Daily evening melatonin prolongs survival among patients with advanced non-small-cell lung cancer

Figures & data

Table 1. Patient characteristics by three treatment arms

Variable	Placebo arm (n = 29)	AM melatonin (n = 27)	PM melatonin (n = 28)	p-Value
Age (Mean)	63	60.6	60.3	NS
Gender Male Female	21 8	22 5	22 6	NS
Tumor stage IIIB IV	5 24	10 17	5 23	NS
Performance status 0 1 2	11 13 5	10 15 2	10 14 4	NS
Treatment site MRMC VAMC	14 15	14 13	15 13	NS

NS, p-value not significant.

Table 2. Baseline mean QoL and sleep quality scores by three treatment arms

QLQ-C30 (n = 74)	Placebo (n = 24)	AM melatonin (n = 25)	PM melatonin (n = 25)	p-Value
Global	47.2	55.6	51.0	NS
Physical	63.6	66.6	65.8	NS
Role	52.7	58.6	54.0	NS
Emotional	57.8	62.0	60.6	NS
Cognitive	69.4	72.0	71.3	NS
Social	50.0	56.0	61.3	NS
Fatigue	52.7	51.1	50.2	NS
Nausea/Vomiting	13.8	13.3	17.3	NS
Pain	59.8	46.6	58.6	NS
Dyspnea	45.8	45.3	45.3	NS
Insomnia	48.6	52.0	30.6	NS
Appetite loss	40.2	37.3	37.3	NS
Constipation	29.1	26.6	32.0	NS
Diarrhea	11.1	6.6	1.3	NS
QLI (n = 75)	Placebo (n = 24)	AM melatonin (n = 25)	PM melatonin (n = 26)	p-Value
Health and physical	15.5	17.3	15.8	NS
Social and economic	22.2	20.3	20.8	NS
Psychological/Spiritual	21.5	21.4	21.7	NS
Family	25.0	22.4	22.3	NS
Overall HRQOL	19.8	19.6	19.3	NS
PSQI (n = 71)	Placebo (n = 24)	AM Melatonin (n = 21)	PM melatonin (n = 26)	p-Value
Global Sleep Score	7.5	11.7	9.4	0.008

NS, p-value not significant.

Table 3. Mean change (± s.e.m.) in QoL and sleep quality scores and tumor response by three treatment arms

QLQ-C30 (n = 56)	Placebo (n = 18)	AM melatonin (n = 18)	PM melatonin (n = 20)	p-Value
Global	−13.4 ± 9.0	−1.9 ± 8.0	6.3 ± 7.5	NS
Physical	−11.9 ± 5.3	0.7 ± 2.9	−8.0 ± 4.3	NS
Role	−3.7 ± 3.5	3.7 ± 6.3	−5.0 ± 7.1	NS
Emotional	6.2 ± 8.2	8.8 ± 5.0	4.2 ± 8.2	NS
Cognitive	0 ± 5.6	2.8 ± 4.3	−2.5 ± 5.6	NS
Social	4.9 ± 8.9	9.8 ± 5.2	−9.6 ± 6.2	NS
Fatigue	11.8 ± 8.3	−4.3 ± 6.1	4.1 ± 5.4	NS
Nausea/Vomiting	−3.9 ± 5.8	5.6 ± 5.9	9.6 ± 5.7	NS
Pain	−8.8 ± 6.2	−10.2 ± 7.3	−18.4 ± 7.8	NS
Dyspnea	17.6 ± 6.5	−7.4 ± 6.4	−3.5 ± 8.0	0.037
Insomnia	−3.9 ± 8.0	−3.7 ± 6.5	−5.3 ± 8.2	NS
Appetite loss	−15.7 ± 6.5	−5.6 ± 8.6	−1.8 ± 5.4	NS
Constipation	−9.8 ± 10.2	−1.9 ± 7.8	7.0 ± 9.0	NS
Diarrhea	−5.9 ± 6.5	−3.7 ± 2.5	5.3 ± 2.9	NS
QLI (n = 48)	Placebo (n = 15)	AM melatonin (n = 15)	PM melatonin (n = 18)	p-Value
Health and physical	0.4 ± 1.0	1.4 ± 1.2	1.0 ± 1.2	NS
Social and economic	0.6 ± 1.5	2.1 ± 1.4	0.9 ± 1.4	NS
Psychological/Spiritual	−2.3 ± 1.8	−0.2 ± 1.3	0.7 ± 1.5	NS
Family	−1.1 ± 1.6	3.4 ± 1.2	1.2 ± 1.6	NS
Overall HRQOL	−0.5 ± 1.2	1.5 ± 1.0	0.9 ± 1.1	NS
PSQI (n = 50)	Placebo (n = 19)	AM melatonin (n = 14)	PM melatonin (n = 17)	p-Value
Global Sleep Score	5.0 ± 1.2	1.1 ± 0.8	3.1 ± 0.8	0.027
Tumor response (n = 49)	Placebo (n = 19)	AM melatonin (n = 13)	PM melatonin (n = 17)	p-Value
Partial response	2 (10.5%)	1 (7.7%)	5 (29.4%)	NS
Stable disease	14 (73.7%)	10 (76.9%)	9 (52.9%)
Progressive disease	3 (15.8%)	2 (15.4%)	3 (17.6%)
Not evaluable for tumor response (n = 35)	Placebo (n = 10)	AM melatonin (n = 14)	PM melatonin (n = 11)
Nonresponsive to follow-up due to disease progression	8	3	6	NS
Pleural effusions (unmeasurable tumor)	5	12	6	NS

