Pediatr Blood Cancer 2014;61:1337–1338
HIGHLIGHT1,2 by David Malkin,
MD
*
Surveillance for Children at Genetic Risk for Cancer: Are We Ready?
I
n this issue of Pediatric Blood & Cancer, Freidman et al. present compelling data to suggest that patients diagnosed with hereditary retinoblastoma (RB) may benefit from the use of whole body magnetic resonance imaging (WB-MRI) screening for detection of second malignant neoplasms (SMN) [1]. The primary endpoint of the study was to determine sensitivity and specificity of WB-MRI in detecting localized stage soft tissue and bone sarcomas in hereditary RB survivors. Using a retrospective approach, medical records were examined of the 25 survivors who participated in the program, and who were followed over a 4.5-year period. A wide range of median age at first scan, number of scans performed per patient, and the intra-patient interval between scans (for those who had more than one) was documented. This degree of variability across all these parameters is noted by the authors as a significant limitation to the interpretation of their findings—particularly with respect to the accuracy of the rate at which tumors may be detected. Nonetheless, the frequent detection of abnormal findings in this cohort is not a trivial observation. Of eight WB-MRIs (in 8/25 patients), five were suspicious for malignancy. Two of the five were biopsy-proven osteosarcomas, one was a benign neoplasm (chondroblastoma) and two were non-neoplastic lesions. Curiously, the authors include the likely diagnosis of multiple uterine/pelvic fibroids in one patient within a grouping of “benign abnormalities” for which no further work-up was required. As uterine fibroids are tumors of mesenchymal origin, one could very well make the argument that they should be included in the group of WB-MRI detectable lesions for which dedicated imaging, subsequent biopsy/ intervention and follow-up would be appropriate. While the sensitivity (66.7%) [positive predictive value ¼ 0.4] and specificity (92.1%) [positive predictive value ¼ 0.97] of detecting a SMN in this study was modest, the absolute detection rate (3/25 or 4/25 if one includes fibromas) of combined benign and malignant tumors with relatively few scans carried out per patient within a limited timeframe of 4.5 years is not inconsequential. As such, while the authors appropriately raise some doubt as to the benefits of this form of surveillance in long-term hereditary RB survivors, the inherent limitations of the study (small sample size, retrospective, widely variable inter-patient variability in uptake of the protocol) indicate the need to pursue the question more rigorously through a multiinstitutional, prospective clinical trial design from the time of completion of therapy perhaps right through adulthood. While the benefit of WB-MRI surveillance in hereditary RB survivors remains in question based on the findings of this one study, what no longer appears in doubt is the value of surveillance imaging in the context of hereditary cancer predisposition C
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25061 Published online 11 April 2014 in Wiley Online Library (wileyonlinelibrary.com).
syndromes in general. Together with the continued technological advances in WB-MRI technology have come other important changes in pediatric oncology, clinical genetics, and affiliated specialities that have brought great attention to the feasibility and clinical impact of surveillance in these children and their families. Several recent studies highlight the value of WB-MRI surveillance in different groups including Li-Fraumeni syndrome [2], succinyl dehydrogenase associated hereditary paraganglioma families [3], von Hippel-Lindau disease [4], and constitutional mismatch repair deficiency syndrome (CMRDS) [5]. These studies build on older syndrome-specific surveillance protocols for Gorlin syndrome, Beckwith–Wiedemann syndrome (BWS), Cowden syndrome, and the multiple endocrine neoplasias, among many others. They also provide the foundation to develop similar comprehensive surveillance protocols for emerging syndromes such as DICER1 (pleuropulmonary blastoma—familial tumor dysplasia syndrome [PPBFTDS]) syndrome, and the rationale to incorporate them into the management of classic disorders such as reported here for hereditary RB. For some of these, other non-invasive imaging modalities such as ultrasound are effective tools for routine assessment, whereas for others, batteries of biochemical markers have demonstrable value—particularly the use of alpha-fetoprotein for early detection of hepatoblastoma in BWS and familial adenomatous polyposis (FAP), serum or urine catecholamine measurements for early detection of pheochromocytomas or secreting paragangliomas in VHL and SDHx, respectively, or serum adrenocortical hormone profile in LFS. However, as with hereditary RB, many of the SMNs that occur in cancer predisposition syndromes occur in sites that are not otherwise amenable to conventional imaging or biochemical screening— leaving the practitioner with limited effective options. It has taken many years for the pediatric oncology and clinical genetics communities to begin to revise the textbook mantra that a small minority (perhaps less than 5%) of childhood cancers are
