Table 1.
Reference | Study | Country | Duration | Sample size | Median age (years) | Study design | Cancer type | Stage | Surgery | Beta-blocker type | No. of patients
|
Exposure category | Follow-up time (months) | Treatment | HR | 95% CI | Survival outcome | Multivariable analysis | Adjusted for | Study quality (NOS score) | |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Exposure | Control | ||||||||||||||||||||
8 | Grytli et al (2013) | Norway | 2004–2009 | 655 | 72 | PB cohort | Prostate cancer | I/II 60.1%, III/IV 39.9% | NR | Mixed: beta selective (80.2%); non-selective (19.8%) | 80 | 575 | Pre-diagnostic beta-blocker use | 122 | ADT or not | 0.88 | 0.56–1.38 | OS | Yes | Age at diagnosis, metastasis at diagnosis, and level of education | 8 |
0.79 | 0.68–0.91 | CSS | |||||||||||||||||||
9 | Grytli et al (2014) | Norway | 2000–2011 | 3,561 | 76.3 | HB cohort | Prostate cancer | ≤T2A 14.9%; T2b–T2c 18.5%; ≥T3a 66.6% | NR | Mixed: beta 1 selective (77.9%); non-selective (3.0%); alpha and beta mixed (4.5%) | 1,115 | 2,446 | Pre-diagnostic beta-blocker use | 39 | RT or radical prostatectomy | 0.96 | 0.87–1.05 | OS | Yes | Age, prostate-specific antigen level, Gleason score, clinical T stage, presence and type of metastases, performance status, and androgen deprivation, therapy initiated within 6 months after diagnosis | 7 |
0.97 | 0.72–1.31 | CSS | |||||||||||||||||||
10 | Al-Niaimi et al (2016) | USA | 2000–2010 | 185 | 66.2 63.8 | HB cohort | Ovarian cancer | I/II 26%, III/IV 74% | Yes | NR | 70 | 115 | Post-diagnostic beta-blocker use (time-dependent) | 91 | CT | 0.68 | 0.46–0.99 | OS | Yes | Age, stage, grade, cytoreduction status, BMI, and presence or absence of diabetes | 7 |
11 | Aydiner et al (2013) | Turkey | 2003–2011 | 107 | 61 (42–81) | HB case–control | Non-small-cell lung cancer | NR | Mixed | Mixed | 35 | 72 | Post-diagnostic beta-blocker use (time-fixed) | 17.8 (1–102) | CT | 0.69 | 0.36–1.34 | OS | Yes | Age, sex, performance status, histologic subtype, smoking status, presence of comorbidities (COPD, IHD, HT, and DM) | 7 |
12 | Barron et al (2011) | Ireland/USA | 2001–2006 | 4,808 | 69.1 71 | PB cohort | Breast cancer | I/II 75.6%, III/IV 24.4% | NR | Beta non-selective | 70 | 4,738 | Pre-diagnostic beta-blocker use | 42 43.2 32.4 36 |
CT or not | 0.19 | 0.06–0.60 | OS | Yes | Age, stage, grade, and comorbidity | 7 |
12 | Barron et al (2011) | Ireland/USA | 2001–2006 | 5,263 | 69.1 71 | PB cohort | Breast cancer | I/II 75.6%, III/IV 24.4% | NR | Beta selective | 525 | 4,738 | Pre-diagnostic beta-blocker use | 42 43.2 32.4 36 |
CT or not | 1.08 | 0.84–1.40 | OS | Yes | Age, stage, grade, and comorbidity | 7 |
12 | Barron et al (2011) | Ireland/USA | 2001–2006 | 5,801 | 69.1 71 | PB cohort | Breast cancer | I/II 75.6%, III/IV 24.4% | NR | Mixed: beta selective (88%); non-selective (12%) | 595 | 4,738 | Pre-diagnostic beta-blocker use | 42 43.2 32.4 36 |
CT or not | 1.08 | 0.84–1.39 | CSS | Yes | Age, stage, grade, and comorbidity | 7 |
13 | Beg et al (2017) | USA | 2006–2009 | 13,702 | 76 | PB cohort | Pancreatic adenocarcinoma | I/II 38.1%, III/IV 61.9% | Mixed 69.3% | NR | 5,209 | 8,493 | NR | NR | NR | 0.9 | 0.85–0.95 | OS | Yes | Age, sex, race, stage at diagnosis, site of cancer, and Charlson comorbidity index | 8 |
