General Oncology Principles
CLOT trial: LMWH for cancer VTE management
| Article Name: Low-Molecular-Weight Heparin versus a Coumarin for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa025313 |
| Journal and year of publication: NEJM, 2003 |
| Trial Design: Randomized clinical trial |
| Population: 676 cancer patients Key inclusion criteria: – Active cancer – Newly diagnosed VTE Key exclusion criteria: – Weighed 40 kg or less – Had had active or serious bleeding within the previous two weeks – Conditions associated with a high risk of serious bleeding – Platelet count of less than 75,000 per cubic millimeter |
| Intervention Studied: Dalteparin alone for six months (200 IU/kg once daily for one month, then 150 IU/kg daily for five months) |
| Control: Dalteparin at a dose of 200 IU/kg daily for five to seven days and a coumarin derivative for six months (target international normalized ratio, 2.5) |
| Outcomes: – Recurrent Venous thromboembolism occurrence: 27 of 336 (8%) patients in the dalteparin group vs 53 of 336 (15.8%) patients in the oral-anticoagulant group (P=0.002) – Rate of major bleeding: No significant difference between groups The authors concluded that “In patients with cancer and acute venous thromboembolism, dalteparin was more effective than an oral anticoagulant in reducing the risk of recurrent thromboembolism without increasing the risk of bleeding.” |
| Citation: Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. doi: 10.1056/NEJMoa025313. PMID: 12853587. |
CARAVAGGIO trial: Apixaban for cancer VTE management
| Article Name: Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer |
| URL:https://www.nejm.org/doi/10.1056/NEJMoa1915103 |
| Journal and year of publication: NEJM, 2020 |
| Trial Design: Randomized clinical trial |
| Population: 1,155 cancer patients Key inclusion criteria: – Cancer (other than basal-cell or squamous-cell carcinoma of the skin, primary brain tumor, known intracerebral metastases, or acute leukemia) – Newly diagnosed DVT or PE Key exclusion criteria: – ECOG Performance Status III or IV – Thrombectomy, vena cava filter insertion, or thrombolysis used to manage the index episode – Concomitant thienopyridine therapy (clopidogrel, prasugrel, or ticagrelor) or aspirin over 165 mg daily or dual antiplatelet therapy |
| Intervention Studied: Apixaban (10 mg twice daily for the first 7 days, followed by 5 mg twice daily) |
| Control: Dalteparin (200 IU/kg once daily for the first month, then 150 IU/kg once daily) |
| Outcomes: – Primary outcome (recurrent venous thromboembolism occurrence): 5.6% of the apixaban group vs 7.9% of the dalteparin group (P<0.001 for noninferiority) – Major bleeding occurrence: 3.8% of the apixaban group vs 4.0% of the dalteparin group (P=0.60) The authors concluded that “Oral apixaban was noninferior to subcutaneous dalteparin for the treatment of cancer-associated venous thromboembolism without an increased risk of major bleeding.” |
| Citation: Agnelli G, Becattini C, Meyer G, Muñoz A, Huisman MV, Connors JM, Cohen A, Bauersachs R, Brenner B, Torbicki A, Sueiro MR, Lambert C, Gussoni G, Campanini M, Fontanella A, Vescovo G, Verso M; Caravaggio Investigators. Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer. N Engl J Med. 2020 Apr 23;382(17):1599-1607. doi: 10.1056/NEJMoa1915103. Epub 2020 Mar 29. PMID: 32223112. |
MASCC score trial: Febrile Neutropenia risk assessment
| Article Name: The Multinational Association for Supportive Care in Cancer Risk Index: A Multinational Scoring System for Identifying Low-Risk Febrile Neutropenic Cancer Patients |
| URL: https://ascopubs.org/doi/10.1200/jco.2000.18.16.3038 |
| Journal and year of publication: Journal of Clinical Oncology, 2000 |
| Trial Design: Prospective clinical trial |
| Population: 1,139 cancer patients Key inclusion criteria: – Diagnosis of malignancy treated by chemotherapy that was causative of or contributive to neutropenia – Temperature >38°C (measured orally) Key exclusion criteria: – Unclear per manuscript |
| Scoring system: Independent factors assessable at fever onset, predicting low risk of complications, on a randomly selected derivation set, were assigned integer weights to develop a risk-index score |
| Outcomes: – On the derivation set, predictive factors were: 1. A burden of illness indicating the absence or mild symptoms: weight, 5; odds ratio [OR], 8.21; 95% CI, 4.15 to 16.38 2. Moderate symptoms: weight, 3; OR, 3.70; 95% CI, 2.18 to 6.29 3. Absence of hypotension: weight, 5; OR, 7.62; 95% CI, 2.91 to 19.89 4. Absence of chronic obstructive pulmonary disease: weight, 4; OR, 5.35; 95% CI, 1.86 to 15.46 5. Presence of solid tumor or absence of previous fungal infection in patients with hematologic malignancies: weight, 4; OR, 5.07; 95% CI, 1.97 to 12.95 6. Outpatient status: weight, 3; OR, 3.51; 95% CI, 2.02 to 6.04 7. Absence of dehydration: weight, 3; OR, 3.81; 95% CI, 1.89 to 7.73 8. Age less than 60 years: weight, 2; OR, 2.45; 95% CI, 1.51 to 4.01 – On the validation set, a Multinational Association for Supportive Care in Cancer risk-index score ≥ 21 identified low-risk patients with a positive predictive value of 91%, specificity of 68%, and sensitivity of 71%. The authors concluded that “The risk index accurately identifies patients at low risk for complications and may be used to select patients for testing therapeutic strategies that may be more convenient or cost-effective.” |
| Citation: Klastersky J, Paesmans M, Rubenstein EB, Boyer M, Elting L, Feld R, Gallagher J, Herrstedt J, Rapoport B, Rolston K, Talcott J. The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol. 2000 Aug;18(16):3038-51. doi: 10.1200/JCO.2000.18.16.3038. PMID: 10944139. |
Beta-lactam antibiotics for febrile neutropenia
| Article Name: Beta‐lactam versus beta‐lactam‐aminoglycoside combination therapy in cancer patients with neutropenia |
| URL:https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003038.pub2/full |
| Journal and year of publication: Cochrane Library, 2013 |
| Trial Design: Systematic review and meta-analysis |
| Population: 71 trials with >10,000 cancer patients Key inclusion criteria: – Randomised controlled trials (RCTs) comparing any beta‐lactam antibiotic monotherapy with any combination of a beta‐lactam and an aminoglycoside antibiotic, for the initial empirical treatment of febrile neutropenic cancer patients Key exclusion criteria: – Trials with randomly assigned participants with microbiologically documented infection (e.g. Pseudomonas aeruginosa infection, Gram‐negative bacteraemia) – Trials comparing short versus long courses of aminoglycoside treatment |
| Intervention Studied: Single treatment with broad‐spectrum beta‐lactams |
| Control: Combination of a beta‐lactam with an aminoglycoside |
| Outcomes: – All cause mortality: lower with monotherapy (without statistical significance) – RR 0.87, 95% CI 0.75 to 1.02 – Infection-related mortality: significantly lower with monotherapy – RR 0.80, 95% CI 0.64 to 0.99 – Bacterial super‐infections: Occurred with equal frequency – Fungal super‐infections: More common with combination therapy. – Adverse events: More frequent with combination therapy. The authors concluded that “Beta‐lactam monotherapy is advantageous compared with beta‐lactam‐aminoglycoside combination therapy with regard to survival, adverse events and fungal super‐infections. Treatment failure should not be regarded as the primary outcome in open‐label trials, as it reflects mainly treatment modifications.” |
| Citation: Paul M, Dickstein Y, Schlesinger A, Grozinsky-Glasberg S, Soares-Weiser K, Leibovici L. Beta-lactam versus beta-lactam-aminoglycoside combination therapy in cancer patients with neutropenia. Cochrane Database Syst Rev. 2013 Jun 29;2013(6):CD003038. doi: 10.1002/14651858.CD003038.pub2. PMID: 23813455; PMCID: PMC6457814. |
Surgery for malignant spinal cord compression
| Article Name: Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial |
| URL:https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)66954-1/fulltext |
| Journal and year of publication: The Lancet, 2005 |
| Trial Design: Randomized clinical trial |
| Population: 101 patients Key inclusion criteria: – Tissue-proven diagnosis of cancer (not of CNS or spinal column origin) – MRI evidence of malignant spinal cord compression Key exclusion criteria: – Mass that compressed only the cauda equina or spinal roots – Multiple discrete compressive lesions – Patients with certain radiosensitive tumours (lymphomas, leukaemia, multiple myeloma, and germ-cell tumours) – Patients with pre-existing or concomitant neurological problems |
| Intervention Studied: Spinal decompressive surgery + radiotherapy |
| Control: Radiotherapy alone |
| Outcomes: – Primary endpoint (ability to walk): Significantly more patients in the surgery group (42/50, 84%) than in the radiotherapy group (29/51, 57%) were able to walk after treatment ( p=0·001). – The need for corticosteroids and opioid analgesics was significantly reduced in the surgical group. The authors concluded that “Direct decompressive surgery plus postoperative radiotherapy is superior to treatment with radiotherapy alone for patients with spinal cord compression caused by metastatic cancer.” |
| Citation: Patchell RA, Tibbs PA, Regine WF, Payne R, Saris S, Kryscio RJ, Mohiuddin M, Young B. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet. 2005 Aug 20-26;366(9486):643-8. doi: 10.1016/S0140-6736(05)66954-1. PMID: 16112300. |
Breast Cancer
Mammography screening trial
| Article Name: Long-term effects of mammography screening: updated overview of the Swedish randomised trials |
| URL: https://www.sciencedirect.com/science/article/pii/S0140673602080200 |
| Journal and year of publication: The Lancet, 2002 |
| Trial Design: Randomized clinical trial |
