Risk of subsequent gastrointestinal cancer among childhood cancer survivors: A systematic review

Cancer Treatment Reviews 43 (2016) 92–103

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Systematic or Meta-analysis Studies

Risk of subsequent gastrointestinal cancer among childhood cancer survivors: A systematic review Jop C. Teepen a,⇑, Suzanne L. de Vroom a, Flora E. van Leeuwen b, Wim J. Tissing c, Leontien C. Kremer a, Cécile M. Ronckers a a b c

Department of Pediatric Oncology, Emma Children’s Hospital/Academic Medical Center, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands Department of Epidemiology, The Netherlands Cancer Institute, P.O. Box 90203, 1066 CX Amsterdam, The Netherlands Department of Pediatric Oncology and Hematology, University of Groningen, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands

a r t i c l e

i n f o

Article history: Received 20 November 2015 Accepted 7 December 2015

Keywords: Childhood cancer survivors Subsequent gastrointestinal cancer Abdominal radiotherapy Systematic review

a b s t r a c t Background: Childhood cancer survivors (CCS) are at increased risk of developing subsequent malignant neoplasms, including gastrointestinal (GI) cancer. We performed a systematic review to summarize all available literature on the risk of, risk factors for, and outcome after subsequent GI cancer among CCS. Methods: A systematic search of the literature databases Medline/PubMed (1945–2014) and Embase (1947–2014) was performed to identify studies that consisted of P1000 CCS and assessed incidence of or mortality from subsequent GI cancer as an outcome. Results: A total of 45 studies were included. Studies that reported risk measures for subsequent GI cancer compared to the general population showed a 3.2 to 9.7-fold elevated risk in cohort studies including all childhood cancer types. Abdominal radiotherapy was associated with an increased risk of subsequent GI cancer in all four studies that assessed this risk. Survivors who had received procarbazine and platinum agents were also suggested to be at increased risk. Conclusion: Abdominal radiotherapy is a risk factor for developing a subsequent GI cancer. Few studies examined detailed treatment-related risk factors and most studies had small number of GI cancer cases. Therefore, no conclusions could be drawn on the effect of time since childhood cancer on GI cancer risk and on outcome after a subsequent GI cancer. Additional research is necessary to further explore risk factors for and outcome after a subsequent GI cancer, and to systematically evaluate the harms and benefits of GI screening among high-risk survivors in order to give sound screening recommendations. Ó 2015 Elsevier Ltd. All rights reserved.

Introduction Survival rates of children diagnosed with cancer have improved markedly in the past decades. Nowadays, more than 80% of the childhood cancer patients will survive for at least five years [1]. As the majority of the childhood cancer patients will become a long-term survivor, it is essential to evaluate the long-term health outcomes in this growing population. Subsequent malignant neoplasms (SMNs) are one of the most serious long-term morbidities after childhood cancer [2]. After a median follow-up of 28 years, subsequent cancer of the gastrointestinal tract (GI cancer) was found to be the leading cause of

⇑ Corresponding author at: Department of Pediatric Oncology, Emma Children’s Hospital/Academic Medical Center, TKs0-254, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands. Tel.: +31 205662250. E-mail address: [email protected] (J.C. Teepen). http://dx.doi.org/10.1016/j.ctrv.2015.12.002 0305-7372/Ó 2015 Elsevier Ltd. All rights reserved.

SMN-related mortality in a French/UK cohort of 4230 survivors of pediatric solid tumors, accounting for 24% of all deaths due to an SMN [3]. For colorectal cancer, evidence-based screening and surveillance guidelines have been developed for the general population and for high-risk groups with genetic predisposition syndromes [4,5]. Until now there is no consensus internationally about screening for subsequent GI cancer in childhood cancer survivors (CCS). The U.S. Children’s Oncology Group recommends a colonoscopy at a minimum of every 5 years for survivors who received P30 Gy radiation to the abdomen, pelvis, or spine from 10 years after radiation or starting at age 35, whichever occurs last [6]. Other guidelines for follow-up care of CCS do not recommend additional colorectal screening beyond regular population screening efforts [7–9]. Insight into the risk factors of subsequent GI cancer in CCS is essential to identify subgroups of CCS that are at high risk of subsequent GI cancer and who may benefit from surveillance efforts.

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In this systematic review, we evaluate the evidence on the risk of and outcome after subsequent GI cancer (esophagus, stomach, biliary system, pancreas, small intestine, large intestine, rectum, and anus) among CCS and examine the effects of childhood cancer type, treatment, and time since childhood cancer diagnosis on the risk of developing subsequent GI cancer. Materials and methods Search strategy and selection criteria We performed a systematic search of the literature databases Medline/PubMed (1945–2014) and Embase (1947–2014). Search terms for childhood cancer, survivors and late effects, and GI cancer or overall subsequent cancers were combined in our search in these databases (Appendix A). Inclusion criteria for the selection of studies were: (1) the study population consisted of >1000 CCS with at least 95% of the population diagnosed at age 621 years; (2) the study assessed incidence of or mortality from subsequent GI cancer as an outcome; (3) the study was original research; (4) all study designs other than case report/case series. The first inclusion criterion was chosen, because many smaller studies (clinical trials and small cohorts) were identified that ascertained SMNs, but did not have meaningful information with regard to subsequent GI cancer risk and risk factors, due to the small numbers. Two reviewers (J.T. and S.d.V.) independently screened titles and abstracts of all studies identified in the literature search. Full-text documents were obtained from studies that potentially matched the inclusion criteria based on title and abstract. J.T. and S.d.V. independently reviewed the full-text reports and checked whether the study actually matched the inclusion criteria. Discrepancies between reviewers were resolved by consensus or consultation of a third reviewer (C.R.). Furthermore, reference lists of all included studies were screened for possible relevant reports that were not identified through the literature search in Medline/PubMed and Embase. In addition, experts in the field provided relevant papers on overall evaluation of SMN after childhood cancer and on studies among survivors of other types of cancer (e.g., Hodgkin lymphoma) that might have included subgroup analyses on subsequent GI cancer risk in children, but were not captured in the formal search strategy. In case of multiple reports regarding the same cohort, the report with the longest follow-up time or the report that focused most on subsequent GI cancer was included. Data abstraction Two reviewers (J.T. and S.d.V.) independently abstracted data using a standardized data abstraction form. We abstracted data on the first author’s last name, primary cancer diagnosis, publication year, cohort, study design, inclusion period, cohort size for cohort studies and number of cases and controls for case-control studies, age at primary cancer diagnosis, follow-up duration, interval since primary cancer diagnosis, number of subsequent GI cancer cases, risk estimates of subsequent GI cancer among CCS compared to the general population and risk estimates of subsequent GI cancer by primary cancer treatment and by primary cancer diagnosis. Where papers included <5% of patients aged >21 years and reported risk measures for the total cohort, we extracted these risk measures for the total cohort. Quality assessment The quality of included studies was scored independently by two reviewers (J.T. and S.d.V.). For studies reporting risks com-

pared to the general population, quality was scored on confounding bias, selection bias, and attrition bias (Appendix B). For studies focusing on treatment-related risk factors, quality was scored on confounding bias and attrition bias in cohort studies and confounding bias, selection bias, and misclassification bias in case-control studies (Appendix B). Discrepancies between reviewers were resolved by consensus or consultation of a third reviewer (C.R.).

