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Chemotherapy went from a poison that sometimes worked to the backbone of most cures, and is now being given more precisely: to fewer people, at better doses, and increasingly delivered inside an antibody so that it reaches the tumour and not the whole body.
Cytotoxic drugs produced the first cures of disseminated cancer (childhood leukaemia, Hodgkin lymphoma, testicular cancer) by combining agents with different mechanisms so that no single resistance pathway could escape. Platinums, taxanes, anthracyclines, antimetabolites and topoisomerase inhibitors remain curative in several cancers and are the partner that immunotherapy and targeted drugs are added to in most first-line regimens.
The field is now doing three things at once. It is giving chemotherapy to fewer people, using gene-expression tests and residual-disease blood tests to identify who gains nothing from it (TAILORx, RxPONDER, DYNAMIC) and dropping components that add toxicity without benefit (RATHL, SCARLET). It is re-examining dose and schedule, with the FDA's Project Optimus guidance, metronomic oral regimens tested at Tata Memorial, and pharmacogenomic testing before the first dose. And it is moving the cytotoxic payload inside antibody-drug conjugates, which have already replaced chemotherapy as the standard in advanced bladder cancer and parts of breast cancer.
The pace is set by problems that are economic as much as scientific: generic shortages, the absence of any incentive to optimise the dose of an off-patent drug, and the under-measurement of toxicity and quality of life in trials.
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.
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.
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.
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.
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.
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.
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.
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.
Every era's records, trial outcomes and papers, and every watch item, as JSON.
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Proof that a cancer resistant to one taxane is not resistant to all of them, and the beginning of treatment sequencing in castration-resistant disease. The CARD trial later showed that after an androgen receptor drug has failed, cabazitaxel beats switching to the other androgen receptor drug.
One roadmap page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
The moment lung cancer stopped being one disease for treatment purposes. Before this trial the pathology report said cancer or not cancer; after it, the subtype chose the drug, and the tissue had to be preserved well enough to answer the question.
The origin of the European position that adjuvant treatment means chemotherapy alone; CONKO-001, ESPAC-3, ESPAC-4 and PRODIGE 24 all built on it, and the role of radiotherapy remains contested (LAP07, PREOPANC).
The confirmatory half of the 2004 result. Two independent trials, two different docetaxel regimens, the same direction of effect: this is why docetaxel was adopted quickly and why it survived the move into hormone-sensitive disease a decade later.
The end of therapeutic nihilism in castration-resistant prostate cancer. It is also the trial that set the field's expectation of what a positive result looks like in this disease: a hazard ratio near 0.75 and a median gain measured in months, not years.
The ceiling of undirected cytotoxic chemotherapy, measured precisely. Everything that came afterwards, from histology-directed pemetrexed to EGFR inhibitors to checkpoint blockade, is an attempt to break a plateau this trial demonstrated could not be broken by changing the drugs.
The paper that ended therapeutic nihilism in lung cancer. The effect was small, and saying so honestly is what made it credible; every later trial in advanced disease is measured against the platinum doublet this analysis justified.
Shares A prevention programme for chemotherapy nerve damage: SARM1 inhibitors, cooling and compression, Infusion pumps, ports, and ambulatory chemotherapy devices, Dexrazoxane, Sodium thiosulfate (otoprotectant).
Shares Generic oncology drug supply and shortage mitigation, Methotrexate, Vincristine, Oxaliplatin.
Shares Generic oncology drug supply and shortage mitigation, Methotrexate, Vincristine, Oxaliplatin.
Shares Validate low-cost metronomic oral regimens in phase 3 and carry them into guidelines, A platform trial of very-low-cost metronomic chemotherapy in LMIC common cancers, METRO PLUS (Tata Memorial Centre, Varanasi), Oral metronomic chemotherapy vs intravenous cisplatin (Tata Memorial).
Shares POLARIX, Vincristine, Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting, Doxorubicin.
Shares Infusion pumps, ports, and ambulatory chemotherapy devices, Oncology pharmacy automation and compounding robots, Generic oncology drug supply and shortage mitigation, Scalp cooling (cold caps: DigniCap, Paxman).
Shares METRO PLUS (Tata Memorial Centre, Varanasi), Oral metronomic chemotherapy vs intravenous cisplatin (Tata Memorial), Low-dose nivolumab plus metronomic chemotherapy (Tata Memorial), Methotrexate.
Shares ECHELON-1, RATHL, Growth factors: G-CSF and febrile neutropenia prevention, Cardio-oncology.