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Bending the Curve Trial by Trial
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1976–1997

Molecular origins

Visual dialect: chromosome banding, gel bands. Eras are a storytelling frame, not a historical claim.

  1. 1976 · Understanding · Acute myeloid leukaemia (including APL)

    FAB proposals classify the acute leukaemias by morphology

    In 1976 seven haematologists from France, the United States and Britain examined about 200 cases of acute leukaemia under the microscope and proposed a common naming system. They divided acute leukaemia into lymphoblastic and myeloid types, with three and six subgroups, and described conditions that can be mistaken for acute myeloid leukaemia.

    Bennett 1976 (FAB co-operative group): seven haematologists reviewed peripheral blood and bone marrow films from some 200 acute leukaemia cases, independently and then together, using conventional morphological and cytochemical methods. They proposed lymphoblastic and myeloid groups, subdivided into three and six subgroups, and considered dysmyelopoietic syndromes that may be confused with AML. No outcome data are reported in the abstract.

  2. 1976 · Treatment · Bladder cancer

    Intravesical BCG for recurrent superficial bladder tumours

    In 1976 a series reported giving BCG, a bacterial preparation, into the bladder and under the skin of people whose superficial bladder tumours kept returning. The pattern of recurrence changed favourably in nine patients, and the authors called the findings preliminary.

    Treated series, no comparison group mentioned in the abstract: patients with recurrent superficial bladder tumours received vesical and intradermal BCG. In 9 patients the pattern of recurrence was altered favourably; the authors called the findings preliminary and said they appeared to hold promise of a new therapeutic approach. The four-sentence abstract does not say how many patients were treated in all and gives no rates, intervals or follow-up.

  3. 1976 · Treatment · Breast cancer

    Adjuvant CMF chemotherapy after mastectomy (Milan, 1976)

    In Milan, women with cancer in the armpit lymph nodes after mastectomy were randomly given either no further treatment or a year of combination chemotherapy. The first report, after twenty-seven months, described an advantage for chemotherapy in treatment failure. A twenty-year follow-up found better relapse-free and overall survival.

    Milan trial of 386 women with axillary node-positive breast cancer after radical mastectomy: 12 monthly cycles of CMF vs no further treatment. 1976 report at 27 months: treatment failure in 5.3% with CMF vs 24% of controls (term as worded in the journal abstract). 20-year follow-up (median 19.4 years): relative risk of relapse 0.71 (95% CI 0.56-0.90; P=0.004) and of death 0.78 (95% CI 0.62-0.99; P=0.04); benefit in all subgroups except postmenopausal women.

  4. 1976 · Understanding · Foundations

    Viral oncogene traced to a normal cellular gene (1976)

    In 1976 Stehelin, Varmus, Bishop and Vogt reported that DNA related to the cancer-causing gene of avian sarcoma viruses is present in normal bird DNA. The result showed that such viral genes were copies of normal cellular genes that control growth, and it started a wider search for similar genes.

    Nucleic-acid probe study (Nature 1976): DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. The Nobel Committee (1989) states that Bishop and Varmus concluded that the viral oncogene is a normal cellular gene acquired by the virus; oncogene-like sequences were found throughout the animal kingdom; more than 40 oncogenes had been identified by 1989. Bishop and Varmus received the 1989 Nobel Prize in Physiology or Medicine.

  5. 1976 · Treatment · Non-Hodgkin lymphoma (DLBCL and follicular)

    CHOP and HOP chemotherapy in advanced lymphoma (McKelvey, 1976)

    A 1976 report described people with pathologically staged, advanced non-Hodgkin lymphoma treated with CHOP, a four-drug combination, or with the three-drug HOP. Of those who could be evaluated, 71 in 100 given CHOP and 61 in 100 given HOP had a complete remission. A 1993 trial later used CHOP as its comparison regimen.

    Series of pathologically staged advanced non-Hodgkin's lymphoma treated with CHOP (204 evaluable patients) or HOP (216 evaluable). Complete remission 71% (CHOP) and 61% (HOP); overall response 92% and 88%. Complete remission, nodular vs diffuse: 78% vs 67% (CHOP), 67% vs 60% (HOP). Remission maintenance with COP or OAP; projected 1-year disease-free 86% and 80%.

  6. 1976 · Treatment · Neuroblastoma and Wilms tumour

    NWTS-1: randomised trial of radiotherapy and chemotherapy

    The first National Wilms' Tumor Study began in 1969 and randomised children to different combinations of surgery, radiotherapy and chemotherapy. Its 1976 report found that actinomycin D plus vincristine gave better results than either drug alone for children whose tumours were still confined to the abdomen. All of those children also had radiotherapy.

    NWTS-1 (begun 1969): 606 registered, 359 randomised, groups I to IV. Group I under 2 years: postoperative radiotherapy or none after 15 months of actinomycin D; both fared well. Groups II and III (all given postoperative radiotherapy): actinomycin D plus vincristine gave better results than either drug alone. Group IV: preoperative vincristine did not improve results. Mesoblastic nephroma 1%, bilateral tumours 5%, incorrect preoperative diagnosis 5%. The abstract gives no relapse or survival figures.

  7. 1976 · Detection · Testicular germ cell tumors

    Serial hCG and AFP measured to monitor germ-cell tumours

    A 1976 report in Cancer followed nine people with germ-cell tumours, measuring two blood proteins, hCG and AFP, repeatedly during treatment. In all nine, one or both proteins helped follow the disease. In two people the tumour masses did not shrink while the markers fell, and surgery found mature teratoma.

    Perlin E et al., Cancer 1976: case series of nine patients with germinal cell tumours; serial hCG and AFP by double-antibody radioimmunoassay before and during treatment. Eight had an hCG marker and five an AFP marker, four both. Serial values were useful for monitoring disease activity during therapy in all nine. In two, masses did not diminish during chemotherapy while markers fell; surgery showed mature teratoma (one with a microscopic embryonal focus). Primary sites are not stated in the abstract.

  8. 1977 · Understanding · Acute myeloid leukaemia (including APL)

    t(15;17) and the PML-RARA fusion in acute promyelocytic leukemia

    In 1977 a short Lancet report titled "15/17 translocation, a consistent chromosomal change in acute promyelocytic leukaemia" reported the chromosome change. In 1990 and 1991 laboratories showed that the swap fuses the retinoic acid receptor alpha gene on chromosome 17 to a gene on chromosome 15, later named PML.

    Rowley, Golomb and Dougherty (Lancet 1977; indexed as a letter; no abstract available, title only): "15/17 translocation, a consistent chromosomal change" in APL. Borrow 1990: breakpoints in ten APL cases clustered in a 12 kb region within the first intron of RARA; the abstract states the translocation is present in almost 100 percent of cases. de Thé 1990: RARA and/or the chromosome 15 locus rearranged in 6 of 8 patients. Kakizuka and de Thé 1991 described the PML-RARA fusion.

  9. 1977 · Treatment · Testicular germ cell tumors

    PVB: high remission rates in disseminated testis cancer (1977)

    In 1977, 50 patients with disseminated testicular cancer were treated with cisplatin, vinblastine and bleomycin. Of those who could be assessed, about three in four had a complete remission and a quarter a partial remission. In a 2002 review, the lead author wrote that these studies changed the cure rate for disseminated disease from 5% to 60%.

    Single-arm series: 50 patients with disseminated testicular cancer given PVB (cisplatin, vinblastine, bleomycin); 3 inevaluable (early death). Complete remission 74%, partial remission 26%; 85% disease-free after surgery for residual disease in 5 patients with partial remission. Two drug-related deaths. At 6+ to 30+ months, 38 patients alive and 32 alive and disease-free. Uncontrolled; short follow-up.

  10. 1978 · Treatment · Glioblastoma

    Randomised trials of postoperative radiotherapy and nitrosoureas

    A 1978 report randomised 303 people operated on for anaplastic glioma to best conventional care, carmustine, radiotherapy, or both. Median survival was 14 weeks with best conventional care and about 35 weeks with radiotherapy. A 1980 report in 467 people with malignant glioma suggested that radiotherapy is best used after surgery.

    Walker 1978 (303 randomised, 222 in the valid study group; anaplastic glioma): median survival 14 weeks with best conventional care, 18.5 BCNU, 35 radiotherapy, 34.5 BCNU plus radiotherapy; all active arms showed some statistical superiority over best conventional care. Walker 1980 (467 randomised, 358 valid study group; malignant glioma): radiotherapy with or without a nitrosourea improved survival over semustine alone; carmustine plus radiotherapy gave the best survival, not significantly different from semustine plus radiotherapy.

  11. 1978 · Understanding · Neuroblastoma and Wilms tumour

    NWTS-1 histology: anaplastic and sarcomatous tumours fare worse

    In 1978 pathologists reviewing 427 tumours from the first National Wilms' Tumor Study found that tumours with markedly abnormal cells (anaplasia) or mostly sarcoma-like tissue were linked to worse outcomes. About 57 in 100 of those children died of tumour, compared with about 7 in 100 of the rest. Later studies stratified treatment by favourable or unfavourable histology.

    Detailed histological analysis of 427 NWTS-1 cases: 25 with anaplasia and 24 with predominantly sarcomatous lesions, of which 28 (57.1%) died of tumour, versus 26 of 378 (6.9%) with neither feature. Seven of ten tumour deaths in patients diagnosed before 2 years were associated with sarcomatous lesions. A 'clear cell' sarcoma pattern had a predilection for bony metastases. NWTS-5 anaplasia: 4-year EFS 69.5% in stage I versus 92.4% in stage I favourable histology.

  12. 1979 · Treatment · Acute myeloid leukaemia (including APL)

    Allogeneic transplant in first remission of AML

    A 1979 paper reported marrow transplantation for acute non-lymphoblastic leukaemia in first remission. A 1995 European trial found the fewest relapses but the highest mortality after allogeneic transplant, with similar overall survival. A 2009 pooled analysis found a survival benefit of transplant for intermediate- and poor-risk disease, but not for good-risk disease.

    Zittoun 1995 (EORTC/GIMEMA; 623 in remission): allogeneic transplant assigned by sibling donor, others randomised to autologous transplant or intensive chemotherapy; projected 4-year DFS 55%, 48% and 30%, overall survival similar. Koreth 2009 meta-analysis (24 trials, 6007 patients), donor versus no donor: RFS HR 0.80 (95% CI 0.74-0.86), OS HR 0.90 (0.82-0.97); OS HR good-risk 1.07 (0.83-1.38), intermediate 0.83, poor 0.73. Thomas 1979: title only.

  13. 1979 · Treatment · Chronic myeloid leukemia

    Marrow transplant in CML: identical twins, then matched siblings

    In 1979 doctors reported four people with chronic myeloid leukaemia who received marrow from a healthy identical twin after intensive treatment; no leukaemic cells with the Philadelphia chromosome were found afterwards. In 1986 a larger series of seventy people given marrow from matched siblings reported about seven in ten chronic-phase patients alive at two years.

    Fefer 1979: four patients (CGL history 12, 10, 11 and 106 months) given dimethyl busulfan, cyclophosphamide and 920 rads total-body irradiation, then syngeneic marrow; no Ph1-positive cells afterwards; haematologically normal 22 to 31 months. Goldman 1986: HLA-identical sibling allografts (Feb 1981 to Dec 1984). Chronic phase (n=52): actuarial 2-year survival 72%, relapse risk 7%. Advanced phase (n=18): 18% and 42%.