| Population: 247,010 patients from different trials Key inclusion criteria: – Women selected for the Swedish mammography screening trials Key exclusion criteria: – Weighed 40 kg or less – Women diagnosed with invasive epithelial breast cancer before randomisation – Few women younger than 40 years in the Östergötland, Stockholm, and Göteborg trials – Women 75 years and older in the Östergötland trial |
| Intervention Studied: Invitation to breast cancer screening with mammography |
| Control: No screening |
| Outcomes: – Breast cancer deaths: significant 21% reduction in breast cancer mortality in the women invited to breast cancer screening (RR=0.79, 95% CI 0.70-0.89) – Looking at 5-year age groups: -55-59 years (RR=0.76) – Statistically significant effects -60-64 years (RR=0.68) – Statistically significant effects -65-69 years (RR=0.69) – Statistically significant effects -50-54 years (RR=0.95) – Small effect – The benefit in terms of cumulative breast cancer mortality emerged at about 4 years after randomisation and continued to increase to about 10 years. The authors concluded that “The advantageous effect of breast screening on breast cancer mortality persists after long-term follow-up.” |
| Citation: Nyström L, Andersson I, Bjurstam N, Frisell J, Nordenskjöld B, Rutqvist LE. Long-term effects of mammography screening: updated overview of the Swedish randomised trials. Lancet. 2002 Mar 16;359(9310):909-19. doi: 10.1016/S0140-6736(02)08020-0. Erratum in: Lancet 2002 Aug 31;360(9334):724. PMID: 11918907. |
MRISS trial: MRI vs mammography for breast cancer screening
| Article Name: Efficacy of MRI and Mammography for Breast-Cancer Screening in Women with a Familial or Genetic Predisposition |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa031759 |
| Journal and year of publication: NEJM, 2004 |
| Trial Design: Prospective single-arm clinical trial |
| Population: 1,909 women Key inclusion criteria: – Cumulative lifetime risk of breast cancer of 15% or more owing to a familial or genetic predisposition Key exclusion criteria: – Symptoms suggestive of breast cancer – Personal history of breast cancer |
| Intervention Studied: Screening every 6 months with a clinical breast examination and once a year by mammography and MRI |
| Control: N/A |
| Outcomes: – The screening methods for detecting invasive breast cancer: – Clinical breast examination: Sensitivity:17.9%, Specificity: 98.1 – Mammography: Sensitivity: 33.3%, Specificity: 95.0 – MRI: Sensitivity: 79.5%, Specificity: 89.8 – MRI vs Mammography: MRI had significantly better discriminating capacity P<0.05 The authors concluded that “MRI appears to be more sensitive than mammography in detecting tumors in women with an inherited susceptibility to breast cancer.” |
| Citation: Kriege M, Brekelmans CT, Boetes C, Besnard PE, Zonderland HM, Obdeijn IM, Manoliu RA, Kok T, Peterse H, Tilanus-Linthorst MM, Muller SH, Meijer S, Oosterwijk JC, Beex LV, Tollenaar RA, de Koning HJ, Rutgers EJ, Klijn JG; Magnetic Resonance Imaging Screening Study Group. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med. 2004 Jul 29;351(5):427-37. doi: 10.1056/NEJMoa031759. PMID: 15282350. |
Breast-conserving therapy vs total mastectomy
| Article Name: Twenty-Year Follow-up of a Randomized Trial Comparing Total Mastectomy, Lumpectomy, and Lumpectomy plus Irradiation for the Treatment of Invasive Breast Cancer |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa022152 |
| Journal and year of publication: NEJM, 2002 |
| Trial Design: Randomized clinical trial |
| Population: 1,851 patients with breast cancer Key inclusion criteria: – Invasive breast tumors 4 cm or less in largest diameter – Negative or positive axillary lymph nodes (stage I or II breast cancer) – Tumors confined to the breast or breast and axilla – Tumors movable in relation to the underlying muscle and the chest wall Key exclusion criteria: – Previously been treated for current neoplasm – Bilateral breast cancer existed – Tumor was inflammatory or there was skin ulceration >2 cm – Peau d’orange involving more than one-third of the skin of the breast -Satellite or parasternal nodules were present |
| Intervention Studied: 1) Lumpectomy alone 2) Lumpectomy and breast irradiation |
| Control: Total mastectomy |
| Outcomes: – Cumulative incidence of recurrent tumor in ipsilateral breast: 14.3% in those underwent lumpectomy and breast irradiation, 39.2% in those underwent lumpectomy without irradiation (P<0.001) – Disease-free survival: No significant difference between the 3 groups – Overall survival: No significant difference between the 3 groups The authors concluded that “Lumpectomy followed by breast irradiation continues to be appropriate therapy for women with breast cancer, provided that the margins of resected specimens are free of tumor and an acceptable cosmetic result can be obtained.” |
| Citation: Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, Jeong JH, Wolmark N. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med. 2002 Oct 17;347(16):1233-41. doi: 10.1056/NEJMoa022152. PMID: 12393820. |
Tamoxifen for ER positive breast cancers
| Article Name: A Randomized Clinical Trial Evaluating Tamoxifen in the Treatment of Patients with Node-Negative Breast Cancer Who Have Estrogen-Receptor–Positive Tumors |
| URL: https://www.nejm.org/doi/full/10.1056/NEJM198902233200802 |
| Journal and year of publication: NEJM, 1989 |
| Trial Design: Randomized, double-blinded, placebo-controlled clinical trial |
| Population: 2,785 patients with breast cancer Key inclusion criteria: – 70 years old or below – Women with operable primary breast cancer – Axillary nodes negative for cancer – Tumor with positive estrogen-receptor Key exclusion criteria: – Unclear per manuscript |
| Intervention Studied: Tamoxifen (10 mg twice a day) for 5 years |
| Control: Placebo |
| Outcomes: – Overal survival advantage during four years of follow-up: None observed (92% for placebo vs. 93% for tamoxifen P = 0.3) – Disease-free survival: Significant prolongation for tamoxifen group vs placebo (83% vs. 77%, P<0.00001) The authors concluded that “Tamoxifen significantly reduced the rate of treatment failure at local and distant sites, tumors in the opposite breast, and the incidence of tumor recurrence after lumpectomy and breast irradiation. The benefit was attained with a low incidence of clinically appreciable toxic effects. The magnitude of the improvement obtained does not preclude the need for future trials in which patients given tamoxifen could serve as the control group in an evaluation of potentially better therapies.” |
| Citation: Fisher B, Costantino J, Redmond C, Poisson R, Bowman D, Couture J, Dimitrov NV, Wolmark N, Wickerham DL, Fisher ER, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med. 1989 Feb 23;320(8):479-84. doi: 10.1056/NEJM198902233200802. PMID: 2644532. |
ATLAS trial: Tamoxifen for 5 years vs 10 years
| Article Name: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial |
| URL: https://www.thelancet.com/journals/lanonc/article/PIIS0140-6736(12)61963-1/fulltext |
| Journal and year of publication: The Lancet, 2012 |
| Trial Design: Randomized clinical trial |
| Population: 12,894 patients with breast cancer Key inclusion criteria: – Early breast cancer (all detected disease could be removed) – ER-positive and planned to received tamoxifen Key exclusion criteria: – Unclear per manuscript |
| Intervention Studied: Tamoxifen for 10 years |
| Control: Tamoxifen for 5 years |
| Outcomes: – Continuing tamoxifen in women with ER-positive disease had the following effect: – Reduced the risk of breast cancer recurrence: 617 recurrences in 3428 vs 711 in 3418 control group (p=0.002) – Reduced breast cancer mortality: 331 deaths vs 397 deaths in the control group (p=0.01) – Reduced overall mortality: 639 deaths vs 722 deaths in the control group (p=0.01) The authors concluded that “For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis.” |
| Citation: Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, Abraham M, Medeiros Alencar VH, Badran A, Bonfill X, Bradbury J, Clarke M, Collins R, Davis SR, Delmestri A, Forbes JF, Haddad P, Hou MF, Inbar M, Khaled H, Kielanowska J, Kwan WH, Mathew BS, Mittra I, Müller B, Nicolucci A, Peralta O, Pernas F, Petruzelka L, Pienkowski T, Radhika R, Rajan B, Rubach MT, Tort S, Urrútia G, Valentini M, Wang Y, Peto R; Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013 Mar 9;381(9869):805-16. doi: 10.1016/S0140-6736(12)61963-1. Erratum in: Lancet. 2013 Mar 9;381(9869):804. Erratum in: Lancet. 2017 May 13;389(10082):1884. PMID: 23219286; PMCID: PMC3596060. |
Chemotherapy and tamoxifen for node-positive breast cancers
| Article Name: Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial |
| URL: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61523-3/fulltext |
| Journal and year of publication: The Lancet, 2009 |
| Trial Design: Randomized clinical trial |
| Population: 1,477 patients with breast cancer Key inclusion criteria: – Postmenopausal women – Pathological stage T1–3, N1–2 infiltrating adenocarcinoma of the breast – Estrogen-receptor positive or progesterone-receptor positive, or both Key exclusion criteria: – Patients not meeting inclusion criteria |
| Intervention Studied: Adjuvant cyclophosphamide, doxorubicin, and fluorouracil (CAF) given every 4 weeks for six cycles plus 5 years of daily tamoxifen |
| Control: Adjuvant tamoxifen alone |
| Outcomes: – Disease-free survival event occurrence: CAF plus tamoxifen was superior to tamoxifen alone (HR 0.76, 95% CI 0.64–0.91, P=0·002) – Overall survival: HR for CAF plus tamoxifen groups vs tamoxifen alone: 0·83, 0·68–1·01 (p=0·057) The authors concluded that “Chemotherapy with CAF plus tamoxifen given sequentially is more effective adjuvant therapy for postmenopausal patients with endocrine-responsive, node-positive breast cancer than is tamoxifen alone. However, it might be possible to identify some subgroups that do not benefit from anthracycline-based chemotherapy despite positive nodes.” |
