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Bending the Curve Trial by Trial
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1998–2010

Targeted therapy

Visual dialect: precise vectors, lock-and-key geometry. Eras are a storytelling frame, not a historical claim.

  1. 1998 · Understanding · Acute myeloid leukaemia (including APL)

    Diagnostic cytogenetics defines AML prognostic groups

    In 1998 a British trial of 1,612 people with AML reported that chromosome changes found at diagnosis define three groups with different outlooks. A 2002 US study of 1,213 adults also defined three risk groups: five-year survival was about one in two, one in four and one in twenty across the three groups.

    Grimwade 1998 (MRC AML10, n=1612, up to age 55 including children): response, relapse risk and OS defined favourable, intermediate and adverse cytogenetic groups, which also determined outcome of autologous or allogeneic transplant in CR1. Byrd 2002 (CALGB 8461, 1213 adults, de novo AML): favourable, intermediate, adverse: CR 88%, 67%, 32%; 5-year CIR 54%, 67%, 92%; 5-year OS 55%, 24%, 5%.

  2. 1998 · Treatment · Breast cancer

    Trastuzumab approved for HER2-overexpressing metastatic breast cancer

    In 1998 the US regulator approved trastuzumab, an antibody aimed at a protein called HER2 that some breast cancers make in excess. A randomised trial published in 2001 found that adding it to chemotherapy delayed progression of metastatic disease and lengthened survival, with a higher risk of heart problems.

    Randomised trial (469 patients) of chemotherapy with or without trastuzumab in HER2-overexpressing metastatic breast cancer. Median time to progression 7.4 vs 4.6 months (P<0.001); response rate 50% vs 32%; median survival 25.1 vs 20.3 months (P=0.01). NYHA class III or IV cardiac dysfunction: 27% with anthracycline, cyclophosphamide and trastuzumab vs 8% without; 13% with paclitaxel and trastuzumab vs 1% without.

  3. 1998 · Understanding · Breast cancer

    EBCTCG overviews: what adjuvant therapy achieves

    The Early Breast Cancer Trialists' Collaborative Group pools patient-level data from many randomised trials. Its overviews of 1998, 2005 and 2011 reported that years of tamoxifen for oestrogen-receptor-positive disease and months of chemotherapy lowered recurrence and long-term breast cancer death, and that radiotherapy after breast-conserving surgery lowered recurrence.

    Patient-level meta-analyses, each with its own trial set. 1998 tamoxifen (about 5 years vs none; ER-positive or untested): 10-year survival 61.4% vs 50.5% (node-positive), 78.9% vs 73.3% (node-negative). 1998 polychemotherapy: mortality reduced 27% (age under 50), 11% (50-69). 2005: anthracycline-based chemotherapy cut annual breast cancer death rate about 38% and 20% in those groups; tamoxifen 31% (ER-positive). 2011: radiotherapy after breast-conserving surgery cut 10-year recurrence from 35.0% to 19.3%.

  4. 1998 · Understanding · Childhood acute lymphoblastic leukemia (ALL)

    Minimal residual disease predicts relapse in childhood ALL

    In 1998 a European study of 178 children in remission from ALL found that leukemia cells still detectable with a sensitive gene-based test were linked to later relapse. Later studies using other methods supported this, and residual disease became a way to choose how intensive treatment should be.

    Prospective EORTC Children Leukemia Group study at 11 centres: 246 patients enrolled, 178 monitored for residual disease by competitive polymerase chain reaction on clonal immunoglobulin or T-cell receptor rearrangements; median follow-up 38 months. Presence and level of residual leukemia correlated with early relapse at each time studied (P<0.001). In multivariate analysis it was the most powerful independent prognostic factor, ahead of immunophenotype, age, risk group and white-cell count.

  5. 1998 · Treatment · Childhood acute lymphoblastic leukemia (ALL)

    Augmented post-induction therapy for slow early responders

    In a 1998 randomised trial of 311 children with high-risk ALL whose leukemia cleared slowly at the start of treatment, a more intensive course of post-induction chemotherapy was followed by better five-year event-free survival than the standard course: about 75 in 100 versus 55 in 100. The extra treatment had considerable but manageable side effects.

    Randomised trial, January 1991 to June 1995: 311 children with newly diagnosed high-risk ALL, slow early response (more than 25 percent marrow blasts on day 7) and remission after induction; standard (156) versus augmented (155) post-induction chemotherapy. Five-year Kaplan-Meier EFS from end of induction 75.0% versus 55.0% (P<0.001); OS 78.4% versus 66.7% (P=0.02). Difference most pronounced at ages 1 to 9 years. Toxicity considerable but manageable.

  6. 1998 · Understanding · Sarcoma and GIST

    Activating KIT mutations found in gastrointestinal stromal tumours

    In 1998 researchers sequenced the KIT gene in five gastrointestinal stromal tumours and found mutations that kept the KIT growth signal switched on without its usual trigger. A separate 1998 study found KIT on all 78 tumours it examined. Both groups suggested the tumours may arise from the gut's pacemaker cells, the interstitial cells of Cajal.

    Hirota et al. (Science 1998) sequenced KIT cDNA from five GISTs: mutations between the transmembrane and tyrosine kinase domains; mutant proteins constitutively activated; transfection transformed Ba/F3 cells. Kindblom et al. (Am J Pathol 1998): all 78 stromal tumours strongly KIT-immunoreactive, 56 of 78 CD34-positive; 30 of 30 control tumours (including leiomyomas and leiomyosarcomas) KIT-negative. Both proposed an origin from interstitial cells of Cajal.

  7. 1998 · Treatment · Testicular germ cell tumors

    Ifosfamide-based salvage: VeIP, then TIP

    Two series, and a later update, described ifosfamide-based chemotherapy for germ-cell tumours that progressed after cisplatin. With VeIP in 135 patients, about half became disease-free, and one in four stayed free of disease. With TIP in 46 selected favourable-prognosis patients, 63% had a durable complete response; a 2024 report of 104 patients gave 5-year PFS 66%.

    Single-arm series. VeIP second line (135 patients, 1984-1989): disease-free 49.6% after chemotherapy with or without surgery; continuously disease-free 23.7%. TIP second line (46 patients with testicular primary and prior complete response): complete response 70%, durable complete response 63%, 2-year PFS 65% (95% CI 51-79), median follow-up 69 months. TIP long-term (104 patients, median 8.9 years): 5-year PFS 66% (55-74), OS 69% (59-77).

  8. 1999 · Treatment · Bladder cancer

    Neoadjuvant cisplatin-based chemotherapy before cystectomy

    Randomised trials asked whether platinum-based chemotherapy before bladder surgery helps people with muscle-invasive bladder cancer live longer. Two large trials did not reach statistical significance at first report; in one, median survival was 77 months with chemotherapy and 46 without. A pooled analysis of ten trials found five-year survival rose from 45% to 50% with platinum-based combinations.

    US randomised trial (317 enrolled; 154 cystectomy alone vs 153 MVAC then cystectomy): median OS 46 vs 77 months, P=0.06 (ITT); no residual disease at cystectomy 15% vs 38%. MRC/EORTC BA06 30894 (976 patients, no chemotherapy vs CMV): 3-year survival 50.0% vs 55.5% (P=0.075); long-term OS HR 0.84 (95% CI 0.72-0.99), 10-year 30% vs 36%. Meta-analysis (2688 patients, ten trials): platinum-combination OS HR 0.87 (0.78-0.98); 5-year 45% vs 50%.

  9. 1999 · Treatment · Cervical cancer

    Concurrent cisplatin-based chemoradiation: the 1999 trials

    In 1999 several trials reported that adding chemotherapy containing cisplatin to radiotherapy helped women with locally advanced cervical cancer live longer, compared with radiotherapy alone or with another drug. A further trial published in 2002 found no significant difference.

    Randomised trials of cisplatin-containing chemoradiation (RTOG 90-01, GOG 85, GOG 120, GOG 123) favoured it in 1999. RTOG 90-01: 5-year OS 73% vs 58% against extended-field radiotherapy (P=0.004). GOG 120: relative risk of progression or death 0.57 (0.42 to 0.78), weekly cisplatin vs hydroxyurea. GOG 123 (bulky IB, adjuvant hysterectomy): relative risk of progression 0.51 (0.34 to 0.75). The NCIC trial found no significant OS difference (5-year 62% vs 58%, P=0.42).

  10. 1999 · Understanding · Chronic lymphocytic leukaemia

    IGHV mutation status separates two clinical courses

    In 1999 two papers in the same journal issue showed that CLL cells differ in whether their antibody genes carry mutations. People whose cells had unmutated genes had shorter survival. Among 84 patients in one study, early-stage patients with unmutated genes had a median survival of about 8 years, against about 24 years with mutated genes.

    Two Blood papers (1999). Hamblin et al.: IGHV sequencing in 84 patients, 54.8% mutated (>2%); unmutated status associated with advanced stage and progressive disease; stage A median survival 95 vs 293 months (P=.0008). Damle et al.: IGHV mutation status and CD38 (30% cut-off) predicted response to chemotherapy and survival. CLL-IPI 2016 (n=3472): IGHV status is one of five factors; 5-year OS 93.2% to 23.3% (training dataset).

  11. 1999 · Treatment · Endometrial cancer

    Hormonal therapy: progestins to letrozole combinations

    Hormone-based treatment of advanced endometrial cancer began with progestins. A randomised study found oral medroxyprogesterone acetate active, with no benefit from a dose five times higher. Later small phase 2 studies added letrozole to everolimus or palbociclib and reported responses or longer progression-free survival; these are early signals.

    GOG-81 (299 women): oral MPA 200 vs 1000 mg/day; response 25% vs 15%; median PFS 3.2 vs 2.5 months; median survival 11.1 vs 7.0 months. Phase II everolimus-letrozole (38 enrolled, 35 evaluable): clinical benefit rate 40%, objective response 32%. Randomised phase II PALEO (77 patients): letrozole with palbociclib vs placebo, median PFS 8.3 vs 3.1 months; 12-month landmark HR 0.57 (95% CI 0.32-0.99).

  12. 1999 · Understanding · Hepatocellular carcinoma

    BCLC: a staging classification linking stage to treatment

    In 1999 a Barcelona research group proposed a staging system for liver cancer with four stages, each tied to the treatments it considered best for those patients, from curative treatment for small early tumours to symptomatic care for the most advanced disease. The Barcelona Clinic Liver Cancer (BCLC) system has been updated since, including in 2022.

    Review proposing the Barcelona Clinic Liver Cancer (BCLC) classification with four stages: A, asymptomatic early tumours suitable for resection, transplantation or percutaneous treatment; B, asymptomatic multinodular HCC; C, symptomatic tumours and/or vascular invasion or extrahepatic spread; D, Okuda stage III or PST 3-4, symptomatic treatment only. Stages B and C: palliative treatments or new agents within trials. A 2022 update follows an official update in 2018.

  13. 1999 · Understanding · Kidney cancer (renal cell carcinoma)

    pVHL and HIF: oxygen-dependent degradation (1999)

    In 1999 researchers showed in cell experiments that the protein made by the VHL tumour suppressor gene is needed to break down hypoxia-inducible factor when oxygen is available. In 2019 the Nobel Prize in Physiology or Medicine recognised discoveries on how cells sense oxygen.

    Maxwell et al., Nature 1999: in VHL-defective cells HIF alpha-subunits were constitutively stabilised and HIF-1 was active; re-expression of pVHL restored oxygen-dependent instability. pVHL and HIF alpha-subunits co-immunoprecipitated; the interaction was iron dependent and necessary for oxygen-dependent degradation. Laboratory study; no patient outcomes. Nobel Prize in Physiology or Medicine 2019 to Kaelin, Ratcliffe and Semenza for discoveries on cellular oxygen sensing.

  14. 1999 · Treatment · Lung cancer

    Limited-stage SCLC: twice-daily thoracic radiotherapy (Turrisi 1999)

    In 1999 a randomised trial of 417 people with limited-stage small-cell lung cancer compared chest radiotherapy given twice a day over three weeks with once a day over five weeks, both with cisplatin-etoposide chemotherapy. Median survival was 23 months with twice-daily and 19 with once-daily treatment; severe esophagitis was more common with twice-daily (27% vs 11%).

    Turrisi 1999 (417 patients, limited-stage SCLC; four cycles of cisplatin-etoposide with 45 Gy thoracic radiotherapy twice daily over 3 weeks vs once daily over 5 weeks): median survival 23 vs 19 months (P=0.04, log-rank); 2-year survival 47% vs 41%, 5-year 26% vs 16%; grade 3 esophagitis 27% vs 11% (P<0.001). CONVERT (547 patients; 45 Gy twice daily vs 66 Gy once daily): median OS 30 vs 25 months (HR 1.18; 0.95-1.45; P=0.14).

  15. 1999 · Treatment · Lung cancer

    Prophylactic cranial irradiation in SCLC (1999 and 2007)

    Prophylactic cranial irradiation (PCI) is brain radiotherapy given before any brain metastases are seen. A 1999 pooled analysis of seven trials in people with small-cell lung cancer in complete remission found better survival with PCI (3-year survival 20.7% vs 15.3%). A 2007 randomised trial in extensive-stage disease found fewer symptomatic brain metastases and longer survival with PCI.

    Aupérin 1999 (individual-patient-data meta-analysis, 7 trials, N=987, complete remission): relative risk of death 0.84 (95% CI 0.73-0.97; P=0.01); 3-year survival 20.7% vs 15.3%; relative risk of brain metastasis 0.46. Slotman 2007 (randomised, extensive-stage SCLC after chemotherapy response, 143 vs 143): symptomatic brain metastases HR 0.27 (0.16-0.44); 1-year cumulative risk of brain metastases 14.6% vs 40.4%; median OS 6.7 vs 5.4 months. Reported separately, not pooled.

  16. 1999 · Treatment · Multiple myeloma

    Thalidomide shows activity in refractory myeloma

    Thalidomide, a drug that decades earlier had caused severe birth defects when given in pregnancy, was tested in 84 people whose myeloma had not responded to treatment. About one in three had their myeloma protein fall by at least a quarter. Later randomised trials tested it in newly diagnosed myeloma, and the FDA approved it for that use in 2006.

    Single-arm study (n=84, previously treated, refractory myeloma; oral thalidomide 200 to 800 mg daily): response 32% (paraprotein reduction of at least 25%, lasting at least six weeks); 12-month Kaplan-Meier event-free survival 22% and overall survival 58%. Later randomised trials: IFM 99-06, MPT versus MP, median OS 51.6 versus 33.2 months (HR 0.59); thalidomide-dexamethasone versus placebo-dexamethasone, median TTP 22.6 versus 6.5 months (P<0.001).

  17. 1999 · Treatment · Neuroblastoma and Wilms tumour

    Transplant and isotretinoin in high-risk neuroblastoma (CCG-3891)

    Two linked randomized comparisons tested treatments for children with high-risk neuroblastoma. Children assigned to high-dose chemotherapy with their own purged bone marrow had better three-year event-free survival than those given more intensive chemotherapy, about one in three versus about one in five. Isotretinoin afterwards was also linked to better event-free survival.

    CCG-3891, two sequential randomizations. First (N=379): myeloablative chemotherapy, TBI and purged autologous BMT (n=189) vs three cycles of intensive chemotherapy (n=190); 3-year EFS 34% vs 22% (P=0.034). Second (n=130 vs 128, no progression after therapy): 13-cis-retinoic acid for 6 months vs none; 3-year EFS 46% vs 29% (P=0.027). Long-term report: 5-year EFS 30% vs 19% (P=0.04) and 42% vs 31% (not significant).

  18. 1999 · Understanding · Oesophageal cancer

    Reflux as a risk factor for oesophageal adenocarcinoma

    A Swedish population-based study interviewed people with oesophageal adenocarcinoma and a comparison group. People with frequent, long-standing reflux symptoms had a much higher risk of this cancer. A later US registry analysis argued that the rise in oesophageal adenocarcinoma since the 1970s reflects a real increase in disease, not just more diagnosis.

    Lagergren et al. (Sweden, population-based case-control study, 1995 to 1997): 189 oesophageal adenocarcinomas, 262 cardia adenocarcinomas, 167 squamous-cell carcinomas, 820 controls. Recurrent reflux symptoms: odds ratio 7.7 (95% CI 5.3 to 11.4) for oesophageal adenocarcinoma, 2.0 (1.4 to 2.9) for cardia adenocarcinoma, 1.1 (0.7 to 1.9) for squamous-cell carcinoma. Pohl and Welch (SEER): incidence rose about sixfold, 4 to 23 per million, 1975 to 2001.

  19. 1999 · De-escalation · Testicular germ cell tumors

    Smaller radiotherapy fields and lower doses for stage I seminoma

    After surgery for stage I seminoma, radiotherapy was given to abdominal lymph nodes. Two MRC trials tested a smaller field and a lower dose. Relapse rates were low in all groups, the smaller field caused less short-term toxicity, and the lower dose was judged unlikely to raise relapse by more than a few percentage points.

    MRC TE10 (478 men, 30 Gy): para-aortic strip vs dogleg field, 3-year relapse-free survival 96% vs 96.6%; 18 relapses (nine in each group), four pelvic, all after para-aortic radiotherapy. TE18/EORTC 30942 (625 men): 30 vs 20 Gy, median follow-up 61 months, 10 vs 11 relapses (HR 1.11, 90% CI 0.54-2.28); lethargy at 4 weeks 20% vs 5%. Later combined report (TE18 counted as 1094 patients): 20 Gy HR 0.63 (90% CI 0.38-1.04).

  20. 2000 · Treatment · Bladder cancer

    Gemcitabine-cisplatin compared with MVAC in advanced bladder cancer

    In 405 people with advanced bladder (urothelial) cancer who had not had chemotherapy, gemcitabine plus cisplatin and the older four-drug MVAC regimen gave similar survival. The two-drug regimen caused fewer of several serious side effects, such as fever with low white blood cells.

    Randomised phase 3 (N=405; gemcitabine-cisplatin n=203, MVAC n=202). Overall survival HR 1.04 (95% CI 0.82-1.32; P=.75); response rate 49% vs 46%; toxic death 1% vs 3%. Long-term update: median OS 14.0 vs 15.2 months (HR 1.09; 95% CI 0.88-1.34), 5-year OS 13.0% vs 15.3%. Neutropenic sepsis 1% vs 12%.

  21. 2000 · Reversal · Breast cancer

    High-dose chemotherapy with stem-cell rescue: a reversal

    Very high doses of chemotherapy with stem-cell rescue were tested in randomised trials in breast cancer. A randomised trial in metastatic disease found no survival benefit, and a review of 14 trials in earlier disease found no survival gain but more treatment-related deaths. An on-site review of one further study found its records did not match the data presented.

    Metastatic disease, Philadelphia BMT Group (N=199 randomised after response to induction): 3-year survival 32% vs 38% with high-dose chemotherapy plus transplantation vs conventional chemotherapy, not significant; median TTP 9.6 vs 9.0 months. High-risk primary disease, Netherlands (N=885): 5-year RFS 65% vs 59% (HR 0.83; 95% CI 0.66-1.03; P = 0.09). Cochrane, 14 trials, 5600 women: treatment-related deaths RR 7.97 (95% CI 3.99-15.92). Bezwoda records are not evidence.

