A phase 3 trial of bevacizumab in ovarian cancer. Intraoperative chemotherapy with cisplatin and epinephrine after cytoreductive surgery in patients with recurrent ovarian cancer: a phase I study Second-line carboplatin and gemcitabine in platinum sensitive ovarian cancer--a dose-finding study by the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Ovarian Cancer Study Group. β-blockers: a new role in cancer chemotherapy? Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment Effect of β-blockers and other antihypertensive drugs on the risk of melanoma recurrence and death. Impact of beta blocker medication in patients with platinum sensitive recurrent ovarian cancer-a combined analysis of 2 prospective multicenter trials by the AGO Study Group, NCIC-CTG and EORTC-GCG. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: A combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG.
BACKGROUND Angiogenesis plays a role in the biology of ovarian cancer . We examined the effect of bevacizumab , the vascular endothelial growth factor inhibitor , on survival in women with this disease . METHODS We r and omly assigned women with ovarian cancer to  carboplatin  ( area under the curve , 5 or 6 ) and paclitaxel ( 175 mg per square meter of body-surface area ) , given every 3 weeks for 6 cycles , or to this regimen plus bevacizumab ( 7.5 mg per kilogram of body weight ) , given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease . Outcome measures included progression-free survival , first analyzed per protocol and then up date d , and interim overall survival . RESULTS A total of 1528 women from 11 countries were r and omly assigned to one of the two treatment regimens . Their median age was 57 years ; 90 % had epithelial ovarian cancer , 69 % had a serous histologic type , 9 % had high-risk early-stage disease , 30 % were at high risk for progression , and 70 % had stage IIIC or IV ovarian cancer .  Progression-free survival ( restricted mean ) at 36 months was 20.3 months with st and ard therapy , as compared with 21.8 months with st and ard therapy plus bevacizumab ( hazard ratio for progression or death with bevacizumab added , 0.81 ; 95 % confidence interval , 0.70 to 0.94 ; P=0.004 by the log-rank test ) . Nonproportional hazards were detected ( i.e. , the treatment effect was not consistent over time on the hazard function scale ) ( P<0.001 ) , with a maximum effect at 12 months , coinciding with the end of planned bevacizumab treatment and diminishing by 24 months . Bevacizumab was associated with more toxic effects ( most often hypertension of grade 2 or higher ) ( 18 % , vs. 2 % with chemotherapy alone ) . In the up date d analyses , progression-free survival ( restricted mean ) at 42 months was 22.4 months without bevacizumab versus 24.1 months with bevacizumab ( P=0.04 by log-rank test ) ; in patients at high risk for progression , the benefit was greater with bevacizumab than without it , with progression-free survival ( restricted mean ) at 42 months of 14.5 months with st and ard therapy alone and 18.1 months with bevacizumab added , with respective median overall survival of 28.8 and 36.6 months . CONCLUSIONS Bevacizumab improved progression-free survival in women with ovarian cancer . The benefits with respect to both progression-free and overall survival were greater among those at high risk for disease progression . ( Funded by Roche and others ; ICON7 Controlled-Trials.com number , IS RCT N91273375 . ) Background Intraperitoneal ( i.p . ) epinephrine was shown to increase the accumulation of i.p .  cisplatin in tumours , and thus its antitumour effect in a model of peritoneal carcinomatosis in rats . Methods To determine the tolerance to i.p . epinephrine with cisplatin , 18 patients with recurrent ovarian carcinoma were intraoperatively treated in this phase 1 study . After maximal cytoreductive surgery , the peritoneal cavity was filled twice for 1 h with 30 mg/l of cisplatin and increasing concentrations of epinephrine ( 0 , 1 , 2 , 3 mg/l ) in 3 l of saline solution at 37 ° C . Results No deaths occurred . Three patients were treated at each of the 0 , 1 and 2 mg/l epinephrine levels without adverse events . Two of the three patients who received 3 mg/l epinephrine  experienced cardiac intolerance . Six additional patients received 2 mg/l of epinephrine  without toxicity . A relationship between the serum concentration of  epinephrine  and occurrence of cardiac toxicity was established . A 60 % decrease in serum area under the curve of platinum was calculated in patients receiving i.p . epinephrine compared with i.p . cