Comment
Pr J Bernard/Cnri/Science Photo Library
How safe is a standard-risk child with ALL?
Published Online June 20, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70294-3 See Articles page 841
782
Treatment of childhood cancer is one of the major success stories of modern medicine, showing the benefits of multidisciplinary, centralised treatment and high-quality supportive care. For acute lymphoblastic leukaemia (ALL)—the most common childhood cancer—overall 5-year survival is now greater than 85%.1 The first step toward curative therapy for children with ALL (and a turning point for paediatric oncology) was the discovery in 1948, by Sidney Farber and colleagues,2 that aminopterin could induce temporary remission. In the 1960s and 1970s, further progress was made towards cure of ALL, including the following milestones: development of combination chemotherapy regimens, collaborative multicentre trials, prophylactic CNS irradiation, and addition of delayed intensification.3 In recent decades, the continuous improvement in cure rates is a result of better risk grouping and further refinement of treatment by genetic mapping of leukaemic biology; precise monitoring of minimal residual disease; improved drug combinations and dosing (that still use essentially the same drugs as those available 30 years ago); and better CNS-directed intrathecal or high-dose systemic chemotherapy, replacing irradiation in many protocols.4 However, as recognised already 40 years ago, ”cure is not enough”,5 and the price of treatment success has certainly been high. Many survivors of childhood cancer are burdened by a range of long-term late adverse effects of the chemotherapy and radiotherapy given years or even decades earlier. This problem also takes place in the subset of patients who today have survival rates greater than 90%. In Stefan Essig and colleagues’ report6 in The Lancet Oncology, the investigators assessed self-reported health, health status, and socioeconomic outcomes in a subcohort of 556 members of the Childhood Cancer Survivor Study cohort of 5-year survivors of ALL, who had received therapy classified as consistent with contemporary standard-risk protocols, to estimate the risks of late effects in similar patients diagnosed in the present day (ie, in those who had received limited anthracycline and cyclophosphamide therapy and no irradiation). At a median follow-up of 18·4 years (range 0·0–33·0) of the survivors from
5 years after diagnosis, 28 (5%) of participants had died (standardised mortality ratio 3·5, 95% CI 2·3–5·0). By comparison with siblings, survivors of standard-risk ALL had a slight increased risk for second cancers and several chronic medical disorders. Although Essig and colleagues’ findings are generally reassuring, it is uncertain how transferable they are to present-day patients with standardrisk ALL, who could be at much higher risk of late effects than reported here. First, little is known of the effect of the leukaemia subtype itself on the risk of late effects (including presence of subclinical CNS involvement and hyperleukocytosis), and patients classified with standard-risk disease in the present study differ significantly from today’s patients, who are mainly defined by their leukaemic karyotype and early response to therapy. Second, wider use of dexamethasone, high-dose methotrexate, extensive treatment with asparaginase, and more intensive maintenance therapy with mercaptopurine and methotrexate might increase the risks of late effects, including chronic pancreatitis, diabetes, osteonecrosis, cognitive disturbances, and second cancers. Third, secondary myeloid malignancies—the most common second cancer—mainly take place within the first 5 years from diagnosis, and these early events were not included.7 Finally, the risk of late effects that become apparent after age 40 years, including premature ageing, remains uncertain. Some treatment-related toxic effects are immediate and obvious, some are more subtle, and some appear many decades after exposure. Large cohort studies,8 including the Childhood Cancer Survivor Study, have been able to map late effects that take place during several decades after diagnosis, whereas the excess lifetime morbidity associated with childhood cancer and therapy has been unknown until recently.9 Results from large Nordic collaborative studies with long follow-up of more than 40 000 children with cancer have started to fill the gaps in knowledge about very late long-term outcomes. Nordic childhood cancer survivors have a persistent excess risk for second cancers throughout their lifetimes, with the highest age-specific incidences reported for patients treated in the most recent era of intensive, multi-agent www.thelancet.com/oncology Vol 15 July 2014
Comment
chemotherapy.10 The first Nordic publication on data from the ongoing large late-effect study Adult Life after Childhood Cancer in Scandinavia (ALiCCS) showed that endocrine disorders are very common in all types of survivors of childhood cancer, with an increasing risk that does not plateau with ageing, and with the risk remaining very high in patients treated according to the most contemporary protocols.11 Cure is an insufficient goal. When nine out of ten patients survive, attention must be paid to long-term quality of life and health challenges. Novel strategies are needed that ensure the capture of all relevant late effects; identify host factors that put some patients at the highest risk of such side-effects due to, for example, host genome variants, co-medication, or behaviour; and identify patients who can be cured by less intensive treatment to avoid these late effects. New milestones on the road towards cure are still needed.