  22. 2000 · Understanding · Chronic lymphocytic leukaemia

    FISH and TP53: genomic aberrations predict survival in CLL

    In 2000, researchers used a laboratory method called FISH to look for chromosome changes in the leukaemia cells of 325 people. Changes were found in 82 in 100 and were linked to survival: median survival was 32 months with a 17p deletion and 133 months with a lone 13q deletion. A 2010 study linked TP53 mutation to poor outcomes.

    Dohner 2000: FISH in 325 patients, aberrations in 268 (82%); median survival 32 months (17p deletion), 79 (11q), 114 (trisomy 12), 111 (normal karyotype), 133 (13q sole); 17p and 11q deletion, age, Binet stage, LDH and white-cell count independent. Zenz 2010 (CLL4, n=375): TP53 mutation 28 of 328 (8.5%); median PFS 23.3 vs 62.2 months, OS 29.2 vs 84.6.

  23. 2000 · Treatment · Colorectal cancer

    Irinotecan with fluorouracil as first-line therapy for metastatic CRC

    Two randomised trials in 2000 added irinotecan to fluorouracil and leucovorin as the first treatment for bowel cancer that had spread. In both, median survival was longer than with fluorouracil and leucovorin alone: 17.4 versus 14.1 months in one trial and 14.8 versus 12.6 months in the other.

    Douillard (Lancet, 25 March 2000; n=387): irinotecan plus infusional fluorouracil/folinate vs fluorouracil/folinate alone; median OS 17.4 vs 14.1 months (p=0.031); TTP 6.7 vs 4.4 months. FDA approved first-line use 20 April 2000. Saltz (NEJM, 28 September 2000; n=683, ITT): IFL vs bolus fluorouracil/leucovorin; median OS 14.8 vs 12.6 months (P=0.04), PFS 7.0 vs 4.3 months (P=0.004), response 39% vs 21%.

  24. 2000 · Treatment · Colorectal cancer

    Oxaliplatin added to infusional fluorouracil in advanced CRC

    Two randomised trials in 2000 added oxaliplatin to fluorouracil and leucovorin as the first treatment for advanced bowel cancer. Tumours responded more than twice as often with oxaliplatin and took longer to progress, but overall survival was not significantly better in the larger trial and was similar in the other, and nerve damage and diarrhoea were more frequent.

    Giacchetti (n=200; chronomodulated fluorouracil-leucovorin): response 53% vs 16% (P<.001); median PFS 8.7 vs 6.1 months (P=.048); median OS 19.4 vs 19.9 months. de Gramont (n=420; LV5FU2): median PFS 9.0 vs 6.2 months (P=.0003); response 50.7% vs 22.3%; median OS 16.2 vs 14.7 months (P=.12). FDA accelerated approval 9 August 2002; first-line indication 9 January 2004.

  25. 2000 · Understanding · Foundations

    The Hallmarks of Cancer: a framework (2000, 2011, 2022)

    In 2000 D. Hanahan and R. A. Weinberg proposed that the many forms of cancer share a small set of acquired capabilities, which they called hallmarks. They revised the list in 2011, and Hanahan proposed further additions in 2022, such as cell plasticity and the microbiome. It is a way of organising knowledge, not a clinical result.

    Conceptual review series (Cell 2000; Cell 2011; Cancer Discovery 2022). The 2011 paper lists six biological capabilities, with genome instability and inflammation as enabling characteristics, adds two emerging hallmarks (reprogramming of energy metabolism; evading immune destruction) and the tumour microenvironment. The 2022 paper proposes phenotypic plasticity and disrupted differentiation as a hallmark, epigenetic reprogramming and polymorphic microbiomes as enabling characteristics, and senescent cells. A 2026 Cell review synthesises 25 years. No data.

  26. 2000 · De-escalation · Gastric and gastro-oesophageal junction cancer

    Endoscopic resection for early gastric cancer: Gotoda 2000 to JCOG0607

    A report from two large cancer centres in 2000 found no lymph node spread in a group of very early stomach cancers, which supported removing such tumours through the endoscope rather than by gastrectomy. A later single-arm trial of wider criteria reported high five-year survival, without a surgery comparison arm.

    Gotoda 2000 (5265 gastrectomy patients, two centres): none of 1230 well-differentiated intramucosal cancers under 30 mm had nodal metastasis (95% CI 0-0.3%). JCOG0607, single-arm confirmatory trial of ESD for expanded cT1a intestinal-type criteria (470 patients): 5-year OS 97.0% (95% CI 95.0-98.2) against a threshold of 86.1%; en bloc resection 99.1%; additional gastrectomy in 131 (28%).

  27. 2000 · Understanding · Glioblastoma

    MGMT promoter methylation predicts benefit from alkylating agents

    In 2000, researchers linked a silenced repair gene, MGMT, in glioma tissue to better responses to carmustine. In 2005, in samples from a randomised trial, glioblastomas with the silenced gene did better when temozolomide was added to radiotherapy. Without it, the gain was smaller and not statistically significant.

    Esteller 2000: MGMT promoter methylated in 19 of 47 (40%) gliomas from carmustine-treated patients; associated with tumour regression and longer overall and disease-free survival. Hegi 2005 (analysis of specimens from a randomised trial of radiotherapy with or without temozolomide): methylated in 45% of 206 assessable cases; prognostic irrespective of treatment (HR 0.45, 95% CI 0.32 to 0.61). In methylated tumours, median survival 21.7 vs 15.3 months with vs without temozolomide (P=0.007).

  28. 2000 · Understanding · Head and neck cancer

    HPV linked to a distinct subset of head and neck cancers

    From 2000, studies reported that human papillomavirus (HPV) is found in a subset of head and neck cancers, especially in the oropharynx, and is likely a cause. In US registry samples, the share of oropharyngeal cancers with HPV rose from about one in six in the 1980s to about seven in ten by 2000 to 2004.

    Gillison 2000 (253 HNSCC): HPV in 25% (95% CI 19 to 30%); oropharyngeal site OR 6.2 for HPV presence; HPV-positive tumours HR for death 0.41 (0.20 to 0.88). D'Souza 2007 (100 cases, 200 controls): oral HPV-16 infection OR 14.6 (6.3 to 36.6). Chaturvedi 2011 (SEER, 271 tumours): HPV prevalence 16.3% (1984 to 1989) to 71.7% (2000 to 2004); HPV-positive incidence up 225% (1988 to 2004).

  29. 2000 · Understanding · Head and neck cancer

    MACH-NC: chemotherapy added to locoregional treatment (2000)

    Researchers pooled individual patient data from many randomised trials of adding chemotherapy to surgery or radiation for head and neck cancer. The first report found only a small survival gain. Later updates reported benefit for chemotherapy given together with radiation, but not for chemotherapy given before or after.

    Individual-patient-data meta-analyses (MACH-NC). 2000: 63 trials, 10,741 patients, hazard ratio of death 0.90 (95% CI 0.85-0.94; P<0.0001), absolute benefit 4% at 2 and 5 years; three larynx-preservation trials hazard ratio 1.19 (0.97-1.46). 2009 update, 50 concomitant trials: hazard ratio 0.81, absolute benefit 6.5% at 5 years. 2021 update: concomitant 0.83 (0.79-0.86); induction 0.96 (0.90-1.01); adjuvant 1.02 (0.92-1.13).

  30. 2000 · Understanding · Non-Hodgkin lymphoma (DLBCL and follicular)

    Gene expression profiling splits DLBCL into distinct types (2000)

    Using DNA microarrays to read gene activity in lymphoma samples, researchers found that diffuse large B-cell lymphoma splits into two molecular forms: one resembling normal germinal-centre B cells and one resembling activated B cells. People with the germinal-centre form had significantly better overall survival. The authors proposed that outcomes differ because the tumours differ in their biology.

    DNA-microarray gene-expression profiling of B-cell malignancies identified two molecularly distinct forms of DLBCL: germinal centre B-like and activated B-like, reflecting different stages of B-cell differentiation. Patients with germinal centre B-like DLBCL had significantly better overall survival than those with activated B-like DLBCL. The abstract gives no sample size, hazard ratio or p-value.

  31. 2001 · Treatment · Chronic lymphocytic leukaemia

    Alemtuzumab: accelerated approval, then CAM307 against chlorambucil

    Alemtuzumab, an antibody against the CD52 marker on lymphocytes, was approved in the US in 2001 for CLL after other treatments had failed, under rules for accelerated approval. A published single-group study of 93 such people found 33 in 100 responded. A later randomised trial in 297 untreated people found longer time without progression than with chlorambucil.

    FDA accelerated approval 7 May 2001 (BL 103948) for B-CLL after alkylating agents and failure of fludarabine; the FDA review describes three single-arm studies (149 patients), the pivotal one with 93. Published 93-patient study: ORR 33% (CR 2%, PR 31%), median OS 16 months. CAM307 (297 randomised, untreated; vs chlorambucil): PFS HR 0.58 (P=.0001), ORR 83% vs 55%, CR 24% vs 2%. Supplement approved 19 September 2007 fulfilling the commitment.

  32. 2001 · Treatment · Chronic myeloid leukemia

    STI571/imatinib: first clinical results and FDA approval

    In 2001 a dose-finding trial of STI571, later called imatinib, a drug aimed at the BCR-ABL enzyme, reported normal blood counts in 53 of 54 people with chronic-phase CML who had stopped responding to interferon and took 300 mg or more daily. Side effects were mild. The US regulator approved imatinib in May 2001 on response rates, not survival.

    Phase 1 dose escalation (83 patients, chronic phase, interferon alfa failure): complete hematologic response in 53 of 54 patients at 300 mg or more daily; major cytogenetic response 31%, with complete cytogenetic remission in 7 of 54. Companion pilot (58 patients, blast crisis or Ph-positive ALL): responses 55% (myeloid) and 70% (lymphoid or ALL), nearly all lymphoid and ALL patients relapsing. FDA accelerated approval 10 May 2001 on response rates.

  33. 2001 · Understanding · Chronic myeloid leukemia

    Imatinib resistance linked to BCR-ABL mutation or amplification

    In 2001 a Science paper studied people whose leukemia had stopped responding to the first BCR-ABL-blocking drug. In six of nine people, the resistant cells carried a single amino-acid change in the drug's target enzyme. In three people the BCR-ABL gene had been copied many more times. In all cases examined, the BCR-ABL signal had switched back on.

    Analysis of clinical material from patients who relapsed on STI-571: resistance was associated with reactivation of BCR-ABL signal transduction in all cases examined; in 6 of 9 patients with a single amino acid substitution of a threonine residue in the Abl kinase domain that forms a critical hydrogen bond with the drug (threonine to isoleucine, shown sufficient to confer resistance in a reconstitution experiment); in 3 patients with progressive BCR-ABL gene amplification.

  34. 2001 · Treatment · Colorectal cancer

    Dutch TME trial: preoperative radiotherapy plus standardised TME

    In the Netherlands, 1861 people with rectal cancer that could be removed had careful, standardised surgery with or without five days of radiotherapy beforehand. Two years on, cancer had come back locally in about two in every hundred with radiotherapy and about eight in every hundred without. Survival was the same, and was still equal at five years.

    Randomised, 1861 patients: 5 x 5 Gy radiotherapy then TME vs TME alone, with standardised surgery. Two-year local recurrence 2.4% vs 8.2% (P<0.001); two-year survival 82.0% vs 81.8% (P=0.84). At median 6.1 years, five-year local recurrence 5.6% vs 10.9%, overall survival 64.2% vs 63.5%. At median 12 years, ten-year local recurrence 5% vs 11% (P<0.0001); overall survival did not differ.

  35. 2001 · Treatment · Gastric and gastro-oesophageal junction cancer

    INT-0116 adjuvant chemoradiotherapy, then ARTIST and CRITICS

    An intergroup trial reported in 2001 that adding radiotherapy with chemotherapy after stomach surgery lengthened survival. Later trials asked whether radiotherapy adds benefit to chemotherapy in other settings, after more extensive lymph node surgery or alongside preoperative chemotherapy; in their main analyses they did not show a significant difference.

    INT-0116 randomised 556 patients with resected stomach or GEJ adenocarcinoma to surgery alone or adjuvant fluorouracil-leucovorin chemoradiotherapy: median OS 27 vs 36 months, HR for death 1.35 (95% CI 1.09-1.66; P=0.005); at over 10 years OS HR 1.32 (1.10-1.60). ARTIST (D2 surgery, 458): DFS not significantly prolonged (P = .0862). CRITICS (788): median OS 43 vs 37 months, HR 1.01 (0.84-1.22).

  36. 2001 · Understanding · Glioblastoma

    Extent of resection is linked to survival in glioblastoma

    Analyses from 2001 onwards found that people whose glioblastoma was removed more completely lived longer. A 2001 analysis of 416 patients reported median survival of 13 months after removal of 98% or more of the tumour and 8.8 months after less. These are associations, not randomised comparisons; a 2016 meta-analysis rates the evidence moderate to low quality.

    Lacroix 2001 (416 patients, retrospective): resection of 98% or more of tumour volume, median survival 13 months (95% CI 11.4-14.6) vs 8.8 months (7.4-10.2) with less (P<0.0001). Sanai 2011 (500 patients): survival advantage from 78% resection. Brown 2016 meta-analysis (37 studies, 41,117 patients): 1-year mortality RR 0.62 (0.56-0.69) for gross total vs subtotal resection; GRADE evidence moderate to low.

  37. 2001 · Treatment · Kidney cancer (renal cell carcinoma)

    Nephrectomy before interferon alfa: two randomised trials (2001)

    Two randomised trials in the interferon era tested removing the kidney before interferon alfa in people whose kidney cancer had already spread. Both reported longer survival with surgery plus interferon: a median of 11.1 against 8.1 months in one, and 17 against 7 in the other. Both enrolled fewer people than the later CARMENA trial, which revisited the question.

    Flanigan et al. (NEJM): metastatic RCC, nephrectomy then interferon alfa-2b vs interferon alone; median survival 11.1 months (120 eligible) vs 8.1 months (121 eligible), P=0.05. Mickisch et al. (EORTC Genitourinary Group, ITT): 85 patients, nephrectomy plus interferon-alfa-based immunotherapy vs interferon alone; median time to progression 5 vs 3 months (HR 0.60; 95% CI 0.36-0.97); median survival 17 vs 7 months (HR 0.54; 95% CI 0.31-0.94).

  38. 2001 · Understanding · Ovarian cancer

    Fallopian tube precursors reframe the origin of serous carcinoma

    From 2001, pathologists examining fallopian tubes removed from women at high inherited risk found abnormal, dysplastic changes in the tubes. A 2007 study of 55 pelvic serous cancers found tubal involvement in many cases labelled ovarian. A 2010 paper proposed that serous tumours arise from fallopian tube epithelium.

    Piek 2001: dysplasia in the tubes of 6 of 12 women with a hereditary predisposition (7 BRCA1-positive), none in 13 controls. Kindelberger 2007: of 55 evaluable pelvic serous carcinomas, 41 (75%) involved the endosalpinx; tubal intraepithelial carcinoma was found in 5 of 5 tubal, 4 of 6 peritoneal and 20 of 30 ovarian cases, and 93% of these lesions involved the fimbriae. Kurman and Shih 2010 proposed a model in which serous tumours arise from implanted fallopian tube epithelium.

  39. 2001 · Treatment · Pancreatic cancer

    ESPAC-1: adjuvant chemotherapy and chemoradiotherapy compared

    In ESPAC-1, people whose pancreatic cancer had been removed were randomly assigned to chemotherapy, chemoradiotherapy, both or observation, or to one of two simpler comparisons. The first report found no gain from radiotherapy and a possible gain from chemotherapy: median survival about twenty months with chemotherapy against fourteen without. The final report described chemoradiotherapy as deleterious.

    ESPAC-1 (Neoptolemos 2001): 541 eligible patients with resected PDAC, factorial or single-comparison randomisation. Median survival 19.7 vs 14.0 months with vs without chemotherapy (HR 0.66, 95% CI 0.52-0.83, p=0.0005) and 15.5 vs 16.1 months with vs without chemoradiotherapy (HR 1.18, 0.90-1.55, p=0.24). Final 2004 report: 5-year survival 21% vs 8% (chemotherapy) and 10% vs 20% (chemoradiotherapy).

  40. 2001 · Treatment · Sarcoma and GIST

    Imatinib in GIST: case report, phase 2 and FDA approval

    A 2001 case report described the drug STI571, later called imatinib, in one person with metastatic GIST. In February 2002 the US regulator approved imatinib for KIT-positive GIST that could not be removed or had spread, based on response rates. A randomised trial published that August reported partial responses in about half of 147 patients.

    Joensuu (NEJM 2001): single-patient report (no abstract). FDA accelerated approval 1 Feb 2002 (21 CFR 314 subpart H) for KIT-positive unresectable/metastatic GIST on objective response rates; no controlled trials of clinical benefit. Demetri (NEJM 2002), randomised, 147 patients, 400 or 600 mg daily: partial response 53.7% (79 patients), stable disease 27.9%, no complete responses, no significant difference between doses. Long-term: median survival 57 months, median follow-up 63 months.

  41. 2001 · Detection · Testicular germ cell tumors

    FDG-PET to predict viable tumour in residual seminoma masses

    After chemotherapy for seminoma, scans often show leftover masses, and many contain no living tumour. A prospective multicentre study found PET scanning predicted living tumour in these masses more reliably than the size of the mass. A small later study found false-positive PET results to be common.

    SEMPET (prospective, multicentre; 2004 update, 51 patients, 56 scans): FDG-PET correctly predicted all 19 residual lesions above 3 cm and 35 (95%) of 37 lesions of 3 cm or less; specificity 100% (95% CI 92-100%), sensitivity 80% (44-95%), PPV 100%, NPV 96%, versus 74%, 70%, 37% and 92% for the CT size criterion. A separate 20-patient study: PPV 0.25 and NPV 1, with 9 false-positive PET scans.

  42. 2002 · Treatment · Breast cancer

    Aromatase inhibitors versus tamoxifen (ATAC, BIG 1-98)

    In 2002 the ATAC trial showed that, for postmenopausal women with hormone-sensitive early breast cancer, five years of the aromatase inhibitor anastrozole gave slightly better disease-free survival than tamoxifen, with a different side-effect profile. Letrozole showed a similar edge in 2005, and a pooled analysis later found fewer breast cancer deaths with aromatase inhibitors.

    ATAC (N=9366), anastrozole vs tamoxifen: 3-year DFS 89.4% vs 87.4%, HR 0.83 (0.71-0.96); the combination was no better than tamoxifen. At 10 years, DFS HR 0.91 (0.83-0.99) in all randomised patients. BIG 1-98 (N=8010), letrozole vs tamoxifen: DFS HR 0.81 (0.70-0.93). EBCTCG 2015 (5 years of AI vs tamoxifen): 10-year breast cancer mortality 12.1% vs 14.2%, RR 0.85 (0.75-0.96).

  43. 2002 · Treatment · Chronic myeloid leukemia

    IRIS: imatinib versus interferon plus cytarabine, first line

    In late 2002 imatinib was approved in the US for newly diagnosed chronic myeloid leukemia. The IRIS trial compared it with interferon alfa plus low-dose cytarabine in 1,106 people. At 18 months, about 76% on imatinib had no Philadelphia-chromosome-positive cells in the marrow, against 15%. At ten years, about 83% of those who started imatinib were estimated to be alive.

