{"id":"paediatric-oncology-roadmap","name":"Paediatric oncology roadmap: cooperative-group cures → engineered immunity → drugs developed for children first","route":"/roadmaps/paediatric-oncology-roadmap/","eras":[{"era":"1948-1990s","title":"Cooperative groups make childhood cancer curable","description":"Methotrexate produced the first remissions of childhood leukaemia in 1948; St Jude's Total Therapy and the cooperative groups that became the Children's Oncology Group and SIOP Europe turned remission into cure by combining vincristine, mercaptopurine, asparaginase and methotrexate and testing every change against the last regimen. INT-0091 set the Ewing sarcoma backbone; tandem transplant and busulfan-melphalan (HR-NBL1) defined high-risk neuroblastoma therapy. Almost every child in a rich country was enrolled in a trial, which is why progress was so fast.","status":"historic","refs":[{"id":"methotrexate","kind":"drug","name":"Methotrexate","route":"/drugs/methotrexate/","status":"approved","tldr":"The 1948 antifolate that produced the first chemotherapy remissions in childhood leukaemia and the first cure of a solid tumour; still essential in ALL, lymphoma, osteosarcoma and CNS lymphoma."},{"id":"vincristine","kind":"drug","name":"Vincristine","route":"/drugs/vincristine/","status":"approved","tldr":"A plant-derived chemotherapy from the Madagascar periwinkle that has been in almost every childhood leukaemia and lymphoma regimen since the 1960s."},{"id":"mercaptopurine","kind":"drug","name":"Mercaptopurine","route":"/drugs/mercaptopurine/","status":"approved","tldr":"Mercaptopurine is a daily tablet, or a liquid for children, that keeps acute lymphoblastic leukaemia in remission during the long maintenance phase of treatment."},{"id":"asparaginase","kind":"drug","name":"Asparaginase (pegaspargase, calaspargase pegol, Erwinia asparaginase)","route":"/drugs/asparaginase/","status":"approved","tldr":"An enzyme that starves leukaemia cells of an amino acid they cannot make; a mainstay of childhood ALL therapy for 50 years, with new versions solving allergy and supply problems."},{"id":"st-jude","kind":"institution","name":"St. Jude Children's Research Hospital","route":"/institutions/st-jude/","tldr":"The only NCI comprehensive cancer centre devoted to children, where Total Therapy protocols made childhood leukaemia curable; families are never billed for care."},{"id":"childrens-oncology-group","kind":"company","name":"Children's Oncology Group (COG)","route":"/companies/childrens-oncology-group/","tldr":"The Children's Oncology Group is the world's largest paediatric cancer trials organisation; most children with cancer in North America are treated on or according to a COG protocol."},{"id":"siop-europe","kind":"institution","name":"SIOP Europe (European Society for Paediatric Oncology)","route":"/institutions/siop-europe/","tldr":"The European paediatric oncology society and the umbrella for the European clinical trial groups that treat most children with cancer on shared protocols."},{"id":"int-0091","kind":"trial","name":"INT-0091 (Ewing sarcoma)","route":"/trials/int-0091/","status":"positive","tldr":"Adding ifosfamide and etoposide improved cure rates for localised Ewing sarcoma, setting the backbone still used today."},{"id":"tandem-transplant","kind":"technology","name":"Tandem autologous transplant","route":"/technologies/tandem-transplant/","status":"standard-of-care","tldr":"Tandem transplant gives two back-to-back rounds of marrow-destroying chemotherapy, each rescued with the child's own stored stem cells, for high-risk neuroblastoma in North America. It kept more children relapse-free than one transplant in a randomised trial, but adds organ toxicity and hearing loss."},{"id":"anbl0532","kind":"trial","name":"COG ANBL0532","route":"/trials/anbl0532/","status":"positive","tldr":"COG ANBL0532 showed that two transplants in a row beat one in high-risk neuroblastoma."},{"id":"hr-nbl1","kind":"trial","name":"SIOPEN HR-NBL1","route":"/trials/hr-nbl1/","status":"mixed","tldr":"Europe's long-running high-risk neuroblastoma trial set busulfan-melphalan as the transplant regimen and showed that adding IL-2 to anti-GD2 therapy added toxicity but not benefit."},{"id":"interfant-06","kind":"trial","name":"Interfant-06","route":"/trials/interfant-06/","status":"mixed","tldr":"The largest infant leukaemia trial showed that intensifying chemotherapy did not help, and set the stage for adding blinatumomab instead."}],"trials":[{"id":"int-0091","name":"INT-0091 (Ewing sarcoma)","route":"/trials/int-0091/","outcomes":[{"endpoint":"Event-free survival at 5 years (localised)","primary":true,"unit":"%","arms":[{"name":"VDC/IE","n":198,"value":69},{"name":"VDC","n":200,"value":54}],"p":"0.005","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa020890"}],"setting":"Newly diagnosed Ewing sarcoma: VDC alone vs VDC alternating with ifosfamide-etoposide","enrolled":518,"enrolledBasis":"registry"},{"id":"anbl0532","name":"COG ANBL0532","route":"/trials/anbl0532/","outcomes":[{"endpoint":"Event-free survival at 3 years","primary":true,"unit":"%","arms":[{"name":"Tandem transplant","n":176,"value":61.6},{"name":"Single transplant","n":179,"value":48.4}],"p":"0.006","source":"https://jamanetwork.com/journals/jama/fullarticle/2751686"}],"setting":"High-risk neuroblastoma: tandem vs single autologous transplant after induction","enrolled":665,"enrolledBasis":"registry"},{"id":"hr-nbl1","name":"SIOPEN HR-NBL1","route":"/trials/hr-nbl1/","outcomes":[{"endpoint":"Event-free survival at 3 years (R1 conditioning)","unit":"%","arms":[{"name":"Busulfan-melphalan","n":296,"value":50},{"name":"CEM","n":302,"value":38}],"p":"0.0005","source":"https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30070-0/fulltext"},{"endpoint":"Event-free survival at 3 years (R2 immunotherapy)","unit":"%","arms":[{"name":"Dinutuximab beta + IL-2","n":200,"value":56},{"name":"Dinutuximab beta","n":206,"value":60}],"source":"https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30578-3/fulltext"}],"setting":"High-risk neuroblastoma (Europe): multiple randomisations, including busulfan-melphalan vs CEM conditioning and dinutuximab beta ± IL-2","enrolled":3300,"enrolledBasis":"registry"},{"id":"interfant-06","name":"Interfant-06","route":"/trials/interfant-06/","outcomes":[{"endpoint":"Event-free survival at 6 years","primary":true,"unit":"%","arms":[{"name":"All infants","n":651,"value":46.1}],"source":"https://ascopubs.org/doi/10.1200/JCO.19.00261"}],"setting":"Infant ALL (<1 year): standard vs AML-type early intensification; transplant for high-risk KMT2A-rearranged infants","enrolled":651,"enrolledNote":"ClinicalTrials.gov lists an estimated 445 participants and the record's status is unknown, meaning the sponsor has not verified it recently; the JCO 2019 paper reports 651 infants included.","enrolledBasis":"registered"}],"papers":[]},{"era":"1994-2015","title":"Immunotherapy for neuroblastoma, and counting the cost of cure","description":"The anti-GD2 antibody dinutuximab raised cure rates in high-risk neuroblastoma (ANBL0032) and was approved in 2015; radioactive MIBG treated the tumour from inside. Risk-adapted trials gave less to children who needed less: AREN0533 in Wilms tumour, ACNS0331 in medulloblastoma. The Childhood Cancer Survivor Study, following tens of thousands of survivors from 1994, showed the late effects of anthracyclines, radiation and alkylators and produced the long-term follow-up guidelines every survivor clinic uses.","status":"historic","refs":[{"id":"dinutuximab","kind":"drug","name":"Dinutuximab (ch14.18) / dinutuximab beta","route":"/drugs/dinutuximab/","status":"approved","tldr":"The antibody that raised cure rates in high-risk childhood neuroblastoma by about 20 points when given after transplant with immune boosters and retinoid."},{"id":"anbl0032","kind":"trial","name":"COG ANBL0032","route":"/trials/anbl0032/","status":"positive","tldr":"The trial that made anti-GD2 immunotherapy standard for children with high-risk neuroblastoma, improving survival by about 20 points."},{"id":"y-mabs","kind":"company","name":"Y-mAbs Therapeutics","route":"/companies/y-mabs/","tldr":"MSK spin-out that commercialises naxitamab, the humanised anti-GD2 antibody for relapsed neuroblastoma, and develops pretargeted radioimmunotherapy."},{"id":"i131-mibg","kind":"drug","name":"131I-MIBG (iobenguane I-131) therapy","route":"/drugs/i131-mibg/","status":"established","tldr":"High-dose radioactive MIBG delivers radiation from inside neuroblastoma cells that take up noradrenaline; used for relapsed disease and tested in upfront therapy. A branded high-specific-activity form, Azedra, was approved for phaeochromocytoma and paraganglioma in 2018 and discontinued in 2024."},{"id":"mibg-theranostics","kind":"technology","name":"MIBG imaging and 131I-MIBG therapy","route":"/technologies/mibg-theranostics/","status":"established","tldr":"A noradrenaline look-alike that neuroblastoma cells swallow: labelled with a small amount of radioactivity it shows the tumour on a scan; with a large amount it treats it."},{"id":"aren0533","kind":"trial","name":"COG AREN0533","route":"/trials/aren0533/","status":"positive","tldr":"A risk-adapted Wilms tumour trial: children whose lung metastases vanished after six weeks of chemotherapy were spared lung radiation, while those with stubborn nodules or a high-risk chromosome pattern got stronger chemotherapy and did better than in the past."},{"id":"acns0331","kind":"trial","name":"COG ACNS0331","route":"/trials/acns0331/","status":"mixed","tldr":"This trial asked whether children with average-risk medulloblastoma could safely receive less radiation. Shrinking the boost to the tumour bed was safe; cutting the dose to the whole brain and spine in young children was not, so 23.4 Gy remains the floor for most."},{"id":"euramos-1","kind":"trial","name":"EURAMOS-1","route":"/trials/euramos-1/","status":"negative","tldr":"The largest osteosarcoma trial ever run, across four cooperative groups on two continents. Neither adding interferon for good responders nor adding ifosfamide and etoposide for poor responders improved outcomes, so three-drug MAP chemotherapy remained the standard and the field turned to new biology."},{"id":"mifamurtide","kind":"drug","name":"Mifamurtide","route":"/drugs/mifamurtide/","status":"approved","tldr":"An immune-activating drug approved in Europe for osteosarcoma after a trial suggested it improved survival; the FDA never approved it, and it remains one of oncology's transatlantic disagreements."},{"id":"aaml0531","kind":"trial","name":"COG AAML0531","route":"/trials/aaml0531/","status":"positive","tldr":"Adding the antibody-drug conjugate gemtuzumab ozogamicin to chemotherapy lowered the chance of relapse in children with acute myeloid leukaemia. Years after the drug had been withdrawn from the US market, this trial helped bring it back for children."},{"id":"inter-b-nhl-ritux-2010","kind":"trial","name":"Inter-B-NHL Ritux 2010","route":"/trials/inter-b-nhl-ritux-2010/","status":"positive","tldr":"Adding the antibody rituximab to intensive chemotherapy in children with high-risk Burkitt and related lymphomas cut treatment failures by about two-thirds, making an already curable disease more so. It is the model of a joint European-North American children's cancer trial."},{"id":"ccss","kind":"trial","name":"Childhood Cancer Survivor Study (CCSS)","route":"/trials/ccss/","status":"active","tldr":"The largest study of what happens to children after cancer is cured. Following tens of thousands of survivors for decades, it showed that heart damage, second cancers and other late effects were common after older treatments, and that gentler modern protocols have already halved late deaths."},{"id":"survivorship-care-plan","kind":"technology","name":"Survivorship care and late-effects surveillance","route":"/technologies/survivorship-care-plan/","status":"established","tldr":"Organised follow-up for the 18 million US and 50+ million global cancer survivors: watching for recurrence and second cancers, managing long-term side effects such as heart damage, infertility, neuropathy and fatigue, and helping people return to work and life."