Beyond Expert Opinion: Progress in the Development of Evidence-Based Screening Guidelines for Survivors of Childhood Cancer

Beyond Expert Opinion: Progress in the Development of Evidence-Based Screening Guidelines for... In this issue of the Journal, Teepen et al. provide important new findings from the Dutch DCOG‐LATER study that support early surveillance strategies to reduce the burden of colorectal cancer (CRC) in childhood cancer survivors (1). This is of particular importance because second cancers are the greatest cause of premature mortality in adult survivors of childhood cancer. The British Childhood Cancer Survivor Study, for example, found that gastrointestinal malignancies contributed the greatest absolute excess risk among childhood cancer survivors older than age 40 years, and the cumulative incidence of CRC for survivors treated with abdominopelvic radiotherapy (RT) was 1.4% by age 50 years (2). This and other large cohort studies have demonstrated that platinum-based chemotherapy and abdominal or pelvic RT increase CRC risk up to three to four times higher than expected (3). It would be natural to infer from these findings that CRC screening should be initiated sooner among childhood cancer survivors than in the general population, and in fact current guidelines from the Children’s Oncology Group (COG) recommend the initiation of CRC screening with colonoscopy in survivors exposed to abdominal or pelvic radiotherapy at age 35 years or 10 years after abdominal or pelvic RT exposure, whichever occurs later (4). However, other guideline authors have been more cautious, citing the important lack of evidence that early CRC screening would be effective (5). And perhaps with the exception of breast cancer, only a few studies provide the information necessary to guide the development of evidence-driven screening strategies of subsequent cancers in this population. Teepen and colleagues have addressed one substantial gap in our understanding about treatment-induced CRC: whether it passes through a screen-detectable preclinical (ie, adenoma) phase similar to idiopathic CRC, which would be necessary for screening to effectively reduce the subsequent morbidity and mortality. By linking treatment data from a cohort of 5843 five-year childhood cancer survivors (median follow-up = 32.4 years) to a national pathology registry, the authors were able to identify 78 survivors who had at least one colorectal adenoma removed and 41 survivors who had multiple adenomas. By age 45 years, the cumulative incidence of adenoma was 3.6% for survivors who had abdominal/pelvic RT, 2.0% for those without such treatments, and 1.0% for sibling controls (P = .03 for the comparison of RT-treated survivors vs controls). Notably, many of the exposures previously associated with CRC in prior studies were associated with colorectal adenomas in this Dutch cohort. In multivariable Cox regression analysis, abdominal RT was associated with a 2.12-fold increased risk, and similar to the Childhood Cancer Survivor Study (CCSS) finding of CRC risk, cisplatin exposure was statistically significantly associated with increased adenoma risk (hazard ratio [HR] = 2.81, 95% confidence interval [CI] = 1.32 to 5.99) (1). It is notable that the association between treatment exposures and colorectal neoplasia appear to be more complex than those for some other second malignancies. For example, while prior studies have reported consistent findings relating the risk of RT-related breast cancer to increasing radiation dose and exposed breast tissue volume, Teepen et al. could not find a relationship between the estimated radiation dose or the volume of irradiated colon and the risk of subsequent colorectal adenoma. This finding is similar to prior studies that have found that 29% of CRC (3) and 47% of colorectal polyps (6) occur outside the directly irradiated colon. While these findings may simply reflect the challenges of accurately estimating colorectal radiation exposure retrospectively, they also suggest that for some survivors there may be a biological predisposition affecting the entire colonic mucosa, perhaps mediated through indirect effects of RT, systemic therapy, or a currently unknown underlying biological process. Further, the data regarding the effects of chemotherapy are also inconsistent. Teepen et al. found that procarbazine was statistically significantly associated with adenoma risk only among survivors who did not have abdominopelvic radiotherapy or total body irradiation (HR = 2.71, 95% CI = 1.28 to 5.74), which contrasts with the CCSS finding that procarbazine without abdominal RT was not associated with the risk of gastrointestinal second malignancies, although it was statistically significantly associated with this risk among survivors treated with RT (3). An important limitation of the DCOG-LATER study is that it does not provide the true (ie, complete) incidence of adenoma among the study cohort. Approximately 11% to 22% of the average risk population age 40 to 50 years is found to have colorectal adenomas on first colonoscopic screening (7,8), and a recent study found adenomatous polyps in 27.8% of childhood survivors undergoing colonoscopic screening before age 50 years (6). Given these results, the cumulative incidence of adenoma reported by Teepen et al. (3.6% by age 45 years after abdominopelvic RT) almost certainly underrepresents the true biological occurrence among survivors. Similarly, the inconsistent utilization of colonoscopy among survivors and uncertainty regarding indications for the procedure among sibling controls could substantially influence the generalizability and interpretation of the results. There was no information on the use of colonoscopy in more than 98% of the study cohort, and the indication for colonoscopy was unknown for 33% of survivors and all of the sibling controls diagnosed with adenomas. It seems unlikely that survivors were undergoing colonoscopy at the same rate or for the same reasons as their siblings, and more frequent use of colonoscopy among the former could bias the comparison of adenoma incidence between these two groups. Despite these limitations, this DCOG-LATER study adds important new evidence that treatment-related CRC passes through a potentially screen-detectable polyp phase and lends further support to the idea that some survivors of childhood cancer should start CRC screening before age 50 years. Further research should aim to clarify several issues: the doses of different exposures that increase CRC risk sufficiently to warrant early screening, the optimal start time and frequency of screening, the expected magnitude of clinical benefit, and the associated cost-effectiveness. Moreover, bringing more evidence to bear on the creation of follow-up guidelines will only be the first step. Given that less than one-third of potentially eligible high-risk survivors in North America undergo colonoscopy as per COG Guidelines (9), strategies to disseminate and implement these guidelines will become increasingly important to improving the long-term outcomes of childhood cancer survivors. Note Affiliations of authors: Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada (DCH); Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada (DCH); Pediatric Oncology Group of Ontario, Toronto, Ontario, Canada (DCH); Department of Pediatrics, University of Chicago Comer Children’s Hospital, Chicago, IL (TH). The authors have no conflicts of interest to disclose. References 1 Teepen JC , Kok JL , van Leeuwen FE , et al. Colorectal adenomas and cancers after childhood cancer treatment: A DCOG‐LATER record linkage study . J Natl Cancer Inst. 2018 ; 110 7 : 758 – 767 . 2 Fidler MM , Reulen RC , Winter DL et al. , . Long term cause specific mortality among 34 489 five year survivors of childhood cancer in Great Britain: Population based cohort study . BMJ. 2016 ; 354 : i4351 . 3 Henderson TO , Oeffinger KC , Whitton J et al. , . Secondary gastrointestinal cancer in childhood cancer survivors: A cohort study . Ann Intern Med. 2012 ; 156 11 : 757 – 766 , W-260. 4 Children’s Oncology Group . Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer. Volume 4 . 2013 . http://www.survivorshipguidelines.org/ accessed January 9, 2018. 5 Wallace WH , Thompson L , Anderson RA , Guideline Development Group . Long term follow-up of survivors of childhood cancer: Summary of updated SIGN guidance . BMJ. 2013 ; 346 : f1190 . 6 Daly PE , Samiee S , Cino M et al. , . High prevalence of adenomatous colorectal polyps in young cancer survivors treated with abdominal radiation therapy: Results of a prospective trial . Gut. 2017 ; 66 10 : 1797 – 1801 . http://dx.doi.org/10.1136/gutjnl-2016-311501 7 Chung SJ , Kim YS , Yang SY et al. , . Prevalence and risk of colorectal adenoma in asymptomatic Koreans aged 40-49 years undergoing screening colonoscopy. J Gastroenterol Hepatol. 2010 ; 25 3 : 519 – 525 . http://dx.doi.org/10.1111/j.1440-1746.2009.06147.x 8 Hemmasi G , Sohrabi M , Zamani F et al. , . Prevalence of colorectal adenoma in an average-risk population aged 40-50 versus 50-60 years . Eur J Cancer Prev. 2015 ; 24 5 : 386 – 390 . http://dx.doi.org/10.1097/CEJ.0000000000000097 9 Daniel CL , Kohler CL , Stratton KL et al. , . Predictors of colorectal cancer surveillance among survivors of childhood cancer treated with radiation: A report from the Childhood Cancer Survivor Study . Cancer. 2015 ; 121 11 : 1856 – 1863 . http://dx.doi.org/10.1002/cncr.29265 © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI: Journal of the National Cancer Institute Oxford University Press

