Publication

Characteristics

Number of incident cases

Treatment groups

Analysis methods

Conclusions (all types)

Conclusions solid tumours

Conclusions (AML)

Conclusions (NHL)

Bhatia 1996

15 centres (USA, Manchester, Amsterdam); 1955‐1986; MFU = 11.4 yrs.; N = 1 380 (children < 16 yrs.)

88 SMN (+9 excluded non‐melanoma skin cancers); 24 AML (+2 other leukaemias), 47 ST, 9 NHL

RT, CT, RT+CT (total treatment)

Cox regression separately for ST, AML, NHL

All ST: no differences; breast cancer only: RT dose (RR 5.9 for dose > 20 Gy)

No differences reported

Higher risk with more alkylating agents

Biti 1994

1 centre (Florence); 1960‐1988; N = 1 121

73 SMN (+5 excluded basocellular skin cancers); 60 ST, 11 AML (MDS excluded), 2 NHL

(A) RT, CT, RT+CT, CRT; total treatment.

(B) RT, CT, CRT (primary treatment only), censored at relapse

Cox regression

Higher risk after primary CT compared with IF/M alone; higher risk with CT+(S)TNI compared with IF/M alone

Same trend as for all SM

Higher risk with primary CT (±RT); higher risk with more cycles of CT

Boivin 1995

Embedded case‐control study; 14 Canadian and US centres; 1940‐1987; MFU = 7 yrs.; N = 10 472 (9 280 followed for at least one year)

560 SMN; 403 ST, 122 AML, 35 NHL

RT, CT as time‐dependent variables, primary and salvage RT, CT

Cox regression with splenectomy, RT, CT as time‐dependent covariates

Significantly more with CT than without CT (ST and NHL analysed together)

Significantly more with CT than without CT (more with MOPP than with ABVD)

Dietrich 1994

1 centre (France); 1960‐1983; N = 892 (continuously disease‐free HD only)

N = 56 (first FU ‐year excluded); 37 ST (excluding bcc), 11 ANLL/MDS, 8 NHL

RT versus CRT; Mantle‐RT versus EF‐RT; SM before progression/relapse only

Cox regression; All RR compared with IF (= MF/inverted Y‐RT)

Significant excess only with MOPP+EF (RR 10.86, P < 0.001) and MOPP+IF (RR 4.99, P = 0.015).

Same tendency as for SM, but significant only for MOPP+EF

Increased risk only for MOPP+EF (RR 16.55, P = .004)

No difference in treatment

Dores 2002

16 US and European cancer registries; 1935‐1995; N = 32 591

2 153 SMN; 1 726 ST, 169 ANLL, 162 NHL

RT versus CT versus CRT (primary treatment)

No direct comparison between treatment groups: all results as RR according to primary treatment compared with normal population.

Significantly higher RR with CRT (95% CI 2.6‐3.6) compared with either RT alone (2.1‐2.4) or CT alone (1.5‐1.9). Digestic tract and female breast: Significantly higher risks with RT than without RT.

Foss‐Abrahamsen 1993

1 centre (Oslo); 1968‐1985; MFU = 8 yrs.; N = 1 152

68 SMN (+6 excluded non‐melanoma skin cancers); 9 AML, 8 NHL, 51 ST

RT, CT, CT+RT (total treatment)

Cox regression

Greater risk of SM for pts. who received both CT and RT

Koshy 2012

SEER registry database; 1988.2006; N = 12 247

ca. 650 SMN (5.3%)

RT versus no RT (primary treatment)

Kaplan‐Meier; no explicit comparison

no increase due to RT

Mauch 1996

1 centre (JCRT Boston, USA); 1969‐1988; N = 794

72 SMN; 53 ST, 8 AML, 10 NHL

RT(no relapse), RT‐relapse‐CT, CRT; total treatment

RRs compared with normal population, no direct treatment comparisons

RT alone RR 4.1, RT+CT RR 9.75, P < 0.05

Same effect as with all SMN

Same effect as with all SMN

Ng 2002

4 centres (all affil. to Harvard); 1969‐1997; MFU = 12 yrs.; N = 1319 (mainly early stages); (996 pts. with fu > 10 years were included in analysis of treatment effect)

181 SMN (N = 162 for pts. with fu > 10 yrs.); 131 ST, 23 AML, 24 NHL

RT, CRT (total treatment); also separate analyses of non‐relapsed cases and relapsed cases

RRs calculated relative to normal population (age/sex‐specific); CI from Poisson distribution