  14. 1979 · Understanding · Foundations

    p53 discovered, then shown to be a tumour suppressor gene

    In 1979 two groups reported a cellular protein, later called p53, associated with a tumour virus protein in transformed cells. It was first thought to promote cancer. Studies a decade later showed that p53 is a tumour suppressor: its gene was mutated in colorectal tumours and in families with the inherited Li-Fraumeni syndrome.

    1979 (Lane and Crawford, Nature; Linzer and Levine, Cell): a 54K dalton host protein associated with SV40 T antigen in transformed cells; Linzer and Levine also found it in uninfected embryonal carcinoma cells. 1989: 17p deletions in over 75% of colorectal carcinomas; the remaining p53 allele was mutated in both tumours sequenced (codons 143, 175). 1990: germ line p53 mutations in all five Li-Fraumeni families analysed. p53 is a tumour suppressor, not an oncogene (Levine and Oren 2009).

  15. 1979 · Detection · Prostate cancer

    PSA: from purified antigen to serum marker and screening test

    In 1979 researchers reported purifying a prostate-specific antigen. In 1987 a study reported that blood levels of it rose with prostate cancer stage and fell after surgery. A 1991 study of men aged 50 or older tested it as a screening tool. Whether screening saves lives was tested later in randomised trials.

    Stamey 1987 (699 patients, 378 with prostatic cancer): PSA elevated in 122 of 127 with newly diagnosed untreated cancer and in 86% of men with benign prostatic hyperplasia; after radical prostatectomy it fell to undetectable levels (half-life 2.2 days). Catalona 1991 (1653 men aged 50 or older): PSA 4.0 micrograms per litre or higher led to rectal examination and ultrasonography; cancer in 22% of biopsied men with PSA 4.0-9.9 and 67% with 10.0 or higher. Neither abstract reports mortality.

  16. 1980 · Treatment · Endometrial cancer

    Adjuvant pelvic radiotherapy: less recurrence, no survival gain shown

    After surgery for early endometrial cancer, several randomised trials reported from 1980 onwards tested adding radiotherapy to the whole pelvis. It lowered the chance of the cancer returning in the pelvis or vagina, but the trials did not show that women lived longer, and PORTEC-1 recorded more treatment-related complications.

    Randomised trials of adjuvant pelvic radiotherapy versus no further treatment after surgery for early-stage disease. PORTEC-1 (stage 1; 714 evaluable): 5-year locoregional recurrence 4% vs 14% (p<0.001); 5-year OS 81% vs 85% (p=0.31). GOG-99 (392 eligible): 2-year cumulative incidence of recurrence 3% vs 12%; 4-year survival 92% vs 86% (p=0.557). ASTEC/EN.5 (905): OS HR 1.05 (95% CI 0.75-1.48). Radiotherapy vs control in each.

  17. 1981 · Treatment · Acute myeloid leukaemia (including APL)

    Cytarabine with an anthracycline: CALGB trials in AML, 1981-82

    In 1981 and 1982 the Cancer and Leukemia Group B reported randomised treatment of patients with acute myeloid leukaemia. The 1982 report gave cytarabine as a seven-day infusion with daunorubicin or doxorubicin on three days. Remission rates depended on the drug, its dose and age: about seven in ten for people under 60 on the best arm.

    Yates 1982 (CALGB): randomised daunorubicin 30 or 45 mg/m2 or adriamycin 30 mg/m2 on days 1-3 with cytarabine 100 mg/m2/day, 7-day infusion. Complete remission, age under 60: 72% (daunorubicin 45), 59% (daunorubicin 30), 58% (adriamycin 30). Age over 60: 47% (daunorubicin 30), 31% (daunorubicin 45), 35% (adriamycin 30). Induction mortality shifted correspondingly. Rai 1981 (CALGB, Blood) has no PubMed abstract.

  18. 1981 · De-escalation · Breast cancer

    Breast conservation vs mastectomy: Milan I, NSABP B-04 and B-06

    For most of the twentieth century, removing the whole breast was the standard operation for early breast cancer. Randomised trials from Milan and from the NSABP group found that removing only the tumour area, with radiotherapy, gave survival that did not differ significantly from mastectomy. Local recurrence was more common after the breast-conserving operation in the Milan trial.

    Milan I (701 women, tumours up to 2 cm, no palpable axillary nodes): at median 20 years, breast cancer death 26.1% with quadrantectomy plus radiotherapy vs 24.3% with Halsted mastectomy (P=0.8); local recurrence 8.8% vs 2.3% (P<0.001). NSABP B-06 at 20 years: overall survival HR 1.05 (95% CI 0.90-1.23) for lumpectomy and 0.97 (0.83-1.14) for lumpectomy plus irradiation vs total mastectomy; ipsilateral recurrence 14.3% with vs 39.2% without irradiation.

  19. 1981 · Understanding · Chronic lymphocytic leukaemia

    Binet staging for CLL: three prognostic groups (A, B, C)

    In 1981 Binet and colleagues proposed three prognostic groups for CLL: A with few involved areas, B with more, and C with anaemia or low platelets. Median survival was about 7 years in group B and 2 years in group C. A 1977 Binet paper on clinical staging is cited by title only.

    Binet 1977 (title only, no abstract): a clinical staging system for CLL. Binet 1981: 99 retrospective and 196 prospective patients; Cox analysis; three groups. C: anaemia (Hb under 10 g) or platelets under 100,000/mm3, about 15%, median survival 2 years. B: three or more involved areas, about 30%, 7 years. A: fewer areas, about 55%. Confirmed in a series of 146 patients.

  20. 1981 · Understanding · Hepatocellular carcinoma

    Prospective cohort ties hepatitis B carriage to HCC risk

    In 1981, researchers reported following more than 22,000 men in Taiwan. Men who carried the hepatitis B virus developed liver cancer far more often than men who did not. Because infection was measured before the cancer appeared, the study strengthened the case that the virus contributes to liver cancer and that preventing infection could prevent cancer.

    Prospective cohort of 22,707 men in Taiwan. Figures below are quoted from a 2018 appraisal, not from the 1981 paper: 3,454 (15.2%) were HBsAg-positive at entry; average follow-up 3.3 years; HCC incidence 1158 per 100,000 person-years in HBsAg-positive men versus 5 in HBsAg-negative men (relative risk 223, 95% CI 28 to 1479); 41 HCC deaths in total.

  21. 1981 · Treatment · Sarcoma and GIST

    Intergroup Ewing's Sarcoma Studies: multimodal therapy

    Two intergroup studies tested chemotherapy for Ewing sarcoma of bone, given with radiation and surgery. In the first, reported in 1981, adding doxorubicin or lung radiotherapy to a three-drug regimen did better. In the second, reported in 1990, a high-dose intermittent four-drug schedule beat a moderate-dose continuous one at five years, with more heart toxicity.

    IESS-II (214 patients, localized nonpelvic Ewing's sarcoma): high-dose intermittent vs moderate-dose continuous doxorubicin, cyclophosphamide, vincristine, dactinomycin. At 5 years, disease-free 68% vs 48% (P=.02), relapse-free 73% vs 56% (P=.03), surviving 77% vs 63% (P=.05); more severe cardiovascular toxicity with the intermittent schedule. IESS-I (first reported 1981; 1990 follow-up of 342 children): 5-year relapse-free survival 60% with doxorubicin added, 24% without, 44% with pulmonary radiotherapy.

  22. 1982 · Understanding · Chronic myeloid leukemia

    BCR-ABL: from a translocated gene to leukemia in mice (1982-1990)

    Between 1982 and 1990 laboratories traced the Philadelphia chromosome to the genes involved. The ABL gene moves from chromosome 9 to chromosome 22 next to a region called BCR, the two genes are read as one fused RNA, and in 1990 mice that received bone marrow carrying the fused gene developed several blood cancers, including one closely resembling chronic-phase CML.

    Laboratory studies, no trial data. 1982: c-abl sequences translocated from chromosome 9 to 22q- (somatic cell hybrids). 1983: Ph breakpoint position variable; in one patient immediately 5' of or within c-abl. 1984: breakpoints within up to 5.8 kb (bcr) in 17 of 19 patients (the other 2 lacked Ph). 1985: 8-kb CML-specific RNA shown to be a fused abl-bcr transcript. 1990: P210bcr/abl in murine marrow gave a myeloproliferative syndrome resembling chronic-phase CML.

  23. 1982 · Treatment · Colorectal cancer

    Heald reports total excision of the mesorectum (1982)

    In 1982 R. J. Heald reported five patients with small deposits of cancer in the fatty tissue around the rectum, several centimetres below the visible tumour. He removed that tissue, the mesorectum, as part of over a hundred consecutive operations. A later historical review describes total mesorectal excision, developed by Heald in 1982, as the present gold standard.

    Heald, Br J Surg 1982 (case series, no control group): five cases had tumour foci in the mesorectum distal to the primary; total excision of the mesorectum was part of over 100 consecutive anterior resections, and 50 curative or conceivably curative operations followed for over 2 years had no pelvic or staple-line recurrence. Heald and Ryall, Lancet 1986 (consecutive series): 115 patients with curative resection attempted, three pelvic recurrences at an average of 4.2 years; corrected cumulative 5-year survival 87%.

  24. 1982 · Understanding · Pancreatic cancer

    Monoclonal antibodies detect an antigen in pancreatic cancer sera

    In 1982 researchers reported that monoclonal antibodies, including one named 19-9, bind colorectal, gastric and pancreatic cancer cells. In a serum assay with another, 52a, 45 of 49 samples from people with pancreatic cancer were positive versus 2 of 108 healthy donors. A 1990 review called CA 19-9 the most useful blood test in pancreatic cancer.

    Herlyn 1982 (J Clin Immunol): three hybridoma antibodies, including 19-9 and 52a, bound colorectal, gastric and pancreatic carcinoma cells in culture. In a serum inhibition assay with antibody 52a, binding fell by more than 12% with 45 of 49 pancreatic carcinoma sera versus 2 of 108 healthy donors. Steinberg 1990 (review abstract): at 37 U/ml, sensitivity about 80%, specificity 90%.

  25. 1982 · Treatment · Prostate cancer

    LHRH agonists and medical castration (Tolis, 1982)

    In 1982 a small study of ten men with prostate cancer reported that daily doses of LHRH agonists, given by injection or nasally, lowered average testosterone by 75% by the third week, with clinical improvement in some men. The authors suggested the drugs could become an alternative to surgical castration and estrogen therapy.

    Tolis et al., PNAS 1982: ten men with prostatic carcinoma (six stage C, four stage D) given LH-RH agonist analogues for 6 weeks to 12 months; mean plasma testosterone fell 75% by week 3, acid phosphatase fell or normalized by month 2, and serum alkaline phosphatase fell 47% by week 10 in all but one patient. Uncontrolled series. HERO (2020, n=930 treated): sustained castration at 48 weeks 96.7% with oral relugolix versus 88.8% with leuprolide.

  26. 1982 · Treatment · Sarcoma and GIST

    Preoperative chemotherapy tailors osteosarcoma treatment

    In a 1982 series of 57 people with osteosarcoma of a limb, chemotherapy was given before surgery. The removed tumour showed how well it had responded, and that result guided the chemotherapy given afterwards. Most people stayed free of recurrence during follow-up of up to about three years.

    Non-randomised series (n=57, primary osteogenic sarcoma of an extremity): preoperative high-dose methotrexate with citrovorum rescue, doxorubicin and BCD for 4-16 weeks; postoperative regimen chosen by histologic response. Of 35 patients without a good response, given a cisplatin-containing regimen, 32 (91%) were continuously disease-free at 6-34 months. Overall 53 of 57 (93%) were continuously disease-free at 6-35 months (median 20).

