Estimating the Risk for Secondary Cancer After Targeted α-Therapy with 211At Intraperitoneal Radioimmunotherapy

Article Figures & Data

Download figure
Open in new tab
Download powerpoint
Download figure
Open in new tab
Download powerpoint
FIGURE 1.
Pooled ERR/Gy for different organs or organ groups with 95% CI. Data for bladder represent only 1 background study (Nekolla et al. 2009 (10)).

TABLE 1.

Background Thorotrast Data

Study	Design and statistical method	n	Sex (n)	Age (y)	Comparison group	Estimated dosage (mL)^*	Exclusion criteria	Last follow-up	Follow-up time (y)	Alive at analysis	Excess cancers	Excess per 100 subjects	Expected no. of cancers
Becker (5)	Site-specific mortality/SMR	2,326	M: 1,717 (74%); F: 602 (26%)	Mean, 31	1,890	Mean, 21	Survival < 3 y^†	2005	Mean, 34	2%	349	15	114
Travis (9)	Site-specific incidence/SIR and RR	1,204	M: 670 (56%); F: 534 (44%)	Mean, 35^‡	1,180	Mean, 17	Survival < 2 y^†	1992–1993	Mean, 22	7%	229	19	77
Travis (9)	Site-specific mortality/SMR and RR	446	M: 223 (51%); F: 216 (49%)	Mean, 41^‡	212	Mean, 25	Survival < 2 y^†	1992	Mean, 20	10%	50	11	18
dos Santos Silva (6)	Site-specific mortality/SMR and RR	1,096	M: 685 (62.5%); F: 411 (37.5%)	Mean, 35^‡	1,014	Median, 20	Survival < 5 y^†	1996	Mean, 15	6%	86	8	5
Mori (8)	Site-specific mortality/RR	262^§	M: 262 (100%)	Mean, 25	1,630	Mean, 17	Survival < 10 y^†	1998	—	7%	79	30	30
Kido (7)	Site-specific mortality	150^∥	M: 150 (100%)	Mean, 22	1,144	10–19 mL (94%)	Dead before 1979	1998	—	12%	63	42	8
Mori (8)	Autopsy study	386	M: 348 (90%); F: 38 (10%)	Range, 9–47	172,350	Mean, 18	Survival < 10 y^†	1998	Mean, 38; SD, 9	—	214	55	105

↵* Thorotrast dosage refers to volume (mL) of Thorotrast injected.
↵^† From Thorotrast injection.
↵^‡ Estimated age.
↵^§ 61 patients included in autopsy study (8).
↵^∥ 69 patients included in autopsy study (8).
SMR = standardized mortality ratio; SIR = standardized incidence ratio; RR = relative risk.

TABLE 2.

Background ²²⁴Ra Data

Study	Study design and statistical method	n	Sex (n)	Comparison group	Estimated activity (MBq)	Exclusion criteria	Last follow-up	Follow-up time (y)	Alive at analysis	Excess cancers	Excess per 100 subjects	Expected no. of cancers
Nekolla (10)	Site-specific incidence/SIR	682	M: 510 (75%); F: 172 (25%)	None	∼45	Age ≤ 20 y (full cohort, n = 899); lag time^†	2007	∼55	6%	92^*	13^*	56^*
Wick (11)	Site-specific incidence/SIR and RR	1,471	M: 1332 (91%); F: 139 (9%)	1,324	∼10 (0.17/kg)			Mean, 26	32%	23^*	0.3	159

↵* Lung cases not included.
↵^† Nekolla (10) used 5- and 2-y lag times for solid tumors and hematologic malignancies, respectively.
SMR = standardized mortality ratio; SIR = standardized incidence ratio; RR = relative risk.
Mean age was not possible to calculate; reported as <20 y or >20 y.

TABLE 3.

Calculated Absorbed Dose Data and Background Natural Mortality

Organ/group of organs	ICD-10 code	Thorotrast (mGy)	²²⁴Ra, high (mGy)	²²⁴Ra, low (mGy)	²¹¹At (mGy)	Mortality per 100,000 in women aged 65+
Lip, oral cavity, pharynx	C00–C13	174	NA	NA	280	36,9
Stomach	C16	39	99	22	160	80
Colorectum, anal^*	C18–C21	42	297	NA	36	397.2
Liver, intrahepatic bile ducts	C22	6,900	585	130	104	69.6
Trachea, bronchus, lung	C33–C34	1,094	99	22	320	570.5
Bone and articular cartilage	C40–C41	4,800	19,800	NA	182	3.8
Breast (female)	C50	NA	99	22	28	373
Kidney	C64–C65	45	333	74	340	67.3
Urinary bladder	C67	NA	99	NA	380	76.2
Lymphoid, hematopoietic, and related tissues	C81–C96	2,100	1,890	420	30	281.9

↵* Colon (C18–19), 70%; rectum (C20), ∼30%.
NA = dose data not available.
Thorotrast mean administered volume was 20 mL and mean exposure was 30 y using distribution data from Ishikawa et al. (16,18). ²²⁴Ra was 45 MBq (high) and 10 MBq (low), applied to distribution from Lassman et al. (19). ²¹¹At was 200 MBq/L in intraperitoneal infusion, with 24-h dwell time, from Cederkrantz et al. (4). Mortality data are from NORDCAN (14), weighted by natural mortality in age span (data from Statistics Sweden (15)).

TABLE 4.

Influence of Various Assumptions and Competing Risk

		Excess cancer cases per 100 treated
			FIGO stage
Parameter	Adjustment in calculation or used background	Cancer-free	I	II	III	IV
Using ERR/Gy based on “male and female”^*		1.13	0.90	0.64	0.25	0.11
Using ERR/Gy based on “female sex only”^†		1.60	1.28	0.91	0.35	0.16
Age-dependence adjustment if low LET equals high LET^*		1.11	0.89	0.63	0.24	0.11
Other second cancer risk after ovarian cancer primary*^‡		1.53	1.24	0.87	0.34	0.15
Age (25 or 65 y) at time of treatment	ERR/Gy “male and female”^*	1.24–0.90
	ERR/Gy “female sex only”^†	1.84–1.21

↵* Calculations made with “male and female”–derived ERR/Gy in Supplemental Table 4.
↵^† Using ERR/Gy based on “female only.”
^‡ Hazard risks (33), specified in Supplemental Table 4. No adjustment for decreased survival due to second primary cancer was performed.
Excess cancer cases per 100 treated are female patients, 55 y old at treatment. FIGO stage data are 10-y ovarian cancer relative survival according to International Federation of Gynecology and Obstetrics stage I–IV (0.80/0.57/0.22/0.11) (36). Influence of age at treatment (25 and 65 y) is as specified in Supplemental Table 5.