Oncology

General Oncology Principles

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.
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.
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.
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.
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

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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

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.
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.
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.
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.
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.
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.
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.
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.
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

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.
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.
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.
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.
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

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.
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.
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.

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