Study ID

Median Age

Tumour

Median nodes positive

Minimum nodes positive

> 9 nodes

Oestro positive

Progest. positive

Other

Premenop'sal

ACCOG 2004

45

3 cm max.

9

4

45%

31% (ER or PR +ve)

31% (ER or PR +ve)

43% receptor unknown

‐

CALGB 2005

45

3 cm median

14 (range 10 ‐ 52)

10

100%

69%

‐

‐

‐

Dutch pilot 1998

45

T1 5%; T2 30%; T3 45%; T4 10%; Tx 10%

‐

N/A: Had pre‐op chemo

N/A

20%

25%

54% receptor unknown

83%

Dutch Intergp 2003

45.7

T1 22%; T2 60%; T3 16%

‐

4

35.8%

65%

53%

28% oestrogen receptor negative

‐

ECOG 2003

44

‐

‐

10

‐

60%

59%

46% > 14 +ve nodes

72%

GABG 2004

‐

‐

‐

10

100%

60%

40%

‐

58%

IBCSG 2006

46

T1 26%; T2 51%; T3 20%

13

5 ‐ 10 depending on other prognostic factors

73%

‐

‐

40% oestrogen & progesterone receptor ‐ve

67%

ICCG 2005

47 (range 24 ‐ 60)

T1 28%; T2 54%; T3 14%; unknown 4%

9 (range 4 ‐ 36)

4

45%

43%

25%

38% receptor status not known

70%

JCOG 2001

46

‐

16 (range 10 ‐ 49)

10

100%

‐

‐

‐

74%

MDACC 2000

45

‐

‐

10 at diagnosis or 4 after initial chemo

> 60%

50%

45%

5% receptor unknown

68%

MCG 2001

‐

‐

‐

4

62%

‐

‐

‐

‐

PEGASE 01 2003

46 (mean)

‐

13

8

?

31%

‐

‐

68%

NCT00002772

Not stated. 45% were aged 40 ‐ 49 yrs

20% had T3 tumour

8% were N2

‐

‐

‐

‐

66% ER/PgR +ve; 8% receptor unknown

‐

WSG 2005

47

Mean size 3.3 ‐ 3.5 cm

17 ‐ 18

10

100%

63%

‐

‐

53%

Stage

What stage means

I

Breast tumour 2 cm or less in diameter and does not appear to have spread beyond the breast

IIA

Breast tumour over 2 cm in diameter OR has spread to the axillary (underarm) lymph nodes on the same side as the breast cancer. The nodes are not stuck to one another or to the surrounding tissues

IIB

Breast tumour over 2 cm in diameter AND has spread to the axillary nodes on the same side as the breast cancer. The nodes are not stuck together or to the surrounding tissues. OR the tumour is larger than 5 cm in diameter (and nodes are clear)

IIIA

Breast tumour over 5 cms in diameter AND has spread to the axillary lymph nodes on the same side OR tumour has spread to the lymph nodes on the same side as the breast cancer and the nodes are stuck to each other or to the surrounding tissues

IIIB

Breast tumour has spread to chest wall or skin OR tumour has spread to internal mammary lymph nodes on the same side as breast tumour

IV

Tumour has spread from breast to distant sites or to supraclavicular (above collarbone) lymph nodes

Study

Phase 1

Phase 2

ACCOG 2004

doxorubicin 75 mg
4 cycles

cyclophosphamide
methotrexate
fluorouracil
8 cycles (doses not stated)