    IRIS, open-label randomized phase 3 (n=1106; imatinib 553 vs interferon alfa plus low-dose cytarabine 553; crossover permitted). At 18 months (median follow-up 19 months): MCyR 87.1% vs 34.7%, CCyR 76.2% vs 14.5% (both P<0.001); freedom from progression to accelerated phase or blast crisis 96.7% vs 91.5% (P<0.001). At median follow-up 10.9 years, 10-year OS with imatinib was 83.3%; 65.6% of the control arm crossed over, so no valid OS comparison between arms.

  44. 2002 · Treatment · Hepatocellular carcinoma

    Two randomised trials of chemoembolisation for unresectable HCC

    In 2002 two randomised trials compared repeated chemoembolisation (chemotherapy into the tumour's artery, which is then blocked) with conservative care in selected people whose liver cancer could not be removed. At two years about 6 in 10 versus 3 in 10 were alive in one trial, and about 3 in 10 versus 1 in 10 in the other.

    Barcelona RCT (N=112 of 903 assessed; Child-Pugh A/B, Okuda I-II; embolisation, chemoembolisation or conservative treatment), stopped at the ninth sequential inspection: chemoembolisation vs conservative treatment HR of death 0.47 (95% CI 0.25-0.91; p=0.025); 2-year survival 63% vs 27%. Hong Kong RCT (N=80, Asian patients; chemoembolisation vs symptomatic treatment): 3-year survival 26% vs 3% (P=0.002).

  45. 2002 · Treatment · Non-Hodgkin lymphoma (DLBCL and follicular)

    R-CHOP vs CHOP in older DLBCL: GELA LNH98-5 (2002)

    A French trial of 399 people aged 60 to 80 with previously untreated diffuse large B-cell lymphoma compared CHOP chemotherapy with CHOP plus the antibody rituximab. Complete responses occurred in 76 in 100 people given the combination and 63 in 100 given CHOP alone. Ten years on, 44 in 100 given the combination were alive, compared with 28 in 100.

    Randomised trial (GELA) in 399 untreated DLBCL patients aged 60-80: eight cycles of CHOP (197) or CHOP plus rituximab (202). Complete response 76% vs 63% (P=0.005). At median follow-up of two years, EFS P<0.001 and OS P=0.007; risk ratios for treatment failure 0.58 (95% CI 0.44-0.77) and death 0.64 (0.45-0.89). At 10 years: PFS 36.5% vs 20%; OS 43.5% vs 27.6%.

  46. 2002 · Understanding · Melanoma

    BRAF mutations in melanoma (2002) and the TCGA melanoma atlas (2015)

    In 2002 a genome-wide search found changes in the BRAF gene in about two thirds of the melanomas it examined, most of them one specific substitution that made the protein more active. In 2015 a large tumour-sequencing project sorted 333 melanomas into four genomic groups, one of them defined by mutant BRAF.

    Davies 2002 (Nature): somatic BRAF missense mutations in 66% of malignant melanomas and at lower frequency in other cancers; all in the kinase domain, with V599E (V600E in later literature) accounting for 80%; elevated kinase activity, transforming in NIH3T3 cells. TCGA 2015 (Cell): 333 primary and/or metastatic melanomas from 331 patients; four subtypes (mutant BRAF, mutant RAS, mutant NF1, Triple-WT); no significant outcome correlation with genomic class.

  47. 2002 · Reversal · Neuroblastoma and Wilms tumour

    Infant urine screening did not reduce neuroblastoma mortality (2002)

    In 2002 two large studies evaluated urine screening of babies for neuroblastoma, in Quebec (about 477,000 births) and in Germany (over 2.5 million children offered screening). Neither found fewer deaths, and the German study estimated that screening found tumours that would not have benefited from earlier treatment.

    Quebec: screening at 3 weeks and 6 months offered to 476,654 births, 92% participation; cumulative neuroblastoma mortality 4.78 per 100,000 over nine years, with standardized incidence ratios for death of 0.90 to 1.40 against four unscreened control populations (confidence intervals include 1). Germany: screening at about 1 year offered to 2,581,188 children; stage 4 incidence 3.7 vs 3.8 and deaths 1.3 vs 1.2 per 100,000 (screened vs control); overdiagnosis estimated at 7 per 100,000. Population comparisons, not randomised.

  48. 2002 · Understanding · Ovarian cancer

    Cytoreduction and residual disease: maximal surgery linked to survival

    Studies from 1975 onward linked the amount of tumour left after surgery to survival in advanced ovarian cancer. A 2002 analysis of 81 groups of patients found that groups in which more women had maximal surgery lived longer on average. These are observational findings, so fitter patients or less aggressive tumours may explain part of the link.

    Meta-analysis of 81 cohorts (6,885 patients) with stage III or IV disease treated with platinum-based chemotherapy: each 10% increase in maximal cytoreduction was associated with a 5.5% increase in median survival time (P<.001). Cohorts with 25% or less maximal cytoreduction had a mean weighted median survival of 22.7 months, cohorts with more than 75% had 33.9 months. Platinum dose-intensity was not significantly related to survival. Cohort-level, observational.

  49. 2002 · Understanding · Ovarian cancer

    Risk-reducing salpingo-oophorectomy and opportunistic salpingectomy

    Studies of women with BRCA1 or BRCA2 gene changes found that removing the fallopian tubes and ovaries was associated with fewer ovarian and breast cancers and, in a large cohort, fewer deaths. Later population studies of women who had their tubes removed during other operations found lower rates of ovarian cancer. All of these are observational studies.

    Observational studies. Kauff 2002 (170 BRCA carriers aged 35 or older, mean follow-up 24.2 months): hazard ratio for breast or BRCA-related gynecologic cancer 0.25 (95% CI 0.08 to 0.74) with salpingo-oophorectomy. Domchek 2010 (2482 carriers): ovarian cancer HR 0.14 (0.04 to 0.59) with and 0.28 (0.12 to 0.69) without prior breast cancer; all-cause mortality HR 0.40 (0.26 to 0.61). Falconer 2015: salpingectomy HR 0.65 (0.52 to 0.81) for ovarian cancer.

  50. 2002 · Treatment · Prostate cancer

    Prostatectomy vs watchful waiting or observation (SPCG-4, PIVOT)

    Two randomised trials compared removing the prostate with waiting. In a Scandinavian trial, men assigned to surgery were less likely to die of prostate cancer, and the difference persisted for nearly three decades. In an American trial of men diagnosed in the early PSA era, surgery did not significantly reduce deaths from any cause or from prostate cancer.

    SPCG-4 (n=695): prostate-cancer death 8.9% with watchful waiting vs 4.6% with prostatectomy at median 6.2 years (relative hazard 0.50, 95% CI 0.27-0.91); 15-year cumulative incidence 20.7% vs 14.6%; at 29 years relative risk 0.55 (95% CI 0.41-0.74). PIVOT (n=731, median 10.0 years): all-cause mortality 47.0% with prostatectomy vs 49.9% with observation (HR 0.88, 95% CI 0.71-1.08); prostate-cancer or treatment death 5.8% vs 8.4% (HR 0.63, 95% CI 0.36-1.09).

  51. 2002 · De-escalation · Testicular germ cell tumors

    Surveillance and risk-adapted management of stage I seminoma

    After surgery for stage I seminoma, most men do not relapse. A 2002 pooled analysis of surveillance series found larger tumours and invasion of the rete testis predicted relapse. Later programmes used these risk factors to offer carboplatin or surveillance, and a 2024 analysis proposed three risk groups.

    Warde 2002 pooled analysis (638 patients, four surveillance series, median follow-up 7.0 years): 5-year relapse-free rate 82.3%; tumour above 4 cm HR 2.0 (95% CI 1.3-3.2), rete testis invasion HR 1.7 (1.1-2.6). SWENOTECA (non-randomised, 897 patients): relapse 4.0% on surveillance and 2.2% after carboplatin without risk factors; 15.5% and 9.3% with one or two. EAU analysis (1,016 patients): 5-year relapse 8%, 20% and 44% by risk group.

  52. 2003 · De-escalation · Breast cancer

    Sentinel-node biopsy and less axillary surgery (B-32, Z0011)

    Sentinel-node biopsy removes only the first lymph nodes that drain a breast tumour instead of clearing the whole armpit. In randomised trials, leaving the armpit alone did not significantly worsen survival when the sentinel node was clear, or when one or two nodes held cancer in women having breast-conserving surgery with radiotherapy.

    Veronesi 2003 (516 patients, tumours up to 2 cm): sentinel-node status accuracy 96.9%; no overt axillary metastasis in 167 without dissection. NSABP B-32 (5,611 randomised; 3,986 SLN-negative analysed): 8-year OS 90.3% SLN alone vs 91.8% with ALND (HR 1.20, 95% CI 0.96-1.50). ACOSOG Z0011 (891 women, 1-2 positive SLNs, lumpectomy plus whole-breast radiotherapy): 10-year OS 86.3% SLND alone vs 83.6% ALND (HR 0.85; noninferiority P=.02).

  53. 2003 · Understanding · Chronic myeloid leukemia

    BCR-ABL1 transcript monitoring and the international scale

    In 2003 an IRIS substudy measured BCR-ABL RNA in the blood and found that a fall of at least three log (one-thousand-fold) by 12 months was more common with imatinib and went with very low progression risk. In 2006 an expert meeting proposed reporting such results on one international scale and using serial blood tests to follow treatment.

    IRIS substudy: in patients with complete cytogenetic remission, BCR-ABL transcript levels had fallen by at least 3 log at 12 months in 57% of the imatinib group vs 24% of the interferon plus cytarabine group (P=0.003); estimated 39% vs 2% of all patients (P<0.001). With CCyR and a 3-log reduction at 12 months, progression-free probability at 24 months was 100%, vs 95% (CCyR, under 3 log) and 85% (no CCyR) (P<0.001). 2006 consensus: international scale; serial RQ-PCR.

  54. 2003 · Understanding · Foundations

    Human Genome Project completed: first sequence of the human genome

    The Human Genome Project, an international effort launched in October 1990, was completed in April 2003 and produced the first sequence of the human genome. A draft appeared in 2001, and a finishing report in 2004 described a sequence covering about 99% of the euchromatic genome. It is a foundation for later programmes that read the genomes of tumours.

    Not a cancer study. Draft sequence reported in Nature, February 2001. Finishing report (Nature, October 2004): Build 35, 2.85 billion nucleotides with 341 gaps, covering about 99% of the euchromatic genome with an error rate of about 1 event per 100,000 bases; 20,000 to 25,000 protein-coding genes. The NHGRI dates the project from October 1990 to April 2003.

  55. 2003 · Treatment · Head and neck cancer

    RTOG 91-11: concurrent cisplatin for larynx preservation

    In a three-way trial for locally advanced voice-box cancer, radiation with cisplatin given at the same time kept the larynx in place more often at two years than chemotherapy first or radiation alone. Survival was similar across the groups, and serious side effects were more frequent with the chemotherapy-based treatments.

    Intergroup RTOG 91-11, 547 randomised patients with locally advanced laryngeal cancer: induction cisplatin-fluorouracil then radiotherapy, radiotherapy with concurrent cisplatin, or radiotherapy alone. At 2 years, intact larynx 88% (concurrent) vs 75% (induction; P=0.005) and 70% (radiotherapy alone; P<0.001). Long-term report (520 analysed, median follow-up 10.8 years): laryngectomy-free survival HR 0.75 (induction) and 0.78 (concurrent) vs radiotherapy alone; overall survival concurrent vs induction HR 1.25 (95% CI 0.98-1.61).

  56. 2003 · Detection · Hepatocellular carcinoma

    Two Chinese randomised surveillance trials, two answers

    Two randomised trials in China tested six-monthly liver cancer screening in people at high risk. In Shanghai, a blood test plus ultrasound was followed by fewer liver cancer deaths. In Qidong, a blood test alone found cancers earlier but did not significantly change deaths.

    Shanghai (18,816 people aged 35-59 with hepatitis B or chronic hepatitis; AFP plus ultrasound every 6 months; 58.2% of offered screens completed): HCC mortality rate ratio 0.63 (95% CI 0.41-0.98). Qidong (5,581 HBsAg-positive men; AFP alone): stage I 29.6% versus 6.0%; Poisson-model rate ratio of death 0.83 (95% CI 0.68-1.03), not significant. Different tests, populations and follow-up.

  57. 2003 · Treatment · Hodgkin lymphoma

    BEACOPP (GHSG HD9) versus COPP-ABVD in advanced disease

    A German trial of 1,201 people aged 15 to 65 with advanced Hodgkin disease compared three chemotherapy plans. After five years, 87 in 100 people on increased-dose BEACOPP were free of treatment failure, compared with 69 in 100 on COPP-ABVD, and 91 versus 83 in 100 were alive. Ten-year follow-up showed the same pattern.

    GHSG HD9: 1195 evaluable patients aged 15 to 65 with unfavorable stage IIB/IIIA or stage IIIB/IV disease, randomised to eight cycles of COPP-ABVD, BEACOPP or increased-dose BEACOPP. Five-year FFTF 69%, 76%, 87%; OS 83%, 88%, 91% (increased-dose BEACOPP versus COPP-ABVD: FFTF P<0.001, OS P=0.002). Ten-year update (median follow-up 111 months): FFTF 64%, 70%, 82%; OS 75%, 80%, 86%.

  58. 2003 · Understanding · Hodgkin lymphoma

    Cardiovascular late effects after Hodgkin treatment

    A Dutch study of people treated for Hodgkin lymphoma before age 41 found deaths from heart disease and from second solid tumours about six times as common as in the general population. Later Dutch studies showed that chest radiotherapy and anthracycline chemotherapy each raised heart-disease risk, with radiation risk rising with the dose to the heart.

    Aleman 2003 (1261 patients treated before age 41, 1965 to 1987; median follow-up 17.8 years): relative risk of death from cardiovascular disease 6.3, from solid tumours 6.6. van Nimwegen 2015 (2524 patients, treated 1965 to 1995): 40-year cumulative incidence of cardiovascular disease 50% (95% CI 47% to 52%); mediastinal radiotherapy raised coronary heart disease risk (HR 2.7, 95% CI 2.0 to 3.7). van Nimwegen 2016 (nested case-control): excess relative risk 7.4% per Gy mean heart dose.

  59. 2003 · De-escalation · Non-Hodgkin lymphoma (DLBCL and follicular)

    Watch and wait vs immediate chlorambucil, low-grade lymphoma

    A UK trial that recruited from 1981 to 1990 randomised people with advanced, symptom-free low-grade lymphoma to start chlorambucil at once or to wait until it was needed. After a median of 16 years, survival did not differ. A later trial in follicular lymphoma found that rituximab delayed the need for new treatment.

    Randomised trial (n=309, 44 UK centres), asymptomatic advanced-stage low-grade NHL: immediate chlorambucil versus observation. Median follow-up 16 years; median OS 5.9 versus 6.7 years (p=0.84). In the observation group the actuarial chance of not needing chemotherapy at 10 years was 19%. A separate phase 3 trial in low-tumour-burden follicular lymphoma: 3-year freedom from new treatment 46% with watchful waiting versus 88% with maintenance rituximab (HR 0.21, 95% CI 0.14 to 0.31).

  60. 2003 · Treatment · Multiple myeloma

    Bortezomib in relapsed myeloma: SUMMIT phase 2 to APEX

    Bortezomib, an injected proteasome inhibitor, was tested in a phase 2 study of people whose myeloma had returned and was not responding to their last treatment. About one in three responded. A later randomised trial found longer time to progression and better survival than high-dose dexamethasone. The FDA gave accelerated approval in 2003; a 2005 supplement fulfilled the commitments.

    SUMMIT (phase 2, n=202, refractory to last therapy): response 35% in 193 evaluable patients; median OS 16 months; median duration of response 12 months. APEX (phase 3, relapse after 1 to 3 prior therapies): bortezomib versus high-dose dexamethasone, median TTP (primary endpoint) 6.22 versus 3.49 months (HR 0.55; P<0.001); CR+PR 38% versus 18%; OS HR 0.57 (P=0.001), crossover permitted. FDA accelerated approval 13 May 2003; supplement S-006 25 March 2005 fulfilled the 21 CFR 314.510 commitments.

  61. 2003 · Treatment · Ovarian cancer

    Carboplatin versus cisplatin with paclitaxel: GOG-158, AGO-OVAR-3

    Two randomised trials compared carboplatin with cisplatin, each given with paclitaxel, as first-line treatment for advanced ovarian cancer. Neither reported a statistically significant survival difference between the regimens. The authors described the carboplatin combination as less toxic and easier to give (GOG-158) or as an important alternative (AGO-OVAR-3).

    GOG-158 (792 eligible, no residual mass >1.0 cm, non-inferiority): median PFS 19.4 vs 20.7 months and OS 48.7 vs 57.4 months for cisplatin-paclitaxel vs carboplatin-paclitaxel; RR of progression 0.88 (95% CI 0.75-1.03), of death 0.84 (0.70-1.02). AGO-OVAR-3 (798, stage IIB-IV): progression-free at 2 years 40.0% vs 37.5%; median PFS 19.1 vs 17.2 months; median OS 44.1 vs 43.3 months.

  62. 2003 · Treatment · Sarcoma and GIST

    INT-0091: adding ifosfamide and etoposide in Ewing sarcoma

    A randomised trial in children and young adults with Ewing sarcoma added ifosfamide and etoposide to a four-drug regimen. When the cancer had not spread, about seven in ten were free of events at five years, against about half on the standard regimen. When it had spread, the added drugs made no significant difference.

    Randomised trial (518 eligible patients aged 30 or younger): standard doxorubicin, vincristine, cyclophosphamide, dactinomycin vs the same drugs alternating with ifosfamide and etoposide. Nonmetastatic stratum (n=398): 5-year EFS 69% vs 54% (P=0.005); OS 72% vs 61% (P=0.01). Metastatic stratum (n=120): no significant difference in 5-year EFS (P=0.81).

  63. 2003 · Understanding · Sarcoma and GIST

    PDGFRA mutations and KIT genotype shape imatinib response

    In 2003 researchers reported that about 35 percent of GISTs without KIT mutations carried activating mutations in a related gene, PDGFRA. A second 2003 study linked the mutation type to imatinib response: partial responses were most common with KIT exon 11 mutations and did not occur in tumours with no detected KIT or PDGFRA mutation.

    Heinrich (Science 2003): PDGFRA activating mutations in 14 of 40 (about 35%) GISTs lacking KIT mutations; KIT and PDGFRA mutations appeared mutually exclusive. Heinrich (J Clin Oncol 2003): 127 patients from a phase II imatinib study; KIT mutations 88.2%, PDGFRA 4.7%; partial response 83.5% (KIT exon 11), 47.8% (exon 9; P=.0006), 0.0% (no detected mutation; P<.0001).

  64. 2003 · Understanding · Testicular germ cell tumors

    Surgery for small residual retroperitoneal masses after chemotherapy

    After chemotherapy for non-seminoma, a small mass can remain behind the abdomen. In 87 men whose masses were 20 millimetres or smaller, about one in three still contained living tumour or teratoma, and no scan or clinical measure predicted which. The authors concluded surgery remained necessary.

    Oldenburg 2003 (87 patients with metastatic NSGCT, residual retroperitoneal mass 20 mm or less on CT after cisplatin- or carboplatin-based chemotherapy, RPLND): complete fibrosis or necrosis 58 (67%), teratoma 23 (26%), vital malignant germ-cell tumour 6 (7%, one rhabdomyosarcoma). In five of the six, the lesion was 10 mm or less. No pre- or postchemotherapy clinical or radiologic parameter predicted histology.

