Adjuvant cyclophosphamide, methotrexate, and fluorouracil in premonopausal patients with node-positive breast cancer: Indirect comparison of dose and schedule in DBCG trials 77, 82, and 89

Figures & data

Table I.  Patient characteristics.

	DBCG 77 (N = 323) No. %	DBCG 82 (N = 982) No. %	DBCG 89 (N = 908) No. %
Age at enrolment, years
≤ 40	86 (27)	226 (23)	285 (31)
41–45	85 (26)	259 (26)	295 (32)
46–50	74 (23)	292 (30)	265 (29)
51–59	78 (24)	205 (21)	63 (7)
Loco-regional therapy
Breast-conserving surgery	0 (−)	114 (12)	321 (35)
Mastectomy	323 (100)	868 (88)	587 (65)
Nodal status
1–3 positive nodes	207 (64)	702 (71)	536 (59)
4–9 positive nodes	97 (30)	224 (23)	281 (31)
≥ 10 positive nodes	19 (6)	56 (6)	91 (10)
Tumor size
0–20 mm	88 (27)	449 (46)	408 (45)
21–50 mm	127 (39)	446 (45)	390 (43)
> 50 mm	41 (13)	70 (7)	87 (10)
Unknown	67 (21)	17 (2)	23 (3)
Histologic type
Infiltrating ductal carcinoma	277 (86)	865 (88)	774 (85)
Infiltrating lobular carcinoma	19 (6)	63 (6)	76 (8)
Medullary carcinoma	6 (2)	24 (2)	25 (3)
Other carcinomas	15 (5)	23 (2)	21 (2)
Unknown	6 (2)	7 (1)	12 (1)
Malignancy grade (ductal carcinoma only)
Grade I	58 (21)	213 (25)	169 (22)
Grade II	159 (57)	421 (49)	357 (46)
Grade III	57 (21)	208 (24)	231 (30)
Unknown	3 (1)	23 (3)	17 (2)
Hormone receptor
Negative	27 (8)	104 (11)	271 (30)
Positive	82 (25)	442 (45)	543 (60)
Unknown	214 (66)	436 (44)	94 (10)

Figure 1.  Disease-free survival (DFS) comparison between the 77 and 82 programs (Panel A) and the 77 and 89 programs (Panel B).

Table II.  End-points.

	DBCG 77 (N = 323) No. (%)	DBCG 82 (N = 982) No. (%)	DBCG 89 (N = 908) No. (%)
Local or regional recurrence only*	9 (6)	56 (12)	60 (15)
Contralateral breast cancer	13 (9)	28 (6)	45 (11)
Distant metastases	111 (73)	331 (70)	273 (67)
Second primary non-breast cancer	3 (2)	15 (3)	8 (2)
Death without recurrence	17 (11)	45 (9)	22 (5)
Death attributable to any cause	127 (39)	431 (44)	350 (39)
All events included in analysis of DFS	153 (47)	475 (48)	408 (45)

*Breast, chest wall or regional lymph nodes.

Figure 2.  Overall survival (OS) comparison between the 77 and 82 programs (Panel A) and between the 77 and 89 programs (Panel B).

Figure 3.  Forest plots illustrating proportional hazard models for DFS comparison between the 77 and 82 programs (Panel A) and between the 77 and 89 programs (Panel B). Hazard ratios refer to adjusted per protocol estimates obtained in the multivariate analysis.

Figure 4.  Forest plots illustrating proportional hazard models for OS comparison between the 77 and 82 programs (Panel A) and between the 77 and 89 programs (Panel B). Hazard ratios refer to adjusted per protocol estimates obtained in the multivariate analysis.

Figure 5.  Delivered dose-intensity of cyclophosphamide (Panel A), methotrexate (Panel B) and fluorouracil (Panel C) (weekly dose in mg/m²) in the 77 (•) 82 (▪) and 89 (▴) programs.

Table III.  Treatment-related adverse effects (Modified WHO criteria).

	DBCG 77 (N = 323)	DBCG 82 (N = 982)	DBCG 89 (N = 908)
	No. (%)	No. (%)	No. (%)	P
Nausea and vomiting				<0.01
None (Grade 0)	39 (12)	80 (8)	375 (41)
Slight (Grade 1)	132 (41)	213 (22)	268 (30)
Moderate (Grade 2)	116 (36)	403 (41)	127 (14)
Severe (Grade 3–4)	35 (11)	274 (28)	52 (6)
Unknown	1 (−)	12 (1)	86 (9)
Conjunctivitis or stomatitis				<0.01
None (Grade 0)	180 (56)	506 (52)	500 (55)
Slight (Grade 1)	86 (27)	339 (35)	244 (27)
Moderate (Grade 2)	45 (14)	103 (10)	64 (7)
Severe (Grade 3)	10 (3)	22 (2)	6 (1)
Unknown	2 (1)	12 (1)	94 (10)
Alopecia				<0.01
None (Grade 0)	93 (29)	419 (43)	403 (44)
Minimal (Grade 1)	151 (47)	462 (47)	355 (39)
Complete (Grade 2)	73 (23)	84 (9)	51 (6)
Unknown	6 (2)	17 (2)	99 (11)

Toxicity was recorded using a simplified translation of the WHO toxicity scale.

Table IV.  Planned dose-intensity.

	Dose mg/m^2, route	Schedule	Dose-intensity mg/m^2/ week
DBCG 77-B
Cyclophosphamide	80, orally	days 1–14, q 4 weeks	280
Methotrexate	30, i.v.	day 1 + 8, q 4 weeks	15
Fluorouracil	500, i.v.	day 1 + 8, q 4 weeks	250
DBCG 82-B
Cyclophosphamide	600, i.v.	day 1, q 4 weeks	150
Methotrexate	40, i.v.	day 1, q 4 weeks	10
Fluorouracil	600, i.v.	day 1, q 4 weeks	150
DBCG 89 B and D
Cyclophosphamide	600, i.v.	day 1, q 3 weeks	200
Methotrexate	40, i.v.	day 1, q 3 weeks	13.3
Fluorouracil	600, i.v.	day 1, q 3 weeks	200