CALGB 2005

cyclophosphamide 600 mg
doxorubicin 60 mg
fluorouracil 1200 mg
4 cycles

cyclophosphamide 900 mg
cisplatin 90 mg
carmustine 90 mg
1 cycle with GCSF

Dutch Intergp 2003

cyclophosphamide 500 mg
epirubicin 90 mg
fluorouracil 500 mg
5 cycles

‐

Dutch pilot 1998

cyclophosphamide 500 mg
epirubicin 90 mg
fluorouracil 500 mg
4 cycles

‐

ECOG 2003

cyclophosphamide 1400 mg (po)
doxorubicin 60 mg
fluorouracil 1000 mg
X 6 cycles

‐

GABG 2004

cyclophosphamide 600 mg
epirubicin 90 mg
4 cycles

cyclophosphamide 1 gm
methotrexate 80 gm
fluorouracil 1200 mg
3 cycles

IBCSG 2006

doxorubicin 60mg or epirubicin 90 mg
cyclophosphamide 600 mg
3 cycles

cyclophosphamide 1400 mg (po)
fluorouracil 1200 mg
methotrexate 80 mg
3 cycles

ICCG 2005

cyclophosphamide 600 mg
epirubicin 50 mg
fluorouracil 500 mg
1 cycle

cyclophosphamide 1200 mg
epirubicin 100 mg
fluorouracil 1000 mg
5 cycles

JCOG 2001

cyclophosphamide 500 mg
doxorubicin 40 mg
fluorouracil 500 mg
6 cycles

‐

MCG 2001

epirubicin 120 mg 3 cycles

cyclophosphamide 600 mg
methotrexate 40 mg
fluorouracil 600 mg
6 cycles

MDACC 2000

cyclophosphamide 500 mg
doxorubicin 50 mg
fluorouracil 1 gm
8 cycles

‐

PEGASE 01 2003

cyclophosphamide 500 mg
epirubicin 100 mg
fluorouracil 500 mg
4 cycles

‐

NCT00002772

sequential administration of 3 cycles each of doxorubicin 80 mg/m², paclitaxel 200 mg/m², and cyclophosphamide
3 g/m² (total 9 cycles over 18 weeks), with a cumulative doxorubicin dose of 240 mg/m²

‐

WSG 2005

cyclophosphamide 600 mg
epirubicin 90 mg
4 cycles X 2 weekly

cyclophosphamide 600 mg
methotrexate 40 mg
fluorouracil 600 mg
3 cycles X 2 weekly with GCSF

Study

Initial phase

High‐dose cycle 1

High‐dose cycle 2

High‐dose cycle 3

High‐dose cycle 4

Regimen

ACCOG 2004

4 cycles of doxorubicin (as control arm) followed by:

cyclophosphamide 4 gm

cyclophosphamide 6 gm
thiotepa 800 mg

‐

‐

Divided doses over 4 days

CALGB 2005

4 cycles of cyclophosphamide, doxorubicin and fluorouracil (as control arm) followed by:

cyclophosphamide 5.625 gm
cisplatin 165 mg
carmustine 600 mg

‐

‐

‐

Divided doses over 3 days

Dutch Intergp 2003

4 cycles of cyclophosphamide, epirubicin and fluorouracil (doses as control arm) followed by:

cyclophosphamide 6 gm
thiotepa 480 mg
carboplatin 1600 mg

‐

‐

‐

Divided doses over 4 days

Dutch pilot 1998

4 cycles of cyclophosphamide, epirubicin and fluorouracil (as control arm) followed by:

cyclophosphamide 6 gm
thiotepa 480 mg
carboplatin 1600 mg

‐

‐

‐

Divided doses over 4 days

ECOG 2003

6 cycles of cyclophosphamide, doxorubicin and 5FU (as control arm) followed by:

cyclophosphamide 6 gm
thiotepa 800 mg

‐

‐

‐

Continuous infusion over 4 days

GABG 2004

4 cycles of cyclophosphamide and epirubicin (as control arm) followed by:

cyclophosphamide 6 gm
thiotepa 600 mg
mitoxantrone 40 mg

‐

‐

‐

Divided doses over 4 days

IBCSG 2006

No common path with control group protocol

epirubicin 200 mg
cyclophosphamide 4 gm

As cycle 1

As cycle 1

3 X 21‐day cycles

ICCG 2005

2 cycles of cyclophosphamide, epirubicin and fluorouracil (as control arm cycles 1 and 2)

cyclophosphamide 6 gm
thiotepa 600 mg
carboplatin 800 mg

‐

‐

‐

Continuous infusion over 4 days

JCOG 2001

6 cycles of cyclophosphamide, doxorubicin and fluorouracil (as control arm), followed by:

cyclophosphamide 6 gm
thiotepa 600 mg

‐

‐

‐

‐

MCG 2001

No common path with control group protocol

cyclophosphamide 7 gm

methotrexate 8gm

epirubicin 120 mg X 2

thiotepa 600 mg melphalan 160 ‐ 180 mg

4 high‐dose treatments in sequence

MDACC 2000

8 cycles of cyclophosphamide, doxorubicin and fluorouracil (as control arm), followed by:

cyclophosphamide 5.25 gm
cisplatin 165 mg
etoposide 1.2 gm

As cycle 1

‐

‐

Divided doses over 3 days. 2nd cycle given when haematologically safe

PEGASE 01 2003

4 cycles of cyclophosphamide, epirubicin and fluorouracil (as control arm), followed by:

cyclophosphamide 120 mg
mitoxantrone 45 mg
alkeran 140 mg

‐

‐

‐

‐

NCT00002772

4 cycles of doxorubicin 80 mg/m² and cyclophosphamide 600 mg/m² (AC) every 3 weeks

STAMP I or STAMP V HDC regimen.