  65. 2003 · Understanding · Testicular germ cell tumors

    Cardiovascular disease as a late effect of testicular cancer treatment

    From 2003, cohorts followed for many years after testicular cancer reported more heart and blood-vessel disease, or related deaths, after radiotherapy or cisplatin-based chemotherapy, compared with surgery alone or the general population. Estimates differed between studies and not every one reached significance. A 2026 analysis tested a risk-prediction tool in men treated with contemporary chemotherapy.

    Huddart 2003 (UK, 992 patients, median follow-up 10.2 years): age-adjusted relative risk of cardiac events 2.59 after chemotherapy, 2.40 after radiotherapy, 2.78 after both (reference group not stated in the abstract). Van den Belt-Dusebout 2006 (2,512 five-year survivors): BEP, myocardial infarction HR 1.2 (95% CI 0.7 to 2.1), not significant. Haugnes 2010 (990 men): atherosclerotic disease HR 2.6 (1.1 to 5.9), chemotherapy versus surgery only. Observational; no pooling.

  66. 2003 · De-escalation · Thyroid cancer

    Active surveillance for low-risk papillary microcarcinoma

    Small papillary thyroid cancers of 10 millimetres or less are often found by ultrasound. In 2003 a Japanese hospital reported offering observation instead of immediate surgery. Most tumours did not grow. Later reports from Japan and the United States found that no distant spread developed in the observed groups.

    Ito 2003 (Kuma Hospital; 732 patients with papillary microcarcinoma of 10 mm or less; 162 chose observation): more than 70% of tumours unchanged or smaller; 10.2% enlarged by more than 10 mm. Ito 2014 (1235 patients): none developed distant metastasis or died of PTC. Tuttle 2017 (US, n=291, median 25 months): tumour diameter growth of 3 mm or more in 3.8%; cumulative incidence 12.1% at 5 years.

  67. 2003 · Understanding · Thyroid cancer

    BRAF V600E in papillary cancer and the TCGA atlas

    In 2003 researchers found that a change in the BRAF gene was the most common genetic alteration in papillary thyroid cancer, present in just over a third of the tumours tested and absent from other follicular thyroid tumours tested. In 2014 a large sequencing project described the genetic landscape of 496 papillary cancers.

    Kimura 2003 (Cancer Res): somatic BRAF V599E (V600E in later literature) in 28 of 78 papillary cancers (35.8%) and 0 of 46 other differentiated follicular neoplasms; RET/PTC, BRAF and RAS mutations did not overlap and together were present in 66%. TCGA 2014 (Cell): 496 papillary cancers; low somatic alteration frequency; EIF1AX, PPM1D, CHEK2 and fusions added as drivers, cutting cases with unknown driver from 25% to 3.5%; molecular reclassification proposed.

  68. 2004 · Treatment · Cervical cancer

    Cisplatin-paclitaxel and other platinum doublets for advanced disease

    Four randomised trials compared chemotherapy combinations for cervical cancer that had spread or returned. Adding paclitaxel to cisplatin raised the response rate but not median survival; adding topotecan improved survival in one trial; three other pairs were not better than cisplatin-paclitaxel; and carboplatin was non-inferior to cisplatin in a Japanese trial.

    GOG-169 (cisplatin vs cisplatin-paclitaxel): response 19% vs 36%, PFS 2.8 vs 4.8 months, median survival 8.8 vs 9.7 months. GOG-179 (cisplatin vs cisplatin-topotecan): median OS 6.5 vs 9.4 months (P=0.017). GOG-204 (N=513): no doublet beat paclitaxel-cisplatin; OS HR versus paclitaxel-cisplatin 1.15 (vinorelbine), 1.32 (gemcitabine), 1.26 (topotecan). JCOG0505: median OS 18.3 (paclitaxel-cisplatin) vs 17.5 months (paclitaxel-carboplatin); HR 0.994, non-inferiority P=0.032.

  69. 2004 · Treatment · Colorectal cancer

    MOSAIC: oxaliplatin added to adjuvant fluorouracil for colon cancer

    In MOSAIC, people who had surgery for stage II or III colon cancer were randomly given six months of fluorouracil with leucovorin, with or without oxaliplatin. At three years about seventy-eight in a hundred were alive without recurrence with oxaliplatin, against about seventy-three without. At ten years, survival was higher with oxaliplatin in stage III but not stage II.

    MOSAIC (André 2004): 2246 patients with resected stage II or III colon cancer randomised to LV5FU2 or FOLFOX4 for 6 months. Median follow-up 37.9 months: 3-year DFS 78.2% (95% CI 75.6-80.7) vs 72.9% (70.2-75.7); HR for recurrence 0.77, P=0.002. At 10 years, stage III OS 67.1% vs 59.0% (HR 0.80, P=0.016); stage II OS HR 1.00 (P=0.980).

  70. 2004 · Treatment · Colorectal cancer

    Bevacizumab added to first-line irinotecan-based chemotherapy

    In 813 people with untreated bowel cancer that had spread, adding bevacizumab, a drug that targets the growth of blood vessels, to a chemotherapy regimen containing irinotecan lengthened median survival from 15.6 to 20.3 months. The FDA approved it for first-line use in February 2004.

    813 patients with previously untreated metastatic CRC randomised to IFL plus bevacizumab 5 mg/kg every 2 weeks (n=402) or IFL plus placebo (n=411). Primary endpoint OS: median 20.3 vs 15.6 months, HR 0.66, P<0.001. PFS 10.6 vs 6.2 months (HR 0.54, P<0.001); response rate 44.8% vs 34.8% (P=0.004). Grade 3 hypertension 11.0% vs 2.3%. FDA approval 26 February 2004.

  71. 2004 · Treatment · Colorectal cancer

    Cetuximab and panitumumab: anti-EGFR antibodies in refractory CRC

    Cetuximab and panitumumab are antibodies that block EGFR, a growth-signal receptor on tumour cells. In bowel cancer that had stopped responding to chemotherapy, cetuximab was active alone and with irinotecan, and both drugs delayed progression compared with supportive care alone. The FDA approved them in 2004 and 2006 under its accelerated pathway.

    BOND (n=329, irinotecan-refractory): response 22.9% with cetuximab plus irinotecan vs 10.8% with cetuximab alone; median TTP 4.1 vs 1.5 months; median survival 8.6 vs 6.9 months (P=0.48). CO.17 (n=572): cetuximab plus BSC vs BSC, OS HR 0.77 (95% CI 0.64 to 0.92), median 6.1 vs 4.6 months. Panitumumab plus BSC vs BSC (n=463): PFS HR 0.54 (0.44 to 0.66); OS HR 1.00 (0.82 to 1.22). FDA accelerated approvals 12 February 2004 and 27 September 2006.

  72. 2004 · Treatment · Colorectal cancer

    CAO/ARO/AIO-94: preoperative vs postoperative chemoradiotherapy

    German researchers assigned 823 people with advanced rectal cancer to chemoradiotherapy before or after surgery. Five-year survival was about the same, three in four. Cancer returned locally in six in every hundred treated before surgery and thirteen in every hundred treated after, and severe side effects were less common with treatment before surgery.

    Randomised, 823 patients with cT3/T4 or node-positive rectal cancer: preoperative vs postoperative fluorouracil-based chemoradiotherapy; primary endpoint overall survival. Five years: overall survival 76% vs 74% (P=0.80); cumulative incidence of local relapse 6% vs 13% (P=0.006); grade 3-4 acute toxicity 27% vs 40%. At median 134 months: 10-year overall survival 59.6% vs 59.9% (P=0.85); local relapse 7.1% vs 10.1% (P=0.048).

  73. 2004 · De-escalation · Colorectal cancer

    Watch-and-wait after chemoradiotherapy for complete clinical response

    In 2004 a research group in São Paulo reported 265 people with distal rectal cancer treated with chemoradiotherapy. About one in four had no detectable tumour afterwards and were observed rather than operated on. Estimated five-year survival in the observed group was 100%, and 92% were free of disease. The groups were not randomised.

    Non-randomised comparison: 265 patients with distal rectal adenocarcinoma received chemoradiation (5-fluorouracil, leucovorin, 5040 cGy). Complete clinical response in 71 (26.8%), observed without surgery; 22 (8.3%) with incomplete response had pT0N0 specimens. Five-year overall and disease-free survival: 100% and 92% (observation) vs 88% and 83% (resection). Mean follow-up 57.3 vs 48 months; 2 endorectal recurrences in the observation group.

  74. 2004 · Treatment · Endometrial cancer

    Chemotherapy for advanced disease: GOG-107, -177 and -209

    Three Gynecologic Oncology Group trials tested chemotherapy for advanced or recurrent endometrial cancer. Adding cisplatin to doxorubicin shrank more tumours but did not lengthen survival. Adding paclitaxel to doxorubicin and cisplatin lengthened survival but caused more nerve damage. Carboplatin with paclitaxel was later found not to be worse than that three-drug regimen.

    Randomised phase 3 trials. GOG-107 (299 registered): doxorubicin-cisplatin vs doxorubicin, ORR 42% vs 25%, median OS 9.0 vs 9.2 months. GOG-177 (273 registered): paclitaxel, doxorubicin, cisplatin (TAP) vs doxorubicin-cisplatin, median OS 15.3 vs 12.3 months (P=0.037). GOG-209 (1381 enrolled): carboplatin-paclitaxel vs TAP, noninferior for OS (median 37 vs 41 months; HR 1.002; 90% CI 0.9-1.12).

  75. 2004 · Understanding · Gastric and gastro-oesophageal junction cancer

    H. pylori eradication to prevent gastric cancer: trials 2004-2024

    Treating Helicobacter pylori infection has been tested as a way to prevent stomach cancer. A large placebo-controlled trial in China found no overall reduction. Later trials in people who had early cancers removed, in relatives of patients and in whole communities reported fewer stomach cancers with treatment, though the community effect was modest.

    Wong 2004 (1630 carriers, placebo-controlled, 7.5 years): 7 vs 11 cancers (P=.33); none vs 6 (P=.02) in the subgroup without precancerous lesions. After endoscopic resection, metachronous cancer: Choi 2018 HR 0.50 (95% CI 0.26-0.94), Fukase 2008 mITT HR 0.339 (0.157-0.729). Relatives of patients: Choi 2020 HR 0.45 (0.21-0.94). Linqu community trial: HR 0.86 (0.74-0.99).

  76. 2004 · Treatment · Head and neck cancer

    Adding cisplatin to postoperative radiotherapy for high-risk disease

    Two large trials gave people with high-risk head and neck cancer radiation after surgery, with or without cisplatin. Cisplatin improved control of the cancer in the head and neck area in both trials and survival in one, with more severe side effects. Long-term follow-up of one trial found no overall difference.

    RTOG 9501 (N=459): local or regional recurrence HR 0.61 (95% CI 0.41-0.91); DFS HR 0.78; OS HR 0.84 (0.65-1.09; P=0.19). EORTC 22931 (N=334): 5-year PFS 47% vs 36% (HR 0.75); OS 53% vs 40% (HR 0.70; 0.52-0.95). Cisplatin vs radiotherapy alone throughout. Grade 3 or higher adverse effects 77% vs 34% (RTOG 9501), 41% vs 21% (EORTC 22931). RTOG 9501 at 10 years: no significant overall differences; benefit in an unplanned subset.

  77. 2004 · Treatment · Hepatocellular carcinoma

    Lamivudine in advanced hepatitis B: fewer HCC, a borderline finding

    In a placebo-controlled trial of 651 people with advanced hepatitis B, the antiviral lamivudine slowed disease progression. Liver cancer was less frequent with lamivudine, about 4 in 100 versus 7 in 100, but that difference was borderline and the virus often developed resistance.

    Randomised placebo-controlled trial (n=651; 98% Asian, 85% male) of lamivudine 100 mg daily versus placebo (2:1) in hepatitis B with cirrhosis or advanced fibrosis; stopped early at a median treatment duration of 32.4 months. Disease progression (composite including HCC): 7.8% versus 17.7% (HR 0.45, P=0.001). HCC: 3.9% versus 7.4% (HR 0.49, P=0.047). YMDD resistance mutations arose in 49% of lamivudine-treated patients.

  78. 2004 · Treatment · Lung cancer

    Adjuvant cisplatin after resection: IALT, JBR.10 and LACE

    Between 2004 and 2008, three randomised trials and a pooled analysis of five trials tested cisplatin-based chemotherapy after complete surgery for non-small cell lung cancer. In the first trial, IALT, about 44 in 100 patients on chemotherapy and 40 in 100 on observation were alive at five years. Each trial reported its own population and results.

    IALT (n=1867, resected stage I-III): 5-year OS 44.5% vs 40.4% (HR 0.86, 95% CI 0.76-0.98). JBR.10 (n=482, stage IB-II, vinorelbine-cisplatin): median OS 94 vs 73 months (HR 0.69, P=0.04). ANITA (n=840, stage IB-IIIA): median OS 65.7 vs 43.7 months (adjusted HR 0.80, 95% CI 0.66-0.96). LACE pooled five trials (n=4584): OS HR 0.89 (95% CI 0.82-0.96); stage IA HR 1.40 (95% CI 0.95-2.06).

  79. 2004 · Understanding · Lung cancer

    EGFR mutations explain response to gefitinib (2004)

    In 2004 three research groups reported that lung tumours that shrank on gefitinib, a pill that blocks the EGFR growth-signal receptor, usually carried changes in the EGFR gene, while tumours that did not respond mostly did not. This helped explain why only some people benefited and made testing tumours for EGFR changes a logical next step.

    Lynch (NEJM): kinase-domain EGFR mutations in 8 of 9 gefitinib-responsive tumours and 0 of 7 non-responders (P<0.001); 2 of 25 untreated tumours (8%). Paez (Science): mutations in 15 of 58 tumours from Japan and 1 of 61 from the United States. Pao (PNAS): 7 of 10 gefitinib-sensitive and 0 of 8 refractory tumours (P=0.004); 7 of 15 never-smoker adenocarcinomas versus 4 of 81 tumours from smokers (P=0.0001).

  80. 2004 · Treatment · Prostate cancer

    Docetaxel for castration-resistant disease (TAX 327, SWOG 9916)

    In 2004 two trials compared docetaxel-based chemotherapy with mitoxantrone plus prednisone in men whose metastatic prostate cancer no longer responded to hormone therapy. In TAX 327, docetaxel every three weeks gave a median survival of 18.9 months against 16.5 months. The US FDA approved docetaxel with prednisone in May 2004.

    TAX 327 (n=1006; prednisone with mitoxantrone, 3-weekly or weekly docetaxel): median OS 16.5, 18.9 and 17.4 months; 3-weekly docetaxel versus mitoxantrone HR 0.76 (95% CI 0.62-0.94; P=0.009), weekly HR 0.91 (0.75-1.11). SWOG 9916 (docetaxel plus estramustine versus mitoxantrone plus prednisone): median OS 17.5 versus 15.6 months, HR 0.80 (0.67-0.97), P=0.02. TAX 327 update (867 deaths): 19.2 versus 16.3 months.

  81. 2004 · Treatment · Sarcoma and GIST

    Imatinib 400 mg vs 800 mg daily in advanced GIST

    Two randomised trials compared imatinib 400 mg once daily with 400 mg twice daily in advanced GIST. The EORTC trial reported longer progression-free survival on the higher dose; the North American S0033 trial found no significant differences. A pooled analysis of 1,640 patients found a small progression-free survival advantage, mainly with KIT exon 9 mutations, and no survival difference.

    EORTC 62005 (946 randomised, 400 mg once vs twice daily): progression 56% vs 50%, HR 0.82 (0.69-0.98), p=0.026. S0033 (746 enrolled): median PFS 18 vs 20 months, median OS 55 vs 51 months, no significant differences. MetaGIST (1,640 patients, median follow-up 45 months): small PFS advantage for the high dose, identical OS, PFS benefit essentially in KIT exon 9 mutants (772 genotyped).

  82. 2005 · Treatment · Breast cancer

    Adding trastuzumab to adjuvant chemotherapy (HERA, B-31/N9831)

    In 2005 two reports showed that adding trastuzumab to treatment after surgery for HER2-positive early breast cancer led to fewer recurrences, second cancers or deaths in early follow-up. One trial gave trastuzumab after chemotherapy; the other report, a joint analysis of two trials, gave it alongside part of the chemotherapy. Heart problems were a recognised risk.

    HERA (1 year of trastuzumab vs observation after chemotherapy; first interim analysis, median follow-up 1 year): disease-free survival HR 0.54 (95% CI 0.43 to 0.67; P<0.0001). Joint NSABP B-31/NCCTG N9831 analysis (chemotherapy with or without concurrent trastuzumab; first interim analysis): HR 0.48 (P<0.0001), 133 vs 261 events. Designs differ; the results are reported separately and are not comparable across trials.

  83. 2005 · Treatment · Childhood acute lymphoblastic leukemia (ALL)

    Nelarabine for T-cell ALL

    Nelarabine, a drug activated inside T cells, was tested in children and young adults whose T-cell cancer had returned or not responded. In first relapse with marrow involvement more than half responded, and FDA granted accelerated approval in 2005. A later randomised COG trial reported better disease-free survival when it was added to first-line treatment.

    COG phase II (121 enrolled, 106 assessable): CR+PR rates at final doses 55% (stratum 1, first marrow relapse), 27%, 33% and 14%; grade 3 or higher neurologic events in 18% of patients. COG AALL0434 (phase III, 1,562 evaluable T-ALL; randomised intermediate- and high-risk patients): 5-year DFS 88.2% with nelarabine (n=323) vs 82.1% without (n=336), P=0.029; 5-year CNS relapse incidence 1.3% vs 6.9%; 5-year OS 90.3% vs 87.9% (P=0.168).

  84. 2005 · Treatment · Endometrial cancer

    GOG-122: doxorubicin-cisplatin versus whole-abdominal irradiation

    In women with stage III or IV endometrial cancer and little cancer left after surgery, two-drug chemotherapy was compared with radiotherapy to the whole abdomen. Women given chemotherapy were predicted to be alive without progression more often at five years (about half versus about four in ten) and to live longer, with more short-term side effects.

    Randomised phase 3 (422 entered; 396 assessable), stage III or IV disease with at most 2 cm residual: whole-abdominal irradiation (WAI) vs doxorubicin-cisplatin (AP). Stage-adjusted progression HR 0.71 (95% CI 0.55-0.91; p<.01) and death HR 0.68 (0.52-0.89; p<.01), favouring AP. Predicted at 60 months, AP vs WAI: 50% vs 38% alive and disease free; 55% vs 42% alive. Treatment probably contributed to eight deaths (4%) with AP and five (2%) with WAI.

  85. 2005 · Treatment · Glioblastoma

    Temozolomide added to radiotherapy for newly diagnosed glioblastoma

    In 2005 a trial of 573 adults with newly diagnosed glioblastoma compared radiotherapy alone with radiotherapy plus temozolomide, a chemotherapy capsule. Median survival was about 15 months with temozolomide and 12 months without. About one in four people given temozolomide were alive at two years, against about one in ten with radiotherapy alone.