Results Description of studies Our search yielded a total of 2538 reports. After removal of duplicates, 1969 remained for review of titles and abstracts. During title and abstract screening, 74 studies were considered potentially eligible for inclusion. After further full-text evaluation, 41 were included in this systematic review. Reasons for exclusion are shown in Fig. 1. Four additional reports were added from reference lists of included studies [10–13]. In total, 45 reports were included in the review (Fig. 1) [3,10– 53]. All reports described cohort studies, of which two reports also included nested case-control studies (Table 1) [41,52]. Cohort sizes Records identified through database searching (n = 2538)

Records after duplicates removed (n = 1969)

Titles/abstracts screened (n = 1969) Records excluded based on title/abstract (n = 1895) Full-text report assessed for eligibility (n = 74)

Report included after full-text review (n = 41)

Full-text reports excluded (n = 33) Age >21 (n = 2) More recent study of same cohort already included (n = 13) No specification of number of subsequent gastrointestinal cancers in study (n = 13) Cohort size <1000 (n = 1) Wrong study design – case only study (n = 3) Wrong study design – 5 trials discussed separately (n = 1)

Additional records identified through other sources (n = 4) Included reports in review (n = 45)

Fig. 1. Flow diagram for inclusion and exclusion of studies.

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Table 1 Study characteristics of all 45 included studies. Author (year)

Any childhood cancer type Olsen (2009) [42] Inskip (2007) [29] Reulen (2011) [46]

Cohort

Inclusion period

Cohort size

Age at primary cancer diagnosis (years)

Median follow-up time (years)

Interval since primary cancer diagnosis (years)

Number of subsequent GI cancers

Total

CR

ST

PA

SI

ES

LI

UN

1943–2005 1973–2002 1940–1991

47,697 25,965 17,981

<20 Median: 8.2 <15

NM 6.3 24.3

NM NM NM

123 25 105

NM 7 NM

NM 6 NM

NM 6 NM

NM 4 NM

NM 2 NM

NM 0 NM

NM 0 NM

Retrospective cohort Retrospective cohort

1943–2000 1926–1987

16,540 15,452

<15 Median: 5.8

6.5 (mean) 7.2

NM NM

9 27

3 NM

0 NM

1 NM

1 NM

1 NM

3 NM

0 NM

Retrospective cohort

1970–1986

14,358

<21

22.8

NM

45

24

6

8b

4

2

8b

1

Retrospective cohort and nested case-control study

1960–2009

13,048

NM

NM

Median: 24.9

19

NA

NA

NA

NA

NA

NA

13 cancer registries Multicenter, France and UK; cancer registry-based, Nordic countries (only case-control study) Multicenter, France and UK

Retrospective cohort Retrospective cohort and nested case-control study

1943–2000 <1985

10,988 4568

<15 Median: 5.4

10.7 (mean) 25

NM NM

19 (148 controls in group 1; 72 controls in group 2)c 9 58 (167 controls)

5 27

0 10

20 6

0 0

0 4

2 10

0 1

Retrospective cohort

1942–1986

4230

<17

28

32e

NM

NM

NM

NM

NM

NM

NM

Multicenter, Italy British Columbia Cancer Registry St Jude Children’s Research Hospital

Retrospective cohort Retrospective cohort

1960–1986 1970–1995

3310 2322

Median: 4.9 Mean: 10

5.8 11.2 (mean)f

5–14: 4; 15–24: 12;>25: 16 NM NM

2 1

0 NM

0 NM

0 NM

0 NM

0 NM

2 NM

0 NM

Retrospective cohort

1962–1983

2053

NM

NM

1e

0

0

0

0

0

1

0

St Jude Children’s Research Hospital Children’s Hospital of Pittsburgh Tumor Registry Department of Pediatrics, University Medical Centre Ljubljana Hacettepe University (Ankara) Center for International Blood and Marrow Transplant Research Lady Pao Children’s Cancer Centre at Prince of Wales Hospital (Hong Kong) Emma Children’s Hospital AMC

Retrospective cohort

1962–2001

1837

Median: 6.0

Median: 24.7 (earlyera); 14.2 (recent era) 25.8

Median: 23.8

3g

3

0

0

0

0

0

0

Retrospective cohort

1951–1972

1743

<19

1

17

1

1

0

0

0

0

0

0

Retrospective cohort

1961–2000

1577

Mean: 7.2

7.8

NA

0

0

0

0

0

0

0

0

Retrospective cohort

1971–2000

1511

Median: 7.7

8.1

NM

2

0

2

0

0

0

0

0

Retrospective cohort

1987–2003

1487

Median: 8

8

NM

1

0

0

0

0

0

1

0

Retrospective cohort

1984–2009

1374

Median: 6.3

5.3

NA

0

0

0

0

0

0

0

0

Retrospective cohort

1966–1996

1368

Median: 5.9

16.8

NM

1

1

0

0

0

0

0

0

Leukemias, myeloproliferative diseases, and myelodysplastic diseases Bhatia (2002) [15] Children’s Cancer Group Retrospective cohort Löning (2000) [12] 5 BFM ALL trials Clinical trial Perkins (2013) [43] SEER database Retrospective cohort

1983–1995 1979–1995 1973–2003

8831 5006 4806

Median: 4.7 Median: 4.8 Median: 4

5.5 5.7 14.5

NM NA NM

2 0h 3

1 0 1

1 0 0

0 0 0

0 0 0

0 0 1

0 0 0

0 0 1

Henderson (2012) [25] Nottage (2012) [41]

Maule (2011) [37] Tukenova (2012) d [52]

Tukenova (2010) [3]

Rosso (1994) [47] MacArthur (2007) [35] Hudson (1997) [27]