1
Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario; 2Departments of Pediatrics and Medical Biophysics, University of Toronto, Toronto, Ontario Grant sponsor: Canadian Institutes of Health Research (CIHR); Grant number: # MOP-300105
Correspondence to: David Malkin, Division of Hematology/Oncology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8. E-mail: [email protected] Received 20 March 2014; Accepted 20 March 2014
1338
Malkin
genetic [6]. With the emergence of affordable next generation sequencing platforms, more careful ascertainment and ongoing updates of family cancer history, recognition of novel cancer susceptibility syndromes such as those associated with DICER1, biallelic mismatch repair, succinyl dehydrogenase deficiency and others, it is clear that a genetic basis for many childhood cancers must be considered. The clinical recognition of these at-risk patients, and determining the best approach to monitoring them for the development of multiple cancers over their lifetime, is now more complex than ever. Prior statements from American Society of Clinical Oncology [7] and American Society of Human Genetics [8] did not generally endorse genetic testing for children. These statements were based primarily on the notion that in the absence of effective interventions, the potential benefits did not outweigh the psychological risks. However, the playing field has changed dramatically. This change in sentiment is reflected in more current recommendations, such as from the National Comprehensive Cancer Network (NCCN) [9]. Previously, the NCCN had indicated that these individuals should be considered for surveillance, but now such protocols are commonly recommended. This is a subtle but important change in approach. While most of the evidence on which these protocols are being implemented in clinical settings is based on small patient numbers (including the one presented by Fernandez et al.), the cumulative accruing data supports ongoing efforts to conduct multi-center prospective studies as well as to work with regulators, insurers, radiologists, and others to refine the protocols in as patient-specific a manner as possible. While the sensitivity/specificity and impact on health outcomes from early tumor detection are critical factors in determining the value of introduction of surveillance protocols in hereditary RB survivors or any other hereditary cancer predisposition syndrome, Friedman et al. also point out the equally important concern of psychological burden on the patients and their families. These issues have been explored quite extensively in the context of adultonset cancer predisposition syndromes including Lynch and hereditary breast/ovarian cancer syndromes, but there is relatively little published literature focusing on the at-risk pediatric population [10]. Nonetheless, there are at least some indications that while transient psychological anxiety does occur, longstanding clinically significant distress is not generally observed. Importantly, despite as yet unclear clinical benefits to many surveillance protocols, the value of surveillance in the hope to detect tumors at an early stage is accompanied by greater sense of empowerment and security for patients and families [11]. It is also important to point out that whereas adults may show poor adherence to long-term surveillance for themselves, they almost universally
Pediatr Blood Cancer DOI 10.1002/pbc
make concerted efforts to ensure that their children are closely monitored [12]. As familiarity of the risk of secondary tumors in cancer survivors and children with cancer predisposition syndromes continues to increase, we must recognize the urgency to develop more reliable, sensitive, and tumor-specific surveillance protocols. Ongoing technological advances in WB-MRI and other relatively non-invasive imaging modalities will no doubt continue; however, it is unlikely that the challenge of false-positive radiologic findings leading to unnecessary diagnostic surgical procedures will be completely eliminated. The advent of affordable next generation sequencing platforms, discovery of genetic/genomic and epigenetic modifiers of susceptibility gene associated phenotypes, and refinement of methods for detection of early cancers through peripheral blood sampling of circulating tumor cell (CTC) or tumor DNA (ctDNA) will bolster the practitioner’s armamentarium for early tumor detection. Advances in tumor predictive capacity by the eventual incorporation of these approaches into clinical practice will facilitate the oncologist’s and genetic counselor’s task in guiding patients and their families to the role of genetic testing and surveillance. One day, perhaps, chemoprevention will become possible, altogether eliminating the risk of tumor development and perhaps even the need for surveillance in these genetically at-risk children. That is the subject of an article for another day, but we hope it is not too far in the future.
