{"id":"chemotherapy-roadmap","name":"Chemotherapy roadmap: mustard gas → curative combinations → the warhead inside smarter drugs","route":"/roadmaps/chemotherapy-roadmap/","eras":[{"era":"1940s-1970s","title":"From poison to the first cures","description":"Nitrogen mustard, then methotrexate (1948), produced remissions that did not last. The insight that made cure possible was combination: several drugs with different mechanisms, given together at full dose, so that no single resistant clone survived. Childhood leukaemia, Hodgkin lymphoma and, with cisplatin, testicular cancer became curable diseases. Vincristine, cyclophosphamide, doxorubicin and dactinomycin from this era are still in most curative paediatric regimens.","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":"cyclophosphamide","kind":"drug","name":"Cyclophosphamide","route":"/drugs/cyclophosphamide/","status":"approved","tldr":"Cyclophosphamide is an alkylating chemotherapy that damages DNA in dividing cells. It is part of CHOP for lymphoma, AC for breast cancer and VAC for childhood sarcomas, clears lymphocytes before CAR-T and prevents graft-versus-host disease after transplant; bladder bleeding, infertility and secondary leukaemia are its harms."},{"id":"doxorubicin","kind":"drug","name":"Doxorubicin","route":"/drugs/doxorubicin/","status":"approved","tldr":"The red chemotherapy drug from a soil bacterium that is still the backbone of treatment for sarcoma, lymphoma and breast cancer, limited by cumulative heart damage."},{"id":"dactinomycin","kind":"drug","name":"Dactinomycin (actinomycin D)","route":"/drugs/dactinomycin/","status":"approved","tldr":"The first antibiotic used as an anticancer drug (1954) and still the core of chemotherapy for Wilms tumour, rhabdomyosarcoma and gestational trophoblastic disease."},{"id":"cisplatin","kind":"drug","name":"Cisplatin","route":"/drugs/cisplatin/","status":"approved","tldr":"Cisplatin is the original platinum chemotherapy, discovered by accident in 1965; it cures testicular cancer and makes radiation work better in cervical and head and neck cancer."},{"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":"cytotoxic-chemotherapy","kind":"technology","name":"Cytotoxic chemotherapy","route":"/technologies/cytotoxic-chemotherapy/","status":"standard-of-care","tldr":"Cytotoxic chemotherapy drugs (platinums, antimetabolites, microtubule agents and topoisomerase inhibitors) kill rapidly dividing cells by damaging DNA or the mitotic spindle. They still cure testicular cancer, lymphoma and leukaemia, and they are the warhead inside antibody-drug conjugates, but a narrow margin between effective and toxic doses is their limitation."}],"trials":[],"papers":[]},{"era":"1980s-2000s","title":"New classes, adjuvant cures and the supportive care that made them deliverable","description":"Taxanes, third-generation platinums, gemcitabine, irinotecan and oral capecitabine widened the arsenal. Adjuvant chemotherapy after surgery raised cure rates in breast and colon cancer, and temozolomide with radiation became the glioblastoma standard (EORTC 26981, 2005). None of it would have been tolerable without the supportive care built alongside: 5-HT3 antiemetics, G-CSF to prevent febrile neutropenia, implanted ports and ambulatory pumps.","status":"historic","refs":[{"id":"paclitaxel","kind":"drug","name":"Paclitaxel / nab-paclitaxel","route":"/drugs/paclitaxel/","status":"approved","tldr":"A microtubule poison discovered in the Pacific yew tree, among the most used chemotherapies in breast, lung, and ovarian cancer."},{"id":"docetaxel","kind":"drug","name":"Docetaxel","route":"/drugs/docetaxel/","status":"approved","tldr":"The first chemotherapy to extend life in prostate cancer (2004), now part of triplet therapy at first metastatic diagnosis."},{"id":"oxaliplatin","kind":"drug","name":"Oxaliplatin","route":"/drugs/oxaliplatin/","status":"approved","tldr":"The platinum drug that works in bowel cancer where cisplatin does not, the 'OX' in FOLFOX and CAPOX; its cost is nerve damage in hands and feet."},{"id":"carboplatin","kind":"drug","name":"Carboplatin","route":"/drugs/carboplatin/","status":"approved","tldr":"Carboplatin is a platinum chemotherapy that crosslinks DNA; it is part of the standard pre-surgery regimen for triple-negative breast cancer."},{"id":"capecitabine","kind":"drug","name":"Capecitabine","route":"/drugs/capecitabine/","status":"approved","tldr":"Capecitabine (Xeloda) is a tablet form of the chemotherapy fluorouracil. It is a backbone of treatment for bowel cancer and a standard option in advanced breast cancer."},{"id":"gemcitabine","kind":"drug","name":"Gemcitabine","route":"/drugs/gemcitabine/","status":"approved","tldr":"A versatile chemotherapy used in pancreatic, bladder, lung, ovarian, breast and biliary cancers, in nasopharyngeal cancer, and as a bladder instillation."