Dose-tailoring of FEC adjuvant chemotherapy based on leukopenia is feasible and well tolerated. Toxicity and dose intensity in the Scandinavian Breast Group phase 3 adjuvant Trial SBG 2000-1

Figures & data

Tabel I. Dose escalation and reduction scheme (mg/m²).

Leukopenia	Dose level	5-FU	Epirubicin	Cyclophosphamide
Grade 0–1 (≥3.0 × 10^9/l)	3	600	90	1200 + Mesna
Grade 2 (2.0–2.9 × 10^9/l)	2	600	75	900
Grade 3 (1.0–1.9 × 10^9/l)	1	600	60	600
Grade 4 (< 1.0 × 10^9/l)	0	600	45	450

Table II. Consort diagram.

Registration
n = 1535
Course 1
n = 1535
Excluded
Patient wish (n = 67) and WBC unknown (n = 15).
Randomised
n = 1052
Standard		Tailored		Registered
WBC*	n	WBC	n	WBC	n
0–1	183	0–1	222	0–1	0
2	343	2	300	2	0
3	2	3	2	3	387
4	0	4	0	4	14
Total	528	Total	524	Total	401
Course 2–7
Patient not received course 2 excluded (Tailored, n = 1)
Standard and Tailored WBC 3 excluded (n = 4)
Safety population
n = 1448

*Leukocyte grading at nadir following course 1.

Table III. Patient characteristics.

	Standard		Tailored		Registered		Total
	n	%	n	%	n	%	n	%
Country
Denmark	191	(36.3)	193	(37.0)	132	(32.9)	516	(35.6)
Sweden	335	(63.7)	328	(63.0)	269	(67.1)	932	(64.4)
Age at surgery
25–35	39	(7.4)	29	(5.6)	22	(5.5)	90	(6.2)
36–45	159	(30.2)	163	(31.3)	108	(26.9)	430	(29.7)
46–55	255	(48.5)	251	(48.2)	210	(52.4)	716	(49.4)
56–60	73	(13.9)	78	(15.0)	61	(15.2)	212	(14.6)
Menopausal status
Pre-menopausal	375	(71.3)	367	(70.4)	280	(69.8)	1022	(70.6)
Post-menopausal	151	(28.7)	154	(29.6)	121	(30.2)	426	(29.4)
Tumour size (mm)
0–20	253	(48.1)	242	(46.4)	213	(53.1)	708	(48.9)
21–50	248	(47.1)	260	(49.9)	172	(42.9)	680	(47.0)
51−	23	(4.4)	18	(3.5)	16	(4.0)	57	(3.9)
Unknown	2	(0.4)	1	(0.2)	0	(0.0)	3	(0.2)
Tumour positive LN
0	170	(32.3)	165	(31.7)	124	(30.9)	459	(31.7)
1−3	235	(44.7)	235	(45.1)	189	(47.1)	659	(45.5)
4 +	121	(23.0)	121	(23.2)	88	(21.9)	330	(22.8)
Histological grade. ductal tumours
1	42	(8.0)	48	(9.2)	37	(9.2)	127	(8.8)
2	231	(43.9)	201	(38.6)	146	(36.4)	578	(39.9)
3	226	(43.0)	250	(48.0)	202	(50.4)	678	(46.8)
Unknown	27	(5.1)	22	(4.2)	16	(4.0)	65	(4.5)
ER-status
Negative	149	(28.3)	177	(34.0)	129	(32.2)	455	(31.4)
Positive	374	(71.1)	344	(66.0)	271	(67.6)	989	(68.3)
Unknown	3	(0.6)	0	(0.0)	1	(0.2)	4	(0.3)
Total	526	(100.0)	521	(100.0)	401	(100.0)	1448	(100.0)

Table IV. Relative dose intensity.

		Cyclophosphamide			Epirubicin			5-FU
	n	percentile 10^th	Median	90^th	10^th	Median	90^th	10^th	Median	90^th
Standard	526	97.1	100.0	101.6	96.5	100.0	101.6	97.2	100.0	101.6
Tailored	521	74.0	98.0	105.5	82.0	98.0	103.8	96.3	100.0	101.1
Registered	401	86.1	100.0	101.9	86.1	100.0	101.9	87.2	100.0	101.9
Tailored*		113.3	143.3	185.7	104.2	121.9	142.6	96.3	100.0	101.1

*Relative to expected on standard.