Beyond Expert Opinion: Progress in the Development of Evidence-Based Screening Guidelines for Survivors of Childhood Cancer

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0027-8874
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Abstract

In this issue of the Journal, Teepen et al. provide important new findings from the Dutch DCOG‐LATER study that support early surveillance strategies to reduce the burden of colorectal cancer (CRC) in childhood cancer survivors (1). This is of particular importance because second cancers are the greatest cause of premature mortality in adult survivors of childhood cancer. The British Childhood Cancer Survivor Study, for example, found that gastrointestinal malignancies contributed the greatest absolute excess risk among childhood cancer survivors older than age 40 years, and the cumulative incidence of CRC for survivors treated with abdominopelvic radiotherapy (RT) was 1.4% by age 50 years (2). This and other large cohort studies have demonstrated that platinum-based chemotherapy and abdominal or pelvic RT increase CRC risk up to three to four times higher than expected (3). It would be natural to infer from these findings that CRC screening should be initiated sooner among childhood cancer survivors than in the general population, and in fact current guidelines from the Children’s Oncology Group (COG) recommend the initiation of CRC screening with colonoscopy in survivors exposed to abdominal or pelvic radiotherapy at age 35 years or 10 years after abdominal or pelvic RT exposure, whichever occurs later (4). However, other guideline authors have been more cautious, citing the important lack of evidence that early CRC screening would be effective (5). And perhaps with the exception of breast cancer, only a few studies provide the information necessary to guide the development of evidence-driven screening strategies of subsequent cancers in this population. Teepen and colleagues have addressed one substantial gap in our understanding about treatment-induced CRC: whether it passes through a screen-detectable preclinical (ie, adenoma) phase similar to idiopathic CRC, which would be necessary for screening to effectively reduce the subsequent morbidity and mortality. By linking treatment data from a cohort of 5843 five-year childhood cancer survivors (median follow-up = 32.4 years) to a national pathology registry, the authors were able to identify 78 survivors who had at least one colorectal adenoma removed and 41 survivors who had multiple adenomas. By age 45 years, the cumulative incidence of adenoma was 3.6% for survivors who had abdominal/pelvic RT, 2.0% for those without such treatments, and 1.0% for sibling controls (P = .03 for the comparison of RT-treated survivors vs controls). Notably, many of the exposures previously associated with CRC in prior studies were associated with colorectal adenomas in this Dutch cohort. In multivariable Cox regression analysis, abdominal RT was associated with a 2.12-fold increased risk, and similar to the Childhood Cancer Survivor Study (CCSS) finding of CRC risk, cisplatin exposure was statistically significantly associated with increased adenoma risk (hazard ratio [HR] = 2.81, 95% confidence interval [CI] = 1.32 to 5.99) (1). It is notable that the association between treatment exposures and colorectal neoplasia appear to be more complex than those for some other second malignancies. For example, while prior studies have reported consistent findings relating the risk of RT-related breast cancer to increasing radiation dose and exposed breast tissue volume, Teepen et al. could not find a relationship between the estimated radiation dose or the volume of irradiated colon and the risk of subsequent colorectal adenoma. This finding is similar to prior studies that have found that 29% of CRC (3) and 47% of colorectal polyps (6) occur outside the directly irradiated colon. While these findings may simply reflect the challenges of accurately estimating colorectal radiation exposure retrospectively, they also suggest that for some survivors there may be a biological predisposition affecting the entire colonic mucosa, perhaps mediated through indirect effects of RT, systemic therapy, or a currently unknown underlying biological process. Further, the data regarding the effects of chemotherapy are also inconsistent. Teepen et al. found that procarbazine was statistically significantly associated with adenoma risk only among survivors who did not have abdominopelvic radiotherapy or total body irradiation (HR = 2.71, 95% CI = 1.28 to 5.74), which contrasts with the CCSS finding that procarbazine without abdominal RT was not associated with the risk of gastrointestinal second malignancies, although it was statistically significantly associated with this risk among survivors treated with RT (3). An important limitation