},{"id":"irinotecan","kind":"drug","name":"Irinotecan (and liposomal irinotecan)","route":"/drugs/irinotecan/","status":"approved","tldr":"Irinotecan is a topoisomerase-blocking chemotherapy central to bowel and pancreatic cancer regimens (FOLFIRI, FOLFIRINOX, NALIRIFOX) and to salvage therapy in childhood sarcomas; it carries the same warhead as the deruxtecan ADC payloads."},{"id":"temozolomide","kind":"drug","name":"Temozolomide","route":"/drugs/temozolomide/","status":"standard-of-care","tldr":"The only chemotherapy proven to extend life in glioblastoma, given during and after radiation. It works best when the tumour has switched off a repair gene called MGMT."},{"id":"eortc-26981","kind":"trial","name":"EORTC 26981 / NCIC CE.3 (Stupp trial)","route":"/trials/eortc-26981/","status":"positive","tldr":"The 2005 trial that set the treatment every glioblastoma patient still receives. Nothing has replaced it in twenty years."},{"id":"g-csf-growth-factors","kind":"technology","name":"Growth factors: G-CSF and febrile neutropenia prevention","route":"/technologies/g-csf-growth-factors/","status":"standard-of-care","tldr":"Injections of filgrastim or its long-acting form pegfilgrastim after chemotherapy make white cells recover faster, cutting the risk of life-threatening infections and allowing chemotherapy on schedule."},{"id":"infusion-devices-vascular-access","kind":"technology","name":"Infusion pumps, ports, and ambulatory chemotherapy devices","route":"/technologies/infusion-devices-vascular-access/","status":"standard-of-care","tldr":"Infusion devices are the implanted ports, smart pumps, and take-home pumps that deliver chemotherapy safely, including 46-hour infusions patients carry home."}],"trials":[{"id":"eortc-26981","name":"EORTC 26981 / NCIC CE.3 (Stupp trial)","route":"/trials/eortc-26981/","outcomes":[{"endpoint":"Overall survival","primary":true,"unit":"months","arms":[{"name":"Radiotherapy + temozolomide","n":287,"value":14.6},{"name":"Radiotherapy alone","n":286,"value":12.1}],"hr":0.63,"ci":[0.52,0.75],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa043330"},{"endpoint":"Overall survival at 5 years","unit":"%","arms":[{"name":"Radiotherapy + temozolomide","value":9.8},{"name":"Radiotherapy alone","value":1.9}],"source":"https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70025-7/fulltext"}],"setting":"Newly diagnosed glioblastoma: radiotherapy + concurrent and adjuvant temozolomide vs radiotherapy alone","enrolled":575,"enrolledBasis":"registry"}],"papers":[]},{"era":"2010s-2026","title":"The backbone that immunotherapy and ADCs are built on","description":"Most first-line regimens still start with chemotherapy and add something to it: a PD-1 blocker in lung (KEYNOTE-189), stomach (CheckMate 649) and cervical cancer, chemoradiation before oesophageal surgery (CROSS), a four-drug regimen after pancreatic surgery (PRODIGE 24) or as first treatment (NAPOLI 3). INTERLACE showed that six weeks of cheap generic chemotherapy before cervical chemoradiation cuts deaths, an advance usable anywhere. ECHELON-1 and POLARIX swapped one component of a curative regimen for an antibody-drug conjugate and improved outcomes.","status":"current","refs":[{"id":"keynote-024-189","kind":"trial","name":"KEYNOTE-024 & KEYNOTE-189","route":"/trials/keynote-024-189/","status":"positive","tldr":"The two trials that made immunotherapy, alone or with chemotherapy, the first treatment for most advanced lung cancers."},{"id":"checkmate-649","kind":"trial","name":"CheckMate 649","route":"/trials/checkmate-649/","status":"positive","tldr":"The trial that added immunotherapy to first-line stomach cancer chemotherapy; at five years, 16% of patients with PD-L1-rich tumours were alive versus 6%."},{"id":"cross","kind":"trial","name":"CROSS","route":"/trials/cross/","status":"positive","tldr":"The trial that made chemotherapy plus radiation before surgery the standard for oesophageal cancer; the survival gain was still there ten years later."},{"id":"prodige-24","kind":"trial","name":"PRODIGE 24 / CCTG PA6","route":"/trials/prodige-24/","status":"positive","tldr":"Showed that giving the strong four-drug chemotherapy after pancreatic surgery adds years of life for fit patients."},{"id":"napoli-3","kind":"trial","name":"NAPOLI 3","route":"/trials/napoli-3/","status":"positive","tldr":"The first head-to-head trial of the two chemotherapy backbones, won narrowly by the four-drug regimen."},{"id":"interlace","kind":"trial","name":"INTERLACE","route":"/trials/interlace/","status":"positive","tldr":"Six weeks of cheap, generic chemotherapy before standard chemoradiation cut deaths by 40%, an advance usable anywhere in the world."},{"id":"echelon-1","kind":"trial","name":"ECHELON-1","route":"/trials/echelon-1/","status":"positive","tldr":"Swapping bleomycin for the CD30 ADC in first-line chemotherapy improved survival in advanced Hodgkin lymphoma, the first frontline survival gain in decades."},{"id":"polarix","kind":"trial","name":"POLARIX","route":"/trials/polarix/","status":"positive","tldr":"The trial that improved on R-CHOP for the first time in twenty years, by swapping vincristine for an ADC."