14 | Bir et al (2015) | USA | 2001–2013 | 225 | 57.34± 10.98 | HB cohort | Metastatic brain tumors | NR | Yes | Beta 1 selective | 40 | 185 | NR | 10.57 | GKRS | 1.08 | 0.65–1.79 | OS | Yes | MBT kind, metastasis, tumor recurrence, tumor response, GKRS, prognostic factor | 7 |
15 | De Giorgi et al (2013) | Italy | 1993–2009 | 741 | 64 53 | HB cohort | Thick melanoma | NR | Mixed | Mixed: beta 1 selective (73%); non-selective (27%) | 79 | 662 | Post-diagnostic beta-blocker use (time-dependent) | 50.4 | NR | 0.03 | 0.01–0.17 | DFS | Yes | Age, Breslow thickness, and ulceration | 7 |
0.04 | 0.00–0.38 | OS | |||||||||||||||||||
16 | Diaz et al (2012) | USA | 1996–2006 | 248 | 67 | HB cohort | Ovarian cancer | III/IV 100% | Yes | Mixed: beta 1 selective (75%); non-selective (13%); mixed alpha and beta adrenergic antagonist (13%) | 23 | 225 | NR | NR | CT | 0.56 | 0.43–1.26 | OS | Yes | Age, stage, grade, and cytoreduction status | 6 |
17 | Ganz et al (2011) | USA | 1997–2002 | 1,779 | NR | PB cohort | Breast cancer | I/II 96.9%, III/IV 3.1% | NR | Mixed: beta selective (86%); non-selective (14%) | 204 | 1,372 | NR | 98.4 | CT, RT, both or none | 1.04 | 0.72–1.51 | OS | Yes | Age at diagnosis, race, stage of disease, pre-diagnosis BMI, adjuvant treatment, hormone receptor status, tamoxifen use, and self-reported hypertension and diabetes | 8 |
0.86 | 0.57–1.32 | RFS | |||||||||||||||||||
0.76 | 0.44–1.33 | CSS | |||||||||||||||||||
18 | Giampieri et al (2015) | Italy | 2010–2013 | 235 | NR | HB cohort | Colorectal cancer | NR | NR | NR | 29 | 206 | Pre-diagnostic beta-blocker use | NR | CT or with bevacizumab | 1.51 | 0.88–2.31 | OS | Yes | Age, sex, and site of metastases, previous adjuvant chemotherapy, and ECOG performance status | 7 |
1.19 | 0.81–1.72 | PFS | |||||||||||||||||||
19 | Hwa et al (2017) | USA | 1995–2010 | 1,971 | 64 | HB cohort | Myeloma | I/II 75%, III/IV 25% | Mixed | Mixed | 549 | 1,733 | Post-diagnostic beta-blocker use (time-fixed) | 74.3 | CT | 0.67 | 0.55–0.81 | OS | Yes | Demographics, disease characteristics, diagnosis year, and various chemotherapies | 7 |
0.53 | 0.42–0.67 | CSS | |||||||||||||||||||
20 | Jansen et al (2014) | Germany | 2003–2007 | 1,975 | 68 | PB cohort | Colorectal cancer | I/II 55% III/IV 45% | Mixed 97.3% | Mixed: beta selective (86%); non-selective (14%) | 509 | 1,311 | Pre-diagnostic beta-blocker use | 60 | CT or RT | 0.99 | 0.79–1.22 | OS | Yes | Age at diagnosis, sex, Union for International Cancer Control (UICC) stage (I–IV), surgery, chemotherapy, radiotherapy, body mass index, hypertension, CVD (including heart failure, myocardial infarction, stroke, and cardiac circulatory disorder), diabetes, regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin, regular use of statins, use of hormone replacement therapy (HRT), lifetime pack-years of active smoking, physical activity (quartiles of lifetime metabolic equivalents [METs] in hours per week), and participation in health check-up | 8 |
0.93 | 0.71–1.21 | CSS | |||||||||||||||||||