}],"trials":[{"id":"anbl0032","name":"COG ANBL0032","route":"/trials/anbl0032/","outcomes":[{"endpoint":"Event-free survival at 2 years","primary":true,"unit":"%","arms":[{"name":"Immunotherapy + isotretinoin","n":113,"value":66},{"name":"Isotretinoin","n":113,"value":46}],"p":"0.01","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa0911123"},{"endpoint":"Overall survival at 2 years","unit":"%","arms":[{"name":"Immunotherapy + isotretinoin","value":86},{"name":"Isotretinoin","value":75}],"p":"0.02","source":"https://doi.org/10.1056/NEJMoa0911123"}],"setting":"High-risk neuroblastoma after transplant: ch14.18 (dinutuximab) + GM-CSF + IL-2 + isotretinoin vs isotretinoin alone","enrolled":226,"enrolledNote":"ClinicalTrials.gov lists 1,449 participants (actual) enrolled over the life of the study; the NEJM 2010 analysis randomised 226 eligible patients.","enrolledBasis":"randomised"},{"id":"aren0533","name":"COG AREN0533","route":"/trials/aren0533/","outcomes":[{"endpoint":"4-year event-free survival (all lung-metastasis patients)","primary":true,"unit":"%","arms":[{"name":"AREN0533 risk-adapted","n":292,"value":85.4},{"name":"NWTS-5 (historical)","value":72.5}],"p":"<0.001","source":"https://doi.org/10.1200/JCO.2017.77.1931"},{"endpoint":"4-year event-free survival, LOH 1p/16q stage III-IV, Regimen M","unit":"%","arms":[{"name":"AREN0533 Regimen M","n":51,"value":90.2},{"name":"NWTS-5 (historical)","value":61.3}],"source":"https://doi.org/10.1200/JCO.18.01972"}],"setting":"Stage III-IV favourable-histology Wilms tumour: response-based omission of lung radiotherapy after complete lung nodule response; augmented chemotherapy (Regimen M) for incomplete response or 1p/16q loss of heterozygosity","enrolled":395,"enrolledBasis":"registry"},{"id":"acns0331","name":"COG ACNS0331","route":"/trials/acns0331/","outcomes":[{"endpoint":"5-year event-free survival: boost volume","primary":true,"unit":"%","arms":[{"name":"Involved-field boost","value":82.5},{"name":"Posterior fossa boost","value":80.5}],"hr":0.97,"source":"https://doi.org/10.1200/JCO.20.02730"},{"endpoint":"5-year event-free survival: CSI dose (age 3-7)","primary":true,"unit":"%","arms":[{"name":"18 Gy CSI","value":71.4},{"name":"23.4 Gy CSI","value":82.9}],"hr":1.67,"source":"https://doi.org/10.1200/JCO.20.02730"}],"setting":"Average-risk medulloblastoma, age 3-21: involved-field (tumour bed) vs whole posterior fossa boost; and, in children aged 3-7, 18 Gy vs 23.4 Gy craniospinal irradiation","enrolled":549,"enrolledBasis":"registry"},{"id":"euramos-1","name":"EURAMOS-1","route":"/trials/euramos-1/","outcomes":[{"endpoint":"Event-free survival, poor responders (MAPIE vs MAP)","primary":true,"arms":[{"name":"MAPIE","n":310,"note":"154 events"},{"name":"MAP","n":308,"note":"153 events"}],"hr":0.98,"source":"https://doi.org/10.1016/S1470-2045(16)30214-5"},{"endpoint":"3-year event-free survival, good responders (all randomised)","unit":"%","arms":[{"name":"MAP with or without interferon alfa-2b","n":716,"value":76}],"source":"https://doi.org/10.1200/JCO.2014.60.0734"}],"setting":"Resectable high-grade osteosarcoma, age up to 40: MAP induction, then randomisation by histological response (good responders: MAP vs MAP + pegylated interferon alfa-2b; poor responders: MAP vs MAPIE with ifosfamide and etoposide)","enrolled":2260,"enrolledNote":"ClinicalTrials.gov lists 1,334 participants (actual), the patients randomised (618 poor responders and 716 good responders); the Lancet Oncology 2016 paper reports 2,260 patients registered from 325 sites in 17 countries.","enrolledBasis":"registered"},{"id":"aaml0531","name":"COG AAML0531","route":"/trials/aaml0531/","outcomes":[{"endpoint":"3-year event-free survival","primary":true,"unit":"%","arms":[{"name":"Chemotherapy + gemtuzumab ozogamicin","value":53.1},{"name":"Chemotherapy","value":46.9}],"hr":0.83,"ci":[0.7,0.99],"source":"https://doi.org/10.1200/JCO.2014.55.3628"}],"setting":"Newly diagnosed AML, age 0-29: standard five-course chemotherapy with or without two doses of gemtuzumab ozogamicin","enrolled":1070,"enrolledBasis":"registry"},{"id":"inter-b-nhl-ritux-2010","name":"Inter-B-NHL Ritux 2010","route":"/trials/inter-b-nhl-ritux-2010/","outcomes":[{"endpoint":"3-year event-free survival","primary":true,"unit":"%","arms":[{"name":"Rituximab + LMB chemotherapy","n":164,"value":93.9},{"name":"LMB chemotherapy","n":164,"value":82.3}],"hr":0.32,"ci":[0.15,0.66],"p":"0.00096 (one-sided)","source":"https://doi.org/10.1056/NEJMoa1915315"}],"setting":"High-risk mature B-cell non-Hodgkin lymphoma or B-acute leukaemia in patients under 18 (mostly Burkitt lymphoma): LMB chemotherapy with or without six doses of rituximab","enrolled":482,"enrolledBasis":"registry"},{"id":"ccss","name":"Childhood Cancer Survivor Study (CCSS)","route":"/trials/ccss/","outcomes":[{"endpoint":"15-year cumulative all-cause mortality by treatment era","primary":true,"unit":"%","arms":[{"name":"Diagnosed early 1970s","value":12.4},{"name":"Diagnosed 1990s","value":6}],"p":"<0.001 for trend","source":"https://doi.org/10.1056/NEJMoa1510795"},{"endpoint":"15-year health-related mortality by treatment era","unit":"%","arms":[{"name":"Diagnosed early 1970s","value":3.5},{"name":"Diagnosed 1990s","value":2.1}],"p":"<0.001 for trend","source":"https://doi.org/10.1056/NEJMoa1510795"}],"setting":"Retrospective cohort with prospective follow-up of five-year survivors of childhood cancer diagnosed 1970-1999 at 31 North American centres, with sibling controls","enrolled":50000,"enrolledBasis":"registry"}],"papers":[]},{"era":"2014-2026","title":"Engineered immunity, children first","description":"Blinatumomab, the first T-cell engager (2014), nearly doubled survival in relapsed leukaemia (TOWER) and then, added to standard treatment for average-risk childhood leukaemia (AALL1731), pushed cure rates higher still. Tisagenlecleucel became the first CAR-T ever approved, in 2017, after ELIANA put most children whose leukaemia had returned after every standard treatment into remission. GD2 CAR-T produced durable complete remissions in neuroblastoma (GD2-CART01) and is being taken into the brain for diffuse midline glioma.","status":"current","refs":[{"id":"blinatumomab","kind":"drug","name":"Blinatumomab","route":"/drugs/blinatumomab/","status":"approved","tldr":"Blinatumomab was the first T-cell engager (2014), and is now given to children and adults with leukaemia even when in remission, because it improves survival."