}],"trials":[{"id":"keynote-024-189","name":"KEYNOTE-024 & KEYNOTE-189","route":"/trials/keynote-024-189/","outcomes":[{"endpoint":"KEYNOTE-024: overall survival at 5 years, PD-L1 ≥50%","primary":true,"unit":"%","arms":[{"name":"Pembrolizumab","n":154,"value":31.9},{"name":"Chemotherapy","n":151,"value":16.3}],"hr":0.62,"ci":[0.48,0.81],"source":"https://ascopubs.org/doi/10.1200/JCO.21.00174"},{"endpoint":"KEYNOTE-189: overall survival, non-squamous","primary":true,"unit":"months","arms":[{"name":"Pembrolizumab + chemotherapy","n":410,"value":22},{"name":"Placebo + chemotherapy","n":206,"value":10.6}],"hr":0.6,"ci":[0.5,0.72],"source":"https://ascopubs.org/doi/10.1200/JCO.22.00975"}],"setting":"First-line metastatic NSCLC without EGFR/ALK: pembrolizumab alone (PD-L1 TPS ≥50%, KEYNOTE-024) or pembrolizumab + platinum-pemetrexed (any PD-L1, non-squamous, KEYNOTE-189)","enrolled":921,"enrolledBasis":"registry"},{"id":"checkmate-649","name":"CheckMate 649","route":"/trials/checkmate-649/","outcomes":[{"endpoint":"Overall survival, PD-L1 CPS ≥5","primary":true,"unit":"months","arms":[{"name":"Nivolumab + chemotherapy","n":473,"value":14.4},{"name":"Chemotherapy","n":482,"value":11.1}],"hr":0.71,"ci":[0.61,0.81],"source":"https://www.annalsofoncology.org/article/S0923-7534(26)00059-1/fulltext"},{"endpoint":"Overall survival at 5 years, CPS ≥5","unit":"percent","arms":[{"name":"Nivolumab + chemotherapy","value":16},{"name":"Chemotherapy","value":6}],"source":"https://www.annalsofoncology.org/article/S0923-7534(26)00059-1/fulltext"}],"setting":"First-line HER2-negative advanced gastric/GEJ/oesophageal adenocarcinoma: nivolumab + chemotherapy vs chemotherapy","enrolled":1581,"enrolledNote":"ClinicalTrials.gov lists 2,031 participants (actual) across all three arms; the Lancet 2021 primary analysis concurrently randomised 1,581 patients to nivolumab plus chemotherapy or chemotherapy alone, leaving out the nivolumab plus ipilimumab arm.","enrolledBasis":"randomised"},{"id":"cross","name":"CROSS","route":"/trials/cross/","outcomes":[{"endpoint":"Overall survival","primary":true,"unit":"months","arms":[{"name":"Chemoradiation + surgery","n":178,"value":49.4},{"name":"Surgery alone","n":188,"value":24}],"hr":0.68,"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa1112088"},{"endpoint":"Overall survival at 10 years","unit":"percent","arms":[{"name":"Chemoradiation + surgery","value":38},{"name":"Surgery alone","value":25}],"source":"https://ascopubs.org/doi/10.1200/JCO.20.03614"}],"setting":"Resectable oesophageal or junctional cancer (squamous and adenocarcinoma): weekly carboplatin/paclitaxel + 41.4 Gy radiation then surgery vs surgery alone","enrolled":366,"enrolledBasis":"registry"},{"id":"prodige-24","name":"PRODIGE 24 / CCTG PA6","route":"/trials/prodige-24/","outcomes":[{"endpoint":"Disease-free survival","primary":true,"unit":"months","arms":[{"name":"Adjuvant mFOLFIRINOX","n":247,"value":21.6},{"name":"Adjuvant gemcitabine","n":246,"value":12.8}],"hr":0.58,"ci":[0.46,0.73],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa1809775"},{"endpoint":"Overall survival (5-year update)","unit":"months","arms":[{"name":"Adjuvant mFOLFIRINOX","value":53.5},{"name":"Adjuvant gemcitabine","value":35.5}],"hr":0.68,"source":"https://jamanetwork.com/journals/jamaoncology/fullarticle/2795896"}],"setting":"Adjuvant therapy after resection of PDAC: mFOLFIRINOX vs gemcitabine","enrolled":493,"enrolledBasis":"registry"},{"id":"napoli-3","name":"NAPOLI 3","route":"/trials/napoli-3/","outcomes":[{"endpoint":"Overall survival","primary":true,"unit":"months","arms":[{"name":"NALIRIFOX","n":383,"value":11.1},{"name":"Gemcitabine + nab-paclitaxel","n":387,"value":9.2}],"hr":0.83,"ci":[0.7,0.99],"p":"0.036","source":"https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01366-1/fulltext"}],"setting":"First-line metastatic PDAC: NALIRIFOX vs gemcitabine + nab-paclitaxel","enrolled":770,"enrolledBasis":"registry"},{"id":"interlace","name":"INTERLACE","route":"/trials/interlace/","outcomes":[{"endpoint":"Progression-free survival at 5 years","primary":true,"unit":"%","arms":[{"name":"Induction chemo + CRT","n":250,"value":72},{"name":"CRT alone","n":250,"value":64}],"hr":0.65,"ci":[0.46,0.91],"source":"https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)01438-7/fulltext"},{"endpoint":"Overall survival at 5 years","primary":true,"unit":"%","arms":[{"name":"Induction chemo + CRT","value":80},{"name":"CRT alone","value":72}],"hr":0.6,"ci":[0.4,0.91],"source":"https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)01438-7/fulltext"}],"setting":"Locally advanced cervical cancer: 6 weeks of induction carboplatin-paclitaxel before chemoradiation vs chemoradiation alone","enrolled":500,"enrolledBasis":"registry"},{"id":"echelon-1","name":"ECHELON-1","route":"/trials/echelon-1/","outcomes":[{"endpoint":"Overall survival at 6 years","unit":"%","arms":[{"name":"BV-AVD","n":664,"value":93.9},{"name":"ABVD","n":670,"value":89.4}],"hr":0.59,"ci":[0.4,0.88],"p":"0.009","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2206125"},{"endpoint":"Modified