STAMP I consisted of cyclophosphamide 1.85 g/m²/d and cisplatin 55 mg/m²/d, followed by carmustine 600 mg/m²;

STAMP V consisted of cyclophosphamide 1.5 g/m²/d, carboplatin 200 mg/m²/d, and thiotepa 125 mg/m²/d

‐

‐

‐

‐

WSG 2005

2 cycles of cyclophosphamide and epirubicin (as control arm)

cyclophosphamide 3 gm
epirubicin 90 mg
thiotepa 400 mg

As cycle 1

‐

‐

High‐dose cycles over 28 days

Study ID

Data maturity

Median follow‐up

ACCOG 2004

No

4 years

CALGB 2005

No

7.3 years

Dutch pilot 1998

5 years

6.9 years

Dutch Intergp 2003

3 years

7 years

ECOG 2003

No

6.1 years

GABG 2004

No

6.1 years

IBCSG 2006

No

8.3 years

ICCG 2005

No

4.2 years

JCOG 2001

No

63 months

MDACC 2000

3 years

11.9 years

MCG 2001

No

11.33 years

PEGASE 01 2003

3 years

3.25 years

NCT00002772

No

5.8 years

WSG 2005

3 years

4 years

Study ID

Haemopoietic

Gastrointestinal

Pulmonary

Cardiac events

Neurological

Other toxicity

Late/ long term

Second cancers

Trialist's summary

ACCOG 2004

Standard chemo: Grade 4 neutropenia 15%

Haemorrhage ≥ grade 2:
High‐dose arm 8%
Control arm 1%
Platelet‐related toxicity ≥ grade 3:
High‐dose arm 19%
Control arm 1%
Neutrophil‐related toxicity ≥ grade 4:
High‐dose arm 21%
Control arm 22%

Nausea ≥ grade 3:
High‐dose arm 30%
Control arm 27%
Vomiting ≥ grade 4:
High‐dose arm: 14%
Control arm: 2%
Diarrhoea ≥ grade 3:
High‐dose arm 23%
Control arm 1%

Rhythm toxicity ≥ grade 2:
High‐dose arm 2%
Functional toxicity ≥ grade 2:
High‐dose arm 2%
Pericardial toxicity ≥ grade 1:
High‐dose arm 1%

Cortical neurotoxicity ≥ 1
High‐dose arm 2%
Control arm 1%
Constipation ≥ 3:
High‐dose arm 2%
Control arm 1%

Both trial arms: Menopausal symptoms common.
High‐dose arm: several cases of shingles, which responded to acyclovir.
Nitrogen or creatinine disorder ≥ grade 2 2%
Proteinuria ≥ grade 2 2%
Haematuria ≥ grade 2 5%
Allergy ≥ grade 2 8%
Skin problem ≥ grade 3 6%
Infection ≥ grade 3 28%
Local pain ≥ grade 2 6%
Control arm:
Haematuria ≥ grade 2 2%
Allergy ≥ grade 2 1%
Skin problem ≥ grade 3 2%
Infection ≥ grade 3 4%%

‐

‐

‐

CALGB 2005

Leukopenia and thrombocytopenia common in both groups but more severe and persistent in HDC arm

‐

Toxicity ≥ grade 3:
High‐dose arm: > 10%
Control arm: "infrequent"

‐

Toxicity ≥ grade 3:
High‐dose arm: > 10%
Control arm: "infrequent"

Hepatic toxicity ≥ grade 3:
High‐dose arm: > 10%
Control arm: "infrequent"

‐

By median 7.5 yrs

High‐dose arm: 16 second cancers (4%) (including acute myeloid leukaemia or myelodysplatic syndrome 7; breast cancer 5)
Control arm: 20 second cancers (5%) (including acute myeloid leukaemia or myelodysplastic syndrome 4; breast cancer 8)

9/13 breast cancers considered new primaries

‐

Dutch pilot 1998

High‐dose chemo: all hospitalised for 13 ‐ 30 days for haemopoietic recovery. Median neutropenic fever 5 days Standard chemo: neutropenic fever after 4% of cycles

High‐dose: mucositis 85% (severe in 22%), diarrhoea common. Standard chemo: Mild nausea and vomiting, mucositis (28% of cycles), diarrhoea (4% of cycles)