of the DCOG-LATER study is that it does not provide the true (ie, complete) incidence of adenoma among the study cohort. Approximately 11% to 22% of the average risk population age 40 to 50 years is found to have colorectal adenomas on first colonoscopic screening (7,8), and a recent study found adenomatous polyps in 27.8% of childhood survivors undergoing colonoscopic screening before age 50 years (6). Given these results, the cumulative incidence of adenoma reported by Teepen et al. (3.6% by age 45 years after abdominopelvic RT) almost certainly underrepresents the true biological occurrence among survivors. Similarly, the inconsistent utilization of colonoscopy among survivors and uncertainty regarding indications for the procedure among sibling controls could substantially influence the generalizability and interpretation of the results. There was no information on the use of colonoscopy in more than 98% of the study cohort, and the indication for colonoscopy was unknown for 33% of survivors and all of the sibling controls diagnosed with adenomas. It seems unlikely that survivors were undergoing colonoscopy at the same rate or for the same reasons as their siblings, and more frequent use of colonoscopy among the former could bias the comparison of adenoma incidence between these two groups. Despite these limitations, this DCOG-LATER study adds important new evidence that treatment-related CRC passes through a potentially screen-detectable polyp phase and lends further support to the idea that some survivors of childhood cancer should start CRC screening before age 50 years. Further research should aim to clarify several issues: the doses of different exposures that increase CRC risk sufficiently to warrant early screening, the optimal start time and frequency of screening, the expected magnitude of clinical benefit, and the associated cost-effectiveness. Moreover, bringing more evidence to bear on the creation of follow-up guidelines will only be the first step. Given that less than one-third of potentially eligible high-risk survivors in North America undergo colonoscopy as per COG Guidelines (9), strategies to disseminate and implement these guidelines will become increasingly important to improving the long-term outcomes of childhood cancer survivors. Note Affiliations of authors: Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada (DCH); Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada (DCH); Pediatric Oncology Group of Ontario, Toronto, Ontario, Canada (DCH); Department of Pediatrics, University of Chicago Comer Children’s Hospital, Chicago, IL (TH). The authors have no conflicts of interest to disclose. References 1 Teepen JC , Kok JL , van Leeuwen FE , et al. Colorectal adenomas and cancers after childhood cancer treatment: A DCOG‐LATER record linkage study . J Natl Cancer Inst. 2018 ; 110 7 : 758 – 767 . 2 Fidler MM , Reulen RC , Winter DL et al. , . Long term cause specific mortality among 34 489 five year survivors of childhood cancer in Great Britain: Population based cohort study . BMJ. 2016 ; 354 : i4351 . 3 Henderson TO , Oeffinger KC , Whitton J et al. , . Secondary gastrointestinal cancer in childhood cancer survivors: A cohort study . Ann Intern Med. 2012 ; 156 11 : 757 – 766 , W-260. 4 Children’s Oncology Group . Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer. Volume 4 . 2013 . http://www.survivorshipguidelines.org/ accessed January 9, 2018. 5 Wallace WH , Thompson L , Anderson RA , Guideline Development Group . Long term follow-up of survivors of childhood cancer: Summary of updated SIGN guidance . BMJ. 2013 ; 346 : f1190 . 6 Daly PE , Samiee S , Cino M et al. , . High prevalence of adenomatous colorectal polyps in young cancer survivors treated with abdominal radiation therapy: Results of a prospective trial . Gut. 2017 ; 66 10 : 1797 – 1801 . http://dx.doi.org/10.1136/gutjnl-2016-311501 7 Chung SJ , Kim YS , Yang SY et al. , . Prevalence and risk of colorectal adenoma in asymptomatic Koreans aged 40-49 years undergoing screening colonoscopy. J Gastroenterol Hepatol. 2010 ; 25 3 : 519 – 525 . http://dx.doi.org/10.1111/j.1440-1746.2009.06147.x 8 Hemmasi G , Sohrabi M , Zamani F et al. , . Prevalence of colorectal adenoma in an average-risk population aged 40-50 versus 50-60 years . Eur J Cancer Prev. 2015 ; 24 5 : 386 – 390 . http://dx.doi.org/10.1097/CEJ.0000000000000097 9 Daniel CL , Kohler CL , Stratton KL et al. , . Predictors of colorectal cancer surveillance among survivors of childhood cancer treated with radiation: A report from the Childhood Cancer Survivor Study . Cancer. 2015 ; 121 11 : 1856 – 1863 . http://dx.doi.org/10.1002/cncr.29265 © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

JNCI: Journal of the National Cancer InstituteOxford University Press

Published: Feb 26, 2018

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