  27. 1982 · De-escalation · Sarcoma and GIST

    Randomised trial: limb-sparing surgery plus radiotherapy vs amputation

    In a randomised trial of 43 adults with high-grade sarcoma of an arm or leg, limb-sparing surgery with radiotherapy was compared with amputation; everyone also had chemotherapy. Five-year survival was similar (83% and 88%). Cancer returned locally in four people who kept the limb and in none who had amputation.

    Randomised 2:1 (N=43, high-grade extremity STS): limb-sparing resection plus radiotherapy (n=27) vs amputation (n=16); all received postoperative doxorubicin, cyclophosphamide and high-dose methotrexate. Local recurrence 4 vs 0 (p1 = 0.06). Five-year DFS 71% vs 78% (p2 = 0.75); OS 83% vs 88% (p2 = 0.99). Multivariate analysis: final margin was the only correlate of local recurrence.

  28. 1982 · Understanding · Testicular germ cell tumors

    Distribution of nodal metastases in non-seminoma (Donohue, 1982)

    In 1982 Donohue and colleagues published a report on how non-seminoma testis cancer is distributed in the lymph nodes behind the abdomen. The paper has no abstract in the medical literature database, so its findings are not described here.

    Donohue JP, Zachary JM, Maynard BR, 'Distribution of nodal metastases in nonseminomatous testis cancer', J Urol, August 1982. No abstract in PubMed; the text was not read, so no findings or numbers are recorded. Donohue's 2003 historical review states that RPLND for low-stage disease has been reduced to modified templates and nerve-sparing techniques.

  29. 1982 · Understanding · Testicular germ cell tumors

    i(12p) proposed as a specific change in testicular tumours

    In 1982 a short letter in The Lancet asked whether a particular chromosome change, an isochromosome of the short arm of chromosome 12 written i(12p), is specific to testicular tumours. A fuller 1983 report found a small marker chromosome in ten seminomas, one mixed tumour and one malignant teratoma.

    Atkin NB and Baker MC, Lancet 1982: letter asking whether i(12p) is a specific chromosome change in testicular tumours (title only; text not read). Fuller report, Cancer Genet Cytogenet 1983: a small marker chromosome, often in duplicate, in each of ten seminomas, one combined seminoma and teratoma, and one malignant teratoma; identified as i(12p) in the four most favourable tumours, all seminomas. The authors suggest it may be specific to malignant testicular tumours.

  30. 1983 · Treatment · Chronic myeloid leukemia

    Interferon alfa in CML: early clinical reports, 1983 and 1986

    In 1983 a team reported giving human leukocyte interferon to seven people with chronic myeloid leukaemia, and five reached a hematologic remission. In 1986 a report of seventeen people given recombinant interferon found fourteen responded; in six, Philadelphia-positive cells were undetectable on at least one test. The authors called the data preliminary.

    Talpaz 1983 (Blood): partially purified human leukocyte interferon alfa, 9 to 15 million units daily intramuscularly, 7 patients; hematologic remission in 5. Talpaz 1986 (NEJM): recombinant interferon alfa A (Roferon-A), 5 million units per square metre daily, 17 Ph-positive patients; 14 responded (13 hematologic remission, 1 partial); complete suppression of Philadelphia cells at least once in 6 patients. Authors: preliminary.

  31. 1983 · Understanding · Endometrial cancer

    Bokhman: two pathogenetic types of endometrial carcinoma

    In 1983 J. V. Bokhman proposed, from a study of 366 women, that endometrial cancer arises in two different settings. One was linked to obesity and signs of high estrogen and tended to have better-differentiated tumours and better outcomes; the other lacked those features and tended to have poorly differentiated tumours and a less favourable outlook.

    Single-author prospective study (366 patients). First pathogenetic type (65%): obesity, hyperlipidaemia, hyperestrogenism signs; 82.3% G1-G2, 80.2% progestogen sensitivity, 85.6% 5-year survival. Second type (35%): 62.5% G3, 27.8% pelvic-node metastases, 42.5% progestogen sensitivity, 58.8% 5-year survival. These are the author's figures from one series, not trial results.

  32. 1983 · Understanding · Foundations

    HPV 16 and 18 found in cervical cancer (zur Hausen, 1983-1984)

    In 1983 and 1984 Harald zur Hausen's team found two new human papillomavirus types, HPV 16 and HPV 18, in biopsies of cervical cancer. Later work showed that HPV DNA is present in virtually all cervical cancers, which led to vaccines against the virus. zur Hausen received half of the 2008 Nobel Prize for the discovery.

    Dürst et al. (PNAS 1983): HPV 16 cloned from a cervical carcinoma; sequences found in 61.1% (11/18) of German and 34.8% (8/23) of Kenyan and Brazilian cervical cancer biopsies, and in 2 of 33 condylomata. Boshart et al. (EMBO J 1984): HPV 18 found in 9/36 cervical carcinomas from Africa and Brazil and 2/13 from Germany, not in benign lesions tested. Reanalysis (Walboomers 1999): HPV prevalence in cervical carcinoma 99.7%.

  33. 1983 · Origin · Gastric and gastro-oesophageal junction cancer

    H. pylori identified (1983-84), then linked to gastric cancer

    In 1983 Warren and Marshall reported curved bacteria on the stomach lining in gastritis, and their 1984 series linked them with gastritis and ulcers. Later studies tied infection with this organism, Helicobacter pylori, to stomach cancer, and in 1994 an IARC evaluation classed the infection as carcinogenic to humans.

    Warren and Marshall's 1984 series found spiral bacilli in 58 of 100 consecutive gastroscopy patients and proposed a role in gastritis and ulcer. Parsonnet 1991 (nested case-control): prior infection in 84% of 109 gastric adenocarcinoma cases versus 61% of controls (OR 3.6, 95% CI 1.8-7.3), no association for GEJ or cardia tumours. Uemura 2001: cancer in 36 of 1246 infected, none of 280 uninfected. IARC 1994: Group 1.

  34. 1983 · Treatment · Neuroblastoma and Wilms tumour

    SIOP and UK trials of preoperative chemotherapy before nephrectomy

    In Europe, children with Wilms tumour began to receive chemotherapy before surgery rather than operating first. A 1983 SIOP trial concluded that preoperative chemotherapy was as good as preoperative radiotherapy for preventing tumour rupture. A later UK trial of 205 children found that six weeks of chemotherapy first shifted tumours to a lower stage.

    SIOP 1977-1979: 164 eligible patients randomised to preoperative radiotherapy plus chemotherapy (76) or chemotherapy alone (88); authors concluded preoperative chemotherapy was as good for preventing rupture, and 43% of an unselected population could avoid radiotherapy. UKW3: 205 randomised, 186 with Wilms histology; stage III 9.8% (delayed surgery) versus 29.8% (immediate), P = 0.008 for trend; 5-year EFS 79.6% and OS 89.0%, reported as similar between groups.

  35. 1983 · Treatment · Prostate cancer

    Walsh: radical prostatectomy preserving sexual function (1983)

    A 1982 paper addressed impotence after radical prostatectomy, and a 1983 report described a modified operation designed to avoid injuring the nerves that supply the penis. Twelve men assessed two to ten months after surgery all had erections, and five of the six with partners followed for six months or longer were fully potent.

    Walsh, Lepor and Eggleston (Prostate 1983) modified radical retropubic prostatectomy: the lateral pelvic fascia is incised anterior to the neurovascular bundle and the lateral pedicle divided close to the prostate. Pathology of 16 specimens showed no compromise of surgical margins. Of 12 men assessed 2-10 months after surgery, all had erections and six achieved penetration and orgasm; five of six (83%) with partners followed 6 months or longer were fully potent.

  36. 1984 · Understanding · Chronic myeloid leukemia

    Prognostic scores for CML: Sokal, Hasford and ELTS

    Risk scores use age, spleen size and blood counts to estimate how a person with CML is likely to fare. The Sokal score (1984) came from patients treated with chemotherapy, the Hasford score (1998) from patients treated with interferon, and the ELTS score (2016) from patients treated with imatinib. A 2020 comparison found ELTS discriminated survival better than Sokal.

    Sokal 1984: 813 Ph-positive patients from six series, median survival 47 months; Cox model (blasts, spleen size, platelets, age). Hasford 1998: data on 1573 patients from 14 interferon studies; median survival 98, 65 and 42 months across three risk groups. Pfirrmann 2016: 2290 imatinib-treated patients, 8-year OS 89%, 44% of 208 deaths due to CML; long-term survival score. Pfirrmann 2020: ELTS 60% low-risk versus Sokal 40% (5154 patients).

  37. 1984 · Understanding · Neuroblastoma and Wilms tumour

    N-myc amplification linked to advanced neuroblastoma (1984)

    In 1984 researchers reported that a DNA region called N-myc (written MYCN today) was present in many extra copies in tumour tissue from 24 of 63 untreated patients with neuroblastoma, all of them with stage 3 or 4 disease. A 1985 study of 89 patients linked more copies to faster progression.

    Brodeur 1984: N-myc amplification in tumour tissue from 24 of 63 untreated patients (38%); 0 of 15 with stage 1 or 2 disease, 24 of 48 (50%) with stage 3 or 4 (P less than 0.001). Seeger 1985: 89 untreated primary tumours; estimated progression-free survival at 18 months 70%, 30% and 5% for 1, 3 to 10 and more than 10 copies (P less than 0.0001). Tissue series, not trials.

  38. 1984 · Understanding · Neuroblastoma and Wilms tumour

    Shimada classification: histology and age predict outcome

    In 1984 a pathology study of neuroblastic tumours reported that how the tumour looks under the microscope, together with the patient's age, separated tumours with a good outlook from those with a poor one. In 1999 an international committee proposed a modified version for use worldwide.

    Shimada 1984: 295 pretreatment tumours (of 641 studied) divided into stroma-poor (235) and stroma-rich (60); with age, maturation and mitosis-karyorrhexis index, favorable stroma-poor tumours had 84% survival and unfavorable 4.5%; stroma-rich subgroups ranged from 100% (well differentiated) to 18% (nodular). INPC 1999 (227 cases, six pathologists): 3-year EFS 85% with favorable and 41% with unfavorable histology.

  39. 1985 · Treatment · Bladder cancer

    MVAC: combination chemotherapy for advanced urothelial cancer

    In 1985 a series of 25 people reported that four drugs given together, methotrexate, vinblastine, doxorubicin and cisplatin, shrank advanced bladder cancer in most of them, and about half of those with measurable disease had a complete clinical remission. A later randomised trial compared the combination with cisplatin alone.

    1985 single-arm series (N=25): complete clinical remission in 12 of 24 patients with measurable lesions (50%; 95% CI 30-70%); median response duration not reached at 9.5+ months. Randomised intergroup trial (246 assessable): M-VAC vs cisplatin alone, response rate 39% vs 12% (P<0.0001), median PFS 10.0 vs 4.3 months, median OS 12.5 vs 8.2 months.

  40. 1986 · Detection · Foundations

    Organised cervical cytology screening linked to falling mortality

    Studies in the 1980s compared cervical screening programmes. Organised programmes protected women better than uncoordinated testing, screening every three years protected about as well as yearly screening, and Nordic countries with wide organised screening, such as Iceland, saw the largest falls in cervical cancer deaths.