21 | Kim et al (2017) | Korea | 2001–2012 | 1,274 | 61 (20–87) | HB cohort | Head and neck squamous cell carcinoma (HNSCC) | I/II 41.4% III/IV 58.6% | Mixed 69.2% | Mixed: beta 1 selective (84%); non-selective (16%) | 114 | 1,160 | Post-diagnostic beta-blocker use (time-fixed) | 98 | Primary curative surgery, RT, CRT with or without IC, or a combination of these treatments | 1.33 | 0.93–1.91 | DFS | Yes | Age, sex, BMI, CCI, smoking, alcohol, tumor site, tumor classification T3–4, nodal classification N1–3, overall TNM stage III–IV, primary treatment, second primary cancer, hypertension | 6 |
1.49 | 0.99–2.22 | CSS | |||||||||||||||||||
1.54 | 1.17–2.05 | OS | |||||||||||||||||||
22 | Lemeshow et al (2011) | Denmark | Since 1943 | 4,179 | 66 | PB cohort | Melanoma | I/II 63.8%, III/IV 36.2% | Mixed | Mixed | 372 | 3,807 | Pre-diagnostic beta-blocker use | 58.8 | NR | 0.81 | 0.67–0.97 | OS | Yes | Age and comorbidity index score | 7 |
0.87 | 0.64–1.2 | CSS | |||||||||||||||||||
23 | Melhem-Bertrandt et al (2011) | USA | 1995–2007 | 1,413 | 57 49 | HB cohort | Breast cancer | I/II 55.6%, III/IV 44.4% | Yes | Mixed: beta selective (89%); non-selective (11%) | 102 | 1,311 | Post-diagnostic beta-blocker use (time-fixed) | 58.8 | Anthracylines and taxane-based neoadjuvant CT | 0.3 | 0.10–0.87 | RFS | Yes | Age, race, stage, grade, receptor status, lymphovascular invasion, body mass index, diabetes, hypertension, and angiotensin-converting enzyme inhibitor use | 7 |
0.76 | 0.44–1.33 | CSS | |||||||||||||||||||
0.35 | 0.12–1.00 | OS | |||||||||||||||||||
24 | Springate et al (2015) | NR | 1997–2006 | 11,302 | NR | HB cohort | Mixed cancer | NR | NR | Mixed | 4,030 | 7,272 | Pre-diagnostic beta-blocker use | 29 30 | NR | 1.03 | 0.93–1.14 | OS | No | No | 7 |
24 | Springate et al (2015) | NR | 1997–2006 | 6,274 | NR | HB cohort | Mixed cancer | NR | NR | Mixed | 1,406 | 4,868 | Pre-diagnostic beta-blocker use | 29 30 | NR | 1.18 | 1.04–1.33 | OS | No | No | 7 |
25 | Udumyan et al (2017) | Swedish | 2006–2009 | 2,394 | 70.9 67.1 | PB cohort | Pancreatic adenocarcinoma | I/II 21%, III/IV 79% | NR | Mixed: beta 1 selective (89%); non-selective (11%) | 522 | 1,872 | Pre-diagnostic beta-blocker use | 5 | NR | 0.79 | 0.70–0.90 | OS | Yes | Sociodemographic factors, tumor characteristics, comorbidity score, and other medications | 8 |
0.77 | 0.69–0.87 | CSS | |||||||||||||||||||
26 | Wang et al (2013) | USA | 1998–2010 | 722 | 65 (34–95) | HB cohort | Non-small-cell lung cancer | I/II 6.2%, III 93.8% | Mixed | Mixed: beta selective (86%); non-selective (14%) | 155 | 567 | Post-diagnostic beta-blocker use (time-fixed) | 44 (1–155) | Definitive RT | 0.91 | 0.64–1.31 | PFS | Yes | Age, Karnofsky performance score, clinical stage, tumor histology, use of concurrent chemotherapy, radiation dose, GTV, hypertension, chronic obstructive pulmonary disease, and aspirin consumption | 7 |
0.67 | 0.50–0.91 | DMFS | |||||||||||||||||||
0.74 | 0.58–0.95 | DFS | |||||||||||||||||||
0.78 | 0.63–0.97 | OS | |||||||||||||||||||
27 | Watkins et al (2015) | USA | 2000–2010 | 1,425 | 61.6 68 | HB cohort | Ovarian cancer | I/II 10%, III/IV 90% | Yes | Mixed: beta selective (72.1%); non-selective (27.9%) | 269 | 1,156 | Post-diagnostic beta-blocker use (time-fixed) | NR | CT | 0.26 | 0.19–0.37 | OS | No | No | 6 |
0.24 | 0.17–0.34 | CSS | |||||||||||||||||||