Hudson (2013) [28] Blatt (1992) [17] Jazbec (2004) [32]

Caglar (2006) [19] Danner-Koptik (2013) [22]

Sun (2011) [49]

Cardous-Ubbink (2007) [20]

J.C. Teepen et al. / Cancer Treatment Reviews 43 (2016) 92–103

Retrospective cohort Retrospective cohort Retrospective cohort

Maule (2007) [39] Jenkinson (2004) a [33]

Nordic cohort SEER British Childhood Cancer Survivor Study 13 cancer registries National Registry of Childhood Tumours (NCRT) Childhood Cancer Survivor Study Single-center, USA

Study design

Table 1 (continued) Author (year)

Cohort

Socie (2000) [48] Ishida (2014) [30] Renard (2011) [45] Jankovic (1993) i [31]

Hijiya (2007) [26] Kimball Dalton (1998) [34]

Yu (2009) m [53] Eng (1993) [23] Acquaviva (2006) [14] Renal tumors Breslow (2010)

o

[10]

1964–1992

3182

Retrospective cohort

1984–2005

Retrospective cohort Retrospective cohort

Median follow-up time (years)

Interval since primary cancer diagnosis (years)

Number of subsequent GI cancers

Total

CR

ST

PA

SI

ES

LI

UN

NA

0

0

0

0

0

0

0

0

2918

9.5

NA

0

0

0

0

0

0

0

0

1989–1998 1960–1988

2216 2192

NM Median: 4.7

7.5 4.3

NA NA

0 0

0 0

0 0

0 0

0 0

0 0

0 0

0 0

Retrospective cohort

1962–1998

2169

Median: 4.0

18.7

NM

3

0

0

0

0

0

2

1

Retrospective cohort

1972–1995

1597

Median: 5

7.6

8.4

1

1

0

0

0

0

0

0

Retrospective cohort

1935–1994

5925

Median: 17

10.5 (mean)

21

9

5

2

0

4

1

0

Retrospective cohort Retrospective cohort

1943–1987 1955–1986

1641 1380

Median: 16 Median: 11.7

10.4 (mean) 17.0

10–19: esophagus: 1; stomach: 3; colorectal: 5 > 20: esophagus: 3; stomach: 2; colorectal: 4 NM Median colorectal: 20.2; stomach: 17.9

7 11

4 8

0 3

0 0

0 0

3 0

0 0

0 0

Retrospective cohort Retrospective cohort Retrospective cohort

1943–2000 1973–1998 1973–1992

8431 2056 1262

<15 Mean: 9.5 Median: 8.9; 9l

8.6 (mean) NM 4.6 (mean); 4.9 (mean)l

NM NA NM

4 0k 3

3 0 2

0 0 0

0 0 0

0 0 1

0 0 0

1 0 0

0 0 0

National Registry of Childhood Tumours (NCRT) and certain cancer registries and treatment centers New York and Boston New York and Boston Multicenter, Italy

Retrospective cohort

1951–2004

1927

NM

NM

NM

3

0

0

1

0

1

1

0

Retrospective cohort Retrospective cohort Retrospective cohort

1914–1996 1914–1984 1923–2003

1854 1603 1111

NM <18 Median: 1.5

28.5; 29.6n 17 12; 13n

NM NM 1

1e 1e 2e

1 1 0

0 0 0

0 0 0

0 0 2

0 0 0

0 0 0

0 0 0

National Wilms Tumor Study, National Registry of Childhood Tumours (NCRT), Nordic cohort

Retrospective cohort

1969–1995

13,351

Mean: 3.6

11.6

0–9: 4; 10–19: 12; 20–29: 12; 30+: 3

31

NM

NM

NM

NM

NM

NM

NM

Nordic cohort Multicenter, U.S.A.

Retrospective cohort

Age at primary cancer diagnosis (years)

0.9

CNS and miscellaneous intracranial and intraspinal neoplasms Maule (2008) [38] 13 cancer registries Peterson (2006) [44] SEER database Goldstein (1997) [24] SEER/Connecticut tumor registry/Swedish Cancer registry Retinoblastoma MacCarthy (2013) [36]

Cohort size

Median: 10.1 <16

Lymphomas and reticuloendothelial neoplasms Metayer (2000) [40] Multiple cancer and tumor registries, Northern America and Europe

Sankila (1996) j [13] Bhatia (2003) [16]

Inclusion period

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International Bone Marrow Transplant Registry Tokyo Children’s Cancer Study Group EORTC trial 58881 Registry for patients off-therapy after childhood cancer (ROT) St Jude Children’s Research Hospital Dana-Farber Cancer Institute (DFCI) and DFCI ALL Consortium protocols

Study design

(continued on next page)

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96

Table 1 (continued) Number of subsequent GI cancers

Author (year)

Cohort

Study design

Inclusion period

Cohort size

Age at primary cancer diagnosis (years)

Median follow-up time (years)

Interval since primary cancer diagnosis (years)

Total

CR

ST

PA

SI

ES

LI

UN

Breslow (1995) p [18] Carli (1997) [11] Taylor (2008) q [51]

National Wilms Tumor Study Four SIOP trials and studies British Childhood Cancer Survivor Study

Prospective cohort Clinical trial Retrospective cohort

1969–1991 1971–1987 1940–1991

5278 1988 1441

<16 NM Mean: 3.3

7.5 (mean) 7.3 (mean) 19.3 (mean)

NM NA NM

5 0 9

2 0 5

0 0 1

0 0 0

0 0 0

0 0 0

2 0 1

0 0 2

Soft tissue and other extraosseous sarcomas Cohen (2005) [21] SEER

Retrospective cohort

1973–2000

1499

7.1

NM

1

1

0

0

0

0

0

0

Sung (2004) [50]