We declare no competing interests. 1
2
3
4 5 6
7
8 9 10
*Jeanette Falck Winther, Kjeld Schmiegelow Danish Cancer Society Research Center, Copenhagen, DK 2100, Denmark (JFW); Pediatrics and Adolescence Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark (KS); and the Institute for Clinical Medicine, University of Copenhagen, Denmark (KS) [email protected]
11
Pui CH, Mullighan CG, Evans WE, Relling MV. Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? Blood 2012; 120: 1165–74. Farber S, Diamond LK. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl J Med 1948; 238: 787–93. Hudson MM, Neglia JP, Woods WG, et al. Lessons from the past: opportunities to improve childhood cancer survivor care through outcomes investigations of historical therapeutic approaches for pediatric hematological malignancies. Pediatr Blood Cancer 2012; 58: 334–43. Pui CH, Campana D, Pei D, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009; 360: 2730–41. D’Angio GJ. Pediatric cancer in perspective: cure is not enough. Cancer 1975; 35 (3 suppl): 866–70. Essig S, Li Q, Chen Y, et al. Risk of late effects of treatment in children newly diagnosed with standard-risk acute lymphoblastic leukaemia: a report from the Childhood Cancer Survivor Study cohort. Lancet Oncol 2014; published online June 20. http://dx.doi.org/10.1016/S14702045(14)70265-7. Schmiegelow K, Levinsen MF, Attarbaschi A, et al. Second malignant neoplasms after treatment of childhood acute lymphoblastic leukemia. J Clin Oncol 2013; 31: 2469–76. Oeffinger KC, Sklar CA. Childhood cancer, endocrine disorders, and cohort studies. Lancet 2014; 383: 1950–52. Robison LL, Hudson MM. Survivors of childhood and adolescent cancer: life-long risks and responsibilities. Nat Rev Cancer 2014; 14: 61–70. Olsen JH, Moller T, Anderson H, et al. Lifelong cancer incidence in 47 697 patients treated for childhood cancer in the Nordic countries. J Natl Cancer Inst 2009; 101: 806–13. de Fine LS, Winther JF, Gudmundsdottir T, et al. Hospital contacts for endocrine disorders in Adult Life after Childhood Cancer in Scandinavia (ALiCCS): a population-based cohort study. Lancet 2014; 383: 1981–89.
For more on the ALiCCS study see www.aliccs.org
20 years have passed since the discovery of the major breast cancer susceptibility gene, BRCA1. Extraordinary progress has been made in the understanding of how BRCA1 and its associated proteins function, and the clinical consequences of malfunctioning BRCA proteins are now evident.1,2 The initial concerns3 about the risks of genetic testing for women carrying mutations in BRCA1 and BRCA2 seem to have receded. Moreover, the recent ruling by the US Supreme Court that genes are not patentable has opened up the genetic testing field, at least in the USA, in an unprecedented manner.4 Additionally, next-generation sequencing technologies have driven down the price of genetic testing such that to test for 100 genes is as cheap as to test for one. But outside of cancer centres, patients who undergo genetic testing are still in the minority. More so than cheaper tests, what would push genetic testing to the forefront is clear evidence that knowledge of a person’s genetic www.thelancet.com/oncology Vol 15 July 2014
status would substantially affect treatment choice, and moreover, that survival is improved as a result of this treatment. This evidence would place genetic testing for cancer susceptibility firmly at the start of the management plan. In The Lancet Oncology, a study reported by Jonathan Ledermann and colleagues5 suggests that this crucial shift—from risk assessment to therapeutic advantage— might not be very far away, at least for high-grade serous carcinoma of the ovary, fallopian tube, and peritoneum. The investigators did a preplanned retrospective analysis of a completed phase 2 clinical trial (NCT00753545),6 wherein 256 women with the abovementioned cancers, deemed to be platinum sensitive, but who had relapsed after treatment, were randomly assigned to receive maintenance oral therapy with olaparib (a PARP inhibitor) or placebo.6 In the initial analysis,6 done when 58% of the participants had experienced a progression
Steve Gschmeissner/Science Photo Library
Made-to-measure medicine: BRCA and gynaecological cancer
Published Online May 30, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70246-3 See Articles page 852
783
Pr J Bernard/Cnri/Science Photo Library
How safe is a standard-risk child with ALL?