28 | Yusuf et al (2012) | USA | 2000–2006 | 456 | 67 | HB cohort | Mixed cancer | NR | NR | NR | 211 | 245 | NR | 1.2 | Chest RT or CT | 0.64 | 0.51–0.81 | OS | Yes | Age, cancer status, cancer type, previous chemotherapy, chest radiotherapy, hyperlipidemia | 6 |
29 | Botteri et al (2013) | Italy | 1997–2006 | 800 | 62 59 | HB cohort | Breast cancer | I/II 86%, III/IV 14% | Yes | Mixed: beta 1 selective (84.1%); non-selective (4%); alpha and beta mixed (11.9%) | 74 | 726 | Pre-diagnostic beta-blocker use | 72 67.2 | Adjuvant CT and RT | 0.42 | 0.18–0.97 | CSS | Yes | Age, tumor stage, and treatment, peritumoral vascular invasion and use of other antihypertensive drugs, antithrombotics, and statins | 7 |
30 | Spera et al (2017) | Canada | NR | 1,144 | 60 53 | HB cohort | Breast cancer | NR | Yes | Mixed | 153 | 991 | Pre/post-diagnostic beta-blocker use (time-dependent) | 25.1 | CT | 0.81 | 0.66–0.99 | PFS | Yes | Treatment arm (RAM vs PBO), HHRR status, geographic region, THE | 7 |
1.05 | 0.85–1.29 | OS | |||||||||||||||||||
31 | Johannesdottir et al (2013) | Denmark | 1999–2010 | 6,253 | 65 | HB cohort | Ovarian cancer | NR | Mixed | NR | 87 | 6,166 | Pre-diagnostic beta-blocker use | 30.6 | HRT | 1.18 | 0.90–1.55 | OS | Yes | Age, comorbidity level, prior use of diuretics, year of diagnosis, aspirin, and statins | 7 |
31 | Johannesdottir et al (2013) | Denmark | 1999–2010 | 6,539 | 65 | HB cohort | Ovarian cancer | NR | Mixed | NR | 373 | 6,166 | Pre-diagnostic beta-blocker use | 30.6 | HRT | 1.17 | 1.02–1.34 | OS | Yes | Age, comorbidity level, prior use of diuretics, year of diagnosis, aspirin, and statins | 7 |
32 | Assayag et al (2014) | Canada/UK | 1998–2012 | 6,270 | 72.3 | PB cohort | Prostate cancer | NR | Yes | Mixed: beta selective (59.4%); non-selective (40.6%) | 673 | 1,088 | Post-diagnostic beta-blocker use (time-dependent) | 45.6 | Prostatectomy, RT, ADT, and CT | 0.97 | 0.8–1.16 | OS | No | No | 7 |
0.97 | 0.72–1.31 | CSS | |||||||||||||||||||
33 | Cata et al (2014) | USA | NR | 391 | NR | HB cohort | Non-small-cell lung cancer | I/II 75.2%, III 24.8% | Yes | Beta 1 selective | 149 | 242 | NR | NR | NR | 1.304 | 0.973–1.747 | RFS | Yes | Age, stage of disease, BMI, ASA physical status, smoking status, CAD, postoperative radiation treatment, type of surgery, and perioperative blood transfusions | 7 |
1.335 | 0.966–1.846 | OS | |||||||||||||||||||
33 | Cata et al (2014) | USA | NR | 286 | NR | HB cohort | Non-small-cell lung cancer | I/II 75.2%, III 24.8% | Yes | Beta non-selective | 44 | 242 | NR | NR | NR | 0.989 | 0.639–1.532 | RFS | Yes | Age, stage of disease, BMI, ASA physical status, smoking status, CAD, postoperative radiation treatment, type of surgery, and perioperative blood transfusions | 7 |
34 | Heitz et al (2013) | Germany/Canada | NR | 381 | 60 | HB cohort | Ovarian cancer | I/II 6.5%, III/IV 93.5% | Yes | Mixed: beta selective (84%); non-selective (16%) | 1.108 | 0.678–1.812 | OS | ||||||||
38 | 343 | Post-diagnostic beta-blocker use (time-fixed) | 17 | CT | 0.92 | 0.65–1.31 | PFS | Yes | Age, stage, grade, and cytoreduction status | 7 | |||||||||||
35 | Heitz et al (2017) | Germany | 1999–2014 | 801 | 58 (19–90) | HB cohort | Ovarian cancer | I/II 43.3%, III/IV 56.7% | Yes | Beta 1 selective | 0.74 | 0.49–1.11 | OS | ||||||||