Retrospective cohort

1984–1997

1160

Median: 10.3 NM

3.9

NA

0r

0

0

0

0

0

0

0

Intergroup Rhabdomyosarcoma Study Group

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CR = colorectal; ES = esophagus; LI = liver; NA = not applicable; NM = not mentioned; PA = pancreas; SI = small intestine; ST = stomach; UN = unspecified gastrointestinal tract. a Overlaps with Reulen (2011), but is still included, because it gives standardized incidence ratios for subsequent gastrointestinal cancer by treatment modalities. b 8 cases in combined category hepatobiliary tree or pancreas. c Group 1 was matched on age at diagnosis of primary malignancy and follow-up and group 2 additionally matched on primary diagnosis. d Overlaps partly with Reulen (2011), but the amount of overlap is unclear. e Number of deaths due to a subsequent gastrointestinal cancer. f Derived by dividing the person-years by the number of subjects. g Includes 18 unspecified carcinomas, of which location was not further specified, could possibly be of the gastrointestinal tract. h Includes 1 unspecified epithelial carcinoma, of which location was not further specified, could possibly be of the gastrointestinal tract. i Overlaps partly with Rosso (1994), but the amount of overlap is unclear. j Overlaps with Olsen (2009), but is still included, because it gives specific risk estimates for Hodgkin lymphoma survivors. k Includes 8 unspecified carcinomas, of which location was not further specified, could possibly be of the gastrointestinal tract. l For SEER/Connecticut and Swedish Cancer Registry respectively. m Overlaps partly with Eng (1993), but the amount of overlap is unclear. n For heritable and nonheritable retinoblastoma respectively. o Overlaps with Reulen (2011), Olsen (2009), and Breslow (1995), but is still included, because it gives specific risk estimates for survivors of renal tumors. p Overlaps with Breslow (2010), but is still included, because it gives information on survival after subsequent gastrointestinal cancer. q Overlaps with Reulen (2011), but is still included, because it gives information on survival after subsequent gastrointestinal cancer. r Includes 1 squamous cell carcinoma and one unspecified sarcoma, of which location was not further specified, could possibly be of the gastrointestinal tract.

J.C. Teepen et al. / Cancer Treatment Reviews 43 (2016) 92–103

of the studies varied considerably: 8 studies included more than 10,000 CCS [25,29,33,37,39,41,42,46], whereas 19 studies included >1000–2000 survivors [11,13,14,16,17,19–24,28,32,34,36,49–51,5 3]. Median follow-up ranged from 0.9 years to 29.6 years. Five studies assessed mortality from subsequent GI cancer [3,14,23,27,53], while all other studies assessed incidence. The highest numbers of subsequent GI cancer cases were found in the large Nordic and UK-based cohort studies with long-term follow-up, each observing more than 100 subsequent GI cancer cases [42,46]. Risk of subsequent GI cancer compared to general population Table 2 presents the ratios between the observed number of (deaths due to) subsequent GI cancer cases in the cohorts of CCS and the expected number of (deaths due to) GI cancer cases calculated from (age-, sex-, and calendar year-specific) general population rates, expressed as standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs). SIRs and SMRs are shown for all GI cancer types combined and for specific subtypes of GI cancer, where available. In addition, the absolute excess numbers of cases per 10,000 person-years (PYs) of follow-up, expressed as absolute excess risks (AERs), are also presented for all GI cancer types combined. Risk measures per specific childhood cancer subtype (CC subtype) are shown both for studies concerning a single type of childhood cancer, and for cohorts including all types of childhood cancer (any CC) that incorporated subgroup analyses by childhood cancer subtype. Five studies including any CC reported risks for all subsequent GI cancer types combined [25,33,42,46,52]. All five studies found a statistically significantly elevated risk of subsequent GI cancer among CCS compared to the general population, with SIRs ranging from 3.2 to 9.7 and AERs ranging from 1.4 to 8.4 per 10,000 PYs of follow-up. The two largest studies with long-term follow-up showed SIRs of 3.2 (95% CI: 2.7–3.8) [42] and 4.6 (95% CI: 3.8– 5.6) [46], respectively. One study examined GI cancer mortality risk after any CC and found a significantly elevated risk (SMR = 12.2; 95% CI: 8.4–16.9) [3]. All studies that assessed the risk of all subsequent GI cancer types combined by CC type (leukemia, Hodgkin lymphoma, nonHodgkin lymphoma, central nervous system tumors, neuroblastoma, retinoblastoma, renal tumors, malignant bone tumors, and soft tissue and other extraosseous sarcomas) showed elevated SIRs [24,25,40,46], except for one study that assessed risk after nonheritable retinoblastoma, but this result was based on only one subsequent GI cancer case [46]. Highest subsequent GI cancer risks were observed after renal tumors (SIR = 13.0; 95% CI: 8.1–20.8 [46] and SIR = 19.7; 95% CI: 9.4–41.2 [25], respectively). Excess risks for specific subtypes of subsequent GI cancer were observed among most studies that reported risk measures, although number of cases per study and per GI cancer subtype were usually small, particularly for the non-colorectal cancer subtypes. SIRs for colorectal cancer ranged between 3.9 and 10.9 in five studies including any CC [25,29,37,41,52]. In general, higher SIRs were observed following Hodgkin lymphoma and renal tumors than after other CC subtypes. Two studies assessing stomach cancer risk after any CC found a significantly elevated risk (SIR = 13.2; 95% CI: 6.0–24.5 [52] and SIR = 17.0; p < 0.05, no 95% CI provided [29]) and also two studies after Hodgkin lymphoma [16,40] showed a highly increased risk. Esophageal cancer risk was elevated in one study after any CC (SIR = 23.8; p < 0.05, no 95% CI provided) [29], but no significantly increased risk was found in another study (1 case) [52]. Notably, three studies in Hodgkin lymphoma survivors showed over 60-fold elevated risks of esophageal cancer [13,39,40]. Two studies showed a significantly increased pancreatic cancer risk after any CC, with SIRs of 9.9