| Citation: Albain KS, Barlow WE, Ravdin PM, Farrar WB, Burton GV, Ketchel SJ, Cobau CD, Levine EG, Ingle JN, Pritchard KI, Lichter AS, Schneider DJ, Abeloff MD, Henderson IC, Muss HB, Green SJ, Lew D, Livingston RB, Martino S, Osborne CK; Breast Cancer Intergroup of North America. Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. Lancet. 2009 Dec 19;374(9707):2055-2063. doi: 10.1016/S0140-6736(09)61523-3. Epub 2009 Dec 10. PMID: 20004966; PMCID: PMC3140679. |
Aromatase inhibitors for postmenopausal breast cancer patients
| Article Name: Anastrozole Is Superior to Tamoxifen as First-Line Therapy for Advanced Breast Cancer in Postmenopausal Women: Results of a North American Multicenter Randomized Trial |
| URL: https://ascopubs.org/doi/full/10.1200/JCO.2000.18.22.3758?keytype2=tf_ipsecsha&ijkey=c816effab8f99878f59b2c4d144e564e517baddb |
| Journal and year of publication: Journal of Clinical Oncology, 2000 |
| Trial Design: Randomized, double-blinded clinical trial |
| Population: 353 patients with breast cancer Key inclusion criteria: – Postmenopausal – Diagnosis of locally advanced or metastatic breast cancer – Estrogen receptor-positive and/or progesterone receptor-positive or were of unknown receptor status Key exclusion criteria: – Previous systemic therapy for advanced breast cancer |
| Intervention Studied: Anastrazole 1 mg daily |
| Control: Tamoxifen 20 mg daily |
| Outcomes: – Anastrozole had a significant advantage over tamoxifen in terms of median time to progression: 11.1 months for anastrozole vs 5.6 months for tamoxifen (P =.005) – Side effects: – Thromboembolic events: reported in fewer patients receiving anastrozole (4.1% vs 8.2% tamoxifen) – Vaginal bleeding: reported in fewer patients receiving anastrozole (1.2% vs 3.8% for tamoxifen) The authors concluded that “Anastrozole satisfied the predefined criteria for equivalence to tamoxifen. Furthermore, we observed both a significant increase in time to progression and a lower incidence of thromboembolic events and vaginal bleeding with anastrozole. These findings indicate that anastrozole should be considered as first-line therapy for postmenopausal women with advanced breast cancer.” |
| Citation: Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, Steinberg M, Webster A, von Euler M. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol. 2000 Nov 15;18(22):3758-67. doi: 10.1200/JCO.2000.18.22.3758. PMID: 11078488. |
PALOMA 2 trial: Palbociclib and Letrozole in Advanced Breast Cancer
| Article Name: Anastrozole Is Superior to Tamoxifen as First-Line Therapy for Advanced Breast Cancer in Postmenopausal Women: Results of a North American Multicenter Randomized Trial |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1607303 |
| Journal and year of publication: NEJM, 2016 |
| Trial Design: Randomized, double-blinded, placebo-controlled clinical trial |
| Population: 666 patients with breast cancer Key inclusion criteria: – ER-positive, HER2-negative advanced breast cancer Key exclusion criteria: – Advanced, symptomatic, visceral spread at risk for short-term, life-threatening complications |
| Intervention Studied: Palbociclib–letrozole |
| Control: Placebo–letrozole |
| Outcomes: – Median progression-free survival: longer in the Palbociclib–letrozole (24.8 months vs 14.5 months in the placebo–letrozole group; P<0.001) – Notable adverse events (palbociclib–letrozole group vs placebo–letrozole) : – Neutropenia (66.4% vs 1.4%) – Leukopenia (24.8% vs 0%) – Anemia (5.4% vs. 1.8%) The authors concluded that “Among patients with previously untreated ER-positive, HER2-negative advanced breast cancer, palbociclib combined with letrozole resulted in significantly longer progression-free survival than that with letrozole alone, although the rates of myelotoxic effects were higher with palbociclib–letrozole.” |
| Citation: Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, Harbeck N, Lipatov ON, Walshe JM, Moulder S, Gauthier E, Lu DR, Randolph S, Diéras V, Slamon DJ. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med. 2016 Nov 17;375(20):1925-1936. doi: 10.1056/NEJMoa1607303. PMID: 27959613. |
HERA trial: Trastuzumab for HER-2 positive breast cancer
| Article Name: Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast Cancer |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa052306 |
| Journal and year of publication: NEJM, 2005 |
| Trial Design: Randomized clinical trial |
| Population: 1,694 patients with breast cancer Key inclusion criteria: – Histologically confirmed, completely excised invasive breast cancer with HER2 overexpression or HER2 amplification – Left ventricle ejection fraction of ≥55% after completion of all chemotherapy and radiotherapy Key exclusion criteria: – Distant metastases – Documented congestive heart failure – Uncontrolled hypertension – Unstable arrhythmias |
| Intervention Studied: One or two years of trastuzumab given every three weeks |
| Control: Observation |
| Outcomes: – Primary outcome (recurrence of breast cancer, contralateral breast cancer, second non-breast malignant disease, or death): 127 events in trastuzumab group vs 220 in observation group (P<0.0001) – Overall survival: No significant difference between groups – Severe cardiotoxicity: 0.5% of those on trastuzumab The authors concluded that “One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer.“ |
| Citation: Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Láng I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Rüschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1659-72. doi: 10.1056/NEJMoa052306. PMID: 16236737. |
EMILIA trial: Trastuzumab emtansine for HER-2 positive breast cancer
| Article Name: Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast Cancer |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1209124 |
| Journal and year of publication: NEJM, 2012 |
| Trial Design: Randomized clinical trial |
| Population: 991 patients with breast cancer Key inclusion criteria: – Progression of unresectable, locally advanced or metastatic HER2-positive breast cancer previously treated with a taxane and trastuzumab Key exclusion criteria: – Prior treatment with trastuzumab emtansine (T-DM1), lapatinib, or capecitabine – Peripheral neuropathy of grade 3 or higher – Symptomatic CNS metastases or treatment for these metastases within 2 months |
| Intervention Studied: Trastuzumab emtansine (T-DM1) |
| Control: Lapatinib plus capecitabine |
| Outcomes: – Median progression-free survival: 9.6 months with T-DM1 vs 6.4 months with lapatinib plus capecitabine (P<0.001) – Median overall survival: 30.9 months with T-DM1 vs. 25.1 months with lapatinib plus capecitabine (P<0.001) The authors concluded that “T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane.“ |
| Citation: Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Diéras V, Guardino E, Fang L, Lu MW, Olsen S, Blackwell K; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012 Nov 8;367(19):1783-91. doi: 10.1056/NEJMoa1209124. Epub 2012 Oct 1. Erratum in: N Engl J Med. 2013 Jun 20;368(25):2442. PMID: 23020162; PMCID: PMC5125250. |
CLEOPATRA trial: Pertuzumab and trastuzumab for HER-2 positive breast cancer
| Article Name: Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive Metastatic Breast Cancer |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1413513 |
| Journal and year of publication: NEJM, 2015 |
| Trial Design: Randomized, double-blinded, placebo-controlled clinical trial |
| Population: 991 patients with breast cancer Key inclusion criteria: – Locally recurrent, unresectable, or metastatic HER2-positive breast cancer – Left ventricular ejection fraction (LVEF) of 50% Key exclusion criteria: – CNS metastases |
| Intervention Studied: Pertuzumab, trastuzumab, and docetaxel |
| Control: Placebo, trastuzumab, and docetaxel |
| Outcomes: – Median overall survival: 56.5 months with pertuzumab combination vs 40.8 months with placebo combination (P<0.001) – Median progression-free survival: Improved by 6.3 months with pertuzumab combination (Hazard ratio: 0.68; 95% CI, 0.58 to 0.80) The authors concluded that “In patients with HER2-positive metastatic breast cancer, the addition of pertuzumab to trastuzumab and docetaxel, as compared with the addition of placebo, significantly improved the median overall survival to 56.5 months and extended the results of previous analyses showing the efficacy of this drug combination.“ |
| Citation: Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortés J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. doi: 10.1056/NEJMoa1413513. PMID: 25693012; PMCID: PMC5584549. |
DESTINY-Breast04 Trial: Trastuzumab-deruxtecan for HER-2 low breast cancer
| Article Name: Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa2203690 |
| Journal and year of publication: NEJM, 2022 |
| Trial Design: Randomized, double-blinded, placebo-controlled clinical trial |
| Population: 557 patients with HER-2 low breast cancer Key inclusion criteria: – Unresectable or metastatic breast cancer – Low HER2: score of 1+ on IHC analysis or anIHC score of 2+ and negative results on in situ hybridization Key exclusion criteria: – Interstitial lung disease |
| Intervention Studied: Trastuzumab deruxtecan |
| Control: Physician’s choice of chemotherapy |
| Outcomes: – Median progression-free survival: Trastuzumab deruxtecan group: 9.9 months vs chemotherapy: 5.1 months. HR: 0.50 (P<0.001) – Overall survival: Trastuzumab deruxtecan group: 23.4 months vs chemotherapy 16.8 months. HR: 0.64 (P=0.001) – Occurrence of Grade 3 or higher adverse events: Trastuzumab deruxtecan group: 52.6% vs chemotherapy group: 67.4% of patients The authors concluded that “In this trial involving patients with HER2-low metastatic breast cancer, trastuzumab deruxtecan resulted in significantly longer progression-free and overall survival than the physician’s choice of chemotherapy.“ |