‐

See long‐term events

‐

Both arms: alopecia 100%, fatigue common, lymphoedema of arm in 20% High‐dose: ovarian failure 100%, radiation pneumonitis 10%, Standard dose: radiation pneumonitis 2%

High‐dose arm: 1 case hypothyroidism, 1 case auto‐antibody production
Control arm: 1 case hypothyroidy, 1 myocardial infarction

At median follow‐up of 7 years:
High‐dose arm: 4/41 (basal cell skin cancer 1, colon 1, myelodysplastic syndrome 2)
Control arm: 1/40 (colon)

High‐dose: "Moderately well tolerated but substantial though reversible toxic effects". Standard dose: "Mild toxicity"

Dutch Intergp 2003

High‐dose: transfusion‐dependent 100%
Standard chemo: fever and neutropenia requiring antibiotics 1% of episodes

High‐dose: nausea and vomiting 100%
Standard chemo: moderate or severe mucositis < 1% of courses, moderate or severe nausea 10% of courses

‐

High‐dose: cardiac arrhythmia 1/442, possible heart failure 1/442

‐

High‐dose: high fever (necessitating early termination of treatment): 4 women (1%)

‐

By median follow‐up 7 years:
High‐dose arm: 28/442 women (29 cancers: breast 17, melanoma 3, uterine 3, non melanoma skin cancer 3, head and neck 1, oesophagus 1, pancreas 1).
Control arm: 26/443 women (27 cancers: breast cancer 15, melanoma 2, nonmelanoma skin cancer 1, myelodysplasia or leukaemia 1, ovarian 1, uterine 1, head and neck 2, lung 1, stomach 1, papil vater 1, unclear 1)

High‐dose: "Well tolerated"

ECOG 2003

High‐dose: leukopenia 98%, granulocytopenia 94%, thrombocytopenia 97%, anaemia 62%,
Standard chemo: granulocytopenia and thrombocytopenia 90% (grade 3 or 4)

High‐dose: nausea 32%, vomiting 16%, diarrhoea 22%, stomatitis 37% Standard chemo: nausea 11%, vomiting 8%, stomatitis 4% (all grade 3 or 4)

Standard chemo: 1% (grade 3 or 4)

‐

Standard chemo: 6% (grade 3 or 4)

High‐dose: infection 21%, liver effects 13%, skin effects 11%, diabetes 14% Standard dose: hyperglycaemia 2%, phlebitis 1%, hepatotoxicity 1% (all grade 3 or 4)

‐

By median 6.1 years:
High‐dose: 15/254 (ovary 2, myelodysplastic syndrome or acute myelogenous leukaemia 9, nonmelanoma skin cancer 2, cervix 1, sarcoma 1)
Control arm: 9/257 (thyroid 1, kidney 2, melanoma 2, nonmelanoma skin cancer 1, myeloma 1, endometrium 1, non‐Hodgkin's lymphoma 1)

‐

GABG 2004

‐

High‐dose: Grade 3 or 4 gastrointestinal toxicity < 1%;
Grade 3 or 4 oral mucosal toxicity 5%

Grade 3 or 4 toxicity < 1%

‐

High‐dose: Grade 3 or 4 toxicity nil

High‐dose: Grade 3 or 4 toxicity: Bladder < 1%; kidney nil; liver nil

‐

‐

‐

IBCSG 2006

High‐dose: myelosuppression
Standard dose: neutropenia

High‐dose: nausea and vomiting; mucositis

‐

‐

‐

‐

Permanent amenorrhoea: High‐dose arm 77/95 (81% overall, age < 40 years 61%; age > 40 years 96%); Standard‐dose arm 61/98 (63% overall age < 40 years 24%; age > 40 years 84%)

By median 8.3 years:
High‐ dose: 6/173 (1 AML (with breast cancer recurrence), 2 melanoma, 1 endometrium, 1 ovary, 1 head and neck)
Control arm: 2/171 (1 melanoma, 1 unstated)

High‐dose: Overall toxicities Grade 3 1%; Grade 4 98%;
Standard dose: Overall toxicities Grade 3: 41%, Grade 4: 35%

ICCG 2005

High‐dose: leucopenia and thrombocytopenia presumed 100% but nadir count not always available (grade 3 or 4)
Control group:
(second half of course): leucopenia 14%, thrombocytopenia 0% (grade 3 or 4)

High‐dose: nausea and vomiting 46%, mucositis 22% (grade 3 or 4)
Control group (second half of course): nausea and vomiting 5%, mucositis 2% (grade 3 or 4)