},{"id":"tower","kind":"trial","name":"TOWER","route":"/trials/tower/","status":"positive","tldr":"The first randomised proof that a T-cell engager beats chemotherapy: blinatumomab nearly doubled survival in relapsed adult ALL."},{"id":"aall1731","kind":"trial","name":"COG AALL1731","route":"/trials/aall1731/","status":"positive","tldr":"In children with average-risk leukaemia, adding blinatumomab pushed three-year disease-free survival from 88% to 96%, one of the largest gains in decades."},{"id":"tisagenlecleucel","kind":"drug","name":"Tisagenlecleucel","route":"/drugs/tisagenlecleucel/","status":"approved","tldr":"Tisagenlecleucel was the first CAR-T therapy ever approved (2017), for children and young adults whose leukaemia had come back after everything else."},{"id":"eliana","kind":"trial","name":"ELIANA","route":"/trials/eliana/","status":"positive","tldr":"ELIANA was the global trial behind the first CAR-T approval: a single infusion of tisagenlecleucel put four in five children and young adults with relapsed B-cell acute lymphoblastic leukaemia and no standard treatment remaining into remission, and most responders were still in remission without further therapy at the five-year update. Severe cytokine release syndrome affected almost half."},{"id":"car-t","kind":"technology","name":"CAR-T cell therapy","route":"/technologies/car-t/","status":"approved","tldr":"A patient's T cells are removed, given a synthetic receptor that recognises the cancer, multiplied, and put back as a living drug."},{"id":"gd2-cart01","kind":"trial","name":"GD2-CART01 (Bambino Gesù phase 1/2)","route":"/trials/gd2-cart01/","status":"positive","tldr":"GD2-CART01 was the first CAR-T to produce durable complete remissions in a childhood solid tumour: two-thirds responded and a third achieved complete remission."},{"id":"idea-gd2-car-t-frontline-consolidation","kind":"idea","name":"GD2 CAR-T as consolidation in high-risk neuroblastoma","route":"/ideas/idea-gd2-car-t-frontline-consolidation/","tldr":"Give engineered GD2 T cells to children in remission after standard therapy, where the long-term data show the deepest and longest cures."},{"id":"glioma-car-t","kind":"technology","name":"CAR-T for glioma (IL13Rα2, GD2, EGFRvIII, multi-target)","route":"/technologies/glioma-car-t/","status":"phase-1","tldr":"Engineered immune cells delivered directly into the brain or spinal fluid. Some children with diffuse midline glioma, a brainstem tumour with no curative treatment, have had striking, if temporary, responses."},{"id":"cell-therapy-roadmap","kind":"roadmap","name":"Cell therapy roadmap: CD19 CAR-T → solid tumours → in vivo CAR","route":"/roadmaps/cell-therapy-roadmap/","tldr":"From a cure for some leukaemias in 2017 to the first solid-tumour CAR-T and the prospect of making CAR-T inside the body with an injection."}],"trials":[{"id":"tower","name":"TOWER","route":"/trials/tower/","outcomes":[{"endpoint":"Overall survival (median)","primary":true,"unit":"months","arms":[{"name":"Blinatumomab","n":271,"value":7.7},{"name":"Chemotherapy","n":134,"value":4}],"hr":0.71,"ci":[0.55,0.93],"p":"0.01","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa1609783"},{"endpoint":"Complete remission within 12 weeks","unit":"%","arms":[{"name":"Blinatumomab","value":34},{"name":"Chemotherapy","value":16}],"source":"https://doi.org/10.1056/NEJMoa1609783"}],"setting":"Relapsed or refractory Ph-negative B-ALL, adults: blinatumomab vs standard salvage chemotherapy","enrolled":405,"enrolledBasis":"registry"},{"id":"aall1731","name":"COG AALL1731","route":"/trials/aall1731/","outcomes":[{"endpoint":"Disease-free survival at 3 years","primary":true,"unit":"%","arms":[{"name":"Blinatumomab + chemotherapy","n":722,"value":96},{"name":"Chemotherapy","n":718,"value":87.9}],"hr":0.39,"ci":[0.24,0.64],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2411680"}],"setting":"Newly diagnosed standard-risk B-ALL in children: two cycles of blinatumomab added to chemotherapy vs chemotherapy alone","enrolled":1440,"enrolledNote":"ClinicalTrials.gov lists an estimated 6,720 participants for the whole trial, which enrols all standard-risk patients; the NEJM 2024 interim analysis covered the 1,440 patients randomised (722 chemotherapy, 718 blinatumomab) before randomisation was stopped.","enrolledBasis":"randomised"},{"id":"eliana","name":"ELIANA","route":"/trials/eliana/","outcomes":[{"endpoint":"Overall remission rate within 3 months","primary":true,"unit":"%","arms":[{"name":"Tisagenlecleucel","n":75,"value":81}],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa1709866"},{"endpoint":"Overall survival at 12 months","unit":"%","arms":[{"name":"Tisagenlecleucel","value":76}],"source":"https://doi.org/10.1056/NEJMoa1709866"},{"endpoint":"Overall survival at 5 years","unit":"%","arms":[{"name":"Tisagenlecleucel","value":55}],"source":"https://ascopubs.org/doi/10.1200/JCO.22.00642"}],"setting":"Relapsed or refractory B-ALL, patients aged 3-25: single infusion of tisagenlecleucel","enrolled":79,"enrolledNote":"ClinicalTrials.gov lists 80 participants (actual); the JCO 2023 three-year update reports 79 infused patients and the NEJM 2018 primary analysis 75.","enrolledBasis":"treated"},{"id":"gd2-cart01","name":"GD2-CART01 (Bambino Gesù phase 1/2)","route":"/trials/gd2-cart01/","outcomes":[{"endpoint":"Objective response rate","primary":true,"unit":"%","arms":[{"name":"GD2-CART01","n":27,"value":63}],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2210859"},{"endpoint":"Overall survival at 3 years","unit":"%","arms":[{"name":"GD2-CART01","value":60}],"source":"https://doi.org/10.1056/NEJMoa2210859"}],"setting":"Relapsed/refractory