    IARC collaborative study (1986, eight countries): relative protection higher after two or more negative smears; little difference between yearly and 3-yearly screening; screening only every 5 or 10 years appreciably less protective; organised programmes more effective than uncoordinated screening. Nordic trends (1987): cumulative mortality age 0-74 fell between 1965 and 1982, by 80% in Iceland (widest programme), 50% Finland, 34% Sweden, 25% Denmark (40% covered), 10% Norway (5% covered). Observational data.

  41. 1986 · Treatment · Sarcoma and GIST

    Randomised trials: adjuvant chemotherapy for osteosarcoma

    In 1986 a randomised study of 36 people with osteosarcoma of a limb compared chemotherapy after surgery with observation alone. Two years later, about two in three people given chemotherapy had no relapse, against about one in six who were observed. A second randomised study reported a similar direction.

    Randomised trial (36 patients, nonmetastatic high-grade osteosarcoma of the extremity, after definitive surgery): adjuvant multi-agent chemotherapy vs observation. Two-year actuarial relapse-free survival 66% vs 17% (P<0.001); similar results in 77 further patients who declined randomisation. A separate randomised trial (Eilber 1987; 59 patients, 32 vs 27) reported significantly better disease-free and overall survival with chemotherapy at median 2 years.

  42. 1987 · Understanding · Breast cancer

    HER-2/neu amplification predicts relapse and survival

    In 1987 a laboratory study of 189 breast cancers found extra copies of the HER-2/neu gene in about three in ten tumours. Having the extra copies predicted both time to relapse and overall survival, and this held after accounting for other known prognostic factors. The study did not test any treatment.

    Study of 189 primary breast cancers: HER-2/neu was amplified 2- to greater than 20-fold in 30% of tumours. Amplification was a significant predictor of overall survival and time to relapse, retained after adjustment for other prognostic factors, and had greater prognostic value than most established factors, including hormone receptor status, in node-positive disease.

  43. 1987 · Understanding · Endometrial cancer

    GOG-33: surgical-pathologic spread in stage I disease

    A Gynecologic Oncology Group study operated on over six hundred women with stage I endometrial cancer and examined how far the disease had actually spread. More than one in five had disease outside the uterus, which the authors took as support for a primary surgical approach. FIGO moved to surgical staging in 1988.

    GOG surgical-pathologic study (non-randomised; 621 patients with Stage I carcinoma; hysterectomy, bilateral salpingo-oophorectomy, selective pelvic and paraaortic lymphadenectomy, peritoneal cytology): 144 patients (22% as stated in the abstract) had disease outside the uterus; grade and depth of invasion were related to extrauterine disease. FIGO changed endometrial staging from clinical to surgical/histopathological in 1988 (Creasman and Eddy, 1990).

  44. 1987 · Treatment · Testicular germ cell tumors

    Adjuvant chemotherapy vs observation after RPLND, stage II

    After surgery to remove lymph nodes, some men with testicular cancer still had cancer in the nodes. A randomised study compared two cycles of immediate chemotherapy with careful observation and treatment only at relapse. Chemotherapy almost always prevented relapse, but relapses on observation were usually treated successfully.

    Williams 1987: 195 evaluable patients with completely resected pathological stage II testicular cancer randomised (1979-1984) after orchiectomy and RPLND to two cycles of cisplatin-based adjuvant chemotherapy (n=97) or observation with treatment at relapse (n=98). Median follow-up 4 years: relapse 6% vs 49%; 94 of 97 survived with adjuvant chemotherapy, and 93 of 98 were alive and disease-free after observation. The authors concluded outcomes were equivalent when surgery, follow-up and chemotherapy are optimal.

  45. 1987 · Treatment · Testicular germ cell tumors

    BEP versus PVB: etoposide replaces vinblastine

    In a randomised trial of 261 men with disseminated germ-cell tumours, etoposide replaced vinblastine in a cisplatin and bleomycin regimen. Among 244 evaluable patients, about 83 in 100 on the etoposide regimen and 74 in 100 on the vinblastine regimen became disease-free, a difference that was not statistically significant. Etoposide caused fewer nerve and muscle side effects.

    Randomised trial, 261 men with disseminated germ-cell tumours: cisplatin and bleomycin with vinblastine (PVB) or etoposide (BEP). Among 244 evaluable, disease-free with or without surgery 74% vs 83% (P not significant); in 157 with high tumour volume 61% vs 77% (P < 0.05). Survival was higher with etoposide (P = 0.048). Fewer paresthesias with etoposide (P = 0.02). Authors concluded the etoposide regimen was superior.

  46. 1988 · Treatment · Acute myeloid leukaemia (including APL)

    All-trans retinoic acid induces complete remission in APL

    In 1988 a paper in Blood described giving all-trans retinoic acid, a vitamin A derivative, to 24 people with acute promyelocytic leukemia. All 24 reached complete remission, and in laboratory cultures the leukemic cells of most patients tested matured into granulocytes. Eight later relapsed, after two to five months of remission. Two more series followed in 1990 and 1991.

    Uncontrolled series, abstracts only. Huang 1988: ATRA in 24 patients (16 untreated, 8 nonresponsive or resistant to prior chemotherapy), CR in all without marrow hypoplasia (one patient resistant to ATRA in vitro reached CR after low-dose cytarabine was added); 8 relapsed after 2 to 5 months of remission. Castaigne 1990: 22 patients, 14 CR, four transient responses, one failure, three early deaths. Warrell 1991: 11 patients given oral tretinoin, 9 CR, response linked to maturation of the leukemic clone.

  47. 1988 · Understanding · Head and neck cancer

    Tobacco and alcohol reported to combine in head and neck cancer risk

    Studies of people with and without mouth, throat and laryngeal cancer reported that smoking and drinking together raise risk far more than either alone: the two effects multiply rather than add. A 1988 US study estimated that the two habits together account for about three-quarters of oral and pharyngeal cancers there.

    Case-control and pooled data. Blot 1988 (1114 cases, 1268 controls): oral and pharyngeal cancer risks combined more multiplicatively than additively, over 35-fold at two or more packs and more than four drinks daily. Tuyns 1988 (1,147 male cases, 3,057 controls; larynx/hypopharynx): joint exposure consistent with a multiplicative model. Hashibe 2009 (INHANCE, 11,221 cases, 16,168 controls): greater than multiplicative, psi 2.15 (95% CI 1.53 to 3.04); PAR for tobacco or alcohol 72% (61 to 79%).

  48. 1988 · Treatment · Melanoma

    TIL plus IL-2 in metastatic melanoma: NCI preliminary report (1988)

    In 1988 a US team reported treating 20 people with metastatic melanoma with immune cells taken from their own tumours, grown in the laboratory and returned with the signalling protein interleukin-2. Some tumours shrank in about half of the people, but the authors said it was too early to know whether survival improved.

    Uncontrolled series (NEJM 1988): 20 patients with metastatic melanoma given autologous TIL and IL-2 after cyclophosphamide. Objective regression in 9 of 15 patients (60%) not previously treated with IL-2 and 2 of 5 (40%) after IL-2 failure, lasting 2 to more than 13 months. 2011 report of 93 patients: ORR 49%, 52%, 72% across three lymphodepletion regimens; actuarial OS 36% at 3 and 29% at 5 years.

  49. 1988 · De-escalation · Melanoma

    Narrower excision margins: randomised trials from 1988 to 2016

    Surgeons once took wide margins of skin around a melanoma. Randomised trials in thinner melanomas found similar outcomes with narrower margins, and in one trial fewer skin grafts. A largely UK trial in thicker melanomas found more local and nearby-node recurrence with a 1 cm margin than with 3 cm, and a later analysis reported more melanoma deaths.

    Melanoma up to 2 mm: 1 cm vs 3 cm margins (305 vs 307 patients) gave similar disease-free and overall survival; 2 cm vs 5 cm (989 patients, 0.8-2.0 mm) overall survival HR 0.96 (95% CI 0.75-1.24). 1-4 mm: 2 cm vs 4 cm, 10-year survival 70% vs 77% (not significant). Melanoma of 2 mm or more, 1 cm vs 3 cm (900 patients): locoregional recurrence HR 1.26 (1.00-1.59); melanoma deaths in the long-term analysis HR 1.24 (1.01-1.53).

  50. 1988 · Understanding · Neuroblastoma and Wilms tumour

    International Neuroblastoma Staging System and response criteria

    In 1988 an international group agreed shared rules for diagnosing and staging neuroblastoma and for judging response to treatment, so that studies from different countries could be compared. The rules were revised in 1993 and the response criteria again in 2017.

    Consensus statement (J Clin Oncol 1988): diagnostic criteria, the International Neuroblastoma Staging System (INSS) and International Neuroblastoma Response Criteria (INRC), agreed by major groups in the United States, Europe and Japan. 1993 revisions: midline redefinition, age and marrow restrictions for stage 4S, MIBG scanning recommended. 2017 revision (13 countries): MIBG or FDG-PET, RECIST and standardised marrow assessment; marrow with 5% or less tumour is minimal disease.

  51. 1988 · Understanding · Pancreatic cancer

    c-K-ras codon 12 mutations in 21 of 22 pancreatic carcinomas

    In 1988 a laboratory study tested 22 carcinomas of the exocrine pancreas and found a change in the c-K-ras gene, at codon 12, in 21 of them. Where metastases were also tested (seven cases), they carried it too. Normal tissue did not. The authors judged it critical in most, if not all, such cancers.

    Almoguera 1988 (Cell): PCR amplification with RNase A mismatch cleavage, on frozen and formalin-fixed paraffin-embedded specimens. 21 of 22 exocrine pancreatic carcinomas had c-K-ras codon 12 mutations; in 7 cases tested, both primary tumour and metastasis carried it. None in normal tissue from the same patients or in 5 gallbladder carcinomas. The authors concluded somatic activation is critical in most, if not all, such cancers.

  52. 1988 · Treatment · Sarcoma and GIST

    Intergroup Rhabdomyosarcoma Studies I to IV: successive protocols

    Four successive cooperative-group studies enrolled children and young people with rhabdomyosarcoma between 1972 and 1997. In the first, 5-year survival was 55% among 686 patients. In the fourth, three chemotherapy combinations gave similar 3-year failure-free survival (75% to 77%) in patients without metastases.

    Four sequential Intergroup Rhabdomyosarcoma Studies (IRS-I enrolled patients younger than 21 years). IRS-I (N=686): 5-year OS 55%; 52% in clinical group III, 20% in group IV. IRS-II (N=999): 5-year OS 63%. IRS-III (N=1062): 5-year PFS 65% vs 55% in IRS-II (historical comparison, P<.001). IRS-IV, nonmetastatic (N=883): 3-year FFS 75% (VAC), 77% (VAI), 77% (VIE); P=.42.

  53. 1988 · Treatment · Testicular germ cell tumors

    Nerve-sparing retroperitoneal lymphadenectomy to preserve ejaculation

    Lymph node surgery in the back of the abdomen can damage nerves that control ejaculation. A 1988 series described identifying and sparing individual nerves during a full bilateral dissection. The technique was feasible in two of three consecutive patients, and nine in ten of those men could still ejaculate.

    Jewett 1988 (30 consecutive patients, retroperitoneal lymphadenectomy for testis tumour): nerve-sparing bilateral dissection was technically feasible in 20 of 30, and was impractical with extensive gross disease. Of the 20, 18 (90%) ejaculated; the 20 included 8 with bulky (5 cm or more) residual retroperitoneal disease and 12 with nonbulky disease, all of whom ejaculated. No retroperitoneal recurrences with short follow-up.