    EORTC-NCIC trial (573 randomised): radiotherapy 60 Gy with or without daily temozolomide then six adjuvant cycles. Median OS 14.6 vs 12.1 months, unadjusted HR for death 0.63 (95% CI 0.52-0.75; P<0.001); 2-year survival 26.5% vs 10.4%. Five-year analysis: OS 9.8% vs 1.9% at 5 years. Grade 3 or 4 haematological toxicity 7% with concomitant treatment.

  86. 2005 · Treatment · Kidney cancer (renal cell carcinoma)

    Sorafenib in previously treated RCC: TARGET and FDA approval

    Sorafenib, a pill that blocks signals tumours use to grow, was tested against placebo in 903 people whose kidney cancer had stopped responding to standard treatment. The cancer stayed controlled for a median of 5.5 months with sorafenib and 2.8 months with placebo. Diarrhoea, rash and hand-foot skin reactions were common. The FDA approved it in December 2005.

    TARGET (double-blind phase 3, N=903, RCC resistant to standard therapy): sorafenib 400 mg twice daily vs placebo. At the January 2005 cutoff median PFS was 5.5 vs 2.8 months, HR 0.44 (95% CI 0.35-0.55; P<0.01). First interim OS (May 2005): HR 0.72 (95% CI 0.54-0.94; P=0.02), not significant by the O'Brien-Fleming threshold; crossover from placebo was permitted from May 2005.

  87. 2005 · Reversal · Lung cancer

    Gefitinib: accelerated approval, restriction and EGFR-mutation return

    Gefitinib was approved in the US in 2003 because tumours responded in heavily pretreated patients. A large placebo-controlled trial, ISEL, did not show a significant survival gain overall, and in 2005 the US label was restricted. The approval was withdrawn in 2012 at AstraZeneca's request. In 2015 gefitinib returned for first-line treatment of EGFR-mutated lung cancer.

    FDA accelerated approval 5 May 2003 (ORR 10.6% in 142 patients after platinum and docetaxel). ISEL (n=1692, gefitinib or placebo plus best supportive care): median OS 5.6 vs 5.1 months, HR 0.89 (95% CI 0.77-1.02), p=0.087; never-smokers HR 0.67 (0.49-0.92); Asian patients HR 0.66 (0.48-0.91). Labelling restricted 17 June 2005; withdrawal published 25 April 2012; new NDA approved 13 July 2015 for EGFR exon 19 deletions or L858R.

  88. 2005 · Understanding · Multiple myeloma

    ISS, R-ISS and R2-ISS: myeloma risk staging (2005-2022)

    Myeloma staging moved from tumour-mass estimates to simple blood tests in 2005, when the International Staging System grouped patients into three stages by two blood values. In 2015 and 2022 further versions added chromosome changes and other markers, giving four risk groups in the latest. Survival differed clearly between the groups in each report.

    ISS (2005; 10,750 previously untreated symptomatic patients): stage I (serum β2-microglobulin <3.5 mg/L, albumin ≥3.5 g/dL) median survival 62 months; stage III (β2-microglobulin ≥5.5 mg/L) 29 months. R-ISS (2015; 3,060 patients with complete data) added high-risk cytogenetics or high LDH: 5-year OS 82%, 62%, 40% for stages I to III. R2-ISS (2022; additive score including 1q gain) defines four groups: median OS not reached, 109.2, 68.5, 37.9 months.

  89. 2005 · Understanding · Neuroblastoma and Wilms tumour

    Tumour markers: 1p/16q loss and 1q gain predict relapse

    In 2005 the National Wilms Tumor Study Group reported that favourable-histology Wilms tumours with loss of parts of chromosomes 1p and 16q relapsed more often. A 2016 analysis added gain of chromosome 1q as a marker linked to worse survival. Later Children's Oncology Group studies used these markers to decide how intensively some children were treated.

    NWTS-5 favourable histology. Relative risk of relapse with LOH 1p 1.56 (P = .01) and 16q 1.49 (P = .01). Stage I-II, LOH at both sites: relapse RR 2.9 (P = .001), death RR 4.3 (P = .01); stage III-IV: RR 2.4 and 2.7. In 1,114 informative tumours, 1q gain was present in 28%; 8-year EFS 77% versus 90% without it (P < .001); multivariable relative risk of relapse 2.4. Reported as relative risks, not hazard ratios.

  90. 2005 · Treatment · Sarcoma and GIST

    INT-0133: mifamurtide added to chemotherapy; EU authorisation

    A Children's Oncology Group trial added ifosfamide, a liposomal immune-stimulating drug (muramyl tripeptide, now called mifamurtide), or both to standard chemotherapy for osteosarcoma. The first report could not be read as a simple comparison because the two additions interacted. A later analysis reported better survival with the immune-stimulating drug, and the European Commission authorised it in 2009.

    INT-0133, 2 x 2 factorial (677 patients in 2005; 662 in 2008): ifosfamide and/or MTP added to cisplatin, doxorubicin, high-dose methotrexate. 2005: 3-year EFS 71% standard, 68% +MTP, 61% +ifosfamide, 78% both; interaction precluded factorial analysis. 2008 (no interaction): MTP improved 6-year OS from 70% to 78% (P=.03; HR 0.71, 95% CI 0.52-0.96); ifosfamide did not improve EFS or OS.

  91. 2005 · De-escalation · Testicular germ cell tumors

    TE19: single-dose carboplatin vs radiotherapy, stage I seminoma

    After surgery for stage I seminoma, radiotherapy to the abdominal lymph nodes was a usual next step. A large randomised trial compared it with one carboplatin infusion. Relapse-free rates were similar, and fewer new tumours in the other testis were reported with carboplatin. The authors concluded that either approach could be used.

    MRC TE19/EORTC 30982: 1,477 patients randomised to radiotherapy (n=904) or one carboplatin dose (n=573). Relapse-free rate 96.7% vs 97.7% at 2 years and 95.9% vs 94.8% at 3 years (HR 1.28, 90% CI 0.85-1.93, p=0.32; non-inferiority concluded). At median 6.5 years, 5-year rate 96.0% vs 94.7% (HR 1.25, 90% CI 0.83-1.89); contralateral germ-cell tumours 15 vs 2 (HR 0.22 for carboplatin, 95% CI 0.05-0.95, p=0.03).

  92. 2005 · Understanding · Testicular germ cell tumors

    Second cancers among 40,576 testicular cancer patients

    In 2005 a study combining 14 population cancer registries followed more than 40,000 men with testicular cancer and found a raised risk of second solid cancers that lasted at least 35 years. Later cohorts examined specific treatments, and a 2026 review linked chemotherapy to a higher relative risk of leukaemia, though absolute risk stayed small.

    Travis 2005: 40,576 one-year survivors in 14 registries (1943 to 2001), 2,285 second solid cancers. In 10-year survivors diagnosed at age 35, relative risk 1.9 (95% CI 1.8 to 2.1), still raised at 35 years (1.7, 1.5 to 2.0). By treatment, chemotherapy alone: RR 1.8 (1.3 to 2.5). Fung 2013 (SEER non-seminoma): SIR 1.43 (1.18 to 1.73) after chemotherapy, 0.93 after surgery. Registry cohorts, not randomised.

  93. 2005 · Understanding · Thyroid cancer

    Chernobyl: radioiodine exposure and childhood thyroid cancer

    After the April 1986 Chernobyl accident a large rise in thyroid cancer among children in contaminated areas was reported; a 1992 letter in Nature was titled Thyroid cancer after Chernobyl. A 2005 study in Belarus and Russia found that the risk rose with the radiation dose the thyroid received from radioactive iodine in childhood.

    Cardis 2005 (JNCI): population-based case-control study, Belarus and Russian Federation; 276 thyroid cancer cases through 1998, 1300 matched controls, all younger than 15 years at the accident; individual dose estimates. Dose-response P<.001; odds ratio at 1 Gy 5.5 (95% CI 3.1-9.5) to 8.4 (4.1-17.3) by model; linear to 1.5-2 Gy. Relative risk 3.2 (1.9-5.5) in iodine-deficient areas; 0.34 (0.1-0.9) with potassium iodide versus none. Kazakov 1992 letter read by title only.

  94. 2006 · Understanding · Bladder cancer

    EORTC risk tables for non-muscle-invasive bladder cancer

    In 2006 researchers pooled data from about 2,600 people in seven European trials to build tables that estimate an individual's chance of bladder tumour recurrence and progression after surgery, using six clinical and pathological factors. The estimated five-year chance of recurrence ranged from about three in ten to about four in five.

    Combined analysis of individual data from 2596 patients with stage Ta T1 bladder cancer in seven EORTC trials. A score uses six factors: number of tumours, size, prior recurrence rate, T category, carcinoma in situ and grade. Probability of recurrence ranged from 15% to 61% at one year and 31% to 78% at five years; progression from under 1% to 17% at one year and under 1% to 45% at five years.

  95. 2006 · Treatment · Chronic myeloid leukemia

    Dasatinib and nilotinib for imatinib resistance or intolerance

    In 2006 two early-phase studies reported hematologic and cytogenetic responses to dasatinib and nilotinib in many people whose CML had stopped responding to imatinib; the dasatinib study also enrolled people who could not tolerate imatinib. The US regulator approved dasatinib in June 2006 and nilotinib in October 2007, both under its accelerated approval regulations.

    Dasatinib phase 1 (15 to 240 mg per day): complete hematologic response in 37 of 40 chronic-phase patients; major cytogenetic response 45% (chronic phase) and 25% (accelerated, blast or Ph-positive ALL); responses across BCR-ABL genotypes except T315I. Nilotinib phase 1 (n=119): complete hematologic remission in 11 of 12 chronic-phase patients; hematologic response in 33 of 46 accelerated-phase and 13 of 33 blastic-phase patients. FDA accelerated approvals: dasatinib 28 June 2006, nilotinib 29 October 2007.

  96. 2006 · Detection · Foundations

    First US-licensed HPV vaccine; later data show fewer cervical cancers

    On 8 June 2006 the US regulator licensed Gardasil, which it called the first vaccine developed to prevent cervical cancer, for girls and women aged 9 to 26. A large randomised trial found it prevented nearly all HPV 16 and 18 high-grade cervical lesions in women not already infected; a Swedish study later found fewer cervical cancers in vaccinated women.

    FUTURE II (placebo-controlled RCT, 12,167 women aged 15 to 26, three doses): vaccine efficacy against HPV 16/18-related CIN 2/3, adenocarcinoma in situ or cervical cancer 98% (95.89% CI 86 to 100) in the per-protocol susceptible population; 44% (95% CI 26 to 58) in ITT. Swedish register cohort (1,672,983 females aged 10 to 30): cervical cancer in 19 vaccinated and 538 unvaccinated women; adjusted incidence rate ratio 0.37 (0.21 to 0.57); 0.12 (0.00 to 0.34) if vaccinated before 17.

  97. 2006 · Treatment · Gastric and gastro-oesophageal junction cancer

    MAGIC: perioperative ECF for resectable gastro-oesophageal cancer

    In a randomised trial reported in 2006, people with operable cancer of the stomach, the junction or the lower gullet who had chemotherapy before and after surgery lived longer than people who had surgery alone. About 36 in 100 were alive at five years with chemotherapy, compared with 23 in 100.

    Randomised phase 3 trial of perioperative ECF (three cycles before and three after surgery; 250 patients) versus surgery alone (253) in resectable adenocarcinoma of the stomach, oesophagogastric junction or lower oesophagus. Median follow-up 4 years: OS HR 0.75 (95% CI 0.60-0.93; P=0.009), 5-year survival 36% vs 23%; progression HR 0.66 (0.53-0.81; P<0.001). Postoperative complications 46% vs 45%.

  98. 2006 · Treatment · Glioblastoma

    5-ALA fluorescence-guided surgery increases complete resection

    In 2006 a randomised trial of people with suspected malignant glioma compared surgery guided by a fluorescent dye (5-ALA) with ordinary white-light surgery. Complete removal of the tumour visible on scans was achieved in about two in three people with the dye and about one in three without. Six-month progression-free survival was 41% against 21%.

    Randomised phase 3 trial (322 randomised; interim full-analysis population 270, study terminated at the interim analysis): contrast-enhancing tumour resected completely in 65% with 5-ALA fluorescence guidance vs 36% with white light (difference 29%, 95% CI 17-40; P<0.0001); 6-month PFS 41.0% vs 21.1% (difference 19.9%, 95% CI 9.1-30.7; P=0.0003). The abstract reports no overall survival result.

  99. 2006 · Treatment · Head and neck cancer

    Cetuximab with radiotherapy improves locoregional control and survival

    In this trial, people with advanced head and neck cancer had radiation alone or radiation with the antibody drug cetuximab. Cancer stayed controlled in the head and neck area about ten months longer with cetuximab, and median survival was about twenty months longer, with no more of the common radiation side effects apart from rash and infusion reactions.

    Randomised study, radiotherapy alone (n=213) vs plus weekly cetuximab (n=211), locoregionally advanced head and neck squamous-cell carcinoma. Cetuximab vs radiotherapy alone: median locoregional control 24.4 vs 14.9 months (HR 0.68; P=0.005). At median follow-up 54.0 months, median OS 49.0 vs 29.3 months (HR 0.74; P=0.03). Five-year report: OS HR 0.73 (95% CI 0.56-0.95), 5-year OS 45.6% vs 36.4%. Cetuximab was not compared with cisplatin-based chemoradiotherapy.

  100. 2006 · Understanding · Hepatocellular carcinoma

    REVEAL-HBV: HCC risk rises with serum hepatitis B virus DNA level

    A Taiwanese cohort of about 3,650 people with chronic hepatitis B found that liver cancer became more common as the amount of virus in the blood rose. Over an average of about 11 years of follow-up, roughly 1 in 75 people with the lowest virus levels and about 1 in 7 with the highest developed liver cancer.

    Prospective community cohort of 3,653 HBsAg-positive, anti-HCV-negative adults aged 30-65 in Taiwan (recruited 1991-1992); 164 incident HCC over a mean 11.4 years. Incidence rose with baseline HBV DNA from 108 per 100,000 person-years below 300 copies/mL to 1152 at 1 million copies/mL or more; cumulative incidence 1.3% versus 14.9% (P<.001 for the gradient after adjustment).

  101. 2006 · Treatment · Hepatocellular carcinoma

    Resection versus ablation for small HCC: conflicting trials

    For small liver tumours, three randomised trials compared surgery to remove the tumour with ablation (destroying it with local treatment such as radiofrequency heat). One found similar survival, one found better survival with surgery, and the most recent found no clear advantage for surgery. The trials differed in size limits and ablation methods.

    Chen 2006 (N=180; solitary HCC of 5 cm or less; percutaneous ablation vs resection): 4-year OS 67.9% vs 64.0%, no significant difference. Huang 2010 (N=230; Milan criteria; RFA vs resection): 5-year OS 54.78% vs 75.65% (P=0.001). SURF (N=302; 3 cm or less, up to 3 nodules; surgery vs RFA): 5-year OS 74.6% vs 70.4% (HR 0.96; adjusted P=0.84); 5-year RFS 42.9% vs 42.7%.

  102. 2006 · Treatment · Kidney cancer (renal cell carcinoma)

    Sunitinib versus interferon alfa as first-line therapy (2006-2007)

    Sunitinib, a pill that blocks signals tumours use to grow, was compared with the older injected drug interferon alfa in 750 people with untreated, spread kidney cancer. The cancer stayed controlled for a median of about eleven months with sunitinib and five months with interferon, and tumours shrank far more often. The FDA approved sunitinib in January 2006.

    Randomised phase 3 (N=750), previously untreated metastatic RCC: sunitinib 50 mg (4 weeks on, 2 off) vs interferon alfa 9 MU three times weekly. Primary report: median PFS 11 vs 5 months, HR 0.42 (95% CI 0.32-0.54; P<0.001); ORR 31% vs 6%. Final analysis: median OS 26.4 vs 21.8 months, HR 0.821 (95% CI 0.673-1.001; P=0.051); 33% of the interferon group later received sunitinib.

  103. 2006 · Treatment · Non-Hodgkin lymphoma (DLBCL and follicular)

    MInT: rituximab with CHOP-like therapy, young low-risk DLBCL (2006)

    The MabThera International Trial randomly assigned 824 people aged 18 to 60 with previously untreated, good-prognosis diffuse large B-cell lymphoma to six cycles of CHOP-like chemotherapy with or without rituximab. After about three years, 79 in 100 on the combination had been free of events, against 59 in 100, and 93 against 84 in 100 were alive.

    MInT: 824 patients aged 18-60, age-adjusted IPI 0-1, randomised to six cycles of CHOP-like chemotherapy plus rituximab (413) or alone (411). Median follow-up 34 months: 3-year EFS 79% vs 59% (difference 20%, 95% CI 13-27; log-rank P<0.0001); 3-year OS 93% vs 84% (P=0.0001). Six-year update (median 72 months): EFS 74.3% vs 55.8% (difference 18.5%, 11.5-25.4; P<0.0001).

  104. 2006 · Treatment · Multiple myeloma

    Lenalidomide plus dexamethasone in relapsed myeloma: MM-009, MM-010

    Lenalidomide is an oral drug related to thalidomide. Two placebo-controlled trials added it to high-dose dexamethasone in people who had received at least one earlier treatment for myeloma. In both, the disease took longer to progress and more people responded, and survival was longer. Low blood counts and blood clots were more common with lenalidomide.

    Two phase 3 trials, lenalidomide 25 mg plus dexamethasone versus placebo plus dexamethasone, after at least one prior therapy. MM-009 (n=353): median TTP 11.1 versus 4.7 months, median OS 29.6 versus 20.2 months (P<0.001 for both). MM-010 (n=351): median TTP (primary endpoint) 11.3 versus 4.7 months (P<0.001); OS HR 0.66 (P=0.03). Grade 3 or 4 neutropenia 41.2% versus 4.6% and venous thromboembolism 14.7% versus 3.4% (MM-009).

  105. 2006 · Treatment · Ovarian cancer

    Intraperitoneal chemotherapy in optimal stage III: GOG-172

    In 415 eligible women with stage III ovarian cancer and small residual tumours, adding chemotherapy into the abdominal cavity was linked to median survival of about 66 months instead of about 50. Side effects were more common, and only 42 percent finished six cycles of the abdominal regimen.

    GOG-172: 429 randomised stage III patients with no residual mass >1.0 cm; IV paclitaxel plus IV cisplatin vs IV paclitaxel plus IP cisplatin and IP paclitaxel. Median PFS 18.3 vs 23.8 months (P=0.05); median OS 49.7 vs 65.6 months (P=0.03, log-rank). 42% of the IP group completed six cycles; grade 3-4 toxicities were more common with IP (P<=0.001). Earlier GOG-104: OS HR 0.76 (95% CI 0.61-0.96).

  106. 2006 · Treatment · Sarcoma and GIST

    Sunitinib after imatinib failure in GIST

    In January 2006 the US regulator approved sunitinib for GIST that had progressed on, or could not be treated with, imatinib. In the randomised trial reported that October, the time before tumours grew was a median of about 27 weeks with sunitinib and about 6 weeks with placebo.

    Double-blind, placebo-controlled trial in 312 patients resistant to or intolerant of imatinib, randomised 2:1 to sunitinib (n=207) or placebo (n=105); stopped early at a planned interim analysis. Median time to tumour progression 27.3 weeks (95% CI 16.0-32.1) vs 6.4 weeks (4.4-10.0), HR 0.33, p<0.0001. FDA approval of NDA 21-938 on 26 January 2006.