high-risk neuroblastoma: third-generation GD2 CAR-T with inducible caspase-9 safety switch","enrolled":27,"enrolledNote":"ClinicalTrials.gov lists an estimated 42 participants for the phase 1/2 study, which is still active; the NEJM 2023 paper reports the 27 patients treated.","enrolledBasis":"treated"}],"papers":[]},{"era":"2017-2026","title":"Precision medicine and the regulatory lever","description":"Pediatric MATCH (from 2017) screened children with relapsed cancer nationally and assigned them to targeted drugs by mutation, with ITCC's ESMART as its European counterpart. The RACE for Children Act, in force for applications from August 2020, ended the exemption that let companies skip children when the drug's target matters in a childhood cancer; the ACCELERATE platform, founded in 2013, convenes companies, the FDA, the EMA and parents to decide which drugs to study and how. Paediatric-first drugs followed: tovorafenib for BRAF-driven low-grade glioma (FIREFLY-1), dabrafenib-trametinib beating chemotherapy in the same disease (TADPOLE), selumetinib for neurofibromatosis, and dordaviprone, the first drug for diffuse midline glioma. ACTION is the first placebo-controlled phase 3 ever run in that disease.","status":"current","refs":[{"id":"pediatric-match","kind":"trial","name":"NCI-COG Pediatric MATCH (APEC1621)","route":"/trials/pediatric-match/","status":"active","tldr":"Pediatric MATCH was the first nationwide precision-medicine trial for children: every child with a relapsed solid tumour could have their tumour sequenced and, if a matching drug existed, join a trial arm for it. It proved the plumbing works, even though most single drugs given alone did little."},{"id":"itcc","kind":"company","name":"Innovative Therapies for Children with Cancer (ITCC)","route":"/companies/itcc/","tldr":"Europe's network of children's hospitals that run the first trials of new cancer drugs in children, so that European children can access experimental medicines close to home."},{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/","status":"standard-of-care","tldr":"Sequencing hundreds of cancer genes at once from a biopsy to find the mutations a drug can target."},{"id":"race-for-children-act","kind":"term","name":"RACE for Children Act","route":"/terms/race-for-children-act/","tldr":"A US law that makes drug companies test new targeted cancer drugs in children whenever the drug's target matters in a childhood cancer, instead of letting them skip children because their cancers are rare."},{"id":"accelerate-platform","kind":"institution","name":"ACCELERATE","route":"/institutions/accelerate-platform/","tldr":"ACCELERATE is a Brussels-based forum where children's cancer doctors, drug companies, the EMA and FDA and parents agree which new cancer drugs should be tested in children and how, so that medicines developed for adults are not left untested in childhood cancers."},{"id":"fda-oce","kind":"institution","name":"FDA Oncology Center of Excellence","route":"/institutions/fda-oce/","tldr":"The US regulator's oncology hub, which approves cancer drugs, runs accelerated approval and Project Orbis, and is pushing better dose-finding through Project Optimus."},{"id":"ema","kind":"institution","name":"European Medicines Agency","route":"/institutions/ema/","tldr":"The EU agency whose Committee for Medicinal Products for Human Use recommends the marketing authorisations for cancer drugs across all member states."},{"id":"tovorafenib","kind":"drug","name":"Tovorafenib","route":"/drugs/tovorafenib/","status":"approved","tldr":"Tovorafenib is a pill for the most common childhood brain tumour, low-grade glioma driven by BRAF changes, approved in 2024."},{"id":"firefly-1","kind":"trial","name":"FIREFLY-1","route":"/trials/firefly-1/","status":"positive","tldr":"FIREFLY-1 showed that a once-weekly pill, tovorafenib, shrinks most relapsed childhood low-grade gliomas driven by BRAF changes, including the common KIAA1549-BRAF fusion that older BRAF drugs could not treat safely. It led to the first approval of a drug for this disease."},{"id":"day-one-biopharmaceuticals","kind":"company","name":"Day One Biopharmaceuticals","route":"/companies/day-one-biopharmaceuticals/","tldr":"Paediatric-first oncology company whose tovorafenib became the first targeted therapy approved for childhood low-grade glioma driven by BRAF fusions, following dabrafenib with trametinib (2023) for BRAF V600E tumours."},{"id":"tadpole","kind":"trial","name":"TADPOLE (CDRB436G2201)","route":"/trials/tadpole/","status":"positive","tldr":"The first randomised trial to show that a targeted drug pair beats chemotherapy in children with a brain tumour. Children whose low-grade glioma carries a BRAF V600 mutation had far more tumour shrinkage and a much longer time before progression on dabrafenib plus trametinib than on standard carboplatin and vincristine."},{"id":"dabrafenib-trametinib","kind":"drug","name":"Dabrafenib + trametinib","route":"/drugs/dabrafenib-trametinib/","status":"approved","tldr":"Dabrafenib plus trametinib is the BRAF-plus-MEK pill combination, approved for BRAF V600E lung cancer and, since 2022, for any solid tumour with that mutation."},{"id":"selumetinib","kind":"drug","name":"Selumetinib","route":"/drugs/selumetinib/","status":"approved","tldr":"Selumetinib (Koselugo) is the first medicine for children and adults with neurofibromatosis type 1 whose plexiform neurofibromas, benign but disfiguring and painful nerve tumours, cannot be removed by surgery."},{"id":"larotrectinib","kind":"drug","name":"Larotrectinib","route":"/drugs/larotrectinib/","status":"approved","tldr":"The first drug approved for a gene fusion regardless of where the cancer started; it works in about 75% of NTRK-fusion cancers, from infant fibrosarcoma to salivary and thyroid cancers."},{"id":"dordaviprone","kind":"drug","name":"Dordaviprone","route":"/drugs/dordaviprone/","status":"approved","tldr":"Dordaviprone is the first drug ever approved for a childhood and young-adult brain tumour that had none, diffuse midline glioma with the H3 K27M mutation (August 2025)."