| Citation: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. doi: 10.1056/NEJMoa2203690. Epub 2022 Jun 5. PMID: 35665782. |
RxPONDER trial: Gene assay to guide therapy for node-positive breast cancer
| Article Name: 21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa2108873 |
| Journal and year of publication: NEJM, 2021 |
| Trial Design: Randomized controlled clinical trial |
| Population: 5018 patients Key inclusion criteria: – At least 18 years of age with noninflammatory breast cancer that was: – Hormone-receptor–positive, HER2-negative – Nodal stage N1 – No distant metastasis. – Have undergone primary surgery with sentinel-node biopsy or axillary lymph-node dissection – Eligible for a chemotherapy regimen that contained a taxane, an anthracycline, or both – Oncotype DC recurrence score of 0-25 Key exclusion criteria: – Close or positive surgical margins |
| Intervention Studied: Chemotherapy plus endocrine (chemoendocrine) therapy |
| Control: Endocrine therapy only |
| Outcomes: – The chemotherapy benefit with respect to increasing invasive disease–free survival differed according to menopausal status (P=0.008 for the comparison of chemotherapy benefit in premenopausal and postmenopausal participants) – Among postmenopausal women, invasive disease–free survival at 5 years was 91.9% in the endocrine-only group and 91.3% in the chemoendocrine group, with no chemotherapy benefit – Among premenopausal women, invasive disease–free survival at 5 years was 89.0% with endocrine-only therapy and 93.9% with chemoendocrine therapy (HR, 0.60; 95% CI, 0.43 to 0.83; P=0.002) The authors concluded that “Among premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer invasive disease–free survival and distant relapse–free survival than those who received endocrine-only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy.“ |
| Citation: Kalinsky, K., Barlow, W. E., Gralow, J. R., Meric-Bernstam, F., Albain, K. S., Hayes, D. F., Lin, N. U., Perez, E. A., Goldstein, L. J., Chia, S., Dhesy-Thind, S., Rastogi, P., Alba, E., Delaloge, S., Martin, M., Kelly, C. M., Ruiz-Borrego, M., Gil-Gil, M., Arce-Salinas, C. H., Brain, E., … Hortobagyi, G. N. (2021). 21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer. The New England journal of medicine, 385(25), 2336–2347. https://doi.org/10.1056/NEJMoa2108873. |
Prophylactic mastectomy and salpingo-oophorectomy for BRCA carriers
| Article Name: Association of Risk-Reducing Surgery in BRCA1 or BRCA2 Mutation Carriers With Cancer Risk and Mortality |
| URL: https://jamanetwork.com/journals/jama/fullarticle/186510 |
| Journal and year of publication: JAMA, 2010 |
| Trial Design: Prospective, multicenter cohort study |
| Population: 2482 women Key inclusion criteria: – Women with BRCA1 or BRCA2 mutations Key exclusion criteria: – Recent cancer diagnosis (past 6 months) |
| Intervention Studied: Risk-reducing mastectomy or salpingo-oophorectomy |
| Control: Observation without surgery |
| Outcomes: – Breast cancer diagnosis following risk-reducing mastectomy: 0 breast cancers were diagnosed in those who underwent risk-reducing mastectomy (n= 247), 98 women out of 1372 diagnosed with breast cancer in those who didn’t undergo surgery. – For those who underwent salpingo-oophorectomy, the risk of both ovarian cancer and breast cancer were significantly lower – Mortality: lower all-cause mortality, breast cancer mortality, and ovarian cancer mortality The authors concluded that “Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer–specific mortality, and ovarian cancer–specific mortality.“ |
| Citation: Domchek SM, Friebel TM, Singer CF, Evans DG, Lynch HT, Isaacs C, Garber JE, Neuhausen SL, Matloff E, Eeles R, Pichert G, Van t’veer L, Tung N, Weitzel JN, Couch FJ, Rubinstein WS, Ganz PA, Daly MB, Olopade OI, Tomlinson G, Schildkraut J, Blum JL, Rebbeck TR. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA. 2010 Sep 1;304(9):967-75. doi: 10.1001/jama.2010.1237. PMID: 20810374; PMCID: PMC2948529. |
GI Cancers
COLONPREV trial: FIT vs colonoscopy for colon cancer screening
| Article Name: Colonoscopy versus Fecal Immunochemical Testing in Colorectal-Cancer Screening |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1108895 |
| Journal and year of publication: NEJM, 2012 |
| Trial Design: Randomized controlled trial |
| Population: 57,404 patients Key inclusion criteria: – Asymptomatic patients – Age between 50 and 69 years Key exclusion criteria: – History of colorectal cancer, adenoma, or inflammatory bowel disease – Family history of hereditary or familial colorectal cancer – Previous colectomy |
| Intervention Studied: FIT every 2 years |
| Control: Observation without surgery |
| Outcomes: – Rate of participation: Higher in the FIT group (34.2% vs. 24.6% in the colonoscopy group, P<0.001) – Colorectal cancer Detection: No difference (0.1% in the colonoscopy group and 0.1% in the FIT group, P=0.99) – Adenoma Detection: more identified in colonoscopy group (P<0.001) The authors concluded that “Subjects in the FIT group were more likely to participate in screening than were those in the colonoscopy group. On the baseline screening examination, the numbers of subjects in whom colorectal cancer was detected were similar in the two study groups, but more adenomas were identified in the colonoscopy group.“ |
| Citation: Quintero E, Castells A, Bujanda L, Cubiella J, Salas D, Lanas Á, Andreu M, Carballo F, Morillas JD, Hernández C, Jover R, Montalvo I, Arenas J, Laredo E, Hernández V, Iglesias F, Cid E, Zubizarreta R, Sala T, Ponce M, Andrés M, Teruel G, Peris A, Roncales MP, Polo-Tomás M, Bessa X, Ferrer-Armengou O, Grau J, Serradesanferm A, Ono A, Cruzado J, Pérez-Riquelme F, Alonso-Abreu I, de la Vega-Prieto M, Reyes-Melian JM, Cacho G, Díaz-Tasende J, Herreros-de-Tejada A, Poves C, Santander C, González-Navarro A; COLONPREV Study Investigators. Colonoscopy versus fecal immunochemical testing in colorectal-cancer screening. N Engl J Med. 2012 Feb 23;366(8):697-706. doi: 10.1056/NEJMoa1108895. Erratum in: N Engl J Med. 2016 May 12;374(19):1898. PMID: 22356323. |
FOLFOX for colon cancer
| Article Name: Leucovorin and Fluorouracil With or Without Oxaliplatin as First-Line Treatment in Advanced Colorectal Cancer |
| URL: https://ascopubs.org/doi/10.1200/jco.2000.18.16.2938 |
| Journal and year of publication: Journal of Clinical Oncology, 2000 |
| Trial Design: Randomized controlled trial |
| Population: 420 patients Key inclusion criteria: – Adenocarcinoma of the colon or rectum – Unresectable metastases – Adequate bone marrow, liver, and renal function Key exclusion criteria: – CNS metastases – Second malignancies |
| Intervention Studied: Leucovorin (LV) plus bolus and infusional fluorouracil (5FU) every 2 weeks (LV5FU2) + oxaliplatin |
| Control: LV5FU2 regimen alone |
| Outcomes: – Progression-free survival: significantly longer in patients allocated to oxaliplatin plus LV5FU2 (median: 9.0 months vs 6.2 months with control, P = 0.0003) – Response rate: better response rate with oxaliplatin plus LV5FU2 (50.7% vs 22.3% with control, P = 0.0001) – Overall survival: no significant difference between groups (median: 16.2 v 14.7 months with control, P = 0.12) – Adverse effect grade 3 or above: higher rate with LV5FU2 plus oxaliplatin vs control The authors concluded that “The LV5FU2-oxaliplatin combination seems beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged progression-free survival with acceptable tolerability and maintenance of QoL.“ |
| Citation: de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000 Aug;18(16):2938-47. doi: 10.1200/JCO.2000.18.16.2938. PMID: 10944126. |
BICC-C trial: FOLIRI for colon cancer
| Article Name: Randomized, Controlled Trial of Irinotecan Plus Infusional, Bolus, or Oral Fluoropyrimidines in First-Line Treatment of Metastatic Colorectal Cancer: Results From the BICC-C Study |
| URL: https://ascopubs.org/doi/10.1200/JCO.2007.11.3357 |
| Journal and year of publication: Journal of Clinical Oncology, 2007 |
| Trial Design: Randomized controlled trial |
| Population: 430 patients Key inclusion criteria: – Metastatic adenocarcinoma of the colon or rectum – Adequate bone marrow, hepatic, and renal function – No previous chemotherapy for metastatic disease Key exclusion criteria: – Received prior therapy with irinotecan, topotecan, or bevacizumab – CNS metastases – Pulmonary embolism, or deep vein thrombosis within the past 6 months |
| Intervention Studied: A) FOLFIRI vs mIFL vs CapeIRI B) Celecoxib vs placebo Later: Study was amended with discontinuing (CapeIRI) and include the following: C) FOLFIRI plus bevacizumab vs mILF plus bevacizumab |
| Control: See above |
| Outcomes: – Median progression-free survival: FOLFIRI: 7.6 months vs mIFL: 5.9 months (P = 0.004), vs CapeIRI: 5.8 months (P = 0.015) – Median overall survival: FOLFIRI: 23.1 months vs mIFL: 17.6 months; (P = 0.09), vs CapeIRI: 18.9 months (P = 0.27), vs mIFL+Bev: 19.2 months (P = 0.007), FOLFIRI+Bev: Not yet been reached The authors concluded that “FOLFIRI and FOLFIRI+Bev offered superior activity to their comparators and were comparably safe. An infusional schedule of FU should be the preferred irinotecan-based regimen in first-line metastatic colorectal cancer.“ |
| Citation: Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, Schulz J, Richards D, Soufi-Mahjoubi R, Wang B, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007 Oct 20;25(30):4779-86. doi: 10.1200/JCO.2007.11.3357. PMID: 17947725. |
Resection and RFA for CRC liver metastases
