Second primary malignancy risk after radiotherapy in rectal cancer survivors

Table 1 Patient characters and treatment factors

	All patients	Surgery-only	All radiotherapy	Postoperative	Preoperative	Long	Short
Patient number	28220	21769	6451	4826	1625	1311	314
Male (%)	16297 (58%)	12323 (57%)	3974 (62%)	2940 (61%)	1034 (64%)	831 (63%)	203 (65%)
Median follow-up (IQR), yr	5.19 (5.02)	5.47 (5.18)	4.25 (3.98)	4.29 (4.10)	4.16 (3.61)	4.18 (3.76)	4.10 (3.01)
Median rectal cancer diagnosis age (IQR)	65 (18)	66 (18)	62 (17)	62 (18)	61 (19)	60 (18)	64 (18)
Median rectal cancer diagnosis year (IQR)	2005 (7)	2004 (6)	2006 (6)	2005 (6)	2007 (5)	2007 (5)	2007 (4)
Surgery
LAR	20416	16253	4163	2953	1210	950	260
APR	6285	4453	1832	1471	361	311	50
Other surgery	1519	1063	456	402	54	50	4
Chemotherapy
All chemotherapy (%)	18236 (65%)	12310 (57%)	5926 (92%)	4445 (92%)	1481 (91%)	1276 (97%)	205 (65%)
Fluorouracil	12063	7399	4664	3428	1236	1105	131
Tegafur	11324	8139	3185	2547	638	517	121
Oxaliplatin	4033	2460	1573	1273	300	262	38
Irinotecan	3273	2020	1253	1069	184	151	33
Capecitabine	2620	1632	988	773	215	185	30
Comorbidities
DM	10802	8560	2242	1696	546	427	119
Hypertension	18096	14438	3658	2742	916	720	196
Liver cirrhosis	1521	1227	294	225	69	46	23
Autoimmune disease	1763	1372	391	298	93	76	17
End stage renal disease	5456	4402	1054	825	229	168	61
COPD	10762	8709	2053	1585	468	368	100
Dyslipidemia	11695	9246	2449	1779	670	534	136

IQR: Inter-quantile range; LAR: Low anterior resection; APR: Abdominoperineal resection of rectum; DM: Diabetes mellitus; COPD: Chronic obstructive pulmonary disease.

Table 2 Second primary malignancy of different treatment groups

	All patients	Surgery-only	Long	Short	Post
All SPM	1270 (100)	1056 (100)	49 (100)	10 (100)	155 (100)
Head and neck	89 (7)	69 (6.5)	7 (14.3)	2 (20)	11 (7.1)
Esophagus	31 (2.4)	28 (2.7)	0 (0)	0 (0)	3 (1.9)
Stomach	82 (6.5)	68 (6.4)	4 (8.2)	1 (10)	9 (5.8)
Liver	183 (14.4)	162 (15.3)	3 (6.1)	3 (30)	15 (9.7)
Pancreas	31 (2.4)	26 (2.5)	1 (2)	0 (0)	4 (2.6)
Lung	284 (22.4)	224 (21.2)	16 (32.7)	0 (0)	44 (28.4)
Bone	17 (1.3)	14 (1.3)	0 (0)	0 (0)	3 (1.9)
Skin	31 (2.4)	23 (2.2)	1 (2)	2 (20)	5 (3.2)
Breast	82 (6.5)	71 (6.7)	3 (6.1)	0 (0)	8 (5.2)
Cervix	18 (1.4)	17 (1.6)	0 (0)	0 (0)	1 (0.6)
Uterus	15 (1.2)	10 (0.9)	2 (4.1)	0 (0)	3 (1.9)
Ovary	10 (0.8)	10 (0.9)	0 (0)	0 (0)	0 (0)
Prostate	129 (10.2)	116 (11)	2 (4.1)	1 (10)	10 (6.5)
Bladder	83 (6.5)	63 (6)	2 (4.1)	0 (0)	18 (11.6)
Kidney	45 (3.5)	40 (3.8)	1 (2)	1 (10)	3 (1.9)
Thyroid	18 (1.4)	15 (1.4)	0 (0)	0 (0)	3 (1.9)
Hematologic	59 (4.6)	46 (4.4)	3 (6.1)	0 (0)	10 (6.5)
Others	63 (5)	54 (5.1)	4 (8.2)	0 (0)	5 (3.2)

SPM: Second primary malignancy.

Table 3 Cox regression of second primary malignancy

	Univariate Cox regression		Multi-variate Cox regression
	Hazard ratio (95%CI)	P value	Hazard ratio (95%CI)	P value
Sex(M)	1.57 (1.40-1.75)a	< 0.001	1.47 (1.32-1.65)a	< 0.001
Diagnosis age (1 yr increment)	1.02 (1.01-1.02)a	< 0.001	1.02 (1.01-1.02)a	< 0.001
Diagnosis year	1.06 (1.04-1.08)a	< 0.001	1.06 (1.04-1.08)a	< 0.001
Chemotherapy	0.95 (0.86-1.06)	0.371	0.97 (0.87-1.08)	0.562
DM	1.11 (0.99-1.23)	0.062	1.14 (1.02-1.28)a	0.027
Hypertension	1.01 (0.90-1.13)	0.849	0.86 (0.75-0.97)a	0.017
Liver cirrhosis	2.47 (2.10-2.90)a	< 0.001	2.40 (2.03-2.82)a	< 0.001
Rheumatologic disease	0.78 (0.62-0.99)a	0.038	0.81 (0.64-1.03)	0.080
End stage renal disease	1.01 (0.89-1.16)	0.828	0.91 (0.80-1.05)	0.192
COPD	1.33 (1.20-1.48)a	< 0.001	1.19 (1.06-1.33)a	0.003
Dyslipidemia	0.87 (0.78-0.96)a	0.008	0.85 (0.76-0.95)a	0.006
Radiotherapy1	1.04 (0.90-1.19)	0.625	1.05 (0.91-1.21)	0.494
Long course RT1	1.25 (0.97-1.62)	0.090	1.28 (0.98-1.67)2	0.071
Short course RT1	1.01 (0.56-1.83)	0.976	0.91 (0.50-1.64)2	0.742
Post-OP RT1	0.98 (0.84-1.15)	0.801	1.01 (0.86-1.18)2	0.941

¹Indicates surgery-only as reference;

²Indicates calculated separately with “Radiotherapy” using same model.

^aP < 0.05. DM: Diabetes mellitus; COPD: Chronic obstructive pulmonary disease; Post-OP: Postoperative.