  107. 2007 · Understanding · Childhood acute lymphoblastic leukemia (ALL)

    Genome-wide analysis: IKZF1 loss, Ph-like and other subtypes

    Large genetic studies of leukemia cells from children and young adults found repeated changes in genes that guide B-cell development, such as PAX5 and IKZF1. Loss of IKZF1 was linked to poorer outcomes. A further group, Ph-like ALL, resembles Philadelphia chromosome-positive disease and often carries changes in kinase genes that approved drugs might block.

    Mullighan 2007 (242 paediatric ALL cases, SNP arrays and sequencing): B-cell development genes altered in 40% of B-progenitor cases, PAX5 in 31.7%. Mullighan 2009 (221 high-risk children; IKZF1 altered in 28.6%): a copy-number predictor of poor outcome, strongly associated with IKZF1, validated in 258 patients. Roberts 2014: Ph-like ALL 10% of standard-risk children to 27% of young adults; kinase-activating alterations in 91%.

  108. 2007 · Treatment · Childhood acute lymphoblastic leukemia (ALL)

    Interfant protocols for infants with ALL

    Infants younger than one year with ALL have had worse outcomes than older children. An international group treated 482 infants with a hybrid regimen drawn from both ALL and AML treatment; just under half were event-free at four years. A randomised extra intensive course did not help, and the later Interfant-06 study did not improve outcomes.

    Interfant-99 (17 study groups, 22 countries): hybrid ALL/AML regimen, risk-stratified by prednisone prophase response. In 482 treated infants 4-year EFS was 47.0% (95% CI 41.9-52.1). Randomised late intensification (95 vs 96 patients): 4-year DFS 60.9% vs 57.0% (p=0.81). Interfant-06 (n=651): 6-year EFS 46.1%; randomised myeloid- vs lymphoid-style courses, 6-year DFS 39.3% vs 36.8% (p=0.47).

  109. 2007 · Treatment · Gastric and gastro-oesophageal junction cancer

    Adjuvant S-1 (ACTS-GC) and capecitabine-oxaliplatin (CLASSIC) after D2

    Two randomised trials in East Asia tested chemotherapy after stomach surgery with extended lymph node removal. One used the oral drug S-1 and the other used capecitabine with oxaliplatin; in each, people given chemotherapy had better outcomes than people who had surgery alone.

    ACTS-GC (Japan, stage II-III, D2; 529 S-1 vs 530 surgery only): 3-year OS 80.1% vs 70.1%, HR 0.68 (95% CI 0.52-0.87); 5-year OS 71.7% vs 61.1%, HR 0.669. CLASSIC (South Korea, China, Taiwan; stage II-IIIB, D2; 520 vs 515): 3-year DFS 74% vs 59%, HR 0.56 (0.44-0.72); 5-year OS 78% vs 69%, HR 0.66 (0.51-0.85).

  110. 2007 · Treatment · Glioblastoma

    Radiotherapy improves survival in older people with glioblastoma

    In 2007 a randomised trial of 85 people aged 70 or older with glioblastoma or anaplastic astrocytoma compared radiotherapy plus supportive care with supportive care alone. In the 81 people with glioblastoma, median survival was about 29 weeks with radiotherapy and about 17 weeks without. Quality of life and thinking did not differ significantly between the groups.

    Randomised trial, 85 patients aged 70 or older (Karnofsky score 70 or higher), stopped at the first interim analysis. In 81 with glioblastoma: median survival 29.1 weeks (39 patients) with 50 Gy radiotherapy plus supportive care vs 16.9 weeks (42) with supportive care alone; HR for death 0.47 (95% CI 0.29-0.76; P=0.002). No severe radiotherapy-related adverse events; quality of life and cognition not significantly different.

  111. 2007 · Treatment · Hepatocellular carcinoma

    Sorafenib: SHARP and Asia-Pacific trials in advanced HCC

    Sorafenib, a tablet that blocks several growth signals, was tested against placebo in people with advanced liver cancer who had not had drug treatment. In the main trial, median survival was about 11 months with sorafenib and about 8 months with placebo. A separate Asia-Pacific trial pointed the same way (6.5 versus 4.2 months).

    SHARP (double-blind phase 3, N=602, no prior systemic therapy): sorafenib 400 mg twice daily vs placebo, median OS 10.7 vs 7.9 months, HR 0.69 (95% CI 0.55-0.87; P<0.001), at the second interim analysis (321 deaths). Separate Asia-Pacific phase 3 (226 randomised, Child-Pugh A): median OS 6.5 vs 4.2 months, HR 0.68 (95% CI 0.50-0.93; P=0.014); no predefined primary endpoint.

  112. 2007 · Understanding · Hodgkin lymphoma

    Interim PET predicts outcome in advanced Hodgkin lymphoma

    In a 2007 Italian-Danish study of 260 people with newly diagnosed Hodgkin lymphoma, a PET scan after two cycles of ABVD chemotherapy separated outcomes: about 95 in 100 with a negative scan were free of progression at two years, against about 13 in 100 with a positive scan. Treatment was not changed on the result.

    Prospective Italian-Danish cohort of 260 newly diagnosed patients (190 stages IIB through IVB; 70 stage IIA with adverse factors) treated with ABVD; PET after two cycles (PET-2) with no treatment change allowed. At median follow-up 2.19 years, 2-year progression-free survival was 12.8% for PET-2-positive and 95.0% for PET-2-negative patients (P < .0001); in multivariate analyses only PET-2 was significant.

  113. 2007 · Treatment · Kidney cancer (renal cell carcinoma)

    mTOR inhibitors: temsirolimus (ARCC) and everolimus (RECORD-1)

    Two drugs that block the mTOR growth pathway were tested in kidney cancer. In 626 people with untreated, poor-prognosis disease, weekly temsirolimus was linked to longer survival than interferon alfa (about eleven months against seven). In people whose cancer had progressed on earlier targeted pills, everolimus delayed progression compared with placebo (four months against two).

    Global ARCC (phase 3, N=626, untreated poor-prognosis): temsirolimus vs interferon alfa, median OS 10.9 vs 7.3 months, HR 0.73 (95% CI 0.58-0.92; P=0.008); temsirolimus plus interferon vs interferon HR 0.96 (95% CI 0.76-1.20; P=0.70). RECORD-1 (double-blind phase 3, ITT, progression on sunitinib and/or sorafenib): everolimus (n=272) vs placebo (n=138), median PFS 4.0 vs 1.9 months, HR 0.30 (95% CI 0.22-0.40; P<0.0001).

  114. 2007 · Treatment · Pancreatic cancer

    CONKO-001: adjuvant gemcitabine versus observation

    In CONKO-001, people whose pancreatic cancer had been removed received six months of gemcitabine or observation only. Cancer returned later with gemcitabine: median disease-free survival 13 months against 7 months. A 2013 follow-up reported longer overall survival too: about 21 in 100 alive at five years against 10 in 100.

    CONKO-001 (Oettle 2007, 2013): 368 randomised, 354 eligible; adjuvant gemcitabine for 6 months vs observation after R0/R1 resection. Median DFS 13.4 vs 6.9 months (P<.001); OS not different in 2007 (22.1 vs 20.2 months, P=.06). At 136 months median follow-up: DFS HR 0.55 (0.44-0.69); OS HR 0.76 (95% CI 0.61-0.95, P=.01); 5-year OS 20.7% vs 10.4%.

  115. 2007 · Treatment · Testicular germ cell tumors

    High-dose chemotherapy with stem-cell rescue for relapsed disease

    A 2007 retrospective review of 184 patients whose testicular cancer progressed after cisplatin-based chemotherapy found 116 in complete remission without relapse after high-dose carboplatin and etoposide with stem-cell rescue. It was not a randomised trial. An earlier randomised trial of one high-dose course found no significant gain.

    Einhorn 2007: retrospective review (not randomised), 184 consecutive patients progressing after cisplatin chemotherapy; 173 had two courses of carboplatin 700 mg/m2 plus etoposide 750 mg/m2 with stem-cell rescue. 116 in complete remission without relapse (median follow-up 48 months); 94 of 135 second-line; 22 of 49 third-line or later; 3 drug-related deaths. IT-94 (Pico 2005, randomised, 280): one high-dose course, 3-year EFS 35% vs 42% (P = 0.16).

  116. 2007 · Reversal · Testicular germ cell tumors

    First-line high-dose chemotherapy did not show benefit in trials

    Two randomised trials added high-dose chemotherapy with stem-cell rescue to first-line treatment of poor-prognosis germ-cell tumours. In one of 219 patients (intermediate or poor risk), 52% with high-dose chemotherapy and 48% with BEP alone had a durable complete response at one year, not significantly different. A 131-patient European trial, closed early, also found no significant gain.

    Motzer 2007: phase 3, 219 patients with intermediate or poor-risk germ cell tumours, BEP x4 vs BEP x2 plus high-dose carboplatin-containing chemotherapy: 1-year durable complete response 52% vs 48% (P = .53); in 67 patients with unsatisfactory marker decline 61% vs 34% (P = .03). EORTC 30974 (137 randomised, closed early; 131 analysed): complete response 44.6% vs 33.3% (P = 0.18); 2-year FFS 58.2% vs 44.8% (P = 0.060), high-dose VIP vs BEP.

  117. 2007 · Understanding · Thyroid cancer

    Lobectomy or total thyroidectomy for low-risk papillary cancer

    Whether small papillary thyroid cancers need the whole thyroid removed has been argued from large US database studies. A 2007 analysis linked lobectomy to more recurrence and death for tumours of 1 centimetre or more. A 2014 analysis of patients diagnosed later, adjusting for more factors, found no survival difference.

    Bilimoria 2007 (NCDB 1985-1998; 52,173 patients; 17.1% lobectomy): for tumours of 1 cm or more, lobectomy was associated with higher risk of recurrence (P=0.04) and death (P=0.009); no difference below 1 cm. Adam 2014 (NCDB 1998-2006; 61,775 patients, tumours 1.0 to 4.0 cm; median follow-up 82 months): adjusted overall survival HR 0.96 (95% CI 0.84 to 1.09; P=0.54), total thyroidectomy vs lobectomy.

  118. 2008 · Understanding · Cervical cancer

    Chemoradiation individual patient data meta-analysis (2008)

    A 2008 analysis pooled patient-level data from randomised trials of adding chemotherapy to radiotherapy for cervical cancer. It found a 6 percent improvement in five-year survival with chemoradiation, seen with platinum and non-platinum drugs, and a possible extra benefit from chemotherapy after chemoradiation that needed testing in trials.

    CCCMAC individual patient data meta-analysis (JCO 2008; same analysis republished in the Cochrane Database, 2010). 13 trials of chemoradiotherapy vs the same radiotherapy: 6% improvement in 5-year survival, HR 0.81 (P<.001). Platinum-based trials HR 0.83 (P=.017); non-platinum-based HR 0.77 (P=.009). Local and distant recurrence reduced; acute haematological and gastrointestinal toxicity increased; late toxicity data too sparse.

  119. 2008 · Understanding · Childhood acute lymphoblastic leukemia (ALL)

    Late effects in survivors of childhood ALL (CCSS)

    A study of survivors of childhood ALL diagnosed in 1970-1986 who had lived at least five years followed them to 25 years after diagnosis. About 13 in 100 had died, mostly from relapse or second cancers, and survivors reported more serious chronic health conditions than their siblings. Radiotherapy and relapse carried the greatest risk.

    Childhood Cancer Survivor Study: 5760 eligible five-year ALL survivors diagnosed 1970-1986 (4151 participants), compared with the general population and 3899 siblings. Cumulative mortality 13% at 25 years; recurrent ALL (483 deaths) and second neoplasms (89 deaths) were the major causes of death. Severe or life-threatening chronic conditions: OR 3.6 (95% CI 3.0-4.5) versus siblings. Cumulative incidence of severe conditions including death at 25 years 23.3% in irradiated and 13.4% in nonirradiated survivors.

  120. 2008 · Understanding · Chronic lymphocytic leukaemia

    iwCLL criteria and MRD as a response measure

    Doctors need shared rules to judge whether CLL treatment has worked. An international workshop updated them in 2008 and 2018, adding guidance on measuring tiny amounts of remaining leukemia cells (MRD). A single-centre study linked undetectable MRD with longer survival, and MRD became a trial endpoint.

    iwCLL 2008 updated the NCI-WG 1996 guidelines for diagnosis, response assessment and treatment; iwCLL 2018 added revised response criteria and an update on MRD use. In a retrospective single-institution analysis (up to 18 years of follow-up), MRD negativity (fewer than 1 CLL cell per 10,000 leukocytes) correlated with PFS and OS; in frontline patients 10-year PFS was 65% vs 10% and 10-year OS 70% vs 30% (MRD-negative vs MRD-positive). A 174-member panel (2021) proposed uniform MRD nomenclature.

  121. 2008 · Reversal · Colorectal cancer

    KRAS mutation predicts no benefit: anti-EGFR limited to wild-type

    Cetuximab and panitumumab were first approved for bowel cancers carrying the EGFR receptor. In 2008, two analyses of randomised trials showed that people whose tumours had a KRAS mutation gained no benefit, while those without it did. The FDA later revised the cetuximab label and then limited its use to tumours without the mutation.

    Biomarker analyses of two randomised trials of anti-EGFR antibody plus best supportive care versus best supportive care alone. Panitumumab (KRAS known in 427 of 463): PFS HR 0.45 (95% CI 0.34 to 0.59) in wild-type vs 0.99 (0.73 to 1.36) in mutant tumours. Cetuximab, CO.17 (K-ras tested in 394 of 572): wild-type OS median 9.5 vs 4.8 months, HR 0.55 (0.41 to 0.74); mutant OS HR 0.98 (P=0.89). FDA limited cetuximab to K-ras wild-type disease on 6 July 2012.

  122. 2008 · Reversal · Endometrial cancer

    Systematic lymphadenectomy: no survival benefit shown in two trials

    Two randomised trials tested adding removal of the pelvic lymph nodes to hysterectomy in women whose cancer seemed to be confined to the uterus. The extra surgery found more nodal spread in one trial, but neither trial showed longer survival with it.

    Benedetti Panici (514 eligible, preoperative stage I): 5-year DFS 81.0% vs 81.7% and OS 85.9% vs 90.0% (lymphadenectomy vs none); HR for death 1.20 (95% CI 0.70-2.07); nodal metastases found 13.3% vs 3.2%. ASTEC (1,408, ITT): OS HR 1.16 (0.87-1.54), P = 0.31; RFS HR 1.35 (1.06-1.73), P = 0.017 (both above 1 in favour of standard surgery).

  123. 2008 · Understanding · Foundations

    TCGA: first tumour atlas report (glioblastoma, 2008)

    The Cancer Genome Atlas began in 2006 as a joint effort of two US institutes. Its first report, in 2008, mapped changes in the DNA of 206 glioblastomas. Over the next dozen years the programme profiled over 20,000 tumour and matched normal samples spanning 33 cancer types, and made the data public.

    TCGA pilot, interim analysis (Nature 2008): integrative analysis of DNA copy number, gene expression and methylation in 206 glioblastomas, with sequencing of 91; new roles for ERBB2, NF1 and TP53, frequent PIK3R1 mutations, and a link between MGMT promoter methylation and a hypermutator phenotype from mismatch repair deficiency in treated tumours. Programme (NCI): began 2006, over 20,000 primary cancer and matched normal samples, 33 cancer types, over 2.5 petabytes.

  124. 2008 · Treatment · Gastric and gastro-oesophageal junction cancer

    REAL-2: oxaliplatin and capecitabine, advanced oesophagogastric

    In 2008 a trial led by a UK research group, in about a thousand people with untreated advanced oesophagogastric cancer, swapped in a three-drug regimen oral capecitabine for infused fluorouracil and oxaliplatin for cisplatin. Each swap met the trial's noninferiority test; the version with both swaps had the longest median survival, 11.2 months.

    Two-by-two randomised phase 3 REAL-2: 1002 patients, untreated advanced oesophagogastric cancer; epirubicin plus cisplatin or oxaliplatin, with fluorouracil or capecitabine (ECF, ECX, EOF, EOX). Noninferiority OS: capecitabine vs fluorouracil HR 0.86 (95% CI 0.80 to 0.99); oxaliplatin vs cisplatin HR 0.92 (0.80 to 1.10); margin 1.23. Median OS 9.9, 9.9, 9.3, 11.2 months. EOX vs ECF HR 0.80 (0.66 to 0.97), P=0.02 (secondary).

  125. 2008 · Understanding · Glioblastoma

    IDH1 and IDH2 mutations found in gliomas

    In 2008, genome sequencing of glioblastoma found recurrent changes in the IDH1 gene, often in younger people and in most tumours that had grown from lower-grade ones. A 2009 study found IDH1 or IDH2 changes in most lower-grade gliomas, with better outcomes, and a third showed the changed enzyme makes an unusual molecule.

    Parsons 2008: 20,661 genes sequenced in 22 glioblastoma samples; IDH1 active-site mutations in 12% of patients, frequent in young patients and most secondary glioblastomas, associated with longer overall survival. Yan 2009: IDH1 and IDH2 sequenced in 445 CNS and 494 non-CNS tumours; mutations affecting amino acid 132 of IDH1 in more than 70% of grade II and III astrocytomas and oligodendrogliomas; mutant tumours had better outcome. Dang 2009: mutant IDH1 produces 2-hydroxyglutarate.

  126. 2008 · Treatment · Head and neck cancer

    EXTREME: cetuximab added to platinum-fluorouracil, first line

    People with head and neck squamous cell cancer that had returned or spread, and who had not yet had treatment for that stage, were given chemotherapy with or without the antibody cetuximab. Those who also received cetuximab lived longer on average, about ten months compared with seven, and the cancer took longer to grow.

    Randomised phase 3 trial, untreated recurrent or metastatic SCCHN (N=442): cisplatin or carboplatin plus fluorouracil, with or without weekly cetuximab. Median OS 10.1 vs 7.4 months (HR 0.80; 95% CI 0.64-0.99; P=0.04). Median PFS 5.6 vs 3.3 months (HR 0.54; P<0.001); response rate 36% vs 20%. Sepsis occurred in 9 patients with cetuximab and 1 without. FDA approved this first-line indication on 7 November 2011.

  127. 2008 · Treatment · Multiple myeloma

    VISTA: bortezomib added to melphalan-prednisone, first line

    In people with newly diagnosed myeloma who could not have high-dose therapy, adding bortezomib to melphalan and prednisone lengthened the time before the disease progressed and raised the proportion who responded. An updated report found longer survival with the bortezomib combination. Nerve problems were reported, and most improved.

    Phase 3, n=682, previously untreated and ineligible for high-dose therapy: VMP versus MP, nine 6-week cycles. Median time to progression (primary endpoint) 24.0 versus 16.6 months (HR 0.48; P<0.001); partial response or better 71% versus 35%; complete response 30% versus 4%. Updated analysis, median follow-up 36.7 months: OS HR 0.653 (P<0.001); 3-year OS 68.5% versus 54.0%.

  128. 2008 · Understanding · Neuroblastoma and Wilms tumour

    INRG classification and staging: one risk language across groups

    In 2008 an international task force analysed outcomes of 8,800 children with neuroblastoma and proposed a shared way to group them by risk before treatment, using stage, age, tumour biology and microscopy. Its aim was to let trials run in different regions be compared. The Children's Oncology Group revised its own version in 2021.