  54. 1989 · De-escalation · Neuroblastoma and Wilms tumour

    NWTS-3 and NWTS-4: shorter and pulse-intensive chemotherapy

    Two US trials asked whether children with Wilms tumour could safely have less treatment. NWTS-3 (reported 1989) concluded that less intensive treatment did not worsen results for low-risk children. NWTS-4 (reported 1998) found that giving dactinomycin (and, in high-risk disease, doxorubicin) as a single dose per course, and stopping chemotherapy at six months rather than 15, gave similar relapse-free survival.

    NWTS-3: 1,439 eligible, randomised by stage and histology; 4-year survival 96.5% (607 stage I FH), 92.2% (278 stage II FH), 86.9% (275 stage III FH), 73.0% (279 high-risk); less intensive therapy did not worsen low-risk results. NWTS-4: 2-year RFS, pulse-intensive versus divided-dose, 91.3% v 91.4% (low-risk) and 87.3% v 90.0% (high-risk); 4-year RFS, 6 versus 15 months, 83.7% v 88.2% (low-risk) and 89.7% v 88.8% (high-risk FH).

  55. 1989 · De-escalation · Testicular germ cell tumors

    Three cycles of BEP for good-prognosis disease

    In a randomised trial of 184 patients with favourable-prognosis disseminated germ-cell tumours, three courses of cisplatin, etoposide and bleomycin gave results similar to four: about nine in ten patients in each group were continuously disease-free. The authors preferred three courses, and 10-year follow-up from one centre showed no significant survival difference.

    Southeastern Cancer Study Group randomised phase III, 184 patients with favourable-prognosis (minimal or moderate extent) disseminated germ cell tumours: 3 vs 4 courses of BEP. Initial disease-free status 98% (86/88) vs 97% (93/96); continuously disease-free 92% vs 92% (81/88; 88/96); 10 relapses, 5 per arm. Indiana follow-up (118 patients, median 10.1 years): OS P = .80, DFS P = .93. Authors preferred three courses.

  56. 1990 · Treatment · Chronic myeloid leukemia

    Donor leukocyte transfusions for relapse after transplant (1990)

    In 1990 a group reported three people whose CML returned after a marrow transplant; treated with interferon and white cells from their donor, all three reached complete remission lasting 32 to 91 weeks, and two developed graft-versus-host disease. A 1995 European series of 84 patients with CML reported 54 complete remissions.

    Kolb 1990: 3 patients with hematologic relapse of CML after marrow transplant given interferon alpha plus donor buffy coat; all had complete hematologic and cytogenetic remission, lasting 32 to 91 weeks; GVHD in 2. Kolb 1995 (EBMT Working Party; 135 patients, 84 with CML): complete remission in 54 patients with CML (published as 73%; denominator unconfirmed); probability of remission 87% at 3 years in chronic phase; GVHD grade 2 or more in 52 (41%).

  57. 1990 · Treatment · Colorectal cancer

    Adjuvant fluorouracil plus levamisole for stage III colon cancer

    In a large randomised trial of people with resected colon cancer, one year of fluorouracil plus levamisole lowered the risk of recurrence by about forty percent in cancer that had reached the lymph nodes, compared with observation, and reduced deaths by about a third. The authors concluded this should be standard treatment for that stage.

    Moertel 1990: 1296 patients with resected stage B2 or C colon cancer randomised to observation or 1 year of levamisole plus fluorouracil (stage C also to levamisole alone). Median follow-up 3 years. In stage C, levamisole plus fluorouracil reduced recurrence risk by 41% (P<0.0001) and the death rate by 33% (P approx. 0.006); levamisole alone had no detectable effect; stage B2 results were equivocal. Final report 1995: 929 eligible stage III patients, 40% and 33% reductions.

  58. 1990 · Understanding · Colorectal cancer

    Adenoma-carcinoma sequence and a genetic model of colorectal cancer

    A 1988 study of 172 bowel tumour samples by Vogelstein and colleagues found that DNA changes accumulated as polyps progressed towards cancer: some were common in large polyps and cancers but rare in small polyps. In 1990 Fearon and Vogelstein published a Cell paper presenting a genetic model of colorectal tumour development.

    Vogelstein 1988 (172 specimens): ras mutations in 58% of adenomas over 1 cm, 47% of carcinomas and 9% of smaller adenomas; chromosome 18 deletions in 73% of carcinomas, 47% of advanced adenomas; 17p loss in 75% of carcinomas; alterations accumulated in parallel with clinical progression. The 1990 Cell paper (Fearon, Vogelstein), titled as a genetic model for colorectal tumorigenesis, has no PubMed abstract and was not read, so its content is not summarised.

  59. 1991 · Treatment · Bladder cancer

    BCG versus intravesical doxorubicin, then BCG maintenance

    In a 1991 randomised trial of people whose bladder tumours kept returning, BCG, a bacterial preparation placed in the bladder, kept more people free of disease at five years than the chemotherapy drug doxorubicin (about two in five versus about one in six, without carcinoma in situ). A later randomised study found scheduled BCG maintenance lengthened the time before recurrence.

    Randomised multi-institutional trial of intravesical doxorubicin versus BCG (intravesical and percutaneous), 262 eligible patients, median follow-up 65 months. Ta/T1 without CIS: 5-year disease-free probability 17% versus 37% (P=0.015). CIS: complete response 34% versus 70% (P<0.001). SWOG maintenance trial (384 analysed): median RFS 35.7 versus 76.8 months with maintenance (P<0.0001).

  60. 1991 · Treatment · Chronic lymphocytic leukaemia

    Fludarabine: 1991 US approval and a 2000 trial against chlorambucil

    Fludarabine, a drug that interferes with DNA building blocks in lymphocytes, was first approved by the US FDA in 1991; the approved use then is not documented here. In a randomised trial of 509 untreated people reported in 2000, it gave more remissions and longer time without progression than chlorambucil (20 against 14 months), but survival was not significantly different.

    Fludarabine: FDA original approval action 18 April 1991 (indication not read). Rai 2000 (509 randomised, untreated CLL): fludarabine vs chlorambucil CR 20% vs 4% (P<0.001), median PFS 20 vs 14 months (P<0.001), median OS 66 vs 56 months, not significantly different; fludarabine-plus-chlorambucil arm stopped early. French trial (938, Binet B/C): fludarabine, CAP and ChOP median survival 69, 70 and 67 months.

  61. 1991 · De-escalation · Head and neck cancer

    Induction chemotherapy plus radiation preserved the larynx (VA)

    In a Veterans Affairs study, people with advanced voice-box cancer were randomly assigned to chemotherapy followed by radiation, or to surgery followed by radiation. About two in three people were alive at two years in both groups, and about two in three of those given chemotherapy kept their voice box. The authors called the results preliminary.

    Randomised study, 332 patients with untreated stage III-IV laryngeal squamous carcinoma: induction cisplatin-fluorouracil then radiation (salvage laryngectomy if no response or recurrence) versus laryngectomy plus postoperative radiation. Median follow-up 33 months; estimated 2-year survival 68% in both groups (P = 0.9846). More local recurrences (P = 0.0005) and fewer distant metastases (P = 0.016) with chemotherapy. Larynx preserved in 64%; 59 patients (36%) needed laryngectomy. Authors called the results preliminary.

  62. 1992 · Understanding · Foundations

    PD-1 gene found in dying cells; later shown to be a T-cell brake

    In 1992 Y. Ishida, Tasuku Honjo and colleagues identified a new gene, PD-1, switched on in mouse cells undergoing programmed cell death. Honjo then spent years working out its role. The Nobel Committee describes how PD-1 turned out to act as a brake on T cells, and blocking it became a cancer treatment.

    Gene discovery in mouse cell lines (EMBO J 1992): PD-1, a novel member of the immunoglobulin gene superfamily, isolated by subtractive hybridisation from a T-cell hybridoma and a haematopoietic progenitor line undergoing programmed cell death; mouse expression restricted to thymus. The authors suggested involvement in programmed cell death. The Nobel Committee (2018) states that Honjo's later work showed PD-1 acts as a T-cell brake and cites a key clinical study in 2012.

  63. 1992 · Understanding · Hepatocellular carcinoma

    Urinary aflatoxin markers and HCC risk in a Shanghai cohort

    Researchers measured aflatoxin, a toxin made by moulds on stored food, in urine collected from men in Shanghai before some of them developed liver cancer. Those who later developed it were more likely to have had aflatoxin traces, and the authors reported a strong interaction with markers of hepatitis B infection.

    Nested case-control study within a Shanghai cohort of 18,244 men (35,299 person-years; 22 liver cancer cases, five or ten matched controls each). Any detectable urinary aflatoxin metabolite: relative risk 2.4 (95% CI 1.0 to 5.9); aflatoxin P1 6.2 (1.8 to 21.5); 3.8 (1.2 to 12.2) after adjustment including HBsAg. The authors report a strong interaction with HBsAg. A 1994 follow-up had 55 HCC cases.

  64. 1992 · Treatment · Hodgkin lymphoma

    CALGB: ABVD and MOPP/ABVD versus MOPP in advanced disease

    In a US trial of 361 people with advanced Hodgkin disease, MOPP, ABVD, and the two alternating were compared. Complete remission was reached by 67 in 100 on MOPP, 82 on ABVD and 83 on the alternating regimen. Five-year failure-free survival was 50, 61 and 65 in 100 respectively.

    Randomised multicentre trial (CALGB 8251), 361 eligible patients with advanced Hodgkin's disease: MOPP (123), MOPP alternating with ABVD (123), ABVD (115). Complete response 67% with MOPP, 83% with MOPP-ABVD, 82% with ABVD (P=0.006, MOPP versus the other two). Five-year failure-free survival 50%, 65%, 61%; overall survival 66%, 75%, 73% (P=0.28, MOPP versus doxorubicin regimens). ABVD was less myelotoxic than MOPP.

  65. 1992 · Treatment · Kidney cancer (renal cell carcinoma)

    Cytokine therapy: high-dose interleukin-2 and interferon alfa

    Before targeted drugs, advanced kidney cancer was treated with immune-signalling proteins. High-dose interleukin-2 made tumours shrink in a minority of people, some for a long time, but caused severe side effects and some deaths. In a randomised trial, interferon alfa helped people live somewhat longer than a hormone tablet.

    High-dose IL-2, seven phase 2 trials (255 assessable patients): ORR 14% (90% CI 10-19%), 12 CRs (5%), 24 PRs (9%); 4% died of possibly or probably treatment-related adverse events. MRC randomised trial (interferon-alpha vs medroxyprogesterone acetate, intention to treat, early results): OS HR 0.72 (95% CI 0.55-0.94; P=0.017); median OS 8.5 vs 6 months; 1-year survival 43% vs 31%.

  66. 1992 · Treatment · Melanoma

    Sentinel-node biopsy: Morton 1992 to MSLT-I (2006, 2014)

    In 1992 surgeons described a dye technique to find the first lymph node that drains a melanoma and test it for spread. A large randomised trial later compared this approach with watching the nodes. Disease-free survival was higher with biopsy, but survival from melanoma overall was not significantly different.

    Morton 1992: sentinel node identified in 194 of 237 lymphatic basins; false-negative rate under 1%. MSLT-I (first report, 1269 intermediate-thickness patients): 5-year disease-free survival 78.3% with sentinel-node biopsy vs 73.1% with observation (HR for recurrence 0.74, 95% CI 0.59-0.93, P=0.009); 5-year melanoma-specific survival 87.1% vs 86.6%. Final report (2001 patients): 10-year disease-free survival 71.3% vs 64.7% (intermediate thickness); no significant overall melanoma-specific survival difference.