High‐dose: Pulmonary embolus 1/143; respiratory failure requiring ventilator 1/143

High‐dose: severe cardiac arrhythmia 2% (3/143)

‐

High‐dose: hair loss 100%, fever (no infection) 17%, infection 24%, "other" 28% (grade 3 or 4), deep vein thrombosis 1/143
Control group (second half of course): hair loss 9%, fever (no infection) 0%, infection 3%, "other" 5% (grade 3 or 4), deep vein thrombosis 1/138

After chemotherapy: 227 toxic events occurred (127 in high‐dose arm, 110 in control arm), of which 30% related to tamoxifen. Of the others, 7 events deemed life‐threatening (5 in high‐dose group, 2 in control arm)
All premenopausal women developed amenorrhoea following completion of chemotherapy

High‐dose: 2/143 (breast 1, ovarian 1)
Control arm: 1/138 (ovarian)

JCOG 2001

High‐dose:

All 34 women receiving HDC actually developed grade 4 leukopenia and grade 4 neutropenia; 27 (79%) developed grade 4 and the other 7 grade 3 thrombocytopenia. Standard dose:

7 women (8%) developed grade 4 neutropenia

High‐dose: vomiting 62%, diarrhoea 29%, mucositis 15%, (grade 3 or 4)

‐

High‐dose: grade 3 arrhythmia 3%,

‐

High‐dose: Grade 3 or 4 infection: 6%

‐

‐

‐

MDACC 2000

High‐dose: Length of hospital stay not stated. Standard dose: 22% admitted with infection or fever

High‐dose: mild/moderate vomiting 80%, mild/moderate diarrhoea 58%, mild/moderate mucositis 83%. Standard dose: Nausea and vomiting moderate 75%, severe 16%. Diarrhoea moderate 19%, severe 8%. Mucousitis moderate 36%, severe 10%

High‐dose: 1 case (severe)

High‐dose: moderate/severe 8%. Standard dose: 1 woman (1%) had myocardial infarction

High‐dose: hearing loss 2 cases (6%) ‐ 1 permanent, mild/moderate peripheral neuropathy 11%

High‐dose: Renal: 25% (22% mild, < 3% severe), hepatic (mild/moderate) 31%, bladder (moderate) 25%, skin (mild) 8%

High‐dose: 1 case of avascular necrosis
Standard dose: 1 woman (1%) had cerebrovascular accident, 1 (1%) had hepatic fibrosis

High‐dose: 1 case of acute myeloid leukaemia

"Overall there was greater and more frequent morbidity associated with high dose chemotherapy"

MCG 2001

‐

‐

‐

‐

‐

‐

‐

‐

‐

PEGASE 01 2003

‐

‐

‐

‐

‐

‐

‐

‐

‐

NCT00002772

High‐dose: 62% had haematologic toxicity during induction and 92% had it during transplantation.

3 women had myelodysplastic syndrome

Controls: 59% had haematologic toxicity

2 women had myelodysplastic syndrome

‐

‐

‐

‐

‐

High‐dose: 44% of women experienced

grade 3 or 4 nonhaematologic toxicity during induction while 80%

experienced grade 3 or 4 nonhematologic toxicity during transplantation.

Control arm:

Approximately 63% experienced grade 3 or 4 nonhaematologic toxicity, most commonly fatigue, nausea and vomiting, infection, febrile neutropenia, mucositis,

and sensory neuropathy

‐

High‐dose: 44% had
grade 3 or 4 nonhaematologic toxicity during inductio; 80%
experienced grade 3 or 4 nonhaematologic toxicity during transplantation. Controls: 63% had grade 3 or 4 nonhaematologic toxicity, most commonly fatigue, nausea and vomiting, infection, febrile neutropenia, mucositis,
and sensory neuropathy

WSG 2005

‐

High‐dose arm: nausea 25%, mucositis 18%, diarrhoea 5%
Control arm: nausea 10%, mucositis 10%, diarrhoea 2%
(all grade 3 or 4, percentages are approximate)

High‐dose arm: 1%
Control arm 2% (grade 3 or 4, percentages are approximate)

High‐dose arm: 3%
Control arm: 1%
(grade 3 or 4, percentages are approximate)

‐

High‐dose arm: grade 3 or 4 skin toxicity 3%, amenorrhoea 100%
Control arm: grade 3 or 4 skin toxicity 2%

‐

‐

Both high‐dose chemotherapy and dose‐dense conventional chemotherapy are feasible with tolerable toxicity in a multicentre setting