Published Online June 20, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70294-3 See Articles page 841
782
Treatment of childhood cancer is one of the major success stories of modern medicine, showing the benefits of multidisciplinary, centralised treatment and high-quality supportive care. For acute lymphoblastic leukaemia (ALL)—the most common childhood cancer—overall 5-year survival is now greater than 85%.1 The first step toward curative therapy for children with ALL (and a turning point for paediatric oncology) was the discovery in 1948, by Sidney Farber and colleagues,2 that aminopterin could induce temporary remission. In the 1960s and 1970s, further progress was made towards cure of ALL, including the following milestones: development of combination chemotherapy regimens, collaborative multicentre trials, prophylactic CNS irradiation, and addition of delayed intensification.3 In recent decades, the continuous improvement in cure rates is a result of better risk grouping and further refinement of treatment by genetic mapping of leukaemic biology; precise monitoring of minimal residual disease; improved drug combinations and dosing (that still use essentially the same drugs as those available 30 years ago); and better CNS-directed intrathecal or high-dose systemic chemotherapy, replacing irradiation in many protocols.4 However, as recognised already 40 years ago, ”cure is not enough”,5 and the price of treatment success has certainly been high. Many survivors of childhood cancer are burdened by a range of long-term late adverse effects of the chemotherapy and radiotherapy given years or even decades earlier. This problem also takes place in the subset of patients who today have survival rates greater than 90%. In Stefan Essig and colleagues’ report6 in The Lancet Oncology, the investigators assessed self-reported health, health status, and socioeconomic outcomes in a subcohort of 556 members of the Childhood Cancer Survivor Study cohort of 5-year survivors of ALL, who had received therapy classified as consistent with contemporary standard-risk protocols, to estimate the risks of late effects in similar patients diagnosed in the present day (ie, in those who had received limited anthracycline and cyclophosphamide therapy and no irradiation). At a median follow-up of 18·4 years (range 0·0–33·0) of the survivors from
5 years after diagnosis, 28 (5%) of participants had died (standardised mortality ratio 3·5, 95% CI 2·3–5·0). By comparison with siblings, survivors of standard-risk ALL had a slight increased risk for second cancers and several chronic medical disorders. Although Essig and colleagues’ findings are generally reassuring, it is uncertain how transferable they are to present-day patients with standardrisk ALL, who could be at much higher risk of late effects than reported here. First, little is known of the effect of the leukaemia subtype itself on the risk of late effects (including presence of subclinical CNS involvement and hyperleukocytosis), and patients classified with standard-risk disease in the present study differ significantly from today’s patients, who are mainly defined by their leukaemic karyotype and early response to therapy. Second, wider use of dexamethasone, high-dose methotrexate, extensive treatment with asparaginase, and more intensive maintenance therapy with mercaptopurine and methotrexate might increase the risks of late effects, including chronic pancreatitis, diabetes, osteonecrosis, cognitive disturbances, and second cancers. Third, secondary myeloid malignancies—the most common second cancer—mainly take place within the first 5 years from diagnosis, and these early events were not included.7 Finally, the risk of late effects that become apparent after age 40 years, including premature ageing, remains uncertain. Some treatment-related toxic effects are immediate and obvious, some are more subtle, and some appear many decades after exposure. Large cohort studies,8 including the Childhood Cancer Survivor Study, have been able to map late effects that take place during several decades after diagnosis, whereas the excess lifetime morbidity associated with childhood cancer and therapy has been unknown until recently.9 Results from large Nordic collaborative studies with long follow-up of more than 40 000 children with cancer have started to fill the gaps in knowledge about very late long-term outcomes. Nordic childhood cancer survivors have a persistent excess risk for second cancers throughout their lifetimes, with the highest age-specific incidences reported for patients treated in the most recent era of intensive, multi-agent www.thelancet.com/oncology Vol 15 July 2014
Comment
chemotherapy.10 The first Nordic publication on data from the ongoing large late-effect study Adult Life after Childhood Cancer in Scandinavia (ALiCCS) showed that endocrine disorders are very common in all types of survivors of childhood cancer, with an increasing risk that does not plateau with ageing, and with the risk remaining very high in patients treated according to the most contemporary protocols.11 Cure is an insufficient goal. When nine out of ten patients survive, attention must be paid to long-term quality of life and health challenges. Novel strategies are needed that ensure the capture of all relevant late effects; identify host factors that put some patients at the highest risk of such side-effects due to, for example, host genome variants, co-medication, or behaviour; and identify patients who can be cured by less intensive treatment to avoid these late effects. New milestones on the road towards cure are still needed.