| Article Name: Recurrence and Outcomes Following Hepatic Resection, Radiofrequency Ablation, and Combined Resection/Ablation for Colorectal Liver Metastases |
| URL: https://journals.lww.com/annalsofsurgery/Recurrence_and_Outcomes |
| Journal and year of publication: Annals of Surgery, 2004 |
| Trial Design: Retrospective cohort study |
| Population: 418 patients |
| Intervention Studied: 1) Hepatic resection only 2) Radiofrequency ablation (RFA) plus resection 3) RFA only |
| Control: See above |
| Outcomes: – Overall recurrence: Most common after RFA: RFA: 84%, RFA + resection: 64%, Resection only: 52%, P < 0.001. – 4-year survival rate: highest after resection: After resection: 65%; RFA + resection: 36%; RFA only: 22%, P < 0.0001 The authors concluded that ” Hepatic resection is the treatment of choice for colorectal liver metastases. RFA alone or in combination with resection for unresectable patients does not provide survival comparable to resection, and provides survival only slightly superior to nonsurgical treatment.“ |
| Citation: Abdalla EK, Vauthey JN, Ellis LM, Ellis V, Pollock R, Broglio KR, Hess K, Curley SA. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg. 2004 Jun;239(6):818-25; discussion 825-7. doi: 10.1097/01.sla.0000128305.90650.71. PMID: 15166961; PMCID: PMC1356290. |
PRODIGE 4/ACCORD 11 trial: FOLFIRINOX for pancreatic cancer
| Article Name: PRODIGE 4/ACCORD 11 trial- FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1011923 |
| Journal and year of publication: NEJM, 2011 |
| Trial Design: Randomized controlled trial |
| Population: 342 patients Key inclusion criteria: – Measurable metastatic pancreatic adenocarcinoma not previously treated with chemotherapy – Adequate bone marrow, liver function, and renal function Key exclusion criteria: – Endocrine or acinar pancreatic carcinoma – Cerebral metastases |
| Intervention Studied: FOLFIRINOX (oxaliplatin,irinotecan,leucovorin,fluorouracil) |
| Control: Gemcitabine |
| Outcomes: – Median overall survival: 11.1 months for FOLFIRINOX vs 6.8 months for gemcitabine (P<0.001) – Median progression-free survival: 6.4 months for FOLFIRINOX vs 3.3 for gemcitabine (P<0.001) – Adverse events occurrence: more frequent in the FOLFIRINOX group The authors concluded that “As compared with gemcitabine, FOLFIRINOX was associated with a survival advantage and had increased toxicity. FOLFIRINOX is an option for the treatment of patients with metastatic pancreatic cancer and good performance status.“ |
| Citation: Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. doi: 10.1056/NEJMoa1011923. PMID: 21561347. |
MPACT trial: nab-Paclitaxel plus gemcitabine for pancreatic cancer
| Article Name: Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1304369 |
| Journal and year of publication: NEJM, 2013 |
| Trial Design: Randomized controlled trial |
| Population: 861 patients Key inclusion criteria: – Measurable metastatic pancreatic adenocarcinoma that had not previously been treated with chemotherapy – Karnofsky performance-status score of 70 or more Key exclusion criteria: – Unclear per manuscript |
| Intervention Studied: Nab-paclitaxel plus gemcitabine |
| Control: Gemcitabine |
| Outcomes: – Median overall survival: Nab-paclitaxel–gemcitabine: 8.5 vs Gemcitabine: 6.7 months (P<0.001) – Median progression-free survival: Nab-paclitaxel–gemcitabine: 5.5 vs Gemcitabine: 3.7 months (P<0.001) The authors concluded that “In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased.“ |
| Citation: Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. doi: 10.1056/NEJMoa1304369. Epub 2013 Oct 16. PMID: 24131140; PMCID: PMC4631139. |
POLO trial: Olaparib for BRCA mutated pancreatic cancer
| Article Name: Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1903387 |
| Journal and year of publication: NEJM, 2019 |
| Trial Design: Randomized controlled trial |
| Population: 154 patients Key inclusion criteria: – Pancreas adenocarcinoma receiving initial chemotherapy for metastatic disease – Documented mutation in gBRCA1 or gBRCA2 that is predicted to be deleterious or suspected deleterious Key exclusion criteria: – Previous treatment with a PARP inhibitor, including Olaparib |
| Intervention Studied: Maintenance olaparib tablets (300 mg twice daily) |
| Control: Placebo |
| Outcomes: – Progression-free survival longer in olaparib group, vs placebo: Olaparib: 7.4 months vs Placebo: 3.8 months; HR for disease progression or death: 0.53, 95%CI: 0.35 – 0.82 (P=0.004). – Overall survival (Interim analysis – at a data maturity of 46%): No difference between the olaparib and placebo groups – Health-related quality of life (global quality-of-life score): No significant between-group difference: – Incidence of grade 3 or higher adverse events: Olaparib group: 40% (5% discontinued trial due to adverse event) vs Placebo group: 23% (2% discontinued trial due to adverse event) The authors concluded that “Among patients with a germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo.“ |
| Citation: Golan, T., Hammel, P., Reni, M., Van Cutsem, E., Macarulla, T., Hall, M. J., Park, J. O., Hochhauser, D., Arnold, D., Oh, D. Y., Reinacher-Schick, A., Tortora, G., Algül, H., O’Reilly, E. M., McGuinness, D., Cui, K. Y., Schlienger, K., Locker, G. Y., & Kindler, H. L. (2019). Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. The New England journal of medicine, 381(4), 317–327. |
CROSS trial: Neoadjuvant chemoradiation for esophageal cancer
| Article Name: Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer |
| URL: https://www.nejm.org/doi/10.1056/nejmoa1112088 |
| Journal and year of publication: NEJM, 2012 |
| Trial Design: Randomized controlled trial |
| Population: 366 patients Key inclusion criteria: – Potentially curable squamous-cell carcinoma, adenocarcinoma, or large-cell undifferentiated carcinoma of the esophagus or esophagogastric junction – ECOG 0-2 Key exclusion criteria: – The length and width of the tumor could not exceed 8 cm and 5 cm, respectively |
| Intervention Studied: Chemoradiotherapy followed by surgery |
| Control: Surgery alone |
| Outcomes: – Complete resection with no tumor within 1 mm of the resection margins (R0) was achieved in 92% of patients in the chemoradiotherapy–surgery group versus 69% in the surgery group (P<0.001) – A pathological complete response was achieved in 47 of 161 patients (29%) who underwent resection after chemoradiotherapy – Postoperative complications were similar in the two treatment groups, and in-hospital mortality was 4% in both – Median overall survival was 49.4 months in the chemoradiotherapy–surgery group versus 24.0 months in the surgery group (P=0.003) The authors concluded that “Preoperative chemoradiotherapy improved survival among patients with potentially curable esophageal or esophagogastric-junction cancer. The regimen was associated with acceptable adverse-event rates.“ |
| Citation: van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, Richel DJ, Nieuwenhuijzen GA, Hospers GA, Bonenkamp JJ, Cuesta MA, Blaisse RJ, Busch OR, ten Kate FJ, Creemers GJ, Punt CJ, Plukker JT, Verheul HM, Spillenaar Bilgen EJ, van Dekken H, van der Sangen MJ, Rozema T, Biermann K, Beukema JC, Piet AH, van Rij CM, Reinders JG, Tilanus HW, van der Gaast A; CROSS Group. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012 May 31;366(22):2074-84. doi: 10.1056/NEJMoa1112088. PMID: 22646630. |
TOGA trial: Trastuzumab for HER-2 positive GEJ adenocarcinoma
| Article Name: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial |
| URL: Link |
| Journal and year of publication: The Lancet, 2010 |
| Trial Design: Randomized controlled trial |
| Population: 594 patients Key inclusion criteria: – Inoperable locally advanced, recurrent, or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction – ECOG performance status 0–2 – Tumour samples were scored as 3+ on immunohistochemistry or if they were FISH positive (HER2:CEP17 ratio ≥2) Key exclusion criteria: – Previous chemotherapy for metastatic disease – Congestive heart failure, baseline LVEF < 50% – Active gastrointestinal bleeding. |
| Intervention Studied: Chemotherapy in combination with IV trastuzumab |
| Control: Chemotherapy |
| Outcomes: – Median overall survival: 13.8 months for trastuzumab + chemotherapy vs 11.1 months for chemotherapy alone (p=0.0046) The authors concluded that “Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer.“ |
| Citation: Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. doi: 10.1016/S0140-6736(10)61121-X. Epub 2010 Aug 19. Erratum in: Lancet. 2010 Oct 16;376(9749):1302. PMID: 20728210. |
CheckMate 577: Adjuvant nivolumab in resected esophageal cancer
| Article Name: Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa2032125 |
| Journal and year of publication: NEJM, 2021 |
| Trial Design: Randomized controlled trial |
| Population: 532 patients Key inclusion criteria: – Had resected esophageal or GE junction cancer, and had received neoadjuvant chemoradiotherapy, regardless (PD-L1) expression – Stage II or III esophageal or GE junction cancer at the initial diagnosis Key exclusion criteria: |
| Intervention Studied: Adjuvant nivolumab |
| Control: Matching placebo |
| Outcomes: – Median disease survival: Nivolumab: 22.4 months (95% CI: 16.6 to 34.0) vs Placebo: 11.0 months (95% CI: 8.3 to 14.3); HRfor disease recurrence or death: 0.69 (P<0.001) – Grade 3 or 4 adverse events: Nivolumab: 13% of patients vs Placebo: 6% of patients The authors concluded that “Among patients with resected esophageal or gastroesophageal junction cancer who had received neoadjuvant chemoradiotherapy, disease-free survival was significantly longer among those who received nivolumab adjuvant therapy than among those who received placebo“ |