    INRG Task Force: survival-tree analysis of 8,800 children diagnosed 1990 to 2002 found stage, age, histologic category, differentiation grade, MYCN status, 11q status and ploidy most significant; 18 months chosen as age cutoff; 16 pretreatment groups; 5-year EFS defines very low (above 85%) to high (below 50%) risk. INRGSS (L1, L2, M, MS): 5-year EFS 78% for L2 vs 90% for L1 (P = .0010; 661 patients). COG revision 2021 (N = 4,832) adds segmental chromosome aberrations.

  129. 2008 · De-escalation · Neuroblastoma and Wilms tumour

    Low-risk neuroblastoma: observation or surgery alone

    Between 2008 and 2012 three prospective studies reported on doing less for low-risk neuroblastoma: observation without chemotherapy, or surgery alone. Survival was high in each, for example 99 in 100 at three years among infants in German trials whose tumours were observed, and many tumours shrank on their own. The studies are not directly comparable.

    Three prospective non-randomised cohorts. NB95-S/NB97 (340 eligible infants, no MYCN amplification): 93 observed with unresected tumour, 3-year OS 99%, metastases-free survival 94%; regression in 44. COG P9641 (915 eligible): surgery alone with restricted chemotherapy, 5-year EFS 89%, OS 97%. COG ANBL00P2 (87 infants aged 6 months or younger): 3-year EFS 97.7%, OS 100%; 10-year EFS 93.7%, OS 98.0%.

  130. 2008 · Treatment · Neuroblastoma and Wilms tumour

    European trials: rapid induction and busulfan-melphalan consolidation

    Three randomized European comparisons tested induction and high-dose chemotherapy for high-risk neuroblastoma. Rapid induction was linked to better five-year event-free survival in a 1990s trial, though three- and ten-year differences were not significant. Busulfan-melphalan gave better three-year event-free survival than carboplatin-etoposide-melphalan (50% against 38%). A later trial found no difference between two induction regimens.

    Three randomizations, each with its own result. (1) Rapid COJEC vs standard OPEC/OJEC induction (n=262, 1990 to 1999): 5-year EFS 30.2% vs 18.2% (P=0.022); 3-year EFS HR 0.86 (95% CI 0.66 to 1.14). (2) HR-NBL1, busulfan-melphalan vs carboplatin-etoposide-melphalan (n=598): 3-year EFS 50% (45 to 56) vs 38% (32 to 43), P=0.0005. (3) HR-NBL1.5, MSKCC N5 vs rapid COJEC (n=630): 3-year EFS 47% vs 44%, P=0.527.

  131. 2008 · Understanding · Pancreatic cancer

    Sequencing reveals core pathways and subtypes of pancreatic cancer

    In 2008 a team sequenced 24 pancreatic cancers and found about 63 gene changes per tumour on average, grouped into 12 core pathways altered in most tumours. In 2016 an analysis of 456 tumours described 10 pathways and four subtypes based on gene activity. Neither report describes a treatment result.

    Jones 2008 (Science): 23,219 transcripts sequenced in 24 pancreatic cancers plus copy-number arrays; average 63 genetic alterations, mostly point mutations, defining 12 core pathways each altered in 67 to 100% of tumours. Bailey 2016 (Nature): 456 PDACs, 32 recurrently mutated genes in 10 pathways; four expression subtypes (squamous, pancreatic progenitor, immunogenic, ADEX); squamous described as poor prognosis.

  132. 2008 · Treatment · Sarcoma and GIST

    Adjuvant imatinib after GIST resection: 1 year, then 3 years

    In December 2008 the US regulator approved imatinib after surgery for KIT-positive GIST. A 2009 placebo-controlled trial found fewer recurrences with one year of imatinib. A 2012 trial in high-risk disease found longer recurrence-free and overall survival with three years than one year. A third trial against observation did not meet its main endpoint.

    Z9001 (placebo, 1 year of imatinib; KIT-positive GIST of at least 3 cm): 1-year RFS 98% vs 83%, HR 0.35 (0.22-0.53). SSG XVIII/AIO (high risk; 36 vs 12 months): 5-year RFS 65.6% vs 47.9%, HR 0.46 (0.32-0.65); 5-year OS 92.0% vs 81.7%, HR 0.45 (0.22-0.89). EORTC trial (2 years vs observation): 5-year IFFS 87% vs 83%, HR 0.87, P=0.31 (final). FDA accelerated approval 19 Dec 2008; conversion 31 Jan 2012.

  133. 2009 · Understanding · Acute myeloid leukaemia (including APL)

    ELN risk and WHO/ICC classification of AML (2009-2022)

    Since 2009 international expert panels have repeatedly updated how acute myeloid leukaemia is diagnosed and how its genetic risk is described. European LeukemiaNet recommendations appeared in 2009, 2016 and 2022. In 2022 two separate classifications of myeloid cancers were published, one from the World Health Organization and one from an international consensus group.

    Consensus documents, no trial data. ELN 2010 (online 2009): updated recommendations on diagnosis and management, with a standardised system for reporting cytogenetic and molecular data. ELN 2017: revised genetic categories, MRD-based response category, criteria for progressive disease. ELN 2022: revised genetic risk classification, response criteria and treatment recommendations. WHO 2016 revised the 2008 classification. In 2022 the ICC and the WHO 5th edition were published as separate classifications.

  134. 2009 · Treatment · Acute myeloid leukaemia (including APL)

    Azacitidine and decitabine in older adults with AML

    Azacitidine and decitabine were tested against conventional care in older adults with AML. A 2009 analysis in people with 20 to 30% blasts reported median survival of 24.5 months with azacitidine versus 16.0 months. A later trial with over 30% blasts found 10.4 versus 6.5 months, not statistically significant in its primary comparison.

    Three randomized comparisons (the first a subgroup of a trial designed in MDS). AZA-001 AML subgroup (n=113, 20-30% blasts): median OS 24.5 vs 16.0 months (HR 0.47, 95% CI 0.28-0.79; P=.005). DACO-016 (decitabine, n=485): median OS 7.7 vs 5.0 months (HR 0.85, 95% CI 0.69-1.04; P=.108). AZA-AML-001 (n=488, >30% blasts): median OS 10.4 vs 6.5 months (HR 0.85, 95% CI 0.69-1.03; stratified log-rank P=.1009).

  135. 2009 · De-escalation · Childhood acute lymphoblastic leukemia (ALL)

    Treating ALL without prophylactic cranial irradiation

    In 2009 St Jude reported treating 498 children with ALL without routine radiotherapy to the brain, using chemotherapy matched to risk and early response. About 3 in 100 had a relapse confined to the nervous system within five years. The comparison with earlier patients who had radiotherapy was not randomised.

    St Jude Total Therapy XV: 498 evaluable patients, intensity set by presenting features and MRD after induction, no prophylactic cranial irradiation. 5-year EFS 85.6% (95% CI 79.9-91.3), OS 93.5% (89.8-97.2); cumulative isolated CNS relapse 2.7% (1.1-4.3), any CNS relapse 3.9% (1.9-5.9). Continuous complete remission was longer in 71 patients who would formerly have been irradiated than in 56 historical controls given irradiation (P=0.04). Total Therapy 16 (598 patients): any CNS relapse 1.5% (0.5-2.5).

  136. 2009 · Treatment · Childhood acute lymphoblastic leukemia (ALL)

    Imatinib added to chemotherapy for Ph-positive ALL

    Imatinib blocks the abnormal BCR-ABL1 protein found in Philadelphia chromosome-positive leukemia. When children received it for longer alongside intensive chemotherapy in a Children's Oncology Group study, about eight in ten were free of relapse or other events at three years, compared with about one in three earlier-treated children.

    COG AALL0031 (non-randomised; N=92 Ph+ ALL, ages 1-21): imatinib 340 mg/m2/day with intensive chemotherapy in five cohorts of increasing exposure. Cohort 5 (280 days, n=50): 3-year EFS 80% (95% CI 64%-90%) vs 35% in historical controls (P<0.0001). EsPhALL2004 randomised good-risk patients: 4-year DFS 72.9% vs 61.7% with vs without imatinib (p=0.24; MRD-adjusted HR for any event 0.63, 95% CI 0.28-1.41).

  137. 2009 · Treatment · Endometrial cancer

    LAP2 and LACE: laparoscopic vs open surgery for uterine cancer

    Two large randomised trials compared keyhole (laparoscopic) surgery with open surgery for uterine cancer. Early reports found fewer complications and shorter hospital stays with keyhole surgery. In the stage I trial, 81 to 82 in 100 women in each group were alive without recurrence or new cancer at 4.5 years. The larger trial fell short of its pre-set recurrence margin.

    GOG LAP2 (2,616 women, clinical stage I-IIA, 2:1 laparoscopy vs laparotomy): moderate to severe postoperative adverse events 14% vs 21% (P < .0001); recurrence-free interval non-inferiority not met (HR 1.14; 95% upper bound 1.46); 3-year recurrence 11.4% vs 10.2%. LACE (760 women, stage I endometrioid): 4.5-year disease-free survival 81.6% (TLH) vs 81.3% (TAH), equivalence met (7% margin).

  138. 2009 · Treatment · Glioblastoma

    Bevacizumab approved for progressive glioblastoma on response rate

    In May 2009 the US regulator gave accelerated approval to bevacizumab for glioblastoma that had progressed after earlier treatment. The decision rested on how many tumours shrank on scans, not on survival. In a randomised phase 2 trial of 167 people, about 28 in 100 on bevacizumab alone had a response.

    FDA accelerated approval (BLA 125085, supplement 169; 5 May 2009) for glioblastoma with progressive disease after prior therapy. Supporting phase 2 BRAIN (n=167, randomised, noncomparative; bevacizumab 10 mg/kg alone or with irinotecan): independently assessed ORR 28.2% vs 37.8%, 6-month PFS 42.6% vs 50.3%, median OS 9.2 vs 8.7 months. Traditional approval followed on 5 December 2017 (supplement 319).

  139. 2009 · Treatment · Kidney cancer (renal cell carcinoma)

    Pazopanib approved (2009); COMPARZ compares it with sunitinib

    Pazopanib, a daily pill, delayed progression compared with placebo in people with advanced kidney cancer (median 9.2 months against 4.2). In a later head-to-head trial of 1,110 people it held the cancer back about as well as sunitinib; side effects and quality-of-life results differed between the two drugs.

    Placebo-controlled phase 3 (2:1; 435 patients, 54% treatment-naive): median PFS 9.2 vs 4.2 months, HR 0.46 (95% CI 0.34-0.62; P<0.0001); ORR 30% vs 3%. COMPARZ (N=1110, clear-cell, first line, non-inferiority): independently reviewed PFS HR 1.05 (95% CI 0.90-1.22), meeting the margin (upper bound below 1.25); OS HR 0.91 (95% CI 0.76-1.08).

  140. 2009 · Treatment · Lung cancer

    IPASS: gefitinib vs chemotherapy, by EGFR mutation (2009)

    IPASS compared the pill gefitinib with chemotherapy as first treatment in East Asian people with lung adenocarcinoma who had never smoked or had smoked lightly. Overall gefitinib delayed progression more than chemotherapy, and the result depended on the tumour's EGFR gene: it helped people with an EGFR mutation and did worse than chemotherapy in those without.

    IPASS (gefitinib 609, carboplatin-paclitaxel 608), untreated advanced pulmonary adenocarcinoma, East Asian nonsmokers or former light smokers. 12-month PFS 24.9% vs 6.7%; ITT HR 0.74 (95% CI 0.65-0.85; P<0.001). EGFR-mutation-positive subgroup (n=261): HR 0.48 (0.36-0.64). Mutation-negative subgroup (n=176): HR for progression or death with gefitinib 2.85 (2.05-3.98).

  141. 2009 · Understanding · Melanoma

    AJCC melanoma staging: 2009 version and 2017 eighth edition

    Melanoma staging groups people by tumour thickness, ulceration, spread to nodes and spread to other organs, to estimate outlook and guide care. The 2009 revision used a database of tens of thousands of patients; the eighth edition added a larger database and changed the thin-melanoma categories, the stage III subgroups and the brain-metastasis category.

    2009 version (Balch, JCO): multivariate analysis of 30,946 patients with stages I-III and 7,972 with stage IV; thickness, mitotic rate and ulceration dominant in localized disease; mitotic rate replaced level of invasion for T1b; any microscopic nodal metastasis is stage III. Eighth edition (Gershenwald 2017): over 46,000 patients with stages I-III; T1a under 0.8 mm without ulceration, T1b 0.8-1.0 mm; stage III has four subgroups; new M1d for CNS metastases.

  142. 2009 · De-escalation · Prostate cancer

    Active surveillance cohort: selective delayed intervention (Klotz)

    One academic centre followed almost a thousand men with favourable- or intermediate-risk prostate cancer, offering treatment only if the PSA rose quickly or tests showed progression. After fifteen years, more than nine in ten had not died of prostate cancer and just over half had still not needed treatment.

    Prospective single-arm cohort (n=993; favorable- or intermediate-risk) managed with an initial expectant approach; intervention offered for PSA doubling time under 3 years, Gleason score progression or clinical progression. Median follow-up from first biopsy among survivors 6.4 years; 15 deaths (1.5%) from prostate cancer. Cause-specific survival 98.1% at 10 and 94.3% at 15 years; 75.7%, 63.5% and 55.0% untreated at 5, 10 and 15 years. The 2010 report (450 men) reclassified 30% as higher risk.

  143. 2009 · Detection · Prostate cancer

    Prostate screening trials: ERSPC, PLCO and Goteborg (2009-2010)

    In 2009 two large trials asked whether PSA screening lowers deaths from prostate cancer. The European trial reported fewer deaths with screening; the US trial found no clear difference, and many men in its comparison group were also tested. A Swedish trial reported fewer deaths in 2010. All three found more cancers diagnosed with screening.

    ERSPC (core age group 55-69, n=162,243; median 9 years): prostate cancer death rate ratio 0.80 (95% CI 0.65-0.98). PLCO (76,693 men; annual PSA for 6 years; 7-year follow-up): prostate cancer death rate ratio 1.13 (0.75-1.70); control-arm PSA testing 40% in year 1 to 52% in year 6. Goteborg-1 (20,000 men; PSA every 2 years; median 14 years): rate ratio 0.56 (0.39-0.82). Designs, intervals and follow-up differ; not directly comparable.

  144. 2009 · Understanding · Testicular germ cell tumors

    Genome-wide studies link KITLG and loci to testicular GCT

    In 2009 two research groups published genome-wide scans comparing the DNA of people with testicular germ cell tumours and controls. Both found common inherited variants linked to higher risk, including variants in or near KITLG, a gene for the ligand of the KIT receptor, and a region on chromosome 5.

    Two case-control genome-wide association studies, Nat Genet 2009. Rapley et al. (UK discovery 730 cases, 1,435 controls; replication 571 cases, 1,806 controls): per-allele OR 2.55 (95% CI 2.05-3.19) on chromosome 12, where KITLG may explain the signal; 1.37 (1.19-1.58) on chromosome 5; 1.50 (1.28-1.75) on chromosome 6. Kanetsky et al. (discovery 277 cases, 919 controls; replication ORs): KITLG 3.08 (2.29-4.13); 5q31.3 1.37 (1.14-1.64).

  145. 2009 · Understanding · Thyroid cancer

    ATA guidelines: risk-adapted management, 2009 to 2025

    The American Thyroid Association revised its management guidelines for differentiated thyroid cancer in 2009, 2015 and 2025. The 2015 text says the 2009 version proposed a three-tier system for the risk of recurrence; the 2025 guideline divides the middle tier in two.

    Guidelines are consensus recommendations, not trial results. ATA 2009 (Thyroid): revision covering nodules and differentiated thyroid cancer. ATA 2015: states that the 2009 version proposed a three-tiered clinicopathologic risk stratification (low, intermediate, high risk of recurrence) and proposes modifications that need validation. ATA 2025: DTC-only; Recommendation 28 recommends the 2025 ATA Risk Stratification System for structural recurrence or persistence, with the intermediate category divided in two.

  146. 2010 · Reversal · Acute myeloid leukaemia (including APL)

    Gemtuzumab ozogamicin: approved 2000, withdrawn 2010, back 2017

    Gemtuzumab ozogamicin joins an antibody to a cell-killing drug. It was approved in the United States in 2000 for older people with relapsed AML. In 2010, at the FDA's request, the sponsor moved to withdraw it after a required trial found no survival gain when added to chemotherapy. A new licence followed in 2017 for newly diagnosed and relapsed disease.

    FDA accelerated approval 17 May 2000 (first-relapse CD33-positive AML, age 60 or older; three phase 2 trials, 142 patients). SWOG S0106 (637 registered; daunorubicin-cytarabine with or without GO): CR 69% v 70% (P=.59); 5-year OS 46% v 50% (P=.85). FDA asked for withdrawal 21 May 2010. ALFA-0701 (n=280, age 50-70, fractionated 3 mg/m2): 2-year EFS 40.8% v 17.1% (HR 0.58, 95% CI 0.43-0.78). New BLA approved 1 Sep 2017.

  147. 2010 · Treatment · Childhood acute lymphoblastic leukemia (ALL)

    Mitoxantrone in first relapse; TBI before transplant in childhood ALL

    In a trial in the UK, Ireland, Australia and New Zealand, children with a first relapse given mitoxantrone instead of idarubicin during induction did better at three years, and randomization stopped early. In a later international trial of children in remission before stem cell transplant, total body irradiation gave better survival and fewer relapses than chemotherapy conditioning.

    ALL R3 (open-label RCT, first relapse, 216 randomly assigned, MRD-guided transplant): mitoxantrone vs idarubicin induction, 3-year PFS 64.6% vs 35.9% (p=0.0004), 3-year OS 69.0% vs 45.2% (p=0.004). FORUM (noninferiority phase 3, complete remission before transplant, 54% in first remission; 212 TBI vs 201 chemoconditioning): 2-year OS 91% (95% CI 86 to 95) with TBI plus etoposide vs 75% (95% CI 67 to 81) (p<0.0001); relapse incidence 12% vs 33%.

  148. 2010 · Treatment · Chronic lymphocytic leukaemia

    CLL8: rituximab added to fludarabine and cyclophosphamide

    In a randomised trial of 817 people with untreated CLL who were fit for intensive treatment, adding the antibody rituximab to the chemotherapy pair fludarabine and cyclophosphamide helped. Three years after randomisation, 65 in 100 were free of progression compared with 45 in 100 on chemotherapy alone, and 87 in 100 compared with 83 in 100 were alive.

    CLL8 (NCT00281918): open-label phase 3 in untreated, physically fit, CD20-positive CLL, aged 30 to 81 years; FC with or without rituximab for six courses; n=817, ITT, primary endpoint PFS. At 3 years PFS 65% vs 45% (HR 0.56, 95% CI 0.46-0.69; p<0.0001); OS 87% vs 83% (HR 0.67, 0.48-0.92; p=0.01). Grade 3-4 neutropenia 34% vs 21%. FDA approved rituximab with FC on 18 February 2010.

  149. 2010 · De-escalation · Chronic myeloid leukemia

    STIM: stopping imatinib after sustained molecular response

    In 2010 French investigators reported what happened when 100 people with CML whose disease was undetectable for at least two years stopped imatinib. Of the 69 followed for a year, about two in five were still in remission off treatment; nearly all relapses came within six months, and everyone who relapsed responded again when imatinib was restarted.

