3000; epirubicin 90, thiotepa 400 mg/m² X 2 cycles 28 days apart) plus PBPC transplants (harvested after EC with GCSF priming)
Women in the CDC arm had 4 further cycles of EC 2 weeks apart with GCSF priming ("dose‐intense" regimen)
All women had radiotherapy, and postmenopausal hormone receptor‐positive women also had tamoxifen.

Outcomes

Event‐free survival
Overall survival
Toxicity

Quality of life: European Organisation for Research and Treatment of Cancer quality‐of‐life C30 questionnaire (only administered to "about" the first 200 participants)

Notes

Power calculation: 80% power to detect a 10% absolute reduction in event‐free survival after 3 years
ASCO abstract at 34.6‐month follow‐up gives estimated survival for 2 and 4 years only. 3‐year data reported in our tables are estimated from graphs in 2003 ASCO slide presentation

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Remotely generated, with a random permuted‐block design and stratification by tumour size (<4 cm or >/=4 cm) and by centre."

Allocation concealment (selection bias)

Low risk

"Randomisation was done centrally by telephone or fax in the WSG study office"

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Blinding not mentioned; however this appears unlikely to influence primary review outcomes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All randomised women included in analysis

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

No other potential bias identified