141 | 660 | NR | 40 | CT | 0.94 | 0.69–1.29 | OS | Yes | Age, ECOG, ASA, Charlton comorbidity score (metric), tumor residuals, histology, body mass index, and FIGO stage | 7 | |||||||||||
36 | Holmes et al (2013) | Canada | 2004–2008 | 2,433 | 68.3 | PB cohort | Breast cancer | NR | NR | Mixed | 0.95 | 0.72–1.27 | PFS | ||||||||
36 | Holmes et al (2013) | Canada | 2004–2008 | 2,016 | 68.3 | PB cohort | Colorectal cancer | NR | NR | Mixed | 123 | 2,310 | Pre-diagnostic beta-blocker use | NR | NR | 1.1 | 0.92–1.32 | OS | No | No | 6 |
36 | Holmes et al (2013) | Canada | 2004–2008 | 2,125 | 68.3 | PB cohort | Lung cancer | NR | NR | Mixed | 152 | 1,864 | Pre-diagnostic beta-blocker use | NR | NR | 1.05 | 0.93–1.18 | OS | No | No | 6 |
36 | Holmes et al (2013) | Canada | 2004–2008 | 1,868 | 68.3 | PB cohort | Prostate cancer | NR | NR | Mixed | 196 | 1,929 | Pre-diagnostic beta-blocker use | NR | NR | 1.01 | 0.93–1.11 | OS | No | No | 6 |
37 | Jansen et al (2017) | The Netherlands | 1998–2011 | 2,530 | 73 68 | PB cohort | Colorectal cancer | I/II 55.7%, III/IV 44.3% | Mixed 89.8% | Mixed: beta selective (55%); non-selective (45%) | 163 | 1,705 | Pre-diagnostic beta-blocker use | NR | NR | 1.18 | 0.99–1.40 | OS | No | No | 6 |
37 | Jansen (2017) | The Netherlands | 1998–2011 | 1,374 | 73 68 | PB cohort | Colorectal cance | I/II 55.7%, III/IV 44.3% | Mixed 89.8% | Mixed: beta selective (66%); non-selective (34%) | 1456 | 1,074 | Pre-diagnostic beta-blocker use | 79.2 | NR | 1.07 | 0.96–1.19 | OS | Yes | Age at diagnosis, sex, year of diagnosis, socioeconomic status based on the place of residence, Union for International Cancer Control (UICC) stage (I, II, III, IV), cancer site (colon, rectum/rectosigmoid), surgery, chemotherapy, radiotherapy, cancer, cardiovascular disease, cerebrovascular disease, diabetes, hypertension, time-dependent use of NSAIDs, statins and diabetes medication after diagnosis and number of distinct ATC classes prescribed during 4 months prior to diagnosis (0, 1–3, 4–5, 6+ distinct ATC classes [first letter of the ATC] dispensed during 4 months prior to diagnosis) | 7 |
38 | Livingstone et al (2013) | Germany/The Netherlands | 709 | 67 59 | PB cohort | Melanoma | NR | Mixed | Mixed: beta 1 selective (84%); non-selective (16%) | 919 | 455 | Post-diagnostic beta blocker use (time-dependent) | 79.2 | NR | 1.1 | 0.98–1.23 | OS | Yes | Age at diagnosis, sex, year of diagnosis, socio-economic status based on the place of residence, Union Internationale Contre le Cancer (UICC) stage (I, II, III, IV), cancer site (colon, rectum/rectosigmoid), surgery, chemotherapy, radiotherapy, previous cancer, cardiovascular disease, cerebrovascular disease, diabetes, hypertension, time- dependent use of NSAIDs, statins and diabetes medication after diagnosis and number of distinct ATC classes prescribed during four months prior to diagnosis (0, 1–3, 4–5, 6+ distinct ATC classes [first letter of the ATC] dispensed during four months prior to diagnosis) | 7 | |
120 | 589 | Post-diagnostic beta-blocker use (time-dependent) | 39 | NR | 0.82 | 0.55–1.24 | OS | No | No | 6 | |||||||||||
39 | Musselman et al (2014) | Canada | 2002–2010 | 66,889 | NR | PB cohort | Breast cancer | NR | Yes | NR | 4,372 | 7,013 | NR | 57.6 6 30.5, 43.1 6 28.7, and 53.4 6 31.0 | NR | 0.99 | 0.87–1.13 | OS | No | No | 6 |