    STIM (NCT00478985): prospective, non-randomised, 19 French institutions; imatinib stopped in 100 patients with undetectable BCR-ABL transcripts after more than 2 years of treatment. Interim analysis (69 patients with 12 months' follow-up): persistent complete molecular remission at 12 months 41% (95% CI 29-52); 42 relapsed, 40 before 6 months; all responded to imatinib reintroduction. Final analysis (median 77 months): molecular recurrence-free survival 38% (95% CI 29-47) at 60 months.

  150. 2010 · Treatment · Chronic myeloid leukemia

    DASISION and ENESTnd: second-generation TKIs first line

    In 2010 two randomised trials compared dasatinib and nilotinib with imatinib as first treatment for chronic-phase CML. After 12 months more people on either newer drug had no Philadelphia-chromosome-positive cells in the marrow, and more had a major molecular response. The US regulator approved both drugs for newly diagnosed CML that year.

    DASISION (n=519): confirmed CCyR by 12 months 77% with dasatinib 100 mg daily vs 66% with imatinib 400 mg (P=0.007); MMR 46% vs 28% (P<0.0001). ENESTnd (n=846): MMR at 12 months (primary) 44% (nilotinib 300 mg twice daily), 43% (400 mg twice daily) vs 22% (imatinib), P<0.001; CCyR by 12 months 80%, 78% vs 65%. Separate trials with different primary endpoints, not compared with each other.

  151. 2010 · Reversal · Colorectal cancer

    Adjuvant bevacizumab and cetuximab trials in colon cancer

    Four large randomised trials added a targeted drug, bevacizumab or cetuximab, to oxaliplatin-based chemotherapy after surgery for colon cancer. None improved disease-free survival. In one trial the authors noted overall survival data suggesting a possible harm with bevacizumab, and cetuximab added side effects. Both drugs had shown benefit in advanced disease, which is a different setting.

    Adjuvant colon cancer, DFS primary endpoint. NSABP C-08 (bevacizumab + mFOLFOX6; 2672 analysed): HR 0.89 (95% CI 0.76-1.04), P=0.15. AVANT (3451 randomised; stage III primary analysis): HR 1.17 (0.98-1.39) bevacizumab-FOLFOX4 and 1.07 (0.90-1.28) bevacizumab-XELOX vs FOLFOX4; OS HR 1.27 (1.03-1.57) for bevacizumab-FOLFOX4. N0147 (KRAS wild-type, mFOLFOX6 with or without cetuximab): 3-year DFS 71.5% with vs 74.6% without, HR 1.21 (0.98-1.49). PETACC-8 (KRAS exon 2 wild-type, 1602): HR 1.05 (0.85-1.29).

  152. 2010 · Detection · Colorectal cancer

    Flexible sigmoidoscopy screening trials

    Four randomised trials, in the UK, Italy, the US and Norway, offered flexible sigmoidoscopy (an examination of the lower bowel) or no screening. All four reported fewer bowel cancers in the invited group. Bowel cancer deaths were significantly lower in three; the Italian difference was not significant. Later Norwegian data showed reductions in men, little or no effect in women.

    Colorectal cancer mortality by randomised group in four sigmoidoscopy trials: UK once-only, HR 0.69 (95% CI 0.59-0.82), median 11.2 years; NORCCAP, HR 0.73 (0.56-0.94); PLCO (repeat screening), RR 0.74 (0.63-0.87); SCORE, RR 0.78 (0.56-1.08, not significant). PLCO distal cancer death RR 0.50, proximal 0.97. NORCCAP at 14.8 years: men HR 0.63 (0.47-0.83), women 1.01 (0.77-1.33).

  153. 2010 · De-escalation · Endometrial cancer

    PORTEC-2: vaginal brachytherapy in place of pelvic radiotherapy

    For women with early-stage endometrial cancer at high-intermediate risk, radiotherapy given only inside the vagina was compared with radiotherapy to the whole pelvis. Vaginal recurrence was rare and similar in both groups, and bowel side effects were less common with vaginal treatment. Ten-year follow-up found more pelvic recurrences after vaginal treatment.

    Open-label non-inferiority trial (427 women, stage I or IIA, high-intermediate risk): vaginal brachytherapy (VBT) vs pelvic EBRT. Primary endpoint 5-year vaginal recurrence 1.8% (95% CI 0.6-5.9) vs 1.6% (0.5-4.9); HR 0.78 (0.17-3.49); non-inferiority margin 6%. Acute grade 1-2 gastrointestinal toxicity 12.6% vs 53.8%. At 10 years: vaginal recurrence 3.4% vs 2.4% (p=0.55); pelvic recurrence 6.3% vs 0.9% (p=0.004).

  154. 2010 · Treatment · Gastric and gastro-oesophageal junction cancer

    ToGA: trastuzumab plus chemotherapy in HER2-positive gastric cancer

    In 2010 a large international trial found that adding the antibody trastuzumab to chemotherapy lengthened median survival, from about 11 months to about 14 months, in advanced stomach or gastro-oesophageal junction cancers whose tumours carry the HER2 protein. European and US regulators approved the use in 2010.

    ToGA, open-label phase 3: 594 patients with HER2-positive (IHC or FISH) advanced gastric or GEJ cancer randomised 1:1 to capecitabine or fluorouracil plus cisplatin, with or without trastuzumab. Primary analysis (584 treated): median OS 13.8 vs 11.1 months, HR 0.74 (95% CI 0.60 to 0.91), p=0.0046. Grade 3 or 4 adverse events 68% vs 68%; cardiac adverse events 6% vs 6%.

  155. 2010 · Understanding · Glioblastoma

    Expression subtypes and somatic landscape of glioblastoma

    In 2010, building on the Cancer Genome Atlas catalogue, researchers sorted glioblastomas into four subtypes by gene activity and reported that response to aggressive treatment differed between them. A 2013 analysis of more than 500 tumours described further gene changes, including in the TERT promoter.

    Verhaak 2010 (TCGA data): expression-based classification into proneural, neural, classical and mesenchymal subtypes; EGFR, NF1 and PDGFRA/IDH1 abnormalities defined classical, mesenchymal and proneural; response to aggressive therapy differed by subtype, greatest in classical, none in proneural. Brennan 2013: more than 500 glioblastomas; TERT promoter mutations correlated with mRNA expression; proneural survival advantage attributed to G-CIMP; MGMT methylation may be predictive only in classical subtype.

  156. 2010 · Understanding · Head and neck cancer

    Tumour HPV status found to be a strong, independent prognostic factor

    A retrospective analysis of people with stage III or IV oropharyngeal cancer treated in a chemoradiotherapy trial found that those with HPV-positive tumours did much better: about eight in ten were alive at three years, against about six in ten with HPV-negative tumours. The analysis was not a test of treating them less.

    Retrospective analysis by HPV status of stage III or IV oropharyngeal SCC in RTOG 0129 (accelerated vs standard fractionation radiotherapy, each with cisplatin). HPV-positive 206 of 323 (63.8%). 3-year OS 82.4% vs 57.1% (P<0.001); adjusted HR for death 0.42 (95% CI 0.27 to 0.66); median follow-up 4.8 years. Recursive partitioning (HPV status, pack-years, T and N stage) defined low, intermediate and high risk.

  157. 2010 · De-escalation · Hodgkin lymphoma

    HD10: fewer cycles and lower dose in early favourable HL

    In the German HD10 trial, 1370 people with early-stage Hodgkin lymphoma and a favourable outlook were given four or two cycles of ABVD, then radiotherapy at 30 or 20 gray. Neither the chemotherapy schedules nor the radiation doses differed significantly, and the authors judged two cycles plus 20 gray as effective as, and less toxic than, four plus 30.

    GHSG HD10 (Engert 2010): 1370 patients, early-stage favourable HL, randomised to 4 or 2 cycles of ABVD then 30 or 20 Gy involved-field radiotherapy. Primary endpoint FFTF. 5-year FFTF 93.0% (95% CI 90.5-94.8) with 4 cycles vs 91.1% (88.3-93.2) with 2 (P=0.39); OS P=0.61. Radiation dose 20 vs 30 Gy: FFTF P=1.00, OS P=0.61. Toxicity highest with 4 cycles plus 30 Gy.

  158. 2010 · Treatment · Kidney cancer (renal cell carcinoma)

    EORTC 30904: nephron-sparing surgery versus radical nephrectomy

    Researchers randomly assigned 541 people with small kidney tumours to surgery that spares part of the kidney or to removal of the whole kidney. After about nine years, survival was lower with the kidney-sparing operation in the main analysis, though few deaths came from kidney cancer. The trial closed early and did not show non-inferiority for survival.

    EORTC-GU 30904, randomised noninferiority phase 3, closed early for poor accrual: 541 patients with solitary T1-T2 N0 M0 tumours of 5 cm or less and a normal contralateral kidney; nephron-sparing surgery (n=268) vs radical nephrectomy (n=273). Median follow-up 9.3 years; ITT 10-year OS 75.7% vs 81.1% (HR 1.50; 95% CI 1.03-2.16); noninferiority not shown (p=0.77). 12 of 117 deaths were from renal cancer.

  159. 2010 · Treatment · Lung cancer

    SBRT for medically inoperable early-stage lung cancer (RTOG 0236)

    A North American phase 2 study gave focused, high-dose radiotherapy in three treatments to 55 evaluable patients with early-stage lung cancers under 5 cm who could not have surgery. At three years, an estimated 98 in 100 had no failure of the treated tumour and 56 in 100 were alive. Some patients had serious side effects.

    RTOG 0236, phase 2: 59 accrued, 55 evaluable (44 T1, 11 T2); medically inoperable peripheral T1-T2N0M0 NSCLC; SBRT 18 Gy x 3 (54 Gy). Median follow-up 34.4 months. At 3 years: primary tumour control 97.6% (95% CI 84.3-99.7), primary tumour and involved lobe 90.6%, local-regional control 87.2%, DFS 48.3%, OS 55.8%; median OS 48.1 months. Grade 3 events 12.7%, grade 4 3.6%, no grade 5. One regimen, no comparison group.

  160. 2010 · Treatment · Lung cancer

    Crizotinib for ALK-positive lung cancer (2010-2014)

    In 2010 a trial of crizotinib, a pill that blocks the ALK protein, reported tumour shrinkage in more than half of 82 people whose lung cancers carried an ALK rearrangement. The US FDA approved it in 2011 on the basis of response rate, and randomised trials later found longer time without progression than with chemotherapy.

    Kwak 2010 (single-group expanded cohort, n=82 ALK-positive): ORR 57%; estimated 6-month PFS 72%. PROFILE 1007 (n=347, previously treated): median PFS 7.7 vs 3.0 months, HR 0.49 (0.37-0.64). PROFILE 1014 (n=343, untreated nonsquamous): median PFS 10.9 vs 7.0 months (independent review), HR 0.45 (0.35-0.60); OS HR 0.82 (0.54-1.26).

  161. 2010 · Treatment · Non-Hodgkin lymphoma (DLBCL and follicular)

    CORAL: R-ICE vs R-DHAP before transplant in relapsed DLBCL

    This trial compared two chemotherapy-plus-rituximab regimens used to bring relapsed lymphoma under control before a stem-cell transplant. Responses were similar, about 63 in 100 with each regimen, and survival did not differ significantly. Outcomes were worse when the lymphoma relapsed early or had already been treated with rituximab.

    CORAL: CD20-positive DLBCL in first relapse or refractory, randomised to R-ICE (n=202) or R-DHAP (n=194), median age 55. Overall response after three cycles 63.5% vs 62.8%; primary end point (mobilisation-adjusted response) 52.3% vs 54.5%; 3-year EFS 26% vs 35% (P=.6). Across both regimens, 3-year EFS 21% with vs 47% without prior rituximab. Rituximab maintenance after ASCT, rituximab vs observation: 4-year EFS 52% vs 53% (P=.7).

  162. 2010 · Treatment · Non-Hodgkin lymphoma (DLBCL and follicular)

    PRIMA: two years of rituximab maintenance after induction (2010)

    In people with untreated follicular lymphoma who responded to rituximab plus chemotherapy, two more years of rituximab every eight weeks lowered the chance of progression: about three in four were progression-free at a median follow-up of three years, versus about three in five with observation. Infections and other serious side effects were more common.

    Open-label phase 3 (1217 enrolled; 1019 responders randomised, 505 to rituximab maintenance and 513 to observation). Median follow-up 36 months: PFS 74.9% versus 57.6% (HR 0.55, 95% CI 0.44 to 0.68; p<0.0001). OS HR 0.87 (95% CI 0.51 to 1.47). Grade 3-4 adverse events 24% versus 17%; grade 2-4 infections 39% versus 24%.

  163. 2010 · Treatment · Melanoma

    Ipilimumab: anti-CTLA-4 survival trials and FDA approval (2010-2011)

    Ipilimumab, an antibody that releases a brake on T cells, was tested in two large trials. In previously treated metastatic melanoma it was linked to longer survival than a vaccine control, and in untreated disease it was linked to longer survival when added to dacarbazine. The FDA approved it in March 2011. Serious immune-related side effects occurred.

    MDX010-20 (n=676, previously treated, HLA-A*0201-positive): median OS 10.0 vs 6.4 months for ipilimumab 3 mg/kg plus gp100 vs gp100 alone (HR 0.68; P<0.001); ipilimumab alone 10.1 months (HR 0.66; P=0.003). CA184-024 (n=502, untreated): ipilimumab 10 mg/kg plus dacarbazine vs dacarbazine plus placebo, median OS 11.2 vs 9.1 months (HR 0.72; P<0.001); grade 3 or 4 adverse events 56.3% vs 27.5%. Pooled analysis of 1,861 patients: 3-year survival 22%.

  164. 2010 · De-escalation · Neuroblastoma and Wilms tumour

    Intermediate-risk neuroblastoma: reduced chemotherapy (COG A3961)

    In 2010 the Children's Oncology Group reported that children with intermediate-risk neuroblastoma, given fewer and lower-dose chemotherapy cycles chosen by tumour biology, had about 96 in 100 alive at three years. This was a single-group study, not a head-to-head comparison with longer treatment.

    COG A3961: prospective, phase 3, nonrandomised trial (1997 to 2005) of 479 eligible patients with intermediate-risk neuroblastoma without MYCN amplification, assigned to four or eight cycles of reduced-dose chemotherapy by tumour biology. Goal: 3-year overall survival above 90%. Result: 96% overall (95% CI 94 to 97), 98% with favorable and 93% with unfavorable biologic features; 3-year EFS 88%. Severe adverse events without progression: 10 patients (2.1%). No comparison arm.

  165. 2010 · Treatment · Neuroblastoma and Wilms tumour

    Anti-GD2 dinutuximab with cytokines after transplant (ANBL0032)

    In a randomized trial of children with high-risk neuroblastoma who had responded to earlier treatment, adding an antibody against GD2 and two cytokines to isotretinoin was linked to better outcomes. After two years about two in three children in the antibody group were free of relapse, progression or other events, compared with fewer than half given isotretinoin alone.

    COG ANBL0032: 226 eligible patients with high-risk neuroblastoma responding to induction and transplant, randomized 1:1 to isotretinoin alone or with ch14.18 (dinutuximab), GM-CSF and IL-2. Stopped early for efficacy: 2-year EFS 66% vs 46% (P=0.01); OS 86% vs 75% (P=0.02, unadjusted for interim analyses). Long-term follow-up: 5-year EFS 56.6% vs 46.1% (P=0.042); OS 73.2% vs 56.6% (P=0.045). FDA approval 10 March 2015.

  166. 2010 · Treatment · Ovarian cancer

    Neoadjuvant chemotherapy vs primary surgery: EORTC 55971, CHORUS

    Two large randomised trials, reported in 2010 and 2015, compared starting with surgery against giving chemotherapy first and operating afterwards. Survival with chemotherapy first was not shown to be worse, and complications after surgery were less frequent. Both trials enrolled women with advanced disease.

    EORTC 55971 (670 randomised, stage IIIC or IV): hazard ratio for death with neoadjuvant chemotherapy and interval debulking versus primary debulking 0.98 (90% CI 0.84 to 1.13; P=0.01 for non-inferiority). CHORUS (552 randomised): median overall survival 22.6 months with primary surgery versus 24.1 months with primary chemotherapy; hazard ratio 0.87 (95% CI 0.72 to 1.05), non-inferiority limit 1.18.

  167. 2010 · Reversal · Pancreatic cancer

    Bevacizumab, cetuximab, PEGPH20 added to chemotherapy: no gain

    Three large trials added a targeted drug to chemotherapy in advanced pancreatic cancer: bevacizumab, cetuximab and PEGPH20. None lengthened survival. Median survival with bevacizumab was about 5.8 months versus 5.9 with placebo, and in the PEGPH20 trial about 11.2 versus 11.5 months.

    Three phase 3 trials, each with overall survival as primary endpoint, were negative. CALGB 80303 (gemcitabine +/- bevacizumab, 602 enrolled): median OS 5.8 vs 5.9 months (P=.95). S0205 (gemcitabine +/- cetuximab, 745 eligible): 6.3 vs 5.9 months, HR 1.06 (0.91-1.23). HALO 109-301 (nab-paclitaxel-gemcitabine +/- PEGPH20, 492 ITT): 11.2 vs 11.5 months, HR 1.00 (0.80-1.27).

  168. 2010 · Treatment · Prostate cancer

    Sipuleucel-T autologous cellular immunotherapy (IMPACT)

    Sipuleucel-T is an immunotherapy made from a patient's own blood cells. In the IMPACT trial of 512 men with metastatic castration-resistant prostate cancer, median survival was 25.8 months with sipuleucel-T and 21.7 months with placebo. The FDA licensed it in April 2010; the EU authorisation was withdrawn in 2015 at the manufacturer's request.

    IMPACT: double-blind, placebo-controlled phase 3, n=512 (2:1), metastatic castration-resistant prostate cancer; sipuleucel-T versus placebo, three infusions every 2 weeks. Median OS 25.8 versus 21.7 months, HR 0.78 (95% CI 0.61-0.98; P=0.03; Cox model adjusted for PSA and LDH); 36-month survival 31.7% versus 23.0%; time to objective progression similar. FDA licensure memo 29 April 2010; EU authorisation 6 September 2013, withdrawn 6 May 2015.

  169. 2010 · Treatment · Prostate cancer

    Cabazitaxel after docetaxel (TROPIC)

    TROPIC compared cabazitaxel plus prednisone with mitoxantrone plus prednisone in 755 men whose metastatic castration-resistant prostate cancer had progressed during or after docetaxel. Median survival was 15.1 months with cabazitaxel and 12.7 months with mitoxantrone. The FDA approved cabazitaxel on 17 June 2010.

    TROPIC: open-label phase 3, n=755, post-docetaxel mCRPC; cabazitaxel 25 mg/m2 versus mitoxantrone 12 mg/m2, each with prednisone. Final OS 15.1 (95% CI 14.1-16.3) versus 12.7 months (11.6-13.7), HR 0.70 (0.59-0.83; P<0.0001); PFS 2.8 versus 1.4 months. Grade 3 or higher neutropenia 82% versus 58%; febrile neutropenia 8% versus 1%. PROSELICA (n=1200): 20 versus 25 mg/m2 met non-inferiority.