| Citation: Kelly RJ, Ajani JA, Kuzdzal J, Zander T, Van Cutsem E, Piessen G, Mendez G, Feliciano J, Motoyama S, Lièvre A, Uronis H, Elimova E, Grootscholten C, Geboes K, Zafar S, Snow S, Ko AH, Feeney K, Schenker M, Kocon P, Zhang J, Zhu L, Lei M, Singh P, Kondo K, Cleary JM, Moehler M; CheckMate 577 Investigators. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer. N Engl J Med. 2021 Apr 1;384(13):1191-1203. doi: 10.1056/NEJMoa2032125. PMID: 33789008. |
CheckMate 694: First line nivolumab + chemo for esophageal and GEJ cancer
| Article Name: First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial |
| URL: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00797-2/fulltext |
| Journal and year of publication: The Lancet, 2021 |
| Trial Design: Randomized controlled trial |
| Population: 1581 patients Key inclusion criteria: – Previously untreated, unresectable, non-HER2-positive gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma, regardless of PD-ligand 1 (PD-L1) expression Key exclusion criteria: |
| Intervention Studied: Group 1: Nivolumab plus chemotherapy (capecitabine and oxaliplatin every 3 weeks or leucovorin, fluorouracil, and oxaliplatin every 2 weeks) Group 2: Nivolumab plus ipilimumab Group 3: Chemotherapy alone |
| Control: See above |
| Outcomes: – In patients with PD-L1 CPS of five or more: – Overall survival: Better with nivolumab plus chemotherapy, vs Chemotherapy alone: Hazard ratio: 0.71 (98.4% CI 0.59–0.86) (P<0.0001) – Progression-free survival: Better with nivolumab plus chemotherapy, vs Chemotherapy alone: Hazard ratio: 0.68 (98% CI 0.56–0.81) (P<0.0001) – Significant improvement in overall survival with progression-free survival benefit, in patients with a PD-L1 CPS of one or more. – Grade 3 or 4 treatment related adverse events were higher with Nivolumab plus chemotherapy (59% of patients) vs chemotherapy alone (44% of patients) The authors concluded that “Nivolumab is the first PD-1 inhibitor to show superior OS, along with PFS benefit and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma. Nivolumab plus chemotherapy represents a new standard first-line treatment for these patients“ |
| Citation: Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40. doi: 10.1016/S0140-6736(21)00797-2. Epub 2021 Jun 5. PMID: 34102137. |
Milan Criteria study
| Article Name: Liver Transplantation for the Treatment of Small Hepatocellular Carcinomas in Patients with Cirrhosis |
| URL: https://www.nejm.org/doi/full/10.1056/nejm199603143341104 |
| Journal and year of publication: NEJM, 1996 |
| Trial Design: Prospective clinical trial |
| Population: 48 patients Key inclusion criteria: – Single hepatocellular carcinoma with tumor size not exceeding 5 cm in diameter OR – Multiple tumors, not more than 3, none exceeding 3 cm in diameter Key exclusion criteria: – Tumor invasion of blood vessels or lymph nodes, evident or suspected |
| Intervention Studied: Liver transplantation |
| Control: N/a |
| Outcomes: – Overall and recurrence-free survival rates (at 4 years): – For those who met the predetermined criteria for the selection of small hepatocellular carcinomas the overall survival rate was 85% and the recurrence-free survival rate was 92% – For those whose tumors exceeded these limits the overall survival rate: was 50% and the recurrence-free survival rate: 59% (P = 0.01 for overall survival; P = 0.002 for recurrence-free survival) The authors concluded that “Liver transplantation is an effective treatment for small, unresectable hepatocellular carcinomas in patients with cirrhosis.“ |
| Citation: Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A, Gennari L. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996 Mar 14;334(11):693-9. doi: 10.1056/NEJM199603143341104. PMID: 8594428. |
SHARP trial: Sorafenib for HCC
| Article Name: Sorafenib in Advanced Hepatocellular Carcinoma |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa0708857 |
| Journal and year of publication: NEJM, 2008 |
| Trial Design: Randomized, double-blinded, placebo-controlled clinical trial |
| Population: 602 patients with HCC Key inclusion criteria: – Confirmed advanced-stage hepatocellular carcinoma – No previous systemic therapy – ECOG 2 or less – Child–Pugh liver function class A Key exclusion criteria: – Previously received molecularly targeted therapies or any other systemic treatment |
| Intervention Studied: Sorafenib |
| Control: Placebo |
| Outcomes: – Median overall survival: 10.7 months with sorafenib vs 7.9 months with placebo (P<0.001) – Median time to radiologic progression: 5.5 months with sorafenib vs 2.8 months with placebo (P<0.001) The authors concluded that “In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo.“ |
| Citation: Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Jul 24;359(4):378-90. doi: 10.1056/NEJMoa0708857. PMID: 18650514. |
Lung Cancer
National Lung Cancer Screening Trial
| Article Name: Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1102873 |
| Journal and year of publication: NEJM, 2011 |
| Trial Design: Randomized clinical trial |
| Population: 53,454 patients Key inclusion criteria: – 55 to 74 years of age – History of cigarette smoking of at least 30 pack-years, and, if former smokers, had quit within the previous 15 years Key exclusion criteria: – Previously received a diagnosis of lung cancer – Had hemoptysis or unexplained weight loss > 6.8 kg (15 lb) in the preceding year |
| Intervention Studied: Three annual screenings with low-dose CT |
| Control: Three annual screenings with single-view posteroanterior chest radiography |
| Outcomes: – Rate of adherence to screening: > 90%. – Rate of positive screening tests: Low-dose CT: 24.2% vs Radiography:6.9% – Rate of false positive results: Low-dose CT: 96.4% vs Radiography: 94.5% – Deaths: Low-dose CT: 247 deaths from lung cancer per 100,000 person-years vs radiography: 309 deaths per 100,000 person-years (P=0.004) The authors concluded that “Screening with the use of low-dose CT reduces mortality from lung cancer.“ |
| Citation: National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, Gareen IF, Gatsonis C, Marcus PM, Sicks JD. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011 Aug 4;365(5):395-409. doi: 10.1056/NEJMoa1102873. Epub 2011 Jun 29. PMID: 21714641; PMCID: PMC4356534. |
PACIFIC trial: Durvalumab for Stage III NSCLC
| Article Name: Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening |
| URL: https://www.nejm.org/doi/full/10.1056/nejmoa1709937 |
| Journal and year of publication: NEJM, 2017 |
| Trial Design: Randomized, double-blinded, placebo-controlled clinical trial |
| Population: 713 patients Key inclusion criteria: – Documented stage III, locally advanced, unresectable NSCLC Key exclusion criteria: – Previous exposure to anti–PD-1 or PD-L1 antibodies – Active or previous autoimmune disease (within the past 2 years) – History of primary immunodeficiency |
| Intervention Studied: Durvalumab |
| Control: Placebo |
| Outcomes: – Median progression-free survival: Durvalumab: 16.8 months vs Placebo: 5.6 months (P<0.001) – Response rate: Durvalumab: 28.4% vs Placebo: 16.0% (P<0.001) The authors concluded that “Progression-free survival was significantly longer with durvalumab than with placebo. The secondary end points also favored durvalumab, and safety was similar between the groups.“ |
| Citation: Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Özgüroğlu M; PACIFIC Investigators. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Nov 16;377(20):1919-1929. doi: 10.1056/NEJMoa1709937. Epub 2017 Sep 8. PMID: 28885881. |
FLAURA trial: Osimertinib for EGFR+ NSCLC
| Article Name: Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer |
| URL: https://www.nejm.org/doi/full/10.1056/nejmoa1713137 |
| Journal and year of publication: NEJM, 2018 |
| Trial Design: Randomized clinical trial |
| Population: 556 patients with NSCLC Key inclusion criteria: – Locally advanced NSCLC, not amenable to curative surgery or radiotherapy – EGFR mutation known to be associated with EGFR-TKI sensitivity, alone or with other EGFR mutations Key exclusion criteria: – Prior treatment with systemic anticancer therapy for NSCLC – Prior treatment with EGFR-TKI – QTc > 470 msec, or clinically important arrhythmias, or factors that increase the risk of arrhythmias or QTc prolongation – Active HBV, HCV, or HIV infections |
| Intervention Studied: Osimertinib |
| Control: Standard EGFR-TKI (gefitinib 250 mg once daily or erlotinib 150 mg once daily) |
| Outcomes: – Median progression-free survival: Osimertinib: 18.9 months vs Standard EGFR-TKIs: 10.2 months (HR for disease progression or death: 0.46) (P<0.001) – Survival rate at 18 months: Osimertinib: 83% (95% CI: 78 to 87) vs standard EGFR-TKIs: 71% (95% CI, 65 to 76), HR for death: 0.63 (P=0.007) – Grade 3 or 4 adverse events: Osimertinib: 34% vs Standard EGFR-TKIs: 45% The authors concluded that “Osimertinib showed efficacy superior to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation–positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events.“ |
| Citation: Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS; FLAURA Investigators. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. doi: 10.1056/NEJMoa1713137. Epub 2017 Nov 18. PMID: 29151359. |
ALEX trial: Alectinib vs crizotinib for ALK+ NSCLC
| Article Name: Alectinib versus Crizotinib in Untreated ALK-Positive Non–Small-Cell Lung Cancer |
| URL: https://www.nejm.org/doi/full/10.1056/nejmoa1704795 |
| Journal and year of publication: NEJM, 2017 |
| Trial Design: Randomized clinical trial |
| Population: 303 patients with NSCLC Key inclusion criteria: – Advanced NSCLC that was ALK-positive – No previous systemic treatment for advanced NSCLC Key exclusion criteria: |
| Intervention Studied: Alectinib |
| Control: Crizotinib |