},{"id":"action-dmg","kind":"trial","name":"ACTION","route":"/trials/action-dmg/","status":"recruiting","tldr":"ACTION is the first placebo-controlled phase 3 trial ever run in diffuse midline glioma, the childhood brain-stem tumour that radiotherapy alone has never cured. It asks whether taking dordaviprone after radiotherapy lengthens life."},{"id":"vorasidenib","kind":"drug","name":"Vorasidenib","route":"/drugs/vorasidenib/","status":"approved","tldr":"The first targeted therapy for low-grade brain tumours, delaying the need for radiation and chemotherapy by years."}],"trials":[{"id":"pediatric-match","name":"NCI-COG Pediatric MATCH (APEC1621)","route":"/trials/pediatric-match/","outcomes":[{"endpoint":"Actionable alteration detected (first 1,000 tumours)","primary":true,"unit":"%","arms":[{"name":"Screened tumours","n":1000,"value":31.5}],"source":"https://doi.org/10.1200/JCO.21.02838"},{"endpoint":"Enrolled on a treatment arm","unit":"%","arms":[{"name":"Screened patients","n":1000,"value":13.1}],"source":"https://doi.org/10.1200/JCO.21.02838"}],"setting":"Relapsed or refractory solid tumours, non-Hodgkin lymphomas and histiocytic disorders, age 1-21: tumour sequencing then assignment to one of a dozen single-agent targeted-therapy phase 2 arms","enrolled":1377,"enrolledBasis":"registry"},{"id":"firefly-1","name":"FIREFLY-1","route":"/trials/firefly-1/","outcomes":[{"endpoint":"Overall response rate (RANO-HGG, independent review)","primary":true,"unit":"%","arms":[{"name":"Tovorafenib (arm 1)","n":77,"value":67}],"source":"https://doi.org/10.1038/s41591-023-02668-y"},{"endpoint":"Overall response rate (RAPNO-LGG, including minor responses)","unit":"%","arms":[{"name":"Tovorafenib (arm 1)","n":77,"value":51}],"source":"https://doi.org/10.1038/s41591-023-02668-y"},{"endpoint":"Median duration of response","unit":"months","arms":[{"name":"Tovorafenib (arm 1)","value":16.6}],"source":"https://doi.org/10.1038/s41591-023-02668-y"}],"setting":"Relapsed or refractory BRAF-altered paediatric low-grade glioma: single-arm tovorafenib (arm 1, n = 77 registrational cohort)","enrolled":141,"enrolledBasis":"registry"},{"id":"tadpole","name":"TADPOLE (CDRB436G2201)","route":"/trials/tadpole/","outcomes":[{"endpoint":"Overall response rate (independent review, RANO)","primary":true,"unit":"%","arms":[{"name":"Dabrafenib + trametinib","n":73,"value":47},{"name":"Carboplatin + vincristine","n":37,"value":11}],"p":"<0.001","source":"https://doi.org/10.1056/NEJMoa2303815"},{"endpoint":"Progression-free survival","unit":"months","arms":[{"name":"Dabrafenib + trametinib","n":73,"value":20.1},{"name":"Carboplatin + vincristine","n":37,"value":7.4}],"hr":0.31,"ci":[0.17,0.55],"p":"<0.001","source":"https://doi.org/10.1056/NEJMoa2303815"}],"setting":"Newly diagnosed BRAF V600-mutant paediatric low-grade glioma needing systemic therapy: dabrafenib + trametinib vs carboplatin + vincristine (2:1 randomisation)","enrolled":110,"enrolledNote":"ClinicalTrials.gov lists 151 participants (actual) across the study's cohorts; the NEJM 2023 low-grade glioma analysis randomised 110 patients (73 dabrafenib plus trametinib, 37 chemotherapy).","enrolledBasis":"randomised"}],"papers":[]},{"era":"2016-2026","title":"Protecting the child who is cured","description":"Sodium thiosulfate, an old antidote, halves permanent hearing loss from cisplatin in two paediatric trials and is now standard; dexrazoxane protects the heart from anthracyclines; fertility preservation is offered before gonadotoxic treatment; risk-based survivorship follow-up is organised from the CCSS evidence. Adults are only now getting the otoprotection children have, a reversal of the usual direction of travel.","status":"current","refs":[{"id":"sodium-thiosulfate","kind":"drug","name":"Sodium thiosulfate (otoprotectant)","route":"/drugs/sodium-thiosulfate/","status":"approved","tldr":"An old antidote proven in two paediatric trials to halve permanent hearing loss from cisplatin, and approved in 2022 as the first drug to prevent a chemotherapy side effect in children."},{"id":"idea-moon-hearing-protection-cisplatin","kind":"idea","name":"Protect hearing from cisplatin in adults as we now do in children","route":"/ideas/idea-moon-hearing-protection-cisplatin/","tldr":"Cisplatin causes permanent hearing loss. A cheap drug, sodium thiosulfate, protects children; test and roll it out for adults too."},{"id":"dexrazoxane","kind":"drug","name":"Dexrazoxane","route":"/drugs/dexrazoxane/","status":"approved","tldr":"Dexrazoxane protects the heart from the cumulative damage of doxorubicin in women with metastatic breast cancer who need to keep receiving it, and, as Totect, limits tissue destruction when an anthracycline leaks out of a vein."},{"id":"fertility-preservation","kind":"technology","name":"Oncofertility and fertility preservation","route":"/technologies/fertility-preservation/","status":"established","tldr":"Protecting the ability to have children before cancer treatment that damages eggs, sperm or the womb: sperm and egg or embryo freezing, ovarian tissue freezing, ovarian shielding and, for some breast cancers, temporary ovarian suppression."},{"id":"ccss","kind":"trial","name":"Childhood Cancer Survivor Study (CCSS)","route":"/trials/ccss/","status":"active","tldr":"The largest study of what happens to children after cancer is cured. Following tens of thousands of survivors for decades, it showed that heart damage, second cancers and other late effects were common after older treatments, and that gentler modern protocols have already halved late deaths."},{"id":"survivorship-care-plan","kind":"technology","name":"Survivorship care and late-effects surveillance","route":"/technologies/survivorship-care-plan/","status":"established","tldr":"Organised follow-up for the 18 million US and 50+ million global cancer survivors: watching for recurrence and second cancers, managing long-term side effects such as heart damage, infertility, neuropathy and fatigue, and helping people return to work and life."