REFERENCES 1. Friedman DN, Lis E, Sklar CA, et al. Whole-body magnetic resonance imaging (WB-MRI) as surveillance for subsequent malignancies in survivors of hereditary retinoblastoma: A pilot study. Pediatr Blood Cancer 2014. 2. Villani A, Tabori U, Schiffman JD, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: A prospective observational study. Lancet Oncol 2011;12:559–567. 3. Jasperson KW, Kohlmann W, Gammon A, et al. Role of rapid sequence whole body MRI screening in SDH-associated hereditary paraganglioma families. Fam Cancer 2013. Epub ahead of print (PMID#23934599). 4. Kruizinga RC, Sluiter WJ, de Vries EGE, et al. Calculating optimal surveillance for detection of von Hippel-Lindau manifestations. Endocr Related Cancer 2013;21:63–71. 5. Bakry D, Aronson M, Durno C, et al. Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: Report from the constitutional mismatch repair deficiency syndrome consortium. Eur J Cancer 2014;50:987–996. 6. Knapke S, Nagarajan R, Correll J, et al. Herediatry cancer risk assessment in a pediatric oncology followup clinic. Pediatr Blood Cancer 2012;58:85–89. 7. American Society of Clinical Oncology policy statement update: Genetic testing for cancer susceptibility. J Clin Oncol 2003;21:2397–2406. 8. Points to consider: Ethical, legal, and psychosocial implications of genetic testing in children and adolescents. American Society of Human Genetics Board of Directors, American College of Medical Genetics Board of Directors. Am J Hum Genet 1995;57:1233–1241. 9. NCCN. Clinical practice guidelines in oncology. 2014. http://www.nccn.org/professionals/physician_gls/ pdf/genetics_screening.pdf (accessed March 2014). 10. Gopie JP, Vasen HF, Tibben A. Surveillance for hereditary cancer: Does the benefit outweigh the psychological burden. A systemic review. Critical Rev Oncol Hematol 2012;83:329–340. 11. Lammens CR, Bleiker EM, Aaronson NK, et al. Regular surveillance for Li-Fraumeni syndrome: Advice, adherence and perceived benefits. Fam Cancer 2010;9:647–654. 12. Rasmussen A, Alonso E, Ochoa A, et al. Uptake of genetic testing and long-term surveillance in von Hippel-Lindau disease. BMC Med Genet 2010; 11: 4. doi: 10.1186/1471-2350-11-4
HIGHLIGHT1,2 by David Malkin,
MD
*
Surveillance for Children at Genetic Risk for Cancer: Are We Ready?
I
n this issue of Pediatric Blood & Cancer, Freidman et al. present compelling data to suggest that patients diagnosed with hereditary retinoblastoma (RB) may benefit from the use of whole body magnetic resonance imaging (WB-MRI) screening for detection of second malignant neoplasms (SMN) [1]. The primary endpoint of the study was to determine sensitivity and specificity of WB-MRI in detecting localized stage soft tissue and bone sarcomas in hereditary RB survivors. Using a retrospective approach, medical records were examined of the 25 survivors who participated in the program, and who were followed over a 4.5-year period. A wide range of median age at first scan, number of scans performed per patient, and the intra-patient interval between scans (for those who had more than one) was documented. This degree of variability across all these parameters is noted by the authors as a significant limitation to the interpretation of their findings—particularly with respect to the accuracy of the rate at which tumors may be detected. Nonetheless, the frequent detection of abnormal findings in this cohort is not a trivial observation. Of eight WB-MRIs (in 8/25 patients), five were suspicious for malignancy. Two of the five were biopsy-proven osteosarcomas, one was a benign neoplasm (chondroblastoma) and two were non-neoplastic lesions. Curiously, the authors include the likely diagnosis of multiple uterine/pelvic fibroids in one patient within a grouping of “benign abnormalities” for which no further work-up was required. As uterine fibroids are tumors of mesenchymal origin, one could very well make the argument that they should be included in the group of WB-MRI detectable lesions for which dedicated imaging, subsequent biopsy/ intervention and follow-up would be appropriate. While the sensitivity (66.7%) [positive predictive value ¼ 0.4] and specificity (92.1%) [positive predictive value ¼ 0.97] of detecting a SMN in this study was modest, the absolute detection rate (3/25 or 4/25 if one includes fibromas) of combined benign and malignant tumors with relatively few scans carried out per patient within a limited timeframe of 4.5 years is not inconsequential. As such, while the authors appropriately raise some doubt as to the benefits of this form of surveillance in long-term hereditary RB survivors, the inherent limitations of the study (small sample size, retrospective, widely variable inter-patient variability in uptake of the protocol) indicate the need to pursue the question more rigorously through a multiinstitutional, prospective clinical trial design from the time of completion of therapy perhaps right through adulthood. While the benefit of WB-MRI surveillance in hereditary RB survivors remains in question based on the findings of this one study, what no longer appears in doubt is the value of surveillance imaging in the context of hereditary cancer predisposition C
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25061 Published online 11 April 2014 in Wiley Online Library (wileyonlinelibrary.com).