  67. 1992 · Treatment · Oesophageal cancer

    RTOG 85-01: chemoradiotherapy versus radiotherapy alone

    In a US trial, people with localised oesophageal cancer had radiotherapy alone or chemotherapy plus radiotherapy. The trial stopped early because survival was longer with chemotherapy plus radiotherapy, at the cost of more severe side effects. Later trials found no significant survival gain from a higher radiation dose, and shorter median survival when cetuximab was added.

    RTOG 85-01 (N=121 at stopping): fluorouracil and cisplatin with 50 Gy vs 64 Gy alone; median survival 12.5 vs 8.9 months, 24-month survival 38% vs 10% (P<0.001, printed after the 12- and 24-month rates); 5-year OS 26% (95% CI 15 to 37) vs 0% in the long-term report. INT 0123 (218 eligible): 64.8 Gy vs 50.4 Gy, median survival 13.0 vs 18.1 months (not significant). SCOPE1 (N=258): added cetuximab, median OS 22.1 vs 25.4 months (adjusted HR 1.53).

  68. 1992 · De-escalation · Testicular germ cell tumors

    Surveillance after orchidectomy for stage I non-seminoma

    A UK-led study followed men with early-stage non-seminoma testicular cancer after surgery alone, with treatment only if the cancer returned. About three in four stayed free of relapse at two years and nearly all were alive at five years. Men with several risky tumour features relapsed more often.

    MRC prospective surveillance study (stage I NSGCT, orchidectomy alone): 373 of 396 patients entered 1984-1987 were eligible. Relapse-free rate 75% (95% CI 71-79%) at 2 years and 73% at 5 years; 5-year survival 98%; relapse-free rate 54% with three or four risk factors. Randomised TE08 (two vs five surveillance CT scans, median follow-up 40 months): relapses 15% vs 20%; intermediate-prognosis relapse 0.8% vs 0.6%, difference 0.2% (90% CI -1.2 to 1.6).

  69. 1993 · Treatment · Acute myeloid leukaemia (including APL)

    ATRA in randomized trials for newly diagnosed APL, 1993-1997

    Randomized trials in 1993 and 1997 tested retinoic acid in newly diagnosed acute promyelocytic leukemia. In Europe, about 79 in 100 given retinoic acid with chemotherapy had no event after a year, against 50 in 100 on chemotherapy alone. In North America, 67 in 100 given retinoic acid first were alive at three years, against 50 in 100 given chemotherapy.

    European APL 91 (101 randomized when stopped early after the first interim analysis): 12-month EFS 79% vs 50% (P=.001); CR 91% vs 81%, difference not significant. North American Intergroup (346 randomized to induction): CR 72% vs 69% (P=0.56); ITT overall survival at 3 years 67% vs 50% (P=0.003). Long-term report (350 patients): 5-year DFS 69% vs 29%. Different eras, populations and endpoints.

  70. 1993 · Treatment · Chronic myeloid leukemia

    Hydroxyurea versus busulfan: the German CML Study Group trial

    In a randomised trial of 441 people with chronic-phase CML, the German CML Study Group compared hydroxyurea with busulfan. Among Philadelphia-positive patients, median survival was about 58 months with hydroxyurea and 45 months with busulfan. The authors concluded hydroxyurea should be the first drug used.

    German CML Study Group, randomized multicenter (n=441, July 1983 to January 1991; 90.7% Ph-positive; Sokal risk 25.7% low, 38.2% intermediate, 36.2% high). Median survival of Ph-positive patients: busulfan 45.4 months, hydroxyurea 58.2 months (P=.008); advantage in all risk groups. Fewer adverse reactions with hydroxyurea. Authors: hydroxyurea first line; busulfan as secondary therapy.

  71. 1993 · Detection · Colorectal cancer

    Faecal occult blood screening trials and mortality

    In a Minnesota trial, people offered a yearly stool test for hidden blood had fewer deaths from bowel cancer over 13 years than people not offered it; testing every two years did not differ significantly. Trials in England and Denmark also reported fewer deaths. The tests, intervals and uptake differed, so each trial is read against its own control group.

    Randomised faecal occult blood test (FOBT) trials versus unscreened controls. Minnesota (46,551 aged 50-80): 13-year cumulative colorectal cancer mortality per 1,000 was 5.88 annual (about 83% of slides rehydrated), 8.33 biennial, 8.83 control; only annual was significantly lower. At 30 years, relative risk 0.68 annual, 0.78 biennial; all-cause mortality unchanged (1.00). Nottingham (biennial, not rehydrated): 360 vs 420 deaths, odds ratio 0.85 (95% CI 0.74-0.98). Funen: mortality ratio 0.82 (0.68-0.99).

  72. 1993 · Detection · Colorectal cancer

    Polypectomy and colorectal cancer prevention (National Polyp Study)

    The National Polyp Study followed people who had adenomas removed at colonoscopy. Fewer colorectal cancers appeared than expected from comparison groups, and a later report found fewer deaths from the disease than expected in the general population. The comparison was with expected rates, not a randomised control group.

    National Polyp Study (cohort, not randomised). 1993: 1,418 people with adenomas removed, average follow-up 5.9 years (8,401 person-years); 5 asymptomatic early-stage cancers vs 48.3, 43.4 and 20.7 expected from three reference groups (reductions 90, 88 and 76 percent, P<0.001). 2012: 2,602 people, median follow-up 15.8 years; 12 colorectal cancer deaths vs 25.4 expected, standardized incidence-based mortality ratio 0.47 (95% CI 0.26-0.80).

  73. 1993 · Understanding · Colorectal cancer

    Lynch syndrome and DNA mismatch repair genes

    Families with many bowel, stomach and womb cancers had been recorded since 1895. In 1993 and 1994, studies linked such families to a region of chromosome 2, to errors in short repeated stretches of tumour DNA, and to genes that normally repair DNA copying mistakes. The condition is now called Lynch syndrome.

    Papers from 1993 and 1994: familial colorectal cancer linked to chromosome 2 (lod scores 6.39 and 1.45 in two kindreds); widespread microsatellite instability in familial tumours (13% of sporadic cancers shared it); instability in 25 of 90 tumours (28%), more often proximal colon; hMSH2 and hMLH1 proposed as HNPCC genes. Hampel 2008: 44 of 1,566 patients with colorectal cancer (2.8%, 95% CI 2.1-3.8) had Lynch syndrome.

  74. 1993 · Treatment · Hodgkin lymphoma

    High-dose BEAM with transplant for relapsed Hodgkin's disease

    Two randomised trials tested high-dose chemotherapy plus a transplant for people whose Hodgkin disease had returned. A British trial of 40 people and a German-European trial of 161 both found better disease control with transplant. In the larger, among those responding to initial chemotherapy, 55 in 100 versus 34 in 100 had no treatment failure at three years.

    Two randomised trials of high-dose BEAM with transplant. BNLI (40 patients, relapsed or resistant disease; closed early, 66 intended): BEAM plus ABMT versus mini-BEAM; event-free survival P=0.025 and progression-free survival P=0.005 favoured BEAM plus ABMT; deaths 5 versus 9 (P=0.318). GHSG/EBMT (161 randomised, chemosensitive relapse, per protocol): 3-year FFTF 55% with BEAM-HSCT versus 34% with Dexa-BEAM (P=0.019); overall survival did not differ significantly.

  75. 1993 · Understanding · Kidney cancer (renal cell carcinoma)

    The von Hippel-Lindau tumour suppressor gene is identified (1993)

    In 1993 researchers reported finding the gene behind von Hippel-Lindau disease, an inherited condition in which people can develop kidney tumours. A year later, a study of 110 people with non-inherited kidney cancer found changes in this gene in more than half of the clear cell tumours examined.

    Latif 1993 (Science): positional cloning identified the VHL disease tumour suppressor gene; restriction-fragment rearrangements in 28 of 221 VHL kindreds, 18 of them deletions within the candidate gene; intragenic mutations in cell lines from VHL patients and sporadic renal cell carcinomas. Gnarra 1994 (Nat Genet): 110 patients with sporadic renal carcinoma; VHL mutations in 57% of clear cell carcinomas analysed, LOH in 98% of those samples.

  76. 1993 · Reversal · Non-Hodgkin lymphoma (DLBCL and follicular)

    CHOP vs three intensive regimens in advanced lymphoma (1993)

    Single-institution studies had suggested that more intensive chemotherapy might beat CHOP. A trial started by two US cooperative groups, in 899 eligible people with advanced intermediate- or high-grade non-Hodgkin lymphoma, compared CHOP with three such regimens. Three-year survival was 54 in 100 with CHOP and 50 to 52 in 100 with the others, with no significant difference.

    SWOG/ECOG phase III: 1138 registered, 899 eligible, randomised to CHOP, m-BACOD, ProMACE-CytaBOM or MACOP-B. No significant differences in response rates. Three-year alive without disease 41%, 46%, 46%, 41% (P=0.35); 3-year OS 54%, 52%, 50%, 50% (P=0.90), in the order CHOP, m-BACOD, ProMACE-CytaBOM, MACOP-B. Fatal toxic reactions 1%, 5%, 3%, 6% (P=0.09).

  77. 1993 · Understanding · Non-Hodgkin lymphoma (DLBCL and follicular)

    International Prognostic Index for aggressive lymphoma (1993)

    Researchers pooled data from 2,031 adults with aggressive non-Hodgkin lymphoma, treated with doxorubicin-based chemotherapy, to see which features at diagnosis predicted outcome. Age, stage, a blood test (LDH), general fitness and the number of sites outside the lymph nodes sorted people into four groups with predicted five-year survival from 73 in 100 down to 26 in 100.

    Pooled analysis of 2031 adults with aggressive NHL treated 1982-1987 with doxorubicin-containing regimens at 16 institutions and cooperative groups. Age, stage, LDH, performance status and extranodal sites defined four risk groups with predicted 5-year survival 73%, 51%, 43%, 26%. Age-adjusted index (1274 patients aged 60 or younger; stage, LDH, performance status): 83%, 69%, 46%, 32%. Both were more accurate than Ann Arbor stage.

  78. 1993 · Understanding · Thyroid cancer

    RET germline mutations in MEN 2A and prophylactic thyroidectomy

    In 1993 two groups reported inherited changes in the RET gene in families with a hereditary cancer syndrome that includes medullary thyroid cancer. Gene testing could then show which relatives carried the change. In a 2005 series of 50 young carriers who had their thyroid removed, 44 had no detectable calcitonin five to ten years later.

    Germline RET missense mutations in 20 of 23 MEN 2A families (Nature 1993) and RET coding changes in 8 MEN 2A and 4 familial MTC families (Hum Mol Genet 1993). Direct DNA testing in 132 members of 7 kindreds found 21 of 58 at-risk members carrying a mutation (1994). Skinner 2005, uncontrolled series: 50 carriers aged 19 years or younger had total thyroidectomy; 44 (88%; 95% CI 76-95) had basal and stimulated calcitonin at or below detection at 5-10 years.

  79. 1994 · Treatment · Acute myeloid leukaemia (including APL)

    High-dose cytarabine consolidation: CALGB randomised trial, 1994

    In a 1994 trial of 1,088 adults with AML, people in remission were randomly given one of three doses of cytarabine. Among those aged 60 or younger, about four in ten on the highest dose were still in remission after four years, against about one in four on the lowest dose. Over 60, 16% or less stayed disease-free.