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(95% CI: 3.1–23.1) [52] and 24.7 (p < 0.05, no 95% CI provided) [29], while another study did not find a significantly increased risk [37]. Liver cancer risk was significantly elevated in all three studies after any CC [22,37,52]. In one study after any CC, the risk of small intestine cancer was significantly increased (SIR = 29.1; p < 0.05, no 95% CI provided) [29]. Some studies presented SIRs per follow-up period (data not shown) [3,16,29,33,37,40,52]. In most of these studies, the great majority of the subsequent GI cancer cases occurred after at least ten year of follow-up. However, trends in SIRs by follow-up time were hard to examine, because numbers per follow-up interval were small. In general, risk of bias for SIR/SMR/EAR outcomes across studies was low (Appendix C). All studies calculated age-, sex-, and calendar-year specific expected number of subsequent GI cancers. All but six studies were population-based without further important restrictions and therefore had a low risk of selection bias. Since the ascertainment of subsequent GI cancer was done by linkage to a cancer registry in most studies, risk of attrition bias was low. However, two studies had a medium risk of attrition bias and one study did not clearly report on follow-up completeness. Cumulative incidence Four studies estimated the cumulative incidence of subsequent GI cancers (data not shown), but presented time intervals and outcomes varied by study, so no meaningful comparisons between the studies were possible [16,25,41,46]. Risk by childhood cancer treatment Three studies calculated SIRs of subsequent GI cancer by treatment modality [25,33,52] (see Table 3). In a large population-based study in Great Britain, SIRs of GI cancer were 10.4 after radiotherapy (RT) only, 21.1 after chemotherapy (CT) only, and 9.9 after both RT and CT, while the SIR for survivors treated without RT and CT was 6.9 [33]. However, differences in risk between treatment modalities were not statistically significant (p heterogeneity between treatment groups = 0.59). In the Childhood Cancer Survivor Study, strongly elevated risks were shown for all GI cancer types combined (SIR = 11.2; 95% CI: 7.6–16.4) and colorectal cancer (SIR = 8.5; 95% CI: 4.7–15.4) in survivors who received abdominal RT, while less strongly increased risks were observed among those not treated with abdominal RT (SIR = 2.4; 95% CI: 1.4–3.9 for all GI cancer types combined and SIR = 2.6; 95% CI: 1.3–4.9 for colorectal cancer) [25]. Tukenova et al. found significantly increased SIRs for survivors who were treated with CT alone (SIR = 9.1; 95% CI: 2.3– 23.6) and with CT plus RT (SIR = 29.0; 95% CI: 20.5–39.8), but not for treatment with RT alone (SIR = 1.0; 95% CI: 0.2–3.0) and no treatment with CT and RT (SIR = 2.6; 95% CI: 0.4–7.9) [52]. Four studies examined risks of specific treatment factors in multivariable regression models, although treatment details varied by study (Table 3). Reulen et al. observed a non-significantly increased risk of subsequent GI cancer for CCS who were treated with CT (RR = 1.6; 95% CI: 1.0–2.8) compared to those treated without CT [46]. Abdominal RT (RR = 3.3; 95% CI: 1.6–6.8), but not cranial RT (RR = 1.8; 95% CI: 0.8–4.2) or other RT (RR = 1.3; 95% CI: 0.6–2.7), were significantly associated with the development of subsequent GI cancer compared treatments without RT. Henderson et al. showed strongly increased risks of subsequent GI cancer associated with abdominal RT (hazard ratio (HR) = 5.38; 95% CI: 2.58–11.20), cumulative procarbazine dose of more than 7036 mg/m2 (HR = 3.15; 95% CI: 1.06–9.38), and treatment with platinum drugs (HR = 7.57; 95% CI: 2.25–25.51), while no increased risk was found for treatment with anthracyclines and plant alkaloids [25]. A nested case-control study by Tukenova et al. showed

Summary of study characteristics

Risk measures

Author (year)

All gastrointestinal

Cohort Median size follow-up time (years)

Leukemia Reulen (2011) [46] Maule (2007) [39]

NM 6.3 24.3 7.2 22.8 NM 10.7 (mean) 25 28 8

NMf 24.3 12,731 6.5 (mean)

Colorectal

Stomach

Esophagus

Pancreas

Liver

Small intestine

SIR (95% CI)/n

AER

SIR (95% CI)/n

SIR (95% CI)/n

SIR (95% CI)/n

SIR (95% CI)/n

SIR (95% CI)/n

SIR (95% CI)/n

3.2 (2.7–3.8)/123 NM 4.6 (3.8–5.6)/105 8.8 (5.8–12.9)/27 4.6 (3.4–6.1)/45 NM NM 9.7 (7.0–12.8)/42 12.2 (8.4–16.9)/32d NM

8.4 NM 2.2 NM 1.4 NM NM 3.2 2.3e NM

NM 3.9 (p < 0.05)/7 NM NM 4.2 (2.8–6.3)/24 10.9 (6.6–17.0)/19 4.8 (1.5–11.1)/5b 7.2 (4.4–10.9)/19 NM NM

NM 17.0 (p < 0.05)/6 NM NM NM/6 NM NM 13.2 (6.0–24.5)/8 NM NM

NM 23.8 (p < 0.05)/2 NM NM NM/2 NM NM 2.0 (0.1–8.6)/1 NM NM

NM 24.7 (p < 0.05)/6 NM NM NM/8a NM 7.3 (0.9–26.3)/2 9.9 (3.1–23.1)/4 NM NM

NM NM NM NM NM/8a NM 9.5 (1.1–34.3)/2 25.3 (12.7–44.3)/10 NM 89 (2–498)/1

NM 29.1 (p < 0.05)/4 NM NM NM/4 NM NM NM NM NM

3.2 (1.3–7.8)/5 NM

0.4 NM

NM 0 (0–15.4)/0b 0 (0–75.8)/0g NM/0

NM NM

NM 0 (0–556)/0

NM 0 (0–118)/0

NM 24.6 (3.0–89.0)/2

NM 0 (0–233)/0

NM

NM

NM

NM

NM

NM 4.7 (1.3–12.1)/4b 12.4 (4.0–28.9)/5g 5.7 (3.0–11.0)/9 3.6 (0.1–20)/1b 25 (5.1–72)/3g 36.4 (15.7–71.8)/8 9.2 (0.2–51.4)/1b 22.3 (0.6–124)/1g

NM 13.8 (4.4–32.1)/5

NM 65.3 (17.6–167.0)/4

NM 10.8 (1.2–38.9)/2

NM 5.4 (0.1–30.0)/1i

NM NM

NM NM

NM 169 (35–494)/3

NM NM

NM NM

NM NM

63.9 (12.9–186.9)/3 NM

NM 120 (3.0–669)/1

NM 44.4 (1.1–247)/1

NM 0 (0–165)/0

NM 0 (0–358)/0

NM 7.5 (0.2–41.7)/1b 0 (0–66.0)/0g 3.8 (0.9–15.2)/2

NM NM

NM 0 (0–313)/0

NM 0 (0–123)/0

NM 34.7 (0.9–194)/1

NM 105 (2.6–583)/1

NM

NM

NM

NM

NM

Henderson (2012) [25] 4825

22.8

1.0 (0.3–3.9)/2

0.0

Hodgkin lymphoma Reulen (2011) [46] Metayer (2000) [40]

NMf 5925

24.3 10.5 (mean)

5.5 (3.2–9.4)/13 10.0 (p < 0.05)h/22h

3.9 NM

Henderson (2012) [25] 1921 Sankila (1996) j [13] 1641

22.8 10.4 (mean)

7.1 (4.6–11.0)/20 NM

4.9 NM

Bhatia (2003) [16] Maule (2007) [39]

1380 1246

17.0 6.5 (mean)

