Phase II study of whole brain radiotherapy with or without erlotinib in patients with multiple brain metastases from lung adenocarcinoma

Figures & data

Table 1 Eligibility criteria, exclusion criteria, rejection criteria, and suspension criteria

	WBRT group	WBRT + erlotinib group
Eligibility criteria	Lung adenocarcinoma	Equal to WBRT group
	First-line chemotherapy failure Multiple brain metastases diagnosed by CT/MRI RPA class 1 or 2	Having EGFR mutation detection
	Expected survival time ≧6 months Over 4 weeks after blood-brain barrier-crossing cytotoxic drugs medication
	Hb ≧ 90; granulocyte count ≧ 1.5 × 10^9/L; Platelet count ≧ 100 × 10^9/L; Serum bilirubin ≦1.5 × ULN; AST and/or ALT ≦2× ULN; Serum creatinine ≦1.5 × ULN
Exclusion criteria	Double or multiple primary cancer	Equal to WBRT group
	Presence of unstable systemic disease RPA class 3	Unable to take erlotinib
	Leptomeningeal metastases
	Patient is unable to complete WBRT
	Treated with SRS after WBRT
	Previous use of TKI
Rejection criteria	Taking blood–brain barrier-crossing cytotoxic drugs in the period of WBRT or follow-up
	Application of stereotactic radiotherapy in follow-up or WBRT
	Not following the implementation of this program
Suspension criteria	Patient requirement
	Serious adverse reactions

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CT, computed tomography; EGFR, epidermal growth factor receptor; Hb, hemoglobin; MRI, magnetic resonance imaging; RPA, recursive partitioning analysis; SRS, stereotaxic radiosurgery; TKI, tyrosine kinase inhibitors; ULN, upper limit of normal; WBRT, whole brain radiotherapy.

Table 2 Patient and tumor characteristics

Characteristic	WBRT group	WBRT + erlotinib group
Cases	31	23
Sex
Female	18 (58)	13 (57)
Male	13 (42)	10 (43)
Age (y)
Range	43–81	37–76
Median	63	60
PRA class
1	3 (10)	2 (9)
2	29 (90)	21 (91)
KPS score
Range	70–100	70–100
Median	80	80
Initial stage (cases)
I	2 (7)	1 (4)
II	8 (26)	6 (26)
III	11 (35)	8 (35)
IV	10 (32)	8 (35)
EGFR status
EGFR mutation	–	11 (48)
EGFR wild-type	–	12 (52)
EGFR unknown	31 (100)	0 (0)
Previous therapy
Chemoradiotherapy only	16 (52)	11 (48)
Chemoradiotherapy + surgery/surgery + chemoradiotherapy	15 (48)	12 (52)
Tumor control before WBRT
CR	0 (0)	0 (0)
PR	5 (16)	3 (13)
SD	11 (36)	9 (39)
PD	15 (48)	11 (48)
Brain metastases
Range	2–12	2–35
Median	4	4
Size of largest brain metastasis (cm)
Range	0.70–4.10	0.80–4.70
Median	2.10	2.20
Extracranial metastasis or uncontrolled primary tumor
Yes	26 (84)	21 (91)
No	5 (26)	2 (9)
Consecutive chemotherapy
Yes	19 (61)	14 (61)
No	12 (39)	9 (39)

Notes: Data presented as number of patients, with percentages in parentheses. P > 0.05 comparing all the characteristics between the two groups.

Abbreviations: CR, complete response; EGFR, epidermal growth factor receptor; KPS, Karnofsky Performance scale; PD, progressive disease; PR, partial response; PRA, recursive partitioning analysis; SD, stable disease; WBRT, whole brain radiotherapy; y, year.