    Mayer 1994 (CALGB): 1088 adults given daunorubicin and cytarabine; 596 of 693 in CR randomised to four courses of cytarabine 100 mg/m2, 400 mg/m2 or 3 g/m2 every 12 h. Median follow-up 52 months. DFS differed by dose (P=0.003); HR versus 100 mg/m2: 0.67 (95% CI 0.53-0.86) for 3 g, 0.75 (0.60-0.94) for 400 mg. Age 60 or younger: 4-year continuous CR 24%, 29%, 44% (P=0.002); older: 16% or less in each group.

  80. 1994 · Understanding · Breast cancer

    Cloning of BRCA1 (1994) and BRCA2 (1995)

    In 1994 a research team reported a strong candidate for BRCA1, a gene on chromosome 17 in which inherited changes raise the risk of breast and ovarian cancer. In 1995 another team identified BRCA2, a second such gene on chromosome 13. Later large studies estimated how high the risk is for carriers.

    Miki et al. (Science, 1994): positional cloning of a strong candidate for BRCA1 on chromosome 17q; probable predisposing mutations in five of eight kindreds; predicted protein of 1863 amino acids. Wooster et al. (Nature, 1995): six different germline mutations in breast cancer families likely due to BRCA2 (13q12-q13). Later prospective cohort (Kuchenbaecker, JAMA 2017): cumulative breast cancer risk to age 80 years 72% (BRCA1) and 69% (BRCA2).

  81. 1994 · Treatment · Chronic myeloid leukemia

    Randomized trials of interferon alfa in CML, 1994 to 1997

    Three randomised trials tested interferon alfa in chronic-phase CML. In Italy, median survival was 72 months with interferon versus 52 with standard chemotherapy. In Germany, survival was longer with interferon than with busulfan but not significantly longer than with hydroxyurea. In France, adding cytarabine raised three-year survival from about 79 to 86 percent.

    ICSG (n=322): interferon alfa-2a vs hydroxyurea/busulfan, median survival 72 vs 52 months (P=0.002); karyotypic response 30% vs 5%. German CML Study Group (n=513): median survival 5.5 years interferon, 3.8 busulfan (P=.008), 4.7 hydroxyurea (P=.44). French study: interferon plus cytarabine vs interferon, 3-year survival 85.7% vs 79.1%, relative risk of death 0.64 (95% CI 0.44 to 0.93).

  82. 1994 · Understanding · Hodgkin lymphoma

    Second cancers after treatment for Hodgkin lymphoma

    Long-term follow-up of people treated for Hodgkin lymphoma in the Netherlands from 1966 to 1986 found second cancers, including leukemia, lymphoma, lung and breast cancer, were more common than expected, with risks that depended on the treatment given. Later studies followed survivors for up to 40 years.

    Dutch cohort of 1939 patients treated 1966 to 1986: 146 second cancers versus 41.9 expected (relative risk 3.5, 95% CI 2.9 to 4.1); 20-year actuarial risk 20%. Leukemia risk was linked to mechlorethamine-procarbazine cycles. A later cohort of 3905 survivors treated 1965 to 2000: SIR 4.6 (95% CI 4.3 to 4.9); 40-year cumulative incidence of a second cancer 48.5%.

  83. 1994 · Understanding · Hodgkin lymphoma

    Single-cell studies indicate B-cell origin of Reed-Sternberg cells

    In 1994 German researchers picked individual Hodgkin and Reed-Sternberg cells out of tissue sections from three people and found, in each, a single shared antibody-gene pattern. This pointed to a clone of B cells, a question about the cells' origin that had been open for decades. A 1996 study extended it to nine of ten cases.

    Kuppers et al (PNAS 1994) micromanipulated HRS cells from three cases, one of each of three subtypes, and amplified immunoglobulin V genes by PCR: each case showed a single clonal VH rearrangement. Somatic mutation with intraclonal diversity in the lymphocyte-predominant case indicated germinal-centre B-cell origin; the mixed-cellularity case showed only nonfunctional rearrangements. Kanzler et al (1996) found clonally related rearrangements in nine of 10 patients.

  84. 1994 · Treatment · Melanoma

    High-dose IL-2: durable responses in a minority; FDA indication 1998

    High-dose interleukin 2, an immune-stimulating protein, was given to people with metastatic melanoma in single-institution and multi-trial series. A small share had their disease disappear, and most of those who did stayed in remission. Treatment was demanding and caused deaths early on. The FDA added a melanoma indication in January 1998.

    NCI Surgery Branch consecutive series (JAMA 1994): 283 patients with metastatic melanoma or renal cell cancer, IL-2 720,000 IU/kg every 8 hours; melanoma: complete regression in 9 patients (7%), partial in 14 (10%); 15 of 19 complete regressions (both cancers) remained in remission 7 to 91 months. Analysis of 270 patients (JCO 1999): response rate 16% (95% CI 12% to 21%), 17 complete responses (6%); 6 deaths (2%).

  85. 1994 · Treatment · Thyroid cancer

    TSH suppression with thyroxine after thyroid surgery

    After thyroid cancer surgery, patients are often given levothyroxine to lower thyroid-stimulating hormone, or TSH. Three observational studies, from 1994, 1998 and 2007, examined thyroid hormone treatment, TSH and outcomes. The 1998 study found no support for stronger suppression in low-risk patients; the 2007 study linked higher TSH to more relapse and cancer death. None was a randomised trial.

    Mazzaferri and Jhiang 1994 (1,355 patients; median follow-up 15.7 years): iodine-131 plus thyroid hormone therapy was associated with lower likelihood of cancer death. Cooper 1998 (registry; 617 papillary, 66 follicular): TSH score predicted progression in high-risk patients (P=0.03), not after adding radioiodine (P=0.09). Hovens 2007 (n=366; median 8.85 years): median TSH and cancer death HR 2.03 (CI 1.22 to 3.37); relapse HR 1.41 (CI 1.03 to 1.95).

  86. 1995 · Understanding · Lung cancer

    NSCLC chemotherapy meta-analysis of 52 trials (BMJ 1995)

    A 1995 analysis pooled individual patient data from 52 randomised trials covering 9,387 people with non-small cell lung cancer. It reported the risk of death as 13 percent lower when chemotherapy was added to surgery or to radical radiotherapy, and 27 percent lower when added to supportive care.

    NSCLC Collaborative Group, individual patient data meta-analysis: 52 randomised trials, 9387 patients, 7151 deaths. Added chemotherapy: surgery HR 0.87 (absolute benefit 5% at 5 years); radical radiotherapy HR 0.87 (4% at 2 years); supportive care HR 0.73 (10% at 1 year). Modern cisplatin regimens favoured chemotherapy in all comparisons. Older trials with long-term alkylating agents tended to show a detrimental effect of chemotherapy. Confidence intervals not in the abstract.

  87. 1995 · Treatment · Non-Hodgkin lymphoma (DLBCL and follicular)

    PARMA: autologous transplant vs salvage chemotherapy in relapse (1995)

    In a randomised study of people with relapsed non-Hodgkin lymphoma whose disease had responded to two courses of chemotherapy, high-dose chemotherapy with a bone marrow transplant was compared with more conventional chemotherapy. At five years, 46 in 100 were free of events after transplant, compared with 12 in 100 after chemotherapy alone.

    Randomised study (PARMA) in relapsed, chemotherapy-sensitive non-Hodgkin lymphoma: 109 responders to two salvage courses were assigned to four further chemotherapy courses plus radiotherapy (54) or radiotherapy plus intensive chemotherapy and autologous bone marrow transplantation (55). Median follow-up 63 months. 5-year EFS 46% vs 12% (P=0.001); 5-year OS 53% vs 32% (P=0.038). Three deaths from toxic effects in the transplantation group, none in the other group.

  88. 1995 · Reversal · Testicular germ cell tumors

    Is bleomycin needed? EP versus BEP in good-prognosis disease

    Three randomised trials tested leaving bleomycin out of first-line chemotherapy for good-prognosis non-seminoma. Two found worse results without it: 95% versus 87% had a complete response in one, and lower failure-free survival in the other. A French trial of three cycles with bleomycin versus four without found similar results but was underpowered.

    ECOG (178 randomised; 3 cycles): disease-free 94% BEP vs 88% EP; failure-free 86% vs 69% (P = .01); OS 95% vs 86% (P = .01). EORTC (419; 4 cycles): complete response 95% BEP vs 87% EP (P = .0075); relapses 4% per arm; survival P = .262; 2 bleomycin pulmonary deaths on BEP. GETUG T93BP (257; 3 BEP vs 4 EP): 4-year EFS 91% vs 86% (P = 0.135); underpowered. Doses differ between trials.

  89. 1996 · Understanding · Childhood acute lymphoblastic leukemia (ALL)

    Uniform NCI risk classification for childhood ALL

    A 1996 report from a 1993 US workshop of four research groups and the National Cancer Institute set common risk groups for children with B-precursor ALL. Standard risk meant age 1 to 9 years with a white-cell count below 50,000 per microlitre; everyone else was high risk. The authors expected common labels to make trials more efficient.

    NCI Cancer Therapy Evaluation Program workshop, September 1993 (CCG, POG, DFCI, St Jude): outcome data from the groups were combined using weighted averages. B-precursor ALL: standard risk = age 1 to 9 years and WBC below 50,000/microL (4-year EFS approximately 80%); remaining patients high risk (approximately 65%). T-cell ALL: groups differed on risk assignment. DNA index, cytogenetics, early response, immunophenotype and CNS status were to be collected uniformly.

  90. 1996 · Understanding · Chronic myeloid leukemia

    Selective Abl kinase inhibitor suppresses Bcr-Abl-positive cells

    In 1996 laboratory work reported that a compound designed to block the Abl enzyme stopped Bcr-Abl-positive cells from multiplying and forming tumours in test systems. In blood or marrow samples from people with CML, it cut the number of Bcr-Abl colonies by more than nine in ten without stopping normal colonies. The paper's abstract does not name the compound.

    Preclinical study: a compound designed to inhibit the Abl protein tyrosine kinase specifically inhibited cellular proliferation and tumor formation by Bcr-Abl-expressing cells; in colony-forming assays of peripheral blood or bone marrow from patients with CML there was a 92-98% decrease in bcr-abl colonies and no inhibition of normal colony formation. The bcr-abl oncogene is present in 95% of patients with CML (abstract).

  91. 1996 · Understanding · Foundations

    CTLA-4 blockade enhances antitumour immunity in mice (1996)

    In 1996 James Allison's group showed that antibodies blocking a T-cell protein called CTLA-4 made mice reject tumours, including established ones. A 2010 trial of an anti-CTLA-4 antibody, ipilimumab, in previously treated metastatic melanoma lengthened survival, and Allison shared the 2018 Nobel Prize with Tasuku Honjo.

    Preclinical study (Science 1996): antibodies to CTLA-4 given in vivo caused rejection of tumours, including preestablished tumours, and immunity to a secondary exposure. Phase 3 follow-on (Hodi, NEJM 2010; 676 previously treated patients with metastatic melanoma): median OS 10.0 months with ipilimumab plus gp100 vs 6.4 months with gp100 alone (HR 0.68; P<0.001); 10.1 months with ipilimumab alone (HR 0.66; P=0.003); grade 3 or 4 immune-related adverse events 10 to 15% vs 3%; 14 study-drug deaths (2.1%).

  92. 1996 · Treatment · Hepatocellular carcinoma

    Milan criteria: transplantation for small HCC in cirrhosis

    In 1996 a team in Milan reported 48 people with cirrhosis and small liver tumours that could not be removed by surgery, who had transplants under selection limits set in advance. At four years about 85 in 100 of those within the limits were alive, compared with about 50 in 100 of those beyond them.