We declare no competing interests. 1
2
3
4 5 6
7
8 9 10
*Jeanette Falck Winther, Kjeld Schmiegelow Danish Cancer Society Research Center, Copenhagen, DK 2100, Denmark (JFW); Pediatrics and Adolescence Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark (KS); and the Institute for Clinical Medicine, University of Copenhagen, Denmark (KS) [email protected]
11
Pui CH, Mullighan CG, Evans WE, Relling MV. Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? Blood 2012; 120: 1165–74. Farber S, Diamond LK. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl J Med 1948; 238: 787–93. Hudson MM, Neglia JP, Woods WG, et al. Lessons from the past: opportunities to improve childhood cancer survivor care through outcomes investigations of historical therapeutic approaches for pediatric hematological malignancies. Pediatr Blood Cancer 2012; 58: 334–43. Pui CH, Campana D, Pei D, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009; 360: 2730–41. D’Angio GJ. Pediatric cancer in perspective: cure is not enough. Cancer 1975; 35 (3 suppl): 866–70. Essig S, Li Q, Chen Y, et al. Risk of late effects of treatment in children newly diagnosed with standard-risk acute lymphoblastic leukaemia: a report from the Childhood Cancer Survivor Study cohort. Lancet Oncol 2014; published online June 20. http://dx.doi.org/10.1016/S14702045(14)70265-7. Schmiegelow K, Levinsen MF, Attarbaschi A, et al. Second malignant neoplasms after treatment of childhood acute lymphoblastic leukemia. J Clin Oncol 2013; 31: 2469–76. Oeffinger KC, Sklar CA. Childhood cancer, endocrine disorders, and cohort studies. Lancet 2014; 383: 1950–52. Robison LL, Hudson MM. Survivors of childhood and adolescent cancer: life-long risks and responsibilities. Nat Rev Cancer 2014; 14: 61–70. Olsen JH, Moller T, Anderson H, et al. Lifelong cancer incidence in 47 697 patients treated for childhood cancer in the Nordic countries. J Natl Cancer Inst 2009; 101: 806–13. de Fine LS, Winther JF, Gudmundsdottir T, et al. Hospital contacts for endocrine disorders in Adult Life after Childhood Cancer in Scandinavia (ALiCCS): a population-based cohort study. Lancet 2014; 383: 1981–89.
For more on the ALiCCS study see www.aliccs.org
20 years have passed since the discovery of the major breast cancer susceptibility gene, BRCA1. Extraordinary progress has been made in the understanding of how BRCA1 and its associated proteins function, and the clinical consequences of malfunctioning BRCA proteins are now evident.1,2 The initial concerns3 about the risks of genetic testing for women carrying mutations in BRCA1 and BRCA2 seem to have receded. Moreover, the recent ruling by the US Supreme Court that genes are not patentable has opened up the genetic testing field, at least in the USA, in an unprecedented manner.4 Additionally, next-generation sequencing technologies have driven down the price of genetic testing such that to test for 100 genes is as cheap as to test for one. But outside of cancer centres, patients who undergo genetic testing are still in the minority. More so than cheaper tests, what would push genetic testing to the forefront is clear evidence that knowledge of a person’s genetic www.thelancet.com/oncology Vol 15 July 2014
status would substantially affect treatment choice, and moreover, that survival is improved as a result of this treatment. This evidence would place genetic testing for cancer susceptibility firmly at the start of the management plan. In The Lancet Oncology, a study reported by Jonathan Ledermann and colleagues5 suggests that this crucial shift—from risk assessment to therapeutic advantage— might not be very far away, at least for high-grade serous carcinoma of the ovary, fallopian tube, and peritoneum. The investigators did a preplanned retrospective analysis of a completed phase 2 clinical trial (NCT00753545),6 wherein 256 women with the abovementioned cancers, deemed to be platinum sensitive, but who had relapsed after treatment, were randomly assigned to receive maintenance oral therapy with olaparib (a PARP inhibitor) or placebo.6 In the initial analysis,6 done when 58% of the participants had experienced a progression
Steve Gschmeissner/Science Photo Library
Made-to-measure medicine: BRCA and gynaecological cancer
Published Online May 30, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70246-3 See Articles page 852
783