RR higher with CRT than RT alone (6.1 versus 4.0, P = 0.015); (non‐relapsed cases only: 5.9 versus 3.7, P = 0.016). Analysed by radiation field size, this effect was only significant for TNI (±CT). RR higher with CT+TNI than for CT+Mantle/EF

Rodriguez 1993

1 centre (M.D. Anderson, Houston, USA); 1966‐1987; N = 1 013

66 SMN (first FU‐year excluded); 38 ST, 14 AML/MDS, 14 NHL

IF versus EF (+MOPP); CT versus CRT; RT versus CRT. Total therapy

Cox regression

RT versus CRT: no difference (P = 0.37). CT versus CRT: less SM with CRT (P = 0.001). But less courses of CT with CRT than with CT only!

Scholz 2011

Multi‐centre (mainly Germany); 1978‐1998);

N = 5 357

67 AML, 97 NHL

Primary: RT, conventional CT for intermediate stage, conventional CT for advanced stage, escalated BEACOPP

Parametric model; separate effects of primary and salvage treatment

Higher risk with escalated BEACOPP than conventional CT

No differences

Swerdlow 1992

> 60 BNLI centres, UK; 1970‐1987;

N = 2 846

113 SMN; 80 ST, 16 AML, 17 NHL

Alkyl. CT, Alkyl. CT +RT, IF‐RT (+/‐ nonalk. CT), EF‐RT (+/‐ nonalk. CT) (total treatment)

Poisson regression

No difference overall (nor for lung ca. alone)

More with CT or CRT (similar) than with RT

No differences

Swerdlow 2000

BNLI, Royal Marsden, St. Bartholomews; 1963‐1993; N = 5 519

322 SMN; 228 ST, 44 AML, 50 NHL

CT, RT, CRT (total treatment)

Poisson regression. RR compared with normal population, no direct treatment comparisons

Higher RR for CRT (SIR 3.9, 95% CI 3.2 ‐ 4.6) than for CT (SIR 2.6, 95% CI 2.1 ‐ 3.2) or RT (SIR 2.3, 95% CI 1.9 ‐ 2.8).

Higher risk for CRT (SIR 38.1, 95% CI 24.6‐55.9) or CT (SIR 31.6, 95% CI 19.7‐47.6) than for RT (SIR 1.2, 95% CI 0.1‐5.2)

No significant differences

Swerdlow 2011

UK,

1963‐2001

459 SMN; 302 ST, 75 AML, 82 NHL

CT, CRT

Higher risk for CRT than for CT alone

Tucker 1988

Stanford UMC; 1968 ‐ ?(year needed); N = 1 507

83 SMN (first FU‐year excluded); 46 ST, 28 AML, 9 NHL

RT, RT+adj. CT, RT+salvage CT, RT+intravenous‐gold, CT (total treatment)

Kaplan‐Meier, Gehan test

No differences (except: more with radiotherapy + intravenous‐gold)

Higher risk with CT than RT

No differences

van Leeuwen 1994a

2 centres (the Netherlands); 1966‐1986; MFU = 9 yrs.;

N = 1 939

146 SMN; 93 ST, 31 AML, 23 NHL

CT, RT, CRT (total treatment)

(A) Person‐years analysis. (B) Cox regression

B: for lung cancer only: trend to more for RT (P = 0.08) or CRT (P = 0.07) than for CT. Otherwise no differences

A: AML not increased for RT; large increase for CT (CT similar to CRT). B: AML more for CT (P = 0.009) or CRT (P = 0.04) than for RT

B: trend to more for CRT than for either CT or RT (P = 0.06)

Publication

Characteristics

Number of solid tumours / NHL

Treatment groups

Analysis methods

Conclusions (solid tumours)

Conclusions (NHL)

Behringer 2004

Multi‐centre (mainly Germany); 1983‐98; N = 5 367

127

CT, RT, CT+EF, CT+IF/local

RR compared with general population. No direct treatment comparisons.

Birdwell 1997

Stanford UMC (USA); 1961‐1994; MFU = 10.9 yrs.; N = 2 441

25 gastrointestinal cancers

RT, CRT (total treatment)

RR compared with general population. No direct treatment comparisons.