    Series of 48 patients with cirrhosis and small unresectable HCC who underwent transplantation (eligibility: one tumour of 5 cm or less, or up to 3 nodules of 3 cm or less each); median follow-up 26 months. Four-year actuarial survival 75%, recurrence-free survival 83%. At pathological review of the explanted liver, 35 patients met the predetermined criteria (4-year survival 85%, recurrence-free survival 92%) and 13 did not (50% and 59%; P=0.01 and P=0.002).

  93. 1996 · Treatment · Melanoma

    Adjuvant interferon: E1684 (1996) to pegylated interferon (2011)

    In 1996 the ECOG E1684 trial reported that interferon alfa-2b at the maximum tolerated dose after surgery prolonged relapse-free and overall survival compared with observation. A later trial of pegylated interferon in stage III melanoma reported longer relapse-free survival but no overall survival difference, and about a third of patients stopped because of side effects.

    E1684 (N=287): interferon alfa-2b vs observation after resection of T4 or N1 melanoma; median follow-up 6.9 years; RFS P=0.0023 and OS P=0.0237 (one-sided); median OS 3.8 vs 2.8 years. EORTC 18991 (phase 3, N=1,256): pegylated interferon alfa-2b vs observation, 4-year RFS 45.6% vs 38.9% (HR 0.82; 95% CI 0.71-0.96); at 7.6 years HR 0.87 (95% CI 0.76-1.00; P=0.055) and no OS difference (P=0.57).

  94. 1996 · Treatment · Multiple myeloma

    Autologous transplantation trials: IFM 90, MRC VII, IFM 94

    Three randomised trials tested high-dose treatment followed by return of a person's own blood-forming cells. Two compared it with conventional chemotherapy and found more responses and longer survival with the high-dose approach. A third found that two transplants in a row gave longer survival than one.

    IFM 90 (n=200, age under 65): 5-year EFS 28% versus 10% (P=0.01) and 5-year survival 52% versus 12% (P=0.03), high-dose therapy with autologous BMT versus conventional chemotherapy. MRC Myeloma VII (n=407, under 65): median survival 54.1 versus 42.3 months (P=0.04, intention to treat). IFM 94 (n=399, under 60): 7-year survival 42% versus 21% (P=0.01), double versus single transplant.

  95. 1996 · Treatment · Ovarian cancer

    Paclitaxel with platinum in first line: GOG-111, OV-10, ICON3

    Two randomised trials in advanced ovarian cancer found longer progression-free and overall survival when paclitaxel replaced cyclophosphamide in a cisplatin combination. A third trial, ICON3, reported no survival difference between paclitaxel with carboplatin and carboplatin alone or an older three-drug regimen.

    GOG-111 (410 randomised): cisplatin-paclitaxel vs cisplatin-cyclophosphamide, median PFS 18 vs 13 months and OS 38 vs 24 months (both P<0.001). OV-10 (680): median PFS 15.5 vs 11.5 months, OS 35.6 vs 25.8 months. ICON3 (2074; control CAP or carboplatin alone): OS HR 0.98 (95% CI 0.87-1.10), median 36.1 (paclitaxel-carboplatin) vs 35.4 months (control); PFS HR 0.93 (0.84-1.03). Each trial has its own comparator and population.

  96. 1996 · Treatment · Pancreatic cancer

    Gemcitabine versus fluorouracil in advanced pancreatic cancer

    In 1996 the US regulator approved gemcitabine for advanced pancreatic cancer. A trial of 126 people with symptomatic disease compared it with fluorouracil. About 24 in 100 people on gemcitabine and 5 in 100 on fluorouracil gained symptom relief, and median survival was about 5.7 versus 4.4 months.

    Randomised trial, 126 patients with advanced symptomatic pancreas cancer: gemcitabine (63) versus fluorouracil (63). Primary efficacy measure, clinical benefit response: 23.8% vs 4.8% (P=.0022). Median survival 5.65 vs 4.41 months (P=.0025); 12-month survival 18% vs 2%. FDA approved gemcitabine on 15 May 1996 for first-line treatment of advanced or metastatic pancreatic adenocarcinoma.

  97. 1996 · Treatment · Testicular germ cell tumors

    Adjuvant BEP for high-risk stage I non-seminoma

    Some men with early-stage non-seminoma have a high chance of relapse after surgery. A UK study gave two courses of BEP chemotherapy to more than a hundred high-risk men and saw two relapses. Later work tested one course: a German trial against lymph node surgery, and a Swedish and Norwegian population-based programme.

    MRC single-arm study: 114 eligible high-risk patients given two courses of BEP, two relapses at median follow-up 4 years. AUO AH 01/94 (randomised, 382 patients): 2-year recurrence-free survival 99.46% with one course of BEP vs 91.87% with RPLND (HR for recurrence with surgery 7.937, 95% CI 1.808-34.48, P=0.0011). SWENOTECA (non-randomised): 5-year relapse after one course of BEP 3.2% with lymphovascular invasion, 1.6% without.

  98. 1997 · Treatment · Acute myeloid leukaemia (including APL)

    Arsenic trioxide induces remission in relapsed APL

    In 1997 a report in Blood described arsenic trioxide, given into a vein, in 15 people whose acute promyelocytic leukemia had returned after retinoic acid and chemotherapy. Nine of the ten given arsenic alone reached complete remission. The FDA approved the drug in 2000; a US multicenter study of 40 people, published in 2001, reported complete remission in 85%.

    Shen 1997: 15 relapsed patients, As2O3 10 mg/d IV; clinical CR in 9 of 10 given As2O3 alone (the abstract's wording on the five given combinations is ambiguous). Soignet 1998: 12 relapsed patients, 11 CR. Soignet 2001, US multicenter series: 40 patients, CR 85% (34 of 40; 70% by the stricter definition in the FDA label), 18-month OS 66% and RFS 56%, QT prolongation 63%. FDA approval 25 September 2000; EU authorisation 5 March 2002 under exceptional circumstances.

  99. 1997 · Treatment · Colorectal cancer

    Swedish Rectal Cancer Trial: short-course preoperative radiotherapy

    Between 1987 and 1990, 1168 people in Sweden with rectal cancer that could be removed were assigned to five days of radiotherapy before surgery or to surgery alone. Five years on, cancer had come back locally in eleven in every hundred who had radiotherapy and twenty-seven in every hundred who did not. Survival was also higher with radiotherapy.

    Randomised, 1168 patients younger than 80 with resectable rectal cancer: preoperative radiotherapy (25 Gy in five fractions, surgery within one week) vs surgery alone. Five years: local recurrence 11% vs 27% (P<0.001); overall survival 58% vs 48% (P=0.004). Median follow-up 13 years, 908 patients with curative surgery: local recurrence 9% vs 26% (P<0.001); overall survival 38% vs 30% (P=0.008); cancer-specific survival 72% vs 62% (P=0.03).

  100. 1997 · Detection · Foundations

    Taiwan hepatitis B vaccination programme and childhood liver cancer

    Taiwan began vaccinating infants against hepatitis B in July 1984. A 1997 registry study found that liver cancer became less common in children aged 6 to 14, and a 2009 follow-up found the lower rate held into early adulthood. The remaining cases were mostly linked to children of highly infectious mothers.

    Registry-based comparison of birth cohorts after Taiwan's July 1984 universal programme. 1997 (NEJM): hepatocellular carcinoma incidence in children aged 6 to 14 fell from 0.70 per 100,000 (1981-1986) to 0.57 (1986-1990) and 0.36 (1990-1994), P<0.01. 2009 (JNCI; 1958 cases aged 6 to 29, 1983-2004): relative risk 0.31 (P<.001) at ages 6 to 19 for persons vaccinated at birth; incomplete vaccination OR 4.32 (95% CI 2.34 to 7.91); maternal HBsAg seropositivity OR 29.50 (13.98 to 62.60).

  101. 1997 · Treatment · Non-Hodgkin lymphoma (DLBCL and follicular)

    Rituximab for relapsed indolent lymphoma: FDA approval and JCO report

    A study of 166 people with relapsed low-grade or follicular lymphoma found that about half responded to four weekly infusions of rituximab, an antibody that targets the CD20 protein on B cells. The US FDA approved rituximab for this use in November 1997, before the trial was published.

    Multi-institutional study (n=166, 31 centres), relapsed low-grade or follicular lymphoma, rituximab 375 mg/m2 weekly for four doses. Response rate in the intent-to-treat group 48%; projected median time to progression in responders 13.0 months (median follow-up 11.8 months). Grade 3 toxicity 12%, grade 4 3%. FDA approval 26 November 1997 for relapsed or refractory low-grade or follicular B-cell NHL.

  102. 1997 · Treatment · Prostate cancer

    Radiotherapy plus androgen suppression (EORTC 22863)

    Men with locally advanced prostate cancer were randomly assigned radiotherapy alone or radiotherapy plus three years of an androgen-suppressing injection (goserelin). At five years about four in five men given both treatments were alive, compared with about six in ten given radiotherapy alone. Ten-year results pointed the same way.

    EORTC 22863 (n=415; locally advanced disease): radiotherapy with or without goserelin for 3 years. 1997 analysis (401 evaluable, median follow-up 45 months): 5-year OS 79% (95% CI 72-86) vs 62% (52-72) with radiotherapy alone, P=0.001. 10-year (median follow-up 9.1 years): OS 58.1% vs 39.8% (HR 0.60, 95% CI 0.45-0.80); clinical DFS 47.7% vs 22.7% (HR 0.42); prostate-cancer mortality 10.3% vs 30.4% (HR 0.38).

  103. 1997 · Understanding · Testicular germ cell tumors

    IGCCCG prognostic classification of metastatic germ-cell cancer

    Collaborative groups from ten countries pooled data on 5,202 people with non-seminoma and 660 with seminoma treated with cisplatin-containing chemotherapy. They defined good, intermediate and poor prognosis groups, with five-year survival of about 91, 79 and 48 in 100.

    Pooled data from collaborative groups in 10 countries: 5,202 NSGCT and 660 seminoma treated with cisplatin-containing chemotherapy; median follow-up 5 years. NSGCT adverse factors: mediastinal primary, raised AFP, hCG and LDH, non-pulmonary visceral metastases; seminoma: non-pulmonary visceral metastases. 5-year survival: good prognosis (60% of germ cell tumours) 91% (89-93); intermediate (26%) 79% (75-83); poor (14%, non-seminoma only) 48% (42-54). Validated on an independent data set.

  104. 1997 · Reversal · Testicular germ cell tumors

    Carboplatin in place of cisplatin was inferior at trial doses

    In a trial of 598 patients with good-risk non-seminoma, four cycles of BEP were compared with the same regimen using carboplatin instead of cisplatin. Complete response was 94% with cisplatin and 87% with carboplatin, and three-year survival was 97% versus 90%. The authors concluded the carboplatin regimen was inferior at the doses used.

    MRC/EORTC randomised trial, 598 patients with good-risk NSGCT, 4 cycles of BEP vs CEB (etoposide 120 mg/m2 days 1-3, bleomycin 30 U). Complete response 94.4% (253/268) vs 87.3% (227/260), P = .009. Failure-free at 1 year 91% (95% CI 88-94) vs 77% (72-82), P < .001. 3-year survival 97% (95-99) vs 90% (86-94), P = .003 (10 vs 27 deaths). Carboplatin regimen inferior at these doses.