PFS at 2 years","primary":true,"unit":"%","arms":[{"name":"BV-AVD","value":82.1},{"name":"ABVD","value":77.2}],"hr":0.77,"ci":[0.6,0.98],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa1708984"}],"setting":"Untreated stage III-IV classical Hodgkin lymphoma: brentuximab vedotin + AVD vs ABVD","enrolled":1334,"enrolledBasis":"registry"},{"id":"polarix","name":"POLARIX","route":"/trials/polarix/","outcomes":[{"endpoint":"Progression-free survival at 2 years","primary":true,"unit":"%","arms":[{"name":"Pola-R-CHP","n":440,"value":76.7},{"name":"R-CHOP","n":439,"value":70.2}],"hr":0.73,"ci":[0.57,0.95],"p":"0.02","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2115304"},{"endpoint":"Progression-free survival at 5 years","unit":"%","arms":[{"name":"Pola-R-CHP","value":64.9},{"name":"R-CHOP","value":59.1}],"hr":0.77,"ci":[0.62,0.97],"source":"https://ascopubs.org/doi/10.1200/JCO-25-00925"},{"endpoint":"Overall survival at 5 years","unit":"%","arms":[{"name":"Pola-R-CHP","value":82.3},{"name":"R-CHOP","value":79.5}],"hr":0.85,"ci":[0.63,1.15],"source":"https://ascopubs.org/doi/10.1200/JCO-25-00925"}],"setting":"Untreated DLBCL, IPI 2-5, age 18-80: Pola-R-CHP vs R-CHOP","enrolled":879,"enrolledNote":"ClinicalTrials.gov lists 1,000 participants (actual); the NEJM 2022 primary analysis randomised 879 patients (440 Pola-R-CHP, 439 R-CHOP).","enrolledBasis":"randomised"}],"papers":[]},{"era":"2018-2026","title":"Giving it to fewer people","description":"The largest recent gains in chemotherapy have come from not giving it. TAILORx and RxPONDER showed that a gene-expression score identifies most women with hormone-positive breast cancer who can skip it; DYNAMIC halved adjuvant chemotherapy in stage II colon cancer by testing blood for residual disease; RATHL dropped bleomycin after a clear interim PET scan; SCARLET tests dropping the anthracycline from triple-negative breast regimens; and the APT regimen showed a gentle schedule is enough for small HER2-positive tumours.","status":"current","refs":[{"id":"tailorx","kind":"trial","name":"TAILORx","route":"/trials/tailorx/","status":"positive","tldr":"Showed that most women with the commonest breast cancer can safely skip chemotherapy if a gene test says their risk is low or intermediate."},{"id":"rxponder","kind":"trial","name":"RxPONDER (SWOG S1007)","route":"/trials/rxponder/","status":"positive","tldr":"Postmenopausal women with a few positive lymph nodes and a low gene-test score can skip chemotherapy; premenopausal women still benefit from it."},{"id":"dynamic","kind":"trial","name":"DYNAMIC","route":"/trials/dynamic/","status":"positive","tldr":"Showed that a blood test can safely halve the number of colon cancer patients given chemotherapy after surgery."},{"id":"mrd-testing","kind":"technology","name":"MRD / molecular residual disease testing","route":"/technologies/mrd-testing/","status":"established","tldr":"An ultra-sensitive blood test after surgery that detects leftover cancer months before a scan would."},{"id":"rathl","kind":"trial","name":"RATHL","route":"/trials/rathl/","status":"positive","tldr":"Showed that patients whose PET scan is clear after two cycles can safely drop bleomycin and its lung toxicity."},{"id":"scarlet-s2212","kind":"trial","name":"SCARLET (SWOG S2212)","route":"/trials/scarlet-s2212/","status":"recruiting","tldr":"Tests whether the anthracycline can be dropped from TNBC pre-surgery treatment without losing effect."},{"id":"apt-trial","kind":"trial","name":"APT (adjuvant paclitaxel-trastuzumab)","route":"/trials/apt-trial/","status":"positive","tldr":"For small HER2-positive tumours, a gentle regimen of weekly paclitaxel plus trastuzumab gives excellent cure rates, avoiding harsher chemotherapy."}],"trials":[{"id":"tailorx","name":"TAILORx","route":"/trials/tailorx/","outcomes":[{"endpoint":"Invasive disease-free survival at 9 years (RS 11-25)","primary":true,"unit":"%","arms":[{"name":"Endocrine therapy alone","n":3399,"value":83.3},{"name":"Chemo-endocrine therapy","n":3312,"value":84.3}],"hr":1.08,"ci":[0.94,1.24],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa1804710"}],"setting":"HR+/HER2-, node-negative early breast cancer with Oncotype DX recurrence score 11-25: endocrine therapy alone vs chemo-endocrine therapy","enrolled":10273,"enrolledBasis":"registry"},{"id":"rxponder","name":"RxPONDER (SWOG S1007)","route":"/trials/rxponder/","outcomes":[{"endpoint":"5-year iDFS, postmenopausal","primary":true,"unit":"%","arms":[{"name":"Endocrine alone","value":91.9},{"name":"Chemo-endocrine","value":91.3}],"hr":1.02,"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2108873"},{"endpoint":"5-year iDFS, premenopausal","primary":true,"unit":"%","arms":[{"name":"Endocrine alone","value":89},{"name":"Chemo-endocrine","value":93.9}],"hr":0.6,"ci":[0.43,0.83],"source":"https://doi.org/10.1056/NEJMoa2108873"}],"setting":"HR+/HER2- breast cancer with 1-3 positive nodes and recurrence score ≤25: endocrine therapy alone vs chemo-endocrine