syndromes in general. Together with the continued technological advances in WB-MRI technology have come other important changes in pediatric oncology, clinical genetics, and affiliated specialities that have brought great attention to the feasibility and clinical impact of surveillance in these children and their families. Several recent studies highlight the value of WB-MRI surveillance in different groups including Li-Fraumeni syndrome [2], succinyl dehydrogenase associated hereditary paraganglioma families [3], von Hippel-Lindau disease [4], and constitutional mismatch repair deficiency syndrome (CMRDS) [5]. These studies build on older syndrome-specific surveillance protocols for Gorlin syndrome, Beckwith–Wiedemann syndrome (BWS), Cowden syndrome, and the multiple endocrine neoplasias, among many others. They also provide the foundation to develop similar comprehensive surveillance protocols for emerging syndromes such as DICER1 (pleuropulmonary blastoma—familial tumor dysplasia syndrome [PPBFTDS]) syndrome, and the rationale to incorporate them into the management of classic disorders such as reported here for hereditary RB. For some of these, other non-invasive imaging modalities such as ultrasound are effective tools for routine assessment, whereas for others, batteries of biochemical markers have demonstrable value—particularly the use of alpha-fetoprotein for early detection of hepatoblastoma in BWS and familial adenomatous polyposis (FAP), serum or urine catecholamine measurements for early detection of pheochromocytomas or secreting paragangliomas in VHL and SDHx, respectively, or serum adrenocortical hormone profile in LFS. However, as with hereditary RB, many of the SMNs that occur in cancer predisposition syndromes occur in sites that are not otherwise amenable to conventional imaging or biochemical screening— leaving the practitioner with limited effective options. It has taken many years for the pediatric oncology and clinical genetics communities to begin to revise the textbook mantra that a small minority (perhaps less than 5%) of childhood cancers are
1
Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario; 2Departments of Pediatrics and Medical Biophysics, University of Toronto, Toronto, Ontario Grant sponsor: Canadian Institutes of Health Research (CIHR); Grant number: # MOP-300105
Correspondence to: David Malkin, Division of Hematology/Oncology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8. E-mail: [email protected] Received 20 March 2014; Accepted 20 March 2014
1338
Malkin
genetic [6]. With the emergence of affordable next generation sequencing platforms, more careful ascertainment and ongoing updates of family cancer history, recognition of novel cancer susceptibility syndromes such as those associated with DICER1, biallelic mismatch repair, succinyl dehydrogenase deficiency and others, it is clear that a genetic basis for many childhood cancers must be considered. The clinical recognition of these at-risk patients, and determining the best approach to monitoring them for the development of multiple cancers over their lifetime, is now more complex than ever. Prior statements from American Society of Clinical Oncology [7] and American Society of Human Genetics [8] did not generally endorse genetic testing for children. These statements were based primarily on the notion that in the absence of effective interventions, the potential benefits did not outweigh the psychological risks. However, the playing field has changed dramatically. This change in sentiment is reflected in more current recommendations, such as from the National Comprehensive Cancer Network (NCCN) [9]. Previously, the NCCN had indicated that these individuals should be considered for surveillance, but now such protocols are commonly recommended. This is a subtle but important change in approach. While most of the evidence on which these protocols are being implemented in clinical settings is based on small patient numbers (including the one presented by Fernandez et al.), the cumulative accruing data supports ongoing efforts to conduct multi-center prospective studies as well as to work with regulators, insurers, radiologists, and others to refine the protocols in as patient-specific a manner as possible. While the sensitivity/specificity and impact on health outcomes from early tumor detection are critical factors in determining the value of introduction of surveillance protocols in hereditary RB survivors or any other hereditary cancer predisposition syndrome, Friedman et al. also point out the equally important concern of psychological burden on the patients