Risk of gastrointestinal cancer not significantly greater with CRT (RR 3.9, 95% CI 2.2 to 5.6) than with RT (RR 2.0, CI 1.0 to 3.4)

De Bruin 2009

5 centres (the Netherlands); 1965‐1995; N = 1 122

120 breast cancers

RT field and CT regimen in women under 41 years with supradiaphragmatic irradiation (N = 782)

Cox regression

Significantly greater risk of breast cancer with mantle RT than mediastinal RT

Enrici 1998

Rome, Italy; 1972‐1996; MFU = 84 months; N = 391

20 NHL

(A) RT, CT, CRT (initial treatment) censored at relapse.

(B) RT, CT, CRT (total treatment)

Kaplan‐Meier and Cox regression

No difference between treatment modalities

Foss‐Abrahamsen 2002

1 centre (Oslo); 1968‐1985; MFU = 14 yrs.; N = 1 024

26 lung, 23 breast, 31 NHL

RT, CT, CRT (total treatment)

RR compared with general population. No direct treatment comparison

Tendency to greater lung and breast cancer risk with RT or CRT versus CT

No difference between treatment modalities

Hancock 1993

Stanford UMC (USA); 1961‐1990; MFU = 10 yrs.;

N = 885

25 breast cancers

RT, CRT (total treatment)

RR compared with general population. No direct treatment comparisons

RT versus CRT: Tendency of more breast cancers with CRT, but not significant.
RT: RR 3.5 (95% CI 1.9‐5.8), CRT: RR 5.7 (95% CI 3.1‐9.5)

Hodgson 2007

13 cancer registries; 1970‐2001, 5‐year survivors; N = 18 862

1 490 ST

RT, CT, CRT (primary treatment, RT supra‐ or infradiaphragmatic according to SMN site)

RR by Poisson regression

significantly greater risk of breast cancer and other supradiaphragmatic cancer with RT or CRT versus CT

Kaldor 1992

Case‐control study; 12 cancer registries (Europe, Canada), 6 large hospitals (Europe); from 1960 onwards; N = 25 665

98 lung cancers

RT, CT, CRT

Standard case‐control study methods. RR compared with RT

Higher risk with CT, risk increase with number of CT cycles and RT dose to the lung.

Meattini 2010

One centre (Florence, Italy); 1060‐2003; N = 1 538

39 breast cancers

RT, CT, CRT (primary treatment); RT field; CT regimen

Cox regression

No significant differences (breast)

Swerdlow 2001

Nested case‐control study; multi‐centre (Britain); 1963‐1995; N = 5 519

88 lung cancers

RT, CT, CRT (total treatment)

Conditional logistic regression

No significant differences in lung cancer risk between RT, CT, CRT. (exception: adenocarcinomas ‐ greater risk with CT than without.) Risk greater with MOPP than without MOPP

Swerdlow 2012

UK, 1956 ‐ 2003

373 breast cancers

RT, CRT

Breast cancer standardised incidence ratio (SIR) is highest among patients receiving RT at a young age

Travis 2002

Embedded case‐control study; 7 cancer registries; 1965‐1994;

N = 19 046

222 lung cancers

RT, alkylating CT, RT with alk. CT, RT + salvage alk. CT, neither (total treatment)

Conditional logistic regression

Lung cancer risk increases with RT dose to the lung and with use of alkylating agents

Travis 2003

Embedded case‐control study; 6 cancer registries; 1965‐1994;

N = 3 817 women

105 breast cancers

RT, alkylating CT, RT with alk. CT, RT + salvage alk. CT, neither (total treatment)

Conditional logistic regression

Breast cancer risk increases with RT dose to breast and decreases with use of alkylating CT and with radiation of ovaries

van Leeuwen 1995

Embedded case‐control study; 2 centres (the Netherlands); 1966‐1986;

N = 1 939

30 lung cancers

RT, CT, CRT. RT dose to lung (total treatment)

Conditional logistic regression

Risk of lung cancer tended to increase with increasing RT dose (P = 0.01); RR(> 9 Gy versus 0) = 9.6. No significant differences between RT, CT, CRT

van Leeuwen 2003

Embedded case‐control study; 4 centres (the Netherlands); 1965‐88;

N = 2 637

48 breast cancers

RT, CRT. RT dose to breast, ovary. CT cycles, dose of alkylating agents

Conditional logistic regression

Breast cancer risk increases with RT dose and decreases with modality CRT; no CT dose effect

Publication

Characteristics

Number of AML/MDS

Treatment groups

Analysis methods

Conclusions (AML/MDS)

Brusamolino 1998

2 centres (Italy); 1975‐1992; MFU = 10 yrs.; N = 1 659

36 AML/MDS

RT, CT, CT+RT. Total treatment

A.Log‐rank tests (univariate) to compare treatment groups
B.Embedded case‐control study with conditional logistic regression analysis.