therapy","enrolled":5018,"enrolledBasis":"registry"},{"id":"dynamic","name":"DYNAMIC","route":"/trials/dynamic/","outcomes":[{"endpoint":"Recurrence-free survival at 2 years (non-inferiority)","primary":true,"unit":"%","arms":[{"name":"ctDNA-guided management","n":302,"value":93.5,"note":"Non-inferiority met (margin −8.5 points)"},{"name":"Standard management","n":153,"value":92.4}],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2200075"},{"endpoint":"Patients receiving adjuvant chemotherapy","unit":"%","arms":[{"name":"ctDNA-guided management","value":15},{"name":"Standard management","value":28}],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2200075"}],"setting":"Stage II colon cancer: ctDNA-guided adjuvant chemotherapy vs standard management","enrolled":455,"enrolledBasis":"registry"},{"id":"rathl","name":"RATHL","route":"/trials/rathl/","outcomes":[{"endpoint":"Progression-free survival at 3 years (PET2-negative)","primary":true,"unit":"%","arms":[{"name":"ABVD","n":470,"value":85.7},{"name":"AVD","n":465,"value":84.4}],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa1510093"}],"setting":"Advanced Hodgkin lymphoma: interim-PET-guided omission of bleomycin (AVD) vs continued ABVD","enrolled":1214,"enrolledBasis":"registry"},{"id":"apt-trial","name":"APT (adjuvant paclitaxel-trastuzumab)","route":"/trials/apt-trial/","outcomes":[{"endpoint":"7-year disease-free survival","primary":true,"unit":"%","arms":[{"name":"Paclitaxel + trastuzumab","n":406,"value":93}],"source":"https://ascopubs.org/doi/10.1200/JCO.19.00066"}],"setting":"Small (≤3 cm), node-negative HER2+ breast cancer: 12 weeks paclitaxel + 1 year trastuzumab","enrolled":406,"enrolledBasis":"registry"}],"papers":[]},{"era":"2019-2026","title":"The warhead moves inside an antibody","description":"Antibody-drug conjugates carry a cytotoxic payload too potent to give on its own and release it inside or beside the tumour cell. EV-302 ended four decades of platinum chemotherapy as the first-line standard in advanced bladder cancer; DESTINY-Breast06 moved trastuzumab deruxtecan ahead of chemotherapy in hormone-positive breast cancer. The chemistry lessons of the ADC roadmap (linker stability, bystander killing, drug-to-antibody ratio) are what turned chemotherapy from a systemic exposure into a targeted one.","status":"current","refs":[{"id":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/","status":"approved","tldr":"An antibody-drug conjugate is an antibody that homes to a protein on the tumour cell, is swallowed, and releases a chemotherapy payload inside it. That widens chemotherapy's safe dose window about a hundredfold, which is why payloads too toxic to give alone can be used, though lung inflammation, neutropenia and eye toxicity from the payload still occur."},{"id":"trastuzumab-deruxtecan","kind":"drug","name":"Trastuzumab deruxtecan","route":"/drugs/trastuzumab-deruxtecan/","status":"approved","tldr":"Trastuzumab deruxtecan (Enhertu) is the most successful ADC ever. It redefined HER2 by working in tumours with only tiny amounts of the protein, and in 2026 moved into early-stage breast cancer."},{"id":"sacituzumab-govitecan","kind":"drug","name":"Sacituzumab govitecan","route":"/drugs/sacituzumab-govitecan/","status":"approved","tldr":"The first TROP2-targeted ADC. It delivers a strong chemotherapy directly to breast and bladder cancer cells and is now a first-line option in triple-negative breast cancer."},{"id":"enfortumab-vedotin","kind":"drug","name":"Enfortumab vedotin","route":"/drugs/enfortumab-vedotin/","status":"approved","tldr":"Enfortumab vedotin is an ADC against Nectin-4 that, combined with pembrolizumab, nearly doubled survival in advanced bladder cancer."},{"id":"ev-302","kind":"trial","name":"EV-302 / KEYNOTE-A39","route":"/trials/ev-302/","status":"positive","tldr":"Nearly doubled survival in advanced bladder cancer, ending 40 years of platinum chemotherapy as the standard."},{"id":"destiny-breast06","kind":"trial","name":"DESTINY-Breast06","route":"/trials/destiny-breast06/","status":"positive","tldr":"Moved Enhertu ahead of chemotherapy in hormone-positive breast cancer and extended it to 'ultralow' HER2."},{"id":"adc-generations","kind":"roadmap","name":"ADC roadmap: from Mylotarg to bispecific and dual-payload ADCs","route":"/roadmaps/adc-generations/","tldr":"Twenty-five years of trying to make chemotherapy hit only cancer cells, from the unstable first ADC to today's third-generation blockbusters and the fourth generation now in trials."