39 | Musselman et al (2014) | Canada | 2002–2010 | 66,890 | NR | PB cohort | Lung cancer | NR | Yes | NR | 1,901 | 2,314 | NR | 57.6 6 30.5, 43.1 6 28.7, and 53.4 6 31.0 | NR | 1.06 | 0.91–1.24 | OS | No | No | 6 |
39 | Musselman et al (2014) | Canada | 2002–2010 | 66,891 | NR | PB cohort | Colorectal cancer | NR | Yes | NR | 22,170 | 30,118 | NR | 57.6 6 30.5, 43.1 6 28.7, and 53.4 6 31.0 | NR | 1.06 | 0.99–1.02 | OS | No | No | 6 |
40 | Parker et al (2017) | USA | 2000–2010 | 913 | 65 67 | HB cohort | Renal cell carcinoma | I/II 51.6%, III/IV 48.4% | Yes | Mixed: beta 1 selective (90%); non-selective (4%); alpha and beta mixed (6%) | 104 | 809 | Pre-diagnostic beta-blocker use | 98.4 | NR | 0.83 | 0.59–1.16 | OS | Yes | Age at surgery, sex, onstitutional symptoms, smoking history, eGFR category, ECOG performance status, Charlson score, type of surgery, tumor size, 2010 pT classification, grade, coagulative tumor necrosis | 7 |
0.78 | 0.43–1.41 | CSS | |||||||||||||||||||
41 | Sakellakis et al (2014) | Greece | 1983–2013 | 610 | 63 55 | HB cohort | Breast cancer | I/II 73.6%, III/IV 26.4% | Yes | Mixed | 47 | 430 | Post-diagnostic beta-blocker use (time-dependent) | 24 48 | CT | 0.849 | 0.537–1.343 | DFS | No | No | 6 |
42 | Shah et al (2011) | UK | 1997–2009 | 3,462 | HR | PB cohort | Mixed cancer | NR | NR | Mixed: beta selective (83%); non-selective (17%) | 1,406 | 2,056 | Pre-diagnostic beta-blocker use | NR | NR | 1.18 | 1.04–1.33 | OS | No | No | 6 |
43 | Weberpals et al (2017) | Holland | 1998–2011 | 2,221 | 70.4 | PB cohort | Lung cancer | I/II 24.1%, III/IV 75.9% | Mixed 17.4% | Mixed: beta selective (88%); non-selective (12%) | 1,107 | 1,114 | Pre-diagnostic beta-blocker use | 78 | NR | 1 | 0.92–1.08 | OS | Yes | Comorbidities, time-varying treatment, and distinct numbers of medications used | 7 |
43 | Weberpals et al (2017) | Holland | 1998–2011 | 2,221 | 70.4 | PB cohort | Lung cancer | I/II 24.1%, III/IV 75.10% | Mixed 17.5% | Mixed: beta selective (88%); non-selective (13%) | 1,224 | 997 | Post-diagnostic beta-blocker use (time-dependent) | 78 | NR | 1.03 | 0.94–1.11 | OS | Yes | Comorbidities, time-varying treatment, and distinct numbers of medications used | 7 |
Abbreviations: NR, not reported; PB, population-based; HB, hospital-based; RT, radiation therapy; CT, chemotherapy; ADT, androgen deprivation therapy; CRT, concurrent chemoradiotherapy; IC, induction chemotherapy; GKRS, gamma knife radiosurgery; HRT, hormone replacement therapy; OS, overall survival; CSS, cancer-specific survival; DFS, disease-free survival; PFS, progression-free survival; RFS, recurrence-free survival; NOS, Newcastle–Ottawa Quality Assessment Scale; BMI, body mass index; IHD, ischemic heart disease; HT, hypertension; MBT, Metastatic brain tumors; ECOG, electrocorticogram; CVD, cardiovascular disease; GTN,GTV, gross tumor volume; RAM, Ramucirumab; PBO, Placebo; HHRR, hormonal receptor; THE, treatment emergent hypertension; ASA, American Standards Association; CAD, coronary artery disease; DM, diabetes mellitus; FIGO, International Federation of Gynecology and Obstetrics; eGFR, epidermal growth factor receptor; ATC, Anatomical Therapeutic Chemical; CCI, Charlson comorbidity index; DMFS, distant metastasis-free survivall; pT, primary tumour.