A. Higher risk after CT than RT (P = 0.04); higher risk with CT than with CRT (P = 0.05); higher risk with MOPP+RT than with MOPP/ABVD or with ABVD+RT (P = 0.002); higher risk with EF + MOPP than with IF+MOPP (P = 0.01)
B. higher risk after CT than RT (OR 4.1; P = 0.05); higher risk after CRT than RT (OR 6.4; P = 0.02); higher risk after MOPP+RT than ABVD+RT (OR 5.9; P = 0.001) or MOPP/ABVD

Eichenauer 2014

GHSG HD7‐HD15, PROFE, BEACOPP‐14 (1993‐2009); MFU: 72 months, N = 11 952

106 AML/MDS

RT, CT, CRT

Significantly higher risk after 4 or more cycles of escalated BEACOPP

Josting 2003

Multi‐centre (GHSG (Germany) HD1‐HD9); 1981‐1998; MFU = 55 months; N = 5 411

46 AML/MDS

CT, RT, CRT, HDCT with SCT. Primary treatment, not censored at relapse

Kaplan‐Meier. No direct treatment comparison

No significant differences between treatment protocols

Kaldor 1990

Case‐control study; 12 cancer registries (Europe, Canada), 6 large hospitals (Europe); 1960‐?(year needed); N = 29 552

149 AML/MDS (at least one year after HD diagnosis)

RT, CT, CRT. Total treatment

Standard case‐control study methods. RR compared with RT

Higher risk with CT than with RT (RR 9.0; CI 4.1‐20); higher risk with CRT than with RT (RR 7.7; CI 3.9‐15). No difference in CT versus CRT; but there was a dose‐related increase in the risk in pts. who received RT alone

Koontz 2013

Stanford (1974‐2003); N = 754

24 AML/MDS

RT, CT, CRT

Increased risk with higher doses of alkylating agents

Pedersen‐Bjergaard 1987

1 centre (Copenhagen); 1970‐1981; N = 391

20 ANLL/preleukaemia

Low, intermediate, or high dose of alkylating agents. Total treatment

Cox regression

Risk increases with increasing (total) log dose of alkylating agents (P = 0.0024, regr. coefft. = 0.69)

van Leeuwen 1994b

Embedded case‐control study; 2 centres (Netherlands); 1966‐1986; N = 1 939

44 Leukemias (incl. 32 ANLL, 12 MDS)

RT, CT, RT+CT. Total treatment

Conditional logistic regression

More risk with CT than with RT alone; <= 6 cycles: P = 0.08, RR = 8.5; > 6 cycles: P < 0.001, RR = 44

Comparison

Excluded SMN

(standard arm : experimental arm)

OR

P value

Avoidance of RT (after CT)

0 : 1

0.398

0.0054

Smaller RT field (after CT)

5 : 8

0.824

0.21

Lower RT dose (after CT)

1 : 4

0.976

0.90

Fewer CT cycles

3 : 0

0.967

0.87

Intensified CT regimen

0 : 0

no change

Comparison

Numbers of censored SMN

(standard arm : experimental arm)

Peto odds ratio

P value

Avoidance of RT (after CT)

4 : 3

0.348

0.0031

Smaller RT field (after CT)

37 : 39

0.842

0.38

Lower RT dose (after CT)

4 : 4

1.033

0.87

Fewer CT cycles

8 : 10

0.849

0.46

Intensified CT regimen

10 : 19

1.365

0.24

Comparison

Numbers of progressions (standard arm : experimental arm)

Hazard ratio

P value

Avoidance of RT (after CT)

80 : 66

1.77

0.0006

Smaller RT field (after CT)

117 : 171

1.08

0.51

Lower RT dose (after CT)

127 : 147

1.2

0.14

Fewer CT cycles

114 : 107

0.94

0.62

Intensified CT regimen

281 : 276

0.74

0.0008

Comparison

Numbers of deaths

(standard arm : experimental arm)

Hazard ratio

P value

Avoidance of RT (after CT)

32 : 22

0.84

0.54

Smaller RT field (after CT)

84 : 112

0.97

0.81

Lower RT dose (after CT)

53 : 51

1.01

0.96

Fewer CT cycles

63 : 68

1.09

0.64

Intensified CT regimen

141 : 161

0.83

0.12