}],"trials":[{"id":"ev-302","name":"EV-302 / KEYNOTE-A39","route":"/trials/ev-302/","outcomes":[{"endpoint":"Progression-free survival (BICR)","primary":true,"unit":"months","arms":[{"name":"Enfortumab vedotin + pembrolizumab","n":442,"value":12.5},{"name":"Platinum + gemcitabine","n":444,"value":6.3}],"hr":0.45,"ci":[0.38,0.54],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2312117"},{"endpoint":"Overall survival","primary":true,"unit":"months","arms":[{"name":"Enfortumab vedotin + pembrolizumab","value":31.5},{"name":"Platinum + gemcitabine","value":16.1}],"hr":0.47,"ci":[0.38,0.58],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2312117"},{"endpoint":"Objective response rate","unit":"%","arms":[{"name":"Enfortumab vedotin + pembrolizumab","value":67.7},{"name":"Platinum + gemcitabine","value":44.4}],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2312117"}],"setting":"First-line advanced urothelial cancer: enfortumab vedotin + pembrolizumab vs platinum chemotherapy","enrolled":886,"enrolledBasis":"registry"},{"id":"destiny-breast06","name":"DESTINY-Breast06","route":"/trials/destiny-breast06/","outcomes":[{"endpoint":"Progression-free survival, HER2-low (BICR)","primary":true,"unit":"months","arms":[{"name":"Trastuzumab deruxtecan","n":359,"value":13.2},{"name":"Chemotherapy (TPC)","n":354,"value":8.1}],"hr":0.62,"ci":[0.51,0.74],"p":"<0.0001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2407086"},{"endpoint":"Progression-free survival, ITT (HER2-low + ultralow)","unit":"months","arms":[{"name":"Trastuzumab deruxtecan","n":436,"value":13.2},{"name":"Chemotherapy (TPC)","n":430,"value":8.1}],"hr":0.63,"ci":[0.53,0.75],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2407086"},{"endpoint":"Objective response rate, HER2-low","unit":"%","arms":[{"name":"Trastuzumab deruxtecan","value":56.5},{"name":"Chemotherapy (TPC)","value":32.2}],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2407086"}],"setting":"HR+ HER2-low/ultralow breast cancer after endocrine therapy, chemotherapy-naive: T-DXd vs chemotherapy","enrolled":866,"enrolledBasis":"registry"}],"papers":[]},{"era":"2024-2030","title":"The right dose, the right schedule, the right patient","description":"Most chemotherapy doses were set decades ago as the maximum tolerated, calculated from body surface area. The FDA's Project Optimus guidance (August 2024) requires randomised dose comparison for new drugs; the harder task is re-optimising old ones. Tata Memorial's trials showed oral metronomic regimens matching intravenous cisplatin and a fraction of a nivolumab dose improving survival when added to them. Pre-emptive DPYD and UGT1A1 testing, dosing by lean mass rather than surface area, and response-adapted reduction are the next steps, and none has a commercial sponsor.","status":"emerging","refs":[{"id":"b-dose-optimisation","kind":"bottleneck","name":"Wrong doses","route":"/bottlenecks/b-dose-optimisation/","tldr":"Most drug doses were chosen as the highest a person can tolerate, which is often more than they need."},{"id":"metronomic-vs-cisplatin-tmh","kind":"trial","name":"Oral metronomic chemotherapy vs intravenous cisplatin (Tata Memorial)","route":"/trials/metronomic-vs-cisplatin-tmh/","status":"positive","tldr":"Two cheap tablets taken at home matched, and in fact beat, intravenous cisplatin for advanced head and neck cancer in a 422-patient Indian trial, with fewer side effects."},{"id":"metro-plus-varanasi","kind":"trial","name":"METRO PLUS (Tata Memorial Centre, Varanasi)","route":"/trials/metro-plus-varanasi/","status":"positive","tldr":"Adding low-cost oral metronomic tablets to standard paclitaxel-carboplatin doubled median survival from 5 to 10 months in a randomised trial run in Varanasi."},{"id":"low-dose-nivolumab-tmh","kind":"trial","name":"Low-dose nivolumab plus metronomic chemotherapy (Tata Memorial)","route":"/trials/low-dose-nivolumab-tmh/","status":"positive","tldr":"A Mumbai trial that added about one-twentieth of the usual dose of the immunotherapy nivolumab to cheap oral chemotherapy and nearly tripled the share of patients alive at one year."},{"id":"idea-tr1-pre-emptive-pharmacogenomic-testing","kind":"idea","name":"Test DPYD, UGT1A1 and TPMT/NUDT15 before the first dose, everywhere","route":"/ideas/idea-tr1-pre-emptive-pharmacogenomic-testing/","tldr":"A cheap gene test for DPYD, UGT1A1 and TPMT or NUDT15 before fluoropyrimidines, irinotecan or thiopurines identifies people at risk of severe or fatal toxicity so their dose can be lowered. The EMA has recommended DPD testing since 2020; US uptake remains partial."},{"id":"idea-bio2-lean-mass-dosing","kind":"idea","name":"Dose chemotherapy by muscle mass, not body surface area","route":"/ideas/idea-bio2-lean-mass-dosing/","tldr":"Chemotherapy doses are calculated from height and weight, a formula from the 1950s. Doses based on actual muscle mass may cause fewer severe side-effects."},{"id":"idea-tr1-response-adapted-dose-reduction","kind":"idea","name":"Reduce the dose once the cancer responds: response-adapted de-escalation trials","route":"/ideas/idea-tr1-response-adapted-dose-reduction/","tldr":"The dose needed to shrink a tumour may be higher than the dose needed to keep it from growing back. Trials that lower the dose once a response is achieved could reduce long-term side effects without losing control."