},{"id":"survivorship-roadmap","kind":"roadmap","name":"Supportive care and survivorship roadmap: making treatment bearable → proving it extends life → caring for tens of millions afterwards","route":"/roadmaps/survivorship-roadmap/","tldr":"Supportive care began as the drugs that let people get through chemotherapy. It is now a discipline with randomised proof that exercise, early palliative care and symptom monitoring lengthen life, and its next task is organised lifelong care for the growing population of people living after cancer."}],"trials":[{"id":"ccss","name":"Childhood Cancer Survivor Study (CCSS)","route":"/trials/ccss/","outcomes":[{"endpoint":"15-year cumulative all-cause mortality by treatment era","primary":true,"unit":"%","arms":[{"name":"Diagnosed early 1970s","value":12.4},{"name":"Diagnosed 1990s","value":6}],"p":"<0.001 for trend","source":"https://doi.org/10.1056/NEJMoa1510795"},{"endpoint":"15-year health-related mortality by treatment era","unit":"%","arms":[{"name":"Diagnosed early 1970s","value":3.5},{"name":"Diagnosed 1990s","value":2.1}],"p":"<0.001 for trend","source":"https://doi.org/10.1056/NEJMoa1510795"}],"setting":"Retrospective cohort with prospective follow-up of five-year survivors of childhood cancer diagnosed 1970-1999 at 31 North American centres, with sibling controls","enrolled":50000,"enrolledBasis":"registry"}],"papers":[]},{"era":"2026-2030","title":"Next trials, next targets, one global plan","description":"ANBL1531 adds targeted radiation and immunotherapy into neuroblastoma induction; CAR-T for brain tumours is in early trials; degraders for the fusion transcription factors that drive childhood sarcomas are the first credible attack on those drivers. The regulatory proposals: develop drugs in children first when the target is a children's target, make paediatric combination studies part of every relevant adult approval, one global paediatric development plan instead of separate FDA and EMA plans, and automatic reciprocity of orphan designations. A same-day PET tracer could replace two-day MIBG scans.","status":"emerging","refs":[{"id":"anbl1531","kind":"trial","name":"COG ANBL1531","route":"/trials/anbl1531/","status":"active","tldr":"COG ANBL1531 is the current North American high-risk trial, adding targeted radiation during induction and an ALK pill for children whose tumours carry ALK mutations."},{"id":"glioma-car-t","kind":"technology","name":"CAR-T for glioma (IL13Rα2, GD2, EGFRvIII, multi-target)","route":"/technologies/glioma-car-t/","status":"phase-1","tldr":"Engineered immune cells delivered directly into the brain or spinal fluid. Some children with diffuse midline glioma, a brainstem tumour with no curative treatment, have had striking, if temporary, responses."},{"id":"idea-bio1-fusion-tf-degraders","kind":"idea","name":"Degraders for the fusion proteins that drive childhood sarcomas","route":"/ideas/idea-bio1-fusion-tf-degraders/","tldr":"Some sarcomas in children are caused by two genes fused into one abnormal protein. That protein is the whole disease, but no drug binds it. Destroying it instead of blocking it could work."},{"id":"idea-bio2-paediatric-first-development","kind":"idea","name":"Develop drugs in children first when the target is a children's target","route":"/ideas/idea-bio2-paediatric-first-development/","tldr":"Children wait years for drugs because adult trials come first, even when the target belongs to a childhood cancer. Some drugs should start with children."},{"id":"idea-tr2-paediatric-combo-prea","kind":"idea","name":"Make paediatric combination studies part of every relevant adult cancer drug approval","route":"/ideas/idea-tr2-paediatric-combo-prea/","tldr":"Children's cancers are treated with combinations, but companies study new drugs in children one at a time. Approvals should require the combination study children actually need."},{"id":"idea-reg-single-paediatric-plan","kind":"idea","name":"One global paediatric cancer development plan instead of separate FDA and EMA plans","route":"/ideas/idea-reg-single-paediatric-plan/","tldr":"Companies must agree separate plans for testing new cancer drugs in children with US and European regulators. A single agreed plan would get children access sooner."},{"id":"idea-reg-orphan-designation-reciprocity","kind":"idea","name":"Automatic reciprocity of orphan and rare-paediatric designations between regulators","route":"/ideas/idea-reg-orphan-designation-reciprocity/","tldr":"A rare cancer drug designated 'orphan' in the US must reapply in Europe, Japan and elsewhere. Recognising each other's decisions would save small companies months."},{"id":"idea-mfbg-pet-replaces-mibg","kind":"idea","name":"18F-MFBG PET replacing 123I-MIBG scintigraphy","route":"/ideas/idea-mfbg-pet-replaces-mibg/","tldr":"A same-day PET tracer could replace the two-day, low-resolution MIBG scan children now undergo repeatedly."},{"id":"pdx-models","kind":"technology","name":"Patient-derived xenografts","route":"/technologies/pdx-models/","status":"established","tldr":"A patient-derived xenograft is a patient's tumour grown in a mouse, used to test drugs before they reach people."}],"trials":[],"papers":[]},{"era":"2030+","title":"Every child, everywhere","description":"Most children with cancer live in countries where cure rates are a fraction of those in rich ones, and where families abandon curative treatment because they cannot afford transport and food. Guaranteed-quality childhood cancer medicines free of charge in fifty countries, cash stipends to prevent abandonment, a paediatric palliative team in every childhood unit, and an international consortium pooling the outcome of every treated child are the proposals. Advance market commitments and escrowed adult revenue would pay for the drugs no market will.","status":"speculative","refs":[{"id":"idea-acc-childhood-medicines-platform-scale","kind":"idea","name":"Guaranteed-quality childhood cancer medicines free of charge in 50 countries","route":"/ideas/idea-acc-childhood-medicines-platform-scale/","tldr":"Most children with cancer in rich countries are cured; most in poor countries are not, often because cheap drugs are missing. A global platform now ships quality drugs free; scaling it to 50 countries would be one of the highest-value cancer interventions available."