NM NM

NM NM

Non-Hodgkin lymphoma Reulen (2011) [46] NMf Maule (2007) [39] 2563

24.3 6.5 (mean)

5.4 (2.8–10.4)/9 NM

4.0 NM

Henderson (2012) [25] 1078

22.8

2.1 (0.5–8.3)/2

0.5

Central nervous system Reulen (2011) [46] Maule (2008) [38] Henderson (2012) [25] Goldstein (1997) [24]

24.3 8.6 (mean) 22.8 15.4

3.6 (2.5–5.4)/25 NM 5.7 (2.5–12.7)/6 4.3 (0.9–12.7)/3

2.1 NM 1.6 NM

NM 3.6 (0.7–10)/3 6.8 (2.6–18.2)/4 4.5 (0.1–25.3)/1b 10.0 (0.3–55.7)/1g

NM NM NM NM

NM NM NM NM

NM NM NM 15.6 (0.4–87.0)/1

NM 8.4 (0.2–47)/1 NM NM

NM NM NM NM

Neuroblastoma Reulen (2011) [46] NMf Henderson (2012) [25] 955

24.3 22.8

4.5 (1.5–14.0)/3 NM/0

1.4 NM

NM NM/0

NM NM

NM NM

NM NM

NM NM

NM NM

Retinoblastoma Reulen (2011) [46]

24.3

12.5 (6.9–22.6)/11 0.8 (0.1–5.7)/1k NM

6.7 0.1k NM

NM

NM

NM

NM

NM

NM

NM

NM

NM

NM

NM

775 (194–3099)/2d

13.0 (8.1–20.8)/17 19.7 (9.4–41.2)/7

4.6 2.9

NM 15.5 (5.0–47.9)/4

NM NM

NM NM

NM NM

NM NM

NM NM

Acquaviva (2006) [14]

NMf 8431 1872 1262

NMf 1111

Renal tumors Reulen (2011) [46] NMf Henderson (2012) [25] 1255

12; 13 24.3 22.8

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Any childhood cancer type Olsen (2009) [42] 47,697 Inskip (2007) [29] 25,965 Reulen (2011) [46] 17,981 Jenkinson (2004) [33] 15,452 Henderson (2012) [25] 14,358 Nottage (2012) [41] 13,048 Maule (2011) [37] 10,988 c Tukenova (2012) [52] 4568 Tukenova (2010) [3] 4230 Danner-Koptik (2013) 1487 [22]

98

Table 2 Overview of studies with risk measures for subsequent gastrointestinal cancers in survivors of childhood cancer compared to the general population.

AER = absolute excess risk/10,000 person-years of follow-up; CI = confidence interval; NM = not mentioned; n = number of subsequent gastrointestinal cancer cases; SIR = standardized incidence ratio a 8 cases in combined category hepatobiliary tree or pancreas. b Colon only. c Only data from the France/UK cohort. d Standardized mortality ratios and number of deaths due to gastrointestinal cancer. e Absolute excess mortality risk/10,000 person-years of follow-up. f Cohort sizes of specific childhood cancer types not mentioned. Total cohort size is 17,981. g Rectum only. h Derived from Dores et al. [76], which uses the same data. i Liver/gallbladder. j Overlaps with Olsen (2009), but is still included, because it gives specific risk estimates for Hodgkin survivors. k For heritable and nonheritable retinoblastoma respectively.

NM NM NM NM NM NM NM NM NM NM NM NM NM NM NM 1.8 NM 0.4 sarcomas 24.3 7.1 22.8 Soft tissue and other extraosseous Reulen (2011) [46] NMf Cohen (2005) [21] 1499 Henderson (2012) [25] 1245

3.3 (1.6–6.9)/7 NM 1.9 (0.5–7.5)/2

NM 13.9 (0.2–77.6)/1d 3.3 (0.8–13.4)/2

NM NM NM NM NM NM NM NM NM NM 1.3 2.2 24.3 22.8 Malignant bone tumors Reulen (2011) [46] NMf Henderson (2012) [25] 1186

2.3 (0.7–7.0)/3 4.4 (2.0–9.8)/6

NM 3.9 (1.3–5.4)/3

SIR (95% CI)/n SIR (95% CI)/n SIR (95% CI)/n SIR (95% CI)/n SIR (95% CI)/n AER SIR (95% CI)/n

SIR (95% CI)/n

Colorectal Risk measures

All gastrointestinal Author (year)

Cohort Median size follow-up time (years)

Summary of study characteristics

Table 2 (continued)

Stomach

Esophagus

Pancreas

Liver

Small intestine

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99

a trend for an increasing risk of subsequent GI cancer with increasing levels of cumulative absorbed RT dose at the site of the subsequent GI cancer for cases and a similar site for matched controls (p < 0.001), with odds ratios of 5.2 (95% CI: 1.7–16.0) and 9.6 (95% CI: 2.6–35.2) for cumulative absorbed doses of 10–29 Gray (Gy) and 30 or more Gy, respectively, compared to no abdominal radiation exposure [52]. Furthermore, a significantly 1.13-fold increased risk was observed per absorbed Gy to the site of the subsequent GI cancer in a linear relative risk model; the authors did not report on evaluation of possible departure from linearity. Treatment for childhood cancer with alkylating agents, vinca alkaloids, and anthracylines was not significantly associated with subsequent GI cancer risk after adjustment for categories of local dose of radiation. Finally, Nottage et al. demonstrated significantly increased risks of subsequent colorectal cancers after exposure to alkylating agents (OR = 8.8; 95% CI: 1.2–405.4), radiation received to the site of subsequent colorectal cancer (OR = 7.7; 95% CI: 2.0– 44.3), radiation dose delivered to colonic segment where the colorectal cancer developed in a linear model (OR = 1.7; 95% CI: 1.2– 2.5 with 10-Gy dose increments; addition of a quadratic term did not significantly improve the fit), and increased number of colonic segments irradiated (OR = 1.5; 95% CI: 1.2–1.9), while no significantly increased risks were found for exposure to anthracyclines, antimetabolites, and epipodophyllotoxins [41]. Overall, these results indicate a substantially increased risk of subsequent GI cancer after abdominal RT with suggestive evidence of a dose–response relationship. Furthermore, in some but not all four studies that assessed CT treatment effects, CT treatment including alkylating agents, in particular procarbazine and platinum agents seemed to increase subsequent GI cancer risk. Risk of confounding bias was low in both cohort studies and one of two case-control studies that assessed specific treatment factors in internal models, correcting for all important potential confounders (Appendix C). One case-control study scored high on risk of confounding bias, as they were not able to construct complex multivariable models including all potential confounders because of a low number of colorectal cancer cases. Risk of attrition bias was low in one cohort study (cancer registry linkage) and medium in the other. Both case-control studies had a low risk of selection bias. One case-control study had a low risk of misclassification bias and the other study had an unclear risk, since it was not clearly described whether the exposure assessors were blinded for the case-control status.