Table 3 Treatment-related toxicity

NCI-CTC adverse event	Grade (cases: WBRT/WBRT +erlotinib)
	Any	1	2	3	4	5
Constitutional symptoms
Acratia	15/12	12/9	3/3
Fatigue	3/3	3/3
Weight loss	13/12	11/10	2/2
Dermatology
Cheilitis	0/0	1/9
Dry skin	1/9*	0/3	0/1
Nail changes	0/4*	0/9
Pruritus/itching	0/9*	0/9	0/4
Rash	0/13*	4/5
Radiation dermatitis	4/5
Gastrointestinal
Anorexia	8/13*	2/5	2/6	0/2
Constipation	8/10	8/8	0/2
Diarrhea	1/3	1/3
Dyspepsia	1/3	1/3
Nausea	7/11*	6/7	1/4
Vomiting	5/6	1/4	0/2
Mucositis	1/1	1/1
Stomatitis	1/2	1/2
Taste alteration	3/3	3/3
Eyes
Xerophthalmia	0/0
Conjunctivitis	0/0
Headache	6/5	5/1	1/4
Dizziness	6/11*	5/10	0/0	1/1
Pulmonary/upper respiratory
Cough	5/8	5/7	0/1
Dyspnea	0/0
Pneumonitis	7/7	7/7
Blood
Hemoglobin	2/5	2/5
Leucocyte	3/3	3/3
Platelet	2/2	2/2
Liver/renal function
AST	2/4	2/2	0/2
ALT	2/3	2/3
Bilirubin	1/0	1/0
Serum creatinine	2/2	2/2

Note:

* P < 0.05.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; NCI-CTC, National Cancer Institute-Common Toxicity Criteria; WBRT, whole brain radiotherapy.

Figure 1 The LPFS, PFS, and OS of WBRT group versus WBRT+erlotinib group.

Notes: The median LPFS, PFS, and OS were 6.8 months (range, 0–18.7 months), 5.2 months (range, 0–14.7 months), and 8.9 months (range, 4.5–19.7 months), respectively, in the WBRT group and 10.6 months (range, 4.9–20.7 months), 6.8 months (range, 1.5–20.7 months), and 10.7 months (range, 5.3–29.7 months), respectively, in the combination group. There were statistically significant differences in the LPFS, PFS, and OS between the groups.
Abbreviations: CI, confidence interval; HR, hazard ratio; LPFS, local progression-free survival; OS, overall survival; PFS, progression-free survival; WBRT, whole brain radiotherapy.

Figure 2 The LPFS, PFS, and OS of EGFR mutation patients versus EGFR wild-type patients in the combination arm.

Notes: In the combination group, 12 patients had no exons mutations; 11 patients had 19/21 exons mutations, and no patients had k-ras mutations. The median LPFS, PFS, and OS were 9.6 months (range, 6.9–16.4 months), 7.5 months (range, 6.2–16.1 months), and 10.2 months (range, 7.1–16.5 months), respectively, in the EGFR wild-type group and 11.2 months (range, 4.9–20.7 months), 6.1 months (range, 3.2–20.7 months), and 11.5 months (range, 5.3–29.7 months), respectively, in the EGFR mutation group. There were no statistically significant differences in the LPFS, PFS, and OS between the two groups.
Abbreviations: CI, confidence interval; HR, hazard ratio; LPFS, local progression-free survival; MT-EGFR, mutation-type EGFR patients; OS, overall survival; PFS, progression-free survival; WT-EGFR, wild-type EGFR patients; EGFR, epidermal growth factor receptor.

Table 4 Results of multivariate Cox regression analysis for LPFS, PFS, and OS

Factor	Regression coefficient	Wald value	P value	RR value	95% CI
LPFS
Size of largest brain metastasis	0.764	7.566	0.006	2.146	1.245–3.698
Extracranial metastasis or uncontrolled primary tumor	1.566	5.377	0.020	4.788	1.274–17.990
Erlotinib medication	−2.094	13.882	0.000	0.123	0.041–0.371
Chemotherapy	−1.123	6.001	0.014	0.325	0.132–0.799
PFS
Extracranial metastasis or uncontrolled primary tumor	3.094	11.882	0.001	22.062	3.799–128.124
Erlotinib medication	−1.297	7.191	0.007	0.273	0.106–0.705
OS
Extracranial metastasis or uncontrolled primary tumor	1.332	4.145	0.042	3.787	1.051–13.647
Erlotinib medication	−1.012	3.843	0.050	0.364	0.132–1.000
Chemotherapy	−1.296	8.605	0.003	0.274	0.115–0.650

Abbreviations: LPFS, local progression-free survival; CI, confidence interval; OS, overall survival; PFS, progression-free survival; RR, response rate.