},{"id":"idea-acc-abandonment-stipends","kind":"idea","name":"Cash for transport and food to stop families abandoning curative treatment","route":"/ideas/idea-acc-abandonment-stipends/","tldr":"Treatment abandonment is the leading cause of treatment failure for childhood cancer in much of the low- and middle-income world, driven by bus fares, lost income and the cost of food and lodging. Conditional cash, transport vouchers and family accommodation have cut abandonment sharply in Central America, East Africa and India, and should be funded in every curative protocol."},{"id":"idea-acc-paediatric-palliative-in-every-childhood-unit","kind":"idea","name":"A paediatric palliative care team in every childhood cancer unit","route":"/ideas/idea-acc-paediatric-palliative-in-every-childhood-unit/","tldr":"Children with cancer, and their families, need symptom relief and support from diagnosis, not only at the end. Every children's cancer unit should have a palliative team, and most in poorer countries have none."},{"id":"idea-data-paediatric-rwe-consortium","kind":"idea","name":"An international consortium pooling the outcome of every treated child with cancer","route":"/ideas/idea-data-paediatric-rwe-consortium/","tldr":"Childhood cancers are rare, so no one country sees enough cases. Pool the treatment and outcome of every child treated anywhere into one governed dataset."},{"id":"idea-fund-amc-paediatric-rare","kind":"idea","name":"Advance market commitments for paediatric and rare cancer drugs","route":"/ideas/idea-fund-amc-paediatric-rare/","tldr":"Payers would promise in advance to buy a set number of doses at a set price for any drug that meets a defined bar in a rare or childhood cancer, so companies know the market exists before they invest."},{"id":"idea-fund-paediatric-deferral-escrow","kind":"idea","name":"Escrow a share of adult revenue until the paediatric study is done","route":"/ideas/idea-fund-paediatric-deferral-escrow/","tldr":"Companies often delay the childhood cancer studies they are required to do. A slice of the adult drug's revenue would be held back until the paediatric trial is completed."},{"id":"st-jude","kind":"institution","name":"St. Jude Children's Research Hospital","route":"/institutions/st-jude/","tldr":"The only NCI comprehensive cancer centre devoted to children, where Total Therapy protocols made childhood leukaemia curable; families are never billed for care."},{"id":"alexs-lemonade-stand","kind":"collection","name":"Alex's Lemonade Stand Foundation (ALSF)","route":"/collections/alexs-lemonade-stand/","tldr":"A childhood-cancer charity started by a four-year-old patient's lemonade stand that now funds hundreds of grants and runs an open-science data lab for paediatric cancer genomics."},{"id":"st-baldricks","kind":"collection","name":"St. Baldrick's Foundation","route":"/collections/st-baldricks/","tldr":"A head-shaving fundraiser that became the largest charitable funder of children's cancer research in the US, underwriting much of the cooperative-group trial infrastructure that treats most American children with cancer."}],"trials":[],"papers":[]},{"era":"What sets the pace","title":"Markets, regulators, late effects and geography","description":"Each childhood cancer is too small a market for a company to pursue, and orphan incentives only partly correct that. The FDA and EMA require different paediatric plans, so studies are duplicated or delayed. Late effects are recorded in cohorts, not in routine care. And the children who most need the cures already found live where they are not available. Charities and cooperative groups fill the gap that the market leaves.","status":"current","refs":[{"id":"b-rare-cancers","kind":"bottleneck","name":"Rare and paediatric cancers without markets","route":"/bottlenecks/b-rare-cancers/","tldr":"Taken together rare cancers are a fifth of all cancers, but each one alone is too small for a company to invest in."},{"id":"b-incentive-misalignment","kind":"bottleneck","name":"Incentives reward me-too drugs and marginal gains","route":"/bottlenecks/b-incentive-misalignment/","tldr":"The system pays the same for a drug that adds two months as for a cure, so companies race to copy rather than to cure."},{"id":"b-regulatory-fragmentation","kind":"bottleneck","name":"Regulatory divergence between regions","route":"/bottlenecks/b-regulatory-fragmentation/","tldr":"Regulatory divergence means a drug approved in one country can take years to reach another, or never arrive."},{"id":"b-survivorship","kind":"bottleneck","name":"Survivorship and late effects are neglected","route":"/bottlenecks/b-survivorship/","tldr":"Tens of millions of people live after cancer with heart damage, infertility, second cancers and fear, and few services."},{"id":"b-global-access","kind":"bottleneck","name":"Most of the world has almost no cancer care","route":"/bottlenecks/b-global-access/","tldr":"Seven in ten cancer deaths happen in low- and middle-income countries, where radiotherapy, pathology, surgery and drugs are scarce."},{"id":"b-trial-enrolment","kind":"bottleneck","name":"Trials enrol too few, too slowly","route":"/bottlenecks/b-trial-enrolment/","tldr":"Fewer than one in ten adults with cancer joins a trial. Trials close for lack of patients, not lack of ideas."},{"id":"orphan-drug","kind":"term","name":"Orphan drug","route":"/terms/orphan-drug/","tldr":"A drug for a rare disease (in the US, fewer than 200,000 patients) that gets extra incentives, tax credits, fee waivers and seven years of market exclusivity, to make development worthwhile. Most cancers qualify, so most cancer drugs are orphans."},{"id":"accelerated-approval","kind":"term","name":"Accelerated approval","route":"/terms/accelerated-approval/","tldr":"FDA approval based on early evidence (like tumour shrinkage) on condition that a confirmatory trial follows."}],"trials":[],"papers":[]}],"watch":[]}