Outcome after subsequent GI cancer Six studies reported on the outcome of subsequent GI cancer [18,19,25,26,34,51]. Henderson et al. observed 45 patients with subsequent GI cancer in their cohort, of whom 23 (51.1%) were deceased; subsequent GI cancer was the cause of death in 15/23 (65%) patients [25]. Similarly, Caglar et al. [19] reported two patients with subsequent GI cancer, one of whom died before the end of follow-up and Taylor et al. described nine patients with subsequent GI cancer, of whom seven were deceased at end of followup [51]. Unfortunately, these reports [19,25,51] did not report the duration of follow-up from GI cancer diagnosis. Breslow et al. included five patients with subsequent GI cancer among Wilms’ tumor survivors of whom four died within one year after diagnosis and one was still alive 2.8 years after GI cancer diagnosis [18]. Of two CCS with subsequent GI cancer reported by Hijiya, one died within two months after diagnosis and the other one was still alive one year from diagnosis [26]. Kimball-Dalton described one CCS with a subsequent GI cancer, who died 4.8 years after diagnosis [34].

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Table 3 Risks of subsequent gastrointestinal cancers in survivors of childhood cancer by type of treatment. Treatment modality Author (year)

Risk measure RT

CT

Categories Comparison with external rates: observed/expected ratios Jenkinson (2004) [33] SIR (95% CI) RT only Henderson (2012) [25] SIR (95% CI)

No abdominal radiation

b

Abdomininal radiation SIR (95% CI)

RT only

Internal comparisons: multivariable risk models Reulen (2011) [46] RR (95% CI) RT exposuree None Abdominal/pelvic Cranial Other Henderson (2012) [25] HR (95% CI)

Abdominal RT (yes vs. no)

No RT, no CT

Risk estimate

Categories

Risk estimate

Categories

Risk estimate

Categories

Risk estimate

10.4a

CT only

21.1a

Both RT and CT 12.5a

CT only

9.1 (0.2–3.0)

Both RT and CT 29.0 (20.5–39.8) No RT, no CT 2.6 (0.4–7.9)

CT (yes vs. no)

1.6 (1.0–2.8)

No RT, no CT 6.9a

c

2.4 (1.4–3.9) 2.6 (1.3–4.9)d 11.2 (7.6–16.4)c 8.5 (4.7–15.4)d 1.0 (0.2–3.0)

1.0 3.3 1.8 1.3

(ref) (1.6–6.8) (0.8–4.2) (0.6–2.7)

5.38 (2.58–11.20) Procarbazine dose (mg/m2) 0 >0–4200 >4200–7036 >7036 Platinum (yes vs. no) Anthracyclines (yes vs. no) Plant alkaloids (yes vs. no)

1.00 1.02 2.08 3.15 7.57 0.66 0.84

(ref) (0.22–4.80) (0.64–6.78) (1.06–9.38) (2.25–25.51) (0.27–1.63) (0.37–1.92)

Nottage (2012) f[41]

OR (95% CI)

RT received to the site of the 7.7 (2.0–44.3) subsequent colorectal cancer (yes vs. no) 10-Gy dose to the colon increments 1.7 (1.2–2.5) Number of colonic segments irradiated 1.5 (1.2–1.9)

Alkylating agents (yes vs. no) Anthracyclines (yes vs. no) Antimetabolites (yes vs. no) Epipodophyllotoxins (yes vs. no)

8.8 0.9 0.7 1.3

Tukenova (2012) [52]

OR (95% CI)

Local RT dose (Gy)g No exposure 0–9 10–29 30 or more Per Gy to digestive organs

Alkylating agents (yes vs. no)

1.5 (NS)

Vinca alkaloids (yes vs. no)

0.8 (NS)

Anthracyclines (yes vs. no)

2.3 (NS)

1.0 (ref) 1.1 (NS) 5.2 (1.7–16.0) 9.6 (2.6–35.2) 1.13 (1.05–1.32)

(1.2–405.4) (0.3–3.1) (0.2–2.5) (0.3–5.9)

CI = confidence interval; CT = chemotherapy; Gy = Gray; HR = hazard ratio; NS = not significant; OR = odds ratio; ref = reference category; RR = relative risk; RT = radiotherapy; SIR = standardized incidence ratio. a p for heterogeneity between treatment categories = 0.59. b Includes patients without radiotherapy as well as patients with radiotherapy, other than abdominal. c All gastrointestinal cancer. d Colorectal cancer. e p for heterogeneity between radiotherapy categories = 0.008. f Risk measures presented for this study are for colorectal cancer only. g p for trend < 0.001.

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Tukenova (2012) [52]