| Outcomes: – Rate of disease progression or death: Alectinib group: 41% vs Crizotinib group: 68% (P<0.001) – Grade 3 to 5 adverse events: Alectinib group: 41% vs Crizotinib group: 50% The authors concluded that “As compared with crizotinib, alectinib showed superior efficacy and lower toxicity in primary treatment of ALK-positive NSCLC.“ |
| Citation: Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, Ou SI, Pérol M, Dziadziuszko R, Rosell R, Zeaiter A, Mitry E, Golding S, Balas B, Noe J, Morcos PN, Mok T; ALEX Trial Investigators. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Aug 31;377(9):829-838. doi: 10.1056/NEJMoa1704795. Epub 2017 Jun 6. PMID: 28586279. |
Crizotinib in ROS+ NSCLC
| Article Name: Crizotinib in ROS1-Rearranged Non–Small-Cell Lung Cancer |
| URL: https://www.nejm.org/doi/full/10.1056/nejmoa1406766 |
| Journal and year of publication: NEJM, 2014 |
| Trial Design: Prospective clinical trial |
| Population: 50 patients with NSCLC Key inclusion criteria: – NSCLC with a ROS1 rearrangement. – ECOG performance status of 0 to 2 Key exclusion criteria: |
| Intervention Studied: Crizotinib |
| Control: None |
| Outcomes: – Response rate: – 72% (95% CI: 58 to 84) – Complete responses: 3 – Partial responses: 33 – Median duration of response: 17.6 months (95% CI, 14.5 to not reached) – Median progression-free survival:19.2 months (95% CI, 14.4 to not reached) The authors concluded that “In this study, crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active.“ |
| Citation: Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, Riely GJ, Varella-Garcia M, Shapiro GI, Costa DB, Doebele RC, Le LP, Zheng Z, Tan W, Stephenson P, Shreeve SM, Tye LM, Christensen JG, Wilner KD, Clark JW, Iafrate AJ. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Nov 20;371(21):1963-71. doi: 10.1056/NEJMoa1406766. Epub 2014 Sep 27. PMID: 25264305; PMCID: PMC4264527. |
KEYNOTE-042 trial: Pembrolizumab in PD-L1+ NSCLC
| Article Name: Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial |
| URL: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32409-7/fulltext |
| Journal and year of publication: The Lancet, 2019 |
| Trial Design: Randomized clinical trial |
| Population: 1,274 patients with NSCLC Key inclusion criteria: – Locally advanced or metastatic NSCLC – PD-L1 TPS of 1% or greater – Without a sensitizing EGFR mutation or ALK translocation Key exclusion criteria: – History of non-infectious pneumonitis that required systemic glucocorticoids – Active autoimmune disease – Receiving systemic immunosuppressive treatment |
| Intervention Studied: Pembrolizumab |
| Control: Investigator’s choice of platinum-based chemotherapy |
| Outcomes: – Overall survival: pembrolizumab group: significantly longer overall survival vs chemotherapy group: – PD-L1 ≥50% HR 0.69, 95% CI 0.56–0.85; p=0.0003 – PD-L1 ≥20% HR 0.77, 0.64–0.92; p=0·0020 – PD-L1 ≥1% 0.81, 0.71–0.93; p=0·0018 – Grade 3 or more adverse events: pembrolizumab group: 18% of patients vs chemotherapy group: 41% of patients The authors concluded that “The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS.” |
| Citation: Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019 May 4;393(10183):1819-1830. doi: 10.1016/S0140-6736(18)32409-7. Epub 2019 Apr 4. PMID: 30955977. |
KEYNOTE-407 trial: Pembrolizumab + chemotherapy in squamous NSCLC
| Article Name: Pembrolizumab plus Chemotherapy for Squamous Non–Small-Cell Lung Cancer |
| URL: https://www.nejm.org/doi/full/10.1056/nejmoa1810865 |
| Journal and year of publication: NEJM, 2018 |
| Trial Design: Randomized clinical trial |
| Population: 559 patients Key inclusion criteria: – Pathologically confirmed stage IV squamous NSCLC, regardless of PD-L1 status Key exclusion criteria: – Symptomatic central nervous system metastases – Active autoimmune disease |
| Intervention Studied: Pembrolizumab + carboplatin and either paclitaxel or nab–paclitaxel |
| Control: Matching placebo |
| Outcomes: – Median overall survival: Pembrolizumab-combination: 15.9 months (95% CI: 13.2 to not reached) vs Placebo-combination: (95% CI: 9.5 to 14.8); HR for death: 0.64 (95% CI, 0.49 to 0.85) (P<0.001) – Benefit was consistent regardless of the level of PD-L1 expression – Grade 3 or 4 adverse events occurrence: Pembrolizumab-combination: 69.8% of patients vs Placebo-combination: 68.2% of patients The authors concluded that “In patients with previously untreated metastatic, squamous NSCLC, the addition of pembrolizumab to chemotherapy with carboplatin plus paclitaxel or nab-paclitaxel resulted in significantly longer overall survival and progression-free survival than chemotherapy alone.” |
| Citation: Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, Rodríguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM; KEYNOTE-407 Investigators. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018 Nov 22;379(21):2040-2051. doi: 10.1056/NEJMoa1810865. Epub 2018 Sep 25. PMID: 30280635. |
CHECKMATE 227 trial: Ipilimumab-Nivolumab for PD-L1+ NSCLC
| Article Name: Nivolumab plus Ipilimumab in Advanced Non–Small-Cell Lung Cancer |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1910231 |
| Journal and year of publication: NEJM, 2019 |
| Trial Design: Randomized clinical trial |
| Population: 1,739 patients with NSCLC Key inclusion criteria: – Squamous or nonsquamous stage IV or recurrent NSCLC – ECOG score of 0 or 1 Key exclusion criteria: – EGFR mutations sensitive to available targeted inhibitor therapy |
| Intervention Studied: 1) Nivolumab plus ipilimumab 2) Nivolumab alone |
| Control: 3) Chemotherapy |
| Outcomes: – Median duration of overall survival: -PD-L1 expression level of 1% or more — Nivolumab plus ipilimumab: 17.1 months vs chemotherapy: 14.9 months (P=0.007) – PD-L1 expression level < 1% — Nivolumab plus ipilimumab: 17.2 months vs chemotherapy: 12.2 months (95% CI, 9.2 to 14.3) The authors concluded that “First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of overall survival than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level. No new safety concerns emerged with longer follow-up.“ |
| Citation: Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim SW, Carcereny Costa E, Park K, Alexandru A, Lupinacci L, de la Mora Jimenez E, Sakai H, Albert I, Vergnenegre A, Peters S, Syrigos K, Barlesi F, Reck M, Borghaei H, Brahmer JR, O’Byrne KJ, Geese WJ, Bhagavatheeswaran P, Rabindran SK, Kasinathan RS, Nathan FE, Ramalingam SS. Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2019 Nov 21;381(21):2020-2031. doi: 10.1056/NEJMoa1910231. Epub 2019 Sep 28. PMID: 31562796. |
IMpower 133 trial: Atezolizumab for SCLC
| Article Name: First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer |
| URL: https://www.nejm.org/doi/full/10.1056/nejmoa1809064 |
| Journal and year of publication: NEJM, 2018 |
| Trial Design: Randomized, double-blinded, placebo-controlled clinical trial |
| Population: 403 patients with SCLC Key inclusion criteria: – Extensive-stage small-cell lung cancer – Measurable extensive-stage small-cell lung cancer – ECOG score of 0 or 1 Key exclusion criteria: – History of autoimmune disease |
| Intervention Studied: Carboplatin and etoposide + atezolizumab |
| Control: Carboplatin and etoposide + placebo |
| Outcomes: – Median overall survival: atezolizumab group: 12.3 months vs Placebo group: 10.3 months (P=0.007) – Median progression-free survival: Atezolizumab group: 5.2 months vs Placebo group: 4.3 months (P=0.02) The authors concluded that “The addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer resulted in significantly longer overall survival and progression-free survival than chemotherapy alone.“ |
| Citation: Horn L, Mansfield AS, Szczęsna A, Havel L, Krzakowski M, Hochmair MJ, Huemer F, Losonczy G, Johnson ML, Nishio M, Reck M, Mok T, Lam S, Shames DS, Liu J, Ding B, Lopez-Chavez A, Kabbinavar F, Lin W, Sandler A, Liu SV; IMpower133 Study Group. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med. 2018 Dec 6;379(23):2220-2229. doi: 10.1056/NEJMoa1809064. Epub 2018 Sep 25. PMID: 30280641. |
Genitourinary cancers
PLCO trial: Prostate cancer screening with PSA
| Article Name: Mortality Results from a Randomized Prostate-Cancer Screening Trial |
| URL: https://www.nejm.org/doi/full/10.1056/nejmoa0810696 |
| Journal and year of publication: NEJM, 2009 |
| Trial Design: Randomized clinical trial |
| Population: 76,693 men Key inclusion criteria: – Ages of 55 and 74 years Key exclusion criteria: – History of prostate cancer – Current cancer treatment – Having had more than one PSA blood test in the previous 3 years |
| Intervention Studied: Annual screening with PSA and DRE |
| Control: Usual care |
| Outcomes: – Rates of compliance: PSA: 85% DRE: 86% – Incidence of prostate cancer (after 7 years of follow-up) – Screening group: 116 per 10,000 person-years (2820 cancers) – Control group: 95 per 10,000 person-year (2322 cancers) – Incidence of death: – Screening group: 2.0 per 10,000 person-years (50 deaths) – Control group: 1.7 per 10,000 person-years (44 deaths) (Rate ratio: 1.13; 95% CI, 0.75 to 1.70) The authors concluded that “After 7 to 10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the two study groups.“ |
| Citation: Andriole GL, Crawford ED, Grubb RL 3rd, Buys SS, Chia D, Church TR, Fouad MN, Gelmann EP, Kvale PA, Reding DJ, Weissfeld JL, Yokochi LA, O’Brien B, Clapp JD, Rathmell JM, Riley TL, Hayes RB, Kramer BS, Izmirlian G, Miller AB, Pinsky PF, Prorok PC, Gohagan JK, Berg CD; PLCO Project Team. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009 Mar 26;360(13):1310-9. doi: 10.1056/NEJMoa0810696. Epub 2009 Mar 18. Erratum in: N Engl J Med. 2009 Apr 23;360(17):1797. PMID: 19297565; PMCID: PMC2944770. |
CHAARTED trial: Chemohormonal therapy for prostate cancer
| Article Name: Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1503747 |
| Journal and year of publication: NEJM, 2015 |