NS, p-value not significant; s.e.m, standard error of mean.

Figure 1. Change in PSQI total score (2nd administration minus baseline) by treatment arm Shaded Area Represents 95% Confidence Intervals for Median.

Table 4. Mortality through days post treatment

Arm	Time	Number at risk	Number with event	Kaplan–Meier survival rate	Kaplan–Meier event rate	Peto standard error(K-M event rate)	Two-sided 95% CI (K-M event rate)
AM melatonin	Day 0	27	0	100%	0.0%	0.0%	., .
AM melatonin	Month 1	25	2	92.6%	7.4%	5.0%	73.5%, 98.1%
AM melatonin	Month 6	17	10	63.0%	37.0%	9.3%	42.1%, 78.1%
AM melatonin	Month 12 (Year 1)	11	16	40.7%	59.3%	9.5%	22.5%, 58.2%
AM melatonin	Month 24 (Year 2)	6	21	22.2%	77.8%	8.0%	9.0%, 39.0%
AM melatonin	Month 36 (Year 3)	5	22	18.5%	81.5%	7.5%	6.7%, 34.8%
PM melatonin	Day 0	28	0	100%	0.0%	0.0%	., .
PM melatonin	Month 1	28	0	100%	0.0%	0.0%	., .
PM melatonin	Month 6	19	9	67.9%	32.1%	8.8%	47.3%, 81.8%
PM melatonin	Month 12 (Year 1)	12	16	42.9%	57.1%	9.4%	24.6%, 60.0%
PMmelatonin	Month 24 (Year 2)	4	24	14.3%	85.7%	6.6%	4.5%, 29.5%
PM melatonin	Month 36 (Year 3)	4	24	14.3%	85.7%	6.6%	4.5%, 29.5%
Placebo	Day 0	29	0	100%	0.0%	0.0%	., .
Placebo	Month 1	29	1	96.6%	3.4%	3.3%	78.6%, 99.5%
Placebo	Month 6	21	8	72.4%	27.6%	8.3%	52.3%, 85.1%
Placebo	Month 12 (Year 1)	11	18	37.9%	62.1%	9.0%	20.9%, 54.9%
Placebo	Month 24 (Year 2)	3	26	10.3%	89.7%	5.7%	2.6%, 24.3%
Placebo	Month 36 (Year 3)	1	28	3.4%	96.6%	3.4%	0.3%, 14.9%

Log-rank test pvalue: 0.810.

Table 5. Multivariate Cox regression analysis for overall survival

Parameter	Hazard ratio	95% CI	p-Value
MRMC Site (vs VAMC)	2.554	(1.27, 5.12)	0.008
Age (decades of life)	2.050	(1.474, 2.852)	<.0001
AM melatonin ARM (vs placebo)	1.170	(0.776, 1.764)	NS
PM melatonin ARM (vs placebo)	0.610	(0.390, 0.956)	0.031
Sleep efficiency	1.400	(1.098, 1.787)	0.007
Sleep quality	0.536	(0.354,0.811)	0.003
QLI: Family	0.919	(0.858, 0.986)	0.018
Physical function	1.023	(0.994, 1.053)	NS
Role function	0.981	(0.966, 0.996)	0.012
Cognitive function	0.973	(0.954, 0.993)	0.008
Nausea and Vomiting	1.014	(0.996, 1.031)	NS
Insomnia	0.988	(0.977, 0.999)	0.032

NS, p-value not significant; CI, confidence interval. Hazard ratios are per unit increase for all quantitative variables unless specified otherwise.

Figure 2. Overall survival stratified by treatment arm. Univariate Survival analysis derived from N = 84.