Both RT and CT

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Discussion Studies included in this review consistently show an elevated risks of overall subsequent GI cancer among CCS, with risks varying from 3.2-fold to 9.7-fold compared to the general population in studies including any CC. Treatment with abdominal RT and treatment with CT including alkylating agents or platinum agents were found to be risk factors for developing a subsequent GI cancer. Ionizing radiation is a well-known carcinogen and RT is associated with solid cancer risk [54]. It is therefore not surprising that most studies that assessed the risk of subsequent GI cancer associated with treatment factors in our review showed an increased risk for patients who have received RT fields including the GI tract with suggestive evidence of a dose–response relationship from the two included nested case-control studies. These results are in line with several nested case control studies among survivors of adult cancers, which also demonstrated increased risks of subsequent GI cancer associated with RT as well as linear radiation dose–response relationships for stomach cancer among studies in survivors of testicular cancer [55], Hodgkin lymphoma [56], both testicular cancer and Hodgkin lymphoma [57], and cervical cancer [58], for esophageal cancer among survivors of Hodgkin lymphoma [59] and breast cancer [60], and for pancreatic cancer among Hodgkin lymphoma survivors [61]. Also, results from the atomic bomb survivors showed statistically significant radiation dose–response relationships for cancer of the esophagus, stomach, colon, and liver, but not for cancer of the rectum and the pancreas [62]. Two CCS study groups [25,41] reported significantly elevated risks of GI cancer associated with alkylating agents, procarbazine in particular [25], whereas another did not confirm this finding [52]. These findings are consistent with nested case-control studies of subsequent stomach and pancreatic cancer risks among adult cancer survivors [56,57,61]. Two international studies showed an elevated risk of respectively stomach cancer [56] and esophageal cancer [61] associated with the number of alkylating agent-containing CT cycles and with dose of the alkylating agent procarbazine in Hodgkin lymphoma survivors. One of those two studies [56] also found an elevated stomach cancer risk for patients who received treatment with the alkylating agent dacarbazine compared to those who did not and the other study [61] demonstrated increased esophageal cancer with increasing dose of the alkylating agent cyclophosphamide. Procarbazine had been implicated previously in a Dutch adult cancer survivor cohort [57], partly included in the international studies [56,61]. An increased risk of pancreatic cancer was observed in Hodgkin lymphoma survivors who received high doses of the alkylating agents cyclophosphamide and procarbazine [61]. Three other studies, among survivors of breast cancer, testicular cancer, and Hodgkin lymphoma did not confirm this finding, however, few patients received alkylating agents and none received procarbazine in the breast cancer and testicular cancer studies [55,59,60]. Biological effects of alkylating agents are predominantly mediated by O6-methylguanine, which has carcinogenic potential via various mechanisms, such as point mutations and match repairmediated toxicity [63,64]. Henderson et al. observed a more than 7-fold increased risk of subsequent GI cancer after exposure to platinum agents in CCS [25]. This is in line with an increased SMN risk observed after exposure to platinum-containing CT in testicular cancer survivors, although no estimates were reported specifically for GI cancer [65]. No increased risks of subsequent GI cancer in CCS was associated with exposure to anthracylines (three studies) [25,41,52], plant alkaloids/vinca alkaloids (two studies) [25,52], antimetabolites and epipodophyllotoxins (both one study) [41]. Overall, in comparison with the general population, elevated risks among CCS were observed for the subsequent GI cancer

101

subtypes colorectal, stomach, esophagus, pancreas, liver, and small intestine cancer, although numbers of cases are generally quite small. The risks of colorectal cancer and stomach cancer were much higher in the study by Bhatia et al. in childhood Hodgkin lymphoma survivors than in the other studies [16]. Furthermore, the risk of esophageal cancer was highest among Hodgkin lymphoma survivors [13,39,40]. Also, risk of rectal cancer was found to be high in Hodgkin lymphoma survivors [13,39,40]. This might be explained by the high doses and extensive RT fields that were part of most treatment regimens in childhood Hodgkin lymphoma survivors, especially in earlier years (<1970). However, other studies in childhood Hodgkin lymphoma survivors showed more modestly increased risks of especially colon and, to a lesser extent, rectal cancer compared to the combined colorectal cancer risk shown by Bhatia and colleagues [13,25,39,40]. Comparison of SIRs between studies is, nevertheless, complicated owing to differences in follow-up duration, distribution of age at diagnosis, and differences in extent of radiotherapy as well as chemotherapy drugs and doses. Several, but not all studies have shown that survival of some types of SMNs is worse than survival of comparable first primary cancers, possibly due to limitation of treatment options after prior cancer therapy, because of unfavorable SMN tumor characteristics, or because of competing causes of death, such as cardiovascular diseases [66–70]. One study compared the survival of subsequent GI cancers in Hodgkin lymphoma patients with similar de novo GI cancers and found significantly reduced survival in subsequent GI cancers [71]. Unfortunately, too few studies in our review examined the outcome of subsequent GI cancer among CCS to answer whether its survival is different from comparable first primary GI cancers. Most subsequent GI cancer cases across studies occurred after at least ten year of follow-up and subsequent GI cancer was among the most frequently occurring types of SMNs in CCS cohorts that had sufficient follow-up to reach ages where background rates of GI cancer in the general population are rising [42,46]. It is therefore essential to keep following the cohorts and examine the risks in very long term survivors, since most CCS cohorts have not yet reached these ages at which the incidence of subsequent GI cancer is expected to be the highest. Even if the risks of subsequent GI cancer relative to the general population are only slightly increased in elderly survivors, this can then still translate into an emerging number of excess cases, since the incidence in the general population increases at older ages. Because so far only four studies examined detailed treatment-related risk factors for subsequent GI cancer after childhood cancer, it is also important to perform more well-powered epidemiological studies to get more insight into risk factors of and outcome after subsequent GI cancer. A better understanding of risk factors might help identifying subgroups that are at high risk, so follow-up care of CCS can be optimized. Furthermore, it is important to elucidate the pathogenesis of subsequent GI cancer compared to de novo GI cancer, since that may also have implications for screening decisions. If subsequent GI cancer is found to be preceded by adenomatous polyps, screening efforts are possibly more effective, since polyps can be removed before they turn into cancer. Reulen et al. showed that CCS treated with abdominal RT had a similar risk of developing a colorectal cancer than people with P2 first-degree relatives with colorectal cancer, for whom colonoscopy screening is recommended every 5 years, starting at a younger age (40 years or ten years before the youngest case in immediate family) than for the general population screening in the United States (50 years) [5,46]. This systematic literature review can serve as a first step in the development of a surveillance guideline for subsequent GI cancer for CCS, because it identifies subgroups of survivors at highest risk, based on rigorous literature search- and review methodologies. Many other aspects need considerations in order to give sound surveillance recommendations. First, the

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potential benefits of GI cancer screening among CCS need to be addressed, in terms of mortality, treatment-related complications, and quality of life. Similarly, possible harms of screening need to be addressed, such as distress, potentially unnecessary follow-up diagnostic procedures and/or surgery caused by false-positive findings. Finally, evidence is needed on the type of surveillance modality to be used among young adult CCS, considering age-specific diagnostic values, complication rates, and costs. If such evidence is not available for CCS, it may be derived from other (high-risk) populations were GI cancer surveillance of asymptomatic individuals has been implemented and studied [4,5,72,73], as was done for breast cancer surveillance among CCS [74]. Within the International Guideline Harmonization Group [75], a guideline effort to harmonize recommendations for subsequent GI cancer surveillance is planned, including the questions raised above.

[14]

[15]

[16]

[17] [18]

[19]

Conflict of interest The authors declare that there is no conflict of interest.

[20]

Acknowledgements

[21]

The authors thank Edith Leclercq, Ph.D., for her help with developing the search strategies for this review. This work was financially supported by the Dutch Cancer Society (grant numbers DCOG 2011-5027 and UVA2012-5517).

[22]

Appendix A. Supplementary data

[24]

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ctrv.2015.12.002.

[25]

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