| Trial Design: Randomized clinical trial |
| Population: 790 patients with prostate cancer Key inclusion criteria: – Pathological diagnosis of prostate cancer OR – Clinical scenario consistent with prostate cancer with an elevated PSA – Radiologic evidence of metastatic disease – ECOG performance-status score of 0, 1, or 2 Key exclusion criteria: – Unclear from manuscript |
| Intervention Studied: Androgen deprivation therapy (ADT) plus docetaxel |
| Control: ADT alone |
| Outcomes: – Median overall survival: combination therapy: 57.6 months vs ADT alone: 44.0 months (P<0.001) – Median time to disease progression: Combination therapy: 20.2 months vs ADT alone: 11.7 months (P<0.001) The authors concluded that “Six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer resulted in significantly longer overall survival than that with ADT alone.“ |
| Citation: Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, Wong YN, Hahn N, Kohli M, Cooney MM, Dreicer R, Vogelzang NJ, Picus J, Shevrin D, Hussain M, Garcia JA, DiPaola RS. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med. 2015 Aug 20;373(8):737-46. doi: 10.1056/NEJMoa1503747. Epub 2015 Aug 5. PMID: 26244877; PMCID: PMC4562797. |
ARCHES trial: Enzalutamide therapy for prostate cancer
| Article Name: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer |
| URL: https://ascopubs.org/doi/full/10.1200/JCO.19.0079 |
| Journal and year of publication: Journal of Clinical Oncology, 2019 |
| Trial Design: Randomized, double-blinded, placebo-controlled clinical trial |
| Population: 1,150 patients with prostate cancer Key inclusion criteria: – Pathologically confirmed prostate adenocarcinoma, without neuroendocrine differentiation, signet-cell, or small-cell features – ECOG score of 0 or 1 – Hormone-sensitive metastatic disease Key exclusion criteria: – Unclear from manuscript |
| Intervention Studied: Enzalutamide + ADT |
| Control: Placebo + ADT |
| Outcomes: -Risk of radiographic progression or death: significantly lowered with enzalutamide + ADT vs placebo + ADT – hazard ratio: 0.39 (95% CI, 0.30 to 0.50) (P < 0.001) The authors concluded that “Enzalutamide with ADT significantly reduced the risk of metastatic progression or death over time versus placebo plus ADT in men with mHSPC, including those with low-volume disease and/or prior docetaxel, with a safety analysis that seems consistent with the safety profile of enzalutamide in previous clinical trials in castration-resistant prostate cancer.“ |
| Citation: Armstrong AJ, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, Villers A, Azad A, Alcaraz A, Alekseev B, Iguchi T, Shore ND, Rosbrook B, Sugg J, Baron B, Chen L, Stenzl A. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 2019 Nov 10;37(32):2974-2986. doi: 10.1200/JCO.19.00799. Epub 2019 Jul 22. PMID: 31329516; PMCID: PMC6839905. |
TARGET trial – Sorafenib for RCC
| Article Name: Sorafenib in Advanced Clear-Cell Renal-Cell Carcinoma |
| URL: https://www.nejm.org/doi/full/10.1056/nejmoa060655 |
| Journal and year of publication: NEJM, 2007 |
| Trial Design: Randomized, double-blinded, placebo-controlled clinical trial |
| Population: 903 patients with RCC Key inclusion criteria: – Histologically confirmed metastatic clear-cell renal-cell carcinoma, which had progressed after one systemic treatment within the previous 8 months – ECOG score of 0 or 1 Key exclusion criteria: – Brain metastases |
| Intervention Studied: Sorafenib |
| Control: Placebo |
| Outcomes: -Median progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.01) – Partial responses were reported as the best response in 10% of patients receiving sorafenib and in 2% of those receiving placebo (P<0.001) The authors concluded that “As compared with placebo, treatment with sorafenib prolongs progression-free survival in patients with advanced clear-cell renal-cell carcinoma in whom previous therapy has failed; however, treatment is associated with increased toxic effects.“ |
| Citation: Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):125-34. doi: 10.1056/NEJMoa060655. Erratum in: N Engl J Med. 2007 Jul 12;357(2):203. PMID: 17215530. |
BCG for bladder cancer
| Article Name: Bacillus calmette-guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of randomized clinical trials |
| URL: https://www.auajournals.org/doi/10.1097/01.ju.0000162059.64886.1c |
| Journal and year of publication: The Journal of Urology, 2005 |
| Trial Design: Meta-analysis |
| Population: 9 RTCs including 700 patients Key inclusion criteria: – All randomized trials including patients with primary, secondary or concurrent carcinoma in-situ (CIS) and that compared intravesical BCG to intravesical chemotherapy were considered Key exclusion criteria: |
| Intervention Studied: Intravesical BCG |
| Control: Intravesical chemotherapy |
| Outcomes: – Complete response rate: BCG: 68.1% of patients vs Chemotherapy: 51.5% (p=0.0002) – Percentage of patients with no evidence of disease at median followup of 3.6 years: BCG: 46.7% of patients vs Chemotherapy: 26.2% (p <0.0001) The authors concluded that “Intravesical BCG significantly reduces the risk of short and long-term treatment failure compared with intravesical chemotherapy. Therefore, it is considered to be the intravesical agent of choice in the treatment of CIS.“ |
| Citation: Sylvester RJ, van der Meijden AP, Witjes JA, Kurth K. Bacillus calmette-guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of randomized clinical trials. J Urol. 2005 Jul;174(1):86-91; discussion 91-2. doi: 10.1097/01.ju.0000162059.64886.1c. PMID: 15947584. |
Other cancers
CHECKMATE 067 trial: Ipi-Nivo for melanoma
| Article Name: Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma |
| URL: https://www.nejm.org/doi/full/10.1056/nejmoa1504030 |
| Journal and year of publication: NEJM, 2015 |
| Trial Design: Randomized double-blinded clinical trial |
| Population: 945 patients Key inclusion criteria: – Stage III (unresectable) or stage IV melanoma – Received no prior systemic treatment for advanced disease Key exclusion criteria: – Presence of active brain metastases – Ocular melanoma – Autoimmune disease |
| Intervention Studied: 1) Nivolumab alone 2) Nivolumab plus ipilimumab 3) Ipilimumab alone |
| Control: See above |
| Outcomes: – Median progression-free survival: – Nivolumab + ipilimumab: 11.5 months (95% CI: 8.9 to 16.7) – Ipilimumab: 2.9 months (95% CI: 2.8 to 3.4) Hazard ratio for death or disease progression: 0.42 (P<0.001) – Nivolumab: 6.9 months (95% CI: 4.3 to 9.5) Hazard ratio for the comparison with ipilimumab: 0.57 (P<0.001) The authors concluded that “Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1–negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone.“ |
| Citation: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. doi: 10.1056/NEJMoa1504030. Epub 2015 May 31. Erratum in: N Engl J Med. 2018 Nov 29;379(22):2185. PMID: 26027431; PMCID: PMC5698905. |
BRIM 3 trial: Vemurafenib for melanoma
| Article Name: Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1103782 |
| Journal and year of publication: NEJM, 2011 |
| Trial Design: Randomized clinical trial |
| Population: 675 patients with melanoma Key inclusion criteria: – Unresectable, previously untreated stage IIIC or stage IV melanoma that tested positive for the BRAF V600E mutation – ECOG score of 0 or 1 Key exclusion criteria: – Metastases to the central nervous system – Concomitant treatment with any other anticancer therapy |
| Intervention Studied: Vemurafenib |
| Control: Dacarbazine |
| Outcomes: – Overall survival rate (at 6 months): vemurafenib: 84% vs dacarbazine: 64% (P<0.001) – Progression-free survival: 74% in the risk of either death or disease progression (P<0.001) The authors concluded that “Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation.“ |
| Citation: Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O’Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011 Jun 30;364(26):2507-16. doi: 10.1056/NEJMoa1103782. Epub 2011 Jun 5. PMID: 21639808; PMCID: PMC3549296. |
HPV in oropharyngeal cancer
| Article Name: Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer |
| URL: https://www.nejm.org/doi/full/10.1056/NEJMoa0912217 |
| Journal and year of publication: NEJM, 2010 |
| Trial Design: Retrospective analysis of a previous RCT |
| Population: 743 patients Key inclusion criteria: – III or IV oropharyngeal squamous-cell carcinoma who were enrolled in a randomized trial Key exclusion criteria: |
| Outcomes: – As compared with patients with HPV-negative tumors, patients with HPV-positive patients had better 3 year rates of overall survival: – HPV-positive tumors: 82.4% vs HPV-Negative tumors: 57.1% (P<0.001) The authors concluded that “Tumor HPV status is a strong and independent prognostic factor for survival among patients with oropharyngeal cancer.“ |
| Citation: Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, Westra WH, Chung CH, Jordan RC, Lu C, Kim H, Axelrod R, Silverman CC, Redmond KP, Gillison ML. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010 Jul 1;363(1):24-35. doi: 10.1056/NEJMoa0912217. Epub 2010 Jun 7. PMID: 20530316; PMCID: PMC2943767. |
Do you think there are some important trials we should add to our site? Please contact us at landmarktrials@gmail.com with the trial name, link, and why you think it is a landmark paper!
Disclaimer: Please note that articles mentioned on this site are the property of their respective journals. The information from these articles was presented on this site under the Fair Use legal doctrine (Section 107 of the Copyright Act) as the data shared was limited in quantity, factual in nature, already published, and for the purpose of relaying and teaching socially beneficial medical knowledge. The work was attributed to the journals that published them with citations and links provided.