},{"id":"idea-reg-metronomic-lmic-phase3-to-label","kind":"idea","name":"Validate low-cost metronomic oral regimens in phase 3 and carry them into guidelines","route":"/ideas/idea-reg-metronomic-lmic-phase3-to-label/","tldr":"Indian trials have shown that tiny daily doses of old oral chemotherapy drugs can help patients with head and neck cancer at a cost of a few dollars a month. These regimens should be proven and adopted worldwide."},{"id":"idea-acc-metronomic-lmic-platform-trial","kind":"idea","name":"A platform trial of very-low-cost metronomic chemotherapy in LMIC common cancers","route":"/ideas/idea-acc-metronomic-lmic-platform-trial/","tldr":"Frequent tiny doses of cheap old chemotherapy pills have shown surprising benefit in some cancers. A single large trial network in India and Africa could find out where this works and where it does not."}],"trials":[{"id":"metronomic-vs-cisplatin-tmh","name":"Oral metronomic chemotherapy vs intravenous cisplatin (Tata Memorial)","route":"/trials/metronomic-vs-cisplatin-tmh/","outcomes":[{"endpoint":"Median overall survival","primary":true,"unit":"months","arms":[{"name":"Oral metronomic (methotrexate + celecoxib)","n":213,"value":7.5},{"name":"IV cisplatin","n":209,"value":6.1}],"hr":0.773,"ci":[0.615,0.97],"p":"0.026","source":"https://doi.org/10.1016/S2214-109X(20)30275-8"}],"setting":"Recurrent, metastatic or inoperable head and neck carcinoma, palliative intent: oral methotrexate 15 mg/m2 weekly plus celecoxib 200 mg twice daily vs intravenous cisplatin","enrolled":422,"enrolledBasis":"registry"},{"id":"metro-plus-varanasi","name":"METRO PLUS (Tata Memorial Centre, Varanasi)","route":"/trials/metro-plus-varanasi/","outcomes":[{"endpoint":"Median overall survival","primary":true,"unit":"months","arms":[{"name":"Paclitaxel-carboplatin + oral metronomic chemotherapy","n":119,"value":10},{"name":"Paclitaxel-carboplatin","n":119,"value":5}],"hr":0.54,"ci":[0.41,0.72],"p":"<0.001","source":"https://doi.org/10.1200/GO-25-00721"}],"setting":"Advanced unresectable head and neck cancer: paclitaxel-carboplatin with or without oral metronomic chemotherapy","enrolled":238,"enrolledBasis":"registry"},{"id":"low-dose-nivolumab-tmh","name":"Low-dose nivolumab plus metronomic chemotherapy (Tata Memorial)","route":"/trials/low-dose-nivolumab-tmh/","outcomes":[{"endpoint":"Overall survival at 1 year","primary":true,"unit":"%","arms":[{"name":"Metronomic chemotherapy + low-dose nivolumab","n":76,"value":43.4},{"name":"Metronomic chemotherapy","n":75,"value":16.3}],"hr":0.545,"ci":[0.362,0.82],"p":"0.0036","source":"https://doi.org/10.1200/JCO.22.01015"},{"endpoint":"Median overall survival","unit":"months","arms":[{"name":"Metronomic chemotherapy + low-dose nivolumab","value":10.1},{"name":"Metronomic chemotherapy","value":6.7}],"source":"https://doi.org/10.1200/JCO.22.01015"}],"setting":"Recurrent or newly diagnosed advanced head and neck squamous cell carcinoma, palliative intent: triple oral metronomic chemotherapy with or without nivolumab 20 mg every 3 weeks","enrolled":151,"enrolledBasis":"registry"}],"papers":[]},{"era":"2024-2030","title":"Fewer harms from the drugs we keep","description":"Scalp cooling preserves hair, sodium thiosulfate halves permanent hearing loss from cisplatin in children and is now being tested in adults, dexrazoxane protects the heart from anthracyclines, low-dose olanzapine controls nausea and restores appetite for pennies, and cardio-oncology has become a specialty. Chemotherapy-induced neuropathy still has no proven prevention; SARM1 inhibitors, limb cooling and compression are the candidates.","status":"emerging","refs":[{"id":"scalp-cooling","kind":"technology","name":"Scalp cooling (cold caps: DigniCap, Paxman)","route":"/technologies/scalp-cooling/","status":"established","tldr":"A tightly fitted cap chilled to a few degrees above freezing, worn before, during and after each chemotherapy infusion, narrows the blood vessels of the scalp so less drug reaches the hair roots. In a randomised trial about half of women on taxane-based chemotherapy kept most of their hair, compared with none who went without."},{"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":"cardio-oncology","kind":"technology","name":"Cardio-oncology","route":"/technologies/cardio-oncology/","status":"established","tldr":"Cardio-oncology builds heart risk assessment, monitoring and prevention into cancer care so patients can finish curative treatment without trading cancer for heart failure. It targets anthracycline and trastuzumab damage, checkpoint-inhibitor myocarditis and radiation heart disease using echocardiography, troponin tests and protective drugs; specialist clinics are concentrated in large centres."},{"id":"olanzapine-appetite-tmh","kind":"trial","name":"Low-dose olanzapine for cancer anorexia (Tata Memorial)","route":"/trials/olanzapine-appetite-tmh/","status":"positive","tldr":"A double-blind trial at Tata Memorial in India randomised 124 patients starting chemotherapy to 2.5 mg of olanzapine, a decades-old tablet costing a few cents a day, or placebo. Six in ten gained more than 5% of their weight against one in ten on placebo, and ASCO listed it in its 2024 cachexia guideline; it was small and single-centre."