Table V. Treatment feasibility: number of treatments, number of treatment delays and omitted treatments.

	Standard		Tailored		Registered		Total
	n	%	n	%	n	%	n	%
Treatment courses
2	0	(0.0)	2	(0.4)	1	(0.2)	3	(0.2)
3	0	(0.0)	2	(0.4)	2	(0.5)	4	(0.3)
4	2	(0.4)	1	(0.2)	0	(0.0)	3	(0.2)
5	5	(1.0)	4	(0.8)	3	(0.7)	12	(0.8)
6	11	(2.1)	10	(1.9)	10	(2.5)	31	(2.1)
7	508	(96.6)	502	(96.4)	385	(96.0)	1395	(96.3)
Delays*
0	493	(93.7)	479	(91.9)	359	(89.5)	1331	(91.9)
1	32	(6.1)	39	(7.5)	38	(9.5)	109	(7.5)
2	1	(0.2)	3	(0.6)	3	(0.7)	7	(0.5)
3	0	(0.0)	0	(0.0)	1	(0.2)	1	(0.1)
Omitted treatments
0	525	(99.8)	520	(99.8)	401	(100.0)	1446	(99.9)
1	1	(0.2)	1	(0.2)	0	(0.0)	2	(0.1)
Total	526	(100.0)	521	(100.0)	401	(100.0)	1448	(100.0)

*Treatment delayed more than 7 days or treatment omitted.

Figure 1. Distribution of nadir leukocytes after courses 1–7. Cumulative percentage of patients in the three study arms on the x-axis with nadir values below value as indicated on the y-axis.

Table VI. Max grade of leukopenia during courses 2–7.

		Max grade of leukopenia course2-7
Treatment	n	0–1 (%)	2 (%)	3 (%)	4 (%)	PStd-Tai*	PTai-Reg*
Standard	526	17.5	53.6	28.1	0.8
Tailored	521	1.3	9.0	58.3	31.3	< 0.0001
Registered	401	0.7	11.2	80.0	8.0		0.0001
Total	1448	7.0	25.8	53.4	13.7

*Two-sided Mann-Whitney test.

Table VII. Non-haematological side-effects during courses 2–7.

			Maximum CTC-grade
Side-effect	Treatment	n	0 (%)	I (%)	II (%)	II (%)	IV (%)	PStd-Tai*	PTai-Reg*
Mucositis	Standard	484	33.3	40.7	25.0	0.0	1.0
	Tailored	474	22.2	40.1	35.2	1.1	1.5	< .0001
	Registered	375	32.0	40.5	26.1	0.3	1.1		0.0001
	Total	1333	29.0	40.4	29.0	0.5	1.2
Nausea	Standard	486	6.6	55.1	28.8	5.3	4.1
	Tailored	481	7.3	43.7	33.9	8.5	6.7	0.0016
	Registered	376	10.4	46.8	31.4	8.5	2.9		0.021
	Total	1343	7.9	48.7	31.3	7.4	4.7
Vomiting	Standard	486	48.6	17.5	23.3	9.1	1.6
	Tailored	481	30.1	18.1	31.4	17.7	2.7	< .0001
	Registered	375	44.0	21.6	20.3	12.0	2.1		< .0001
	Total	1342	40.7	18.9	25.3	13.0	2.2
Diarrhoea	Standard	484	58.7	33.9	6.4	0.8	0.2
	Tailored	480	55.6	34.2	8.8	1.5	0.0	0.23
	Registered	374	59.1	30.2	9.6	1.1	0.0		0.40
	Total	1338	57.7	33.0	8.1	1.1	0.1
Alopecia	Standard	482	0.6	5.4	94.0	–	–
	Tailored	471	0.2	2.3	97.5	–	–	0.0083
	Registered	371	0.3	4.6	95.1	–	–		0.074
	Total	1324	0.4	4.1	95.5	–	–
Fatigue	Standard	483	1.7	17.6	56.5	20.1	4.1
	Tailored	479	0.6	13.2	55.7	21.5	9.0	0.0023
	Registered	372	2.7	20.7	52.7	16.4	7.5		0.0006
	Total	1334	1.6	16.9	55.2	19.6	6.8

*Two-sided Mann-Whitney test.