and their families. These issues have been explored quite extensively in the context of adultonset cancer predisposition syndromes including Lynch and hereditary breast/ovarian cancer syndromes, but there is relatively little published literature focusing on the at-risk pediatric population [10]. Nonetheless, there are at least some indications that while transient psychological anxiety does occur, longstanding clinically significant distress is not generally observed. Importantly, despite as yet unclear clinical benefits to many surveillance protocols, the value of surveillance in the hope to detect tumors at an early stage is accompanied by greater sense of empowerment and security for patients and families [11]. It is also important to point out that whereas adults may show poor adherence to long-term surveillance for themselves, they almost universally
Pediatr Blood Cancer DOI 10.1002/pbc
make concerted efforts to ensure that their children are closely monitored [12]. As familiarity of the risk of secondary tumors in cancer survivors and children with cancer predisposition syndromes continues to increase, we must recognize the urgency to develop more reliable, sensitive, and tumor-specific surveillance protocols. Ongoing technological advances in WB-MRI and other relatively non-invasive imaging modalities will no doubt continue; however, it is unlikely that the challenge of false-positive radiologic findings leading to unnecessary diagnostic surgical procedures will be completely eliminated. The advent of affordable next generation sequencing platforms, discovery of genetic/genomic and epigenetic modifiers of susceptibility gene associated phenotypes, and refinement of methods for detection of early cancers through peripheral blood sampling of circulating tumor cell (CTC) or tumor DNA (ctDNA) will bolster the practitioner’s armamentarium for early tumor detection. Advances in tumor predictive capacity by the eventual incorporation of these approaches into clinical practice will facilitate the oncologist’s and genetic counselor’s task in guiding patients and their families to the role of genetic testing and surveillance. One day, perhaps, chemoprevention will become possible, altogether eliminating the risk of tumor development and perhaps even the need for surveillance in these genetically at-risk children. That is the subject of an article for another day, but we hope it is not too far in the future.
REFERENCES 1. Friedman DN, Lis E, Sklar CA, et al. Whole-body magnetic resonance imaging (WB-MRI) as surveillance for subsequent malignancies in survivors of hereditary retinoblastoma: A pilot study. Pediatr Blood Cancer 2014. 2. Villani A, Tabori U, Schiffman JD, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: A prospective observational study. Lancet Oncol 2011;12:559–567. 3. Jasperson KW, Kohlmann W, Gammon A, et al. Role of rapid sequence whole body MRI screening in SDH-associated hereditary paraganglioma families. Fam Cancer 2013. Epub ahead of print (PMID#23934599). 4. Kruizinga RC, Sluiter WJ, de Vries EGE, et al. Calculating optimal surveillance for detection of von Hippel-Lindau manifestations. Endocr Related Cancer 2013;21:63–71. 5. Bakry D, Aronson M, Durno C, et al. Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: Report from the constitutional mismatch repair deficiency syndrome consortium. Eur J Cancer 2014;50:987–996. 6. Knapke S, Nagarajan R, Correll J, et al. Herediatry cancer risk assessment in a pediatric oncology followup clinic. Pediatr Blood Cancer 2012;58:85–89. 7. American Society of Clinical Oncology policy statement update: Genetic testing for cancer susceptibility. J Clin Oncol 2003;21:2397–2406. 8. Points to consider: Ethical, legal, and psychosocial implications of genetic testing in children and adolescents. American Society of Human Genetics Board of Directors, American College of Medical Genetics Board of Directors. Am J Hum Genet 1995;57:1233–1241. 9. NCCN. Clinical practice guidelines in oncology. 2014. http://www.nccn.org/professionals/physician_gls/ pdf/genetics_screening.pdf (accessed March 2014). 10. Gopie JP, Vasen HF, Tibben A. Surveillance for hereditary cancer: Does the benefit outweigh the psychological burden. A systemic review. Critical Rev Oncol Hematol 2012;83:329–340. 11. Lammens CR, Bleiker EM, Aaronson NK, et al. Regular surveillance for Li-Fraumeni syndrome: Advice, adherence and perceived benefits. Fam Cancer 2010;9:647–654. 12. Rasmussen A, Alonso E, Ochoa A, et al. Uptake of genetic testing and long-term surveillance in von Hippel-Lindau disease. BMC Med Genet 2010; 11: 4. doi: 10.1186/1471-2350-11-4