},{"id":"idea-moon-olanzapine-antiemetic-everywhere","kind":"idea","name":"Low-dose olanzapine and generic antiemetic bundles in every guideline and formulary","route":"/ideas/idea-moon-olanzapine-antiemetic-everywhere/","tldr":"A cheap, old antipsychotic at a low dose is one of the best anti-sickness drugs for chemotherapy. Make sure every cancer unit in the world uses it."},{"id":"rolapitant","kind":"drug","name":"Rolapitant","route":"/drugs/rolapitant/","status":"approved","tldr":"Rolapitant (Varubi) is a long-lasting anti-sickness tablet taken once before chemotherapy, alongside a 5-HT3 blocker and dexamethasone, to prevent nausea and vomiting in the days after treatment."},{"id":"cannabinoids-nausea","kind":"technology","name":"Cannabinoids for chemotherapy nausea (dronabinol, nabilone, medical cannabis)","route":"/technologies/cannabinoids-nausea/","status":"approved","tldr":"Two synthetic cannabinoid tablets, dronabinol and nabilone, have been approved for chemotherapy nausea since 1985 and can help when standard anti-sickness drugs fail. Modern antiemetics work better for most people, and evidence for herbal cannabis or vaped products is thin."},{"id":"idea-moon-neuropathy-prevention-programme","kind":"idea","name":"A prevention programme for chemotherapy nerve damage: SARM1 inhibitors, cooling and compression","route":"/ideas/idea-moon-neuropathy-prevention-programme/","tldr":"Nerve damage from taxanes and platinum is common, often permanent and has no approved preventive. Test the most promising candidates head to head in one programme."}],"trials":[{"id":"olanzapine-appetite-tmh","name":"Low-dose olanzapine for cancer anorexia (Tata Memorial)","route":"/trials/olanzapine-appetite-tmh/","outcomes":[{"endpoint":"Weight gain greater than 5% at 12 weeks","primary":true,"unit":"%","arms":[{"name":"Olanzapine 2.5 mg","n":63,"value":60},{"name":"Placebo","n":61,"value":9}],"p":"<0.001","source":"https://doi.org/10.1200/JCO.22.01997"}],"setting":"Untreated, locally advanced or metastatic gastric, hepatopancreaticobiliary or lung cancer starting chemotherapy: olanzapine 2.5 mg daily vs placebo for 12 weeks, plus standard nutritional advice","enrolled":124,"enrolledBasis":"registry"}],"papers":[]},{"era":"What sets the pace","title":"Generics, incentives and what trials measure","description":"Cisplatin and carboplatin have gone into shortage in the richest health systems because generic manufacturing has no margin; a non-profit manufacturer and a strategic reserve are the proposed fixes. Nobody is paid to find the lowest effective dose of an off-patent drug, so public funding has to do it. And trials still measure how long people live far better than how they live, which is why toxicity remains under-reported and under-treated.","status":"current","refs":[{"id":"b-generic-repurposing","kind":"bottleneck","name":"No incentive to repurpose cheap drugs","route":"/bottlenecks/b-generic-repurposing/","tldr":"Old, cheap drugs with anti-cancer signals never get the trials they need because no one profits from the result."},{"id":"generic-drug-shortage-response","kind":"technology","name":"Generic oncology drug supply and shortage mitigation","route":"/technologies/generic-drug-shortage-response/","status":"established","tldr":"Keeping cheap, essential chemotherapy drugs like cisplatin available; shortages in 2023 forced rationing in US hospitals."},{"id":"idea-reg-nonprofit-generic-chemo-manufacturer","kind":"idea","name":"A non-profit manufacturer for generic cancer drugs in chronic shortage","route":"/ideas/idea-reg-nonprofit-generic-chemo-manufacturer/","tldr":"Cheap, essential chemotherapy drugs like cisplatin run out because making them is not profitable enough. A non-profit maker could guarantee supply at a fair price."},{"id":"idea-reg-generic-chemo-strategic-reserve","kind":"idea","name":"A strategic reserve of essential generic cancer drugs to end recurring shortages","route":"/ideas/idea-reg-generic-chemo-strategic-reserve/","tldr":"Cancer patients have had treatments delayed because basic chemotherapy drugs ran out. Keeping a national stockpile, like for flu antivirals, would prevent this."},{"id":"b-toxicity-qol","kind":"bottleneck","name":"Toxicity and quality of life are undervalued","route":"/bottlenecks/b-toxicity-qol/","tldr":"Trials measure how long people live, not how they live. Side-effects are under-reported and under-treated."},{"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-cachexia-supportive","kind":"bottleneck","name":"Cachexia, toxicity and the limits of the patient","route":"/bottlenecks/b-cachexia-supportive/","tldr":"Cancer cachexia, the muscle and fat wasting driven by tumour and host inflammatory signals, affects most patients with advanced pancreatic, gastric and lung cancer, and treatment-limiting toxicities decide what dose a patient can receive. Only Japan has an approved cachexia drug, and supportive care research gets a small share of funding relative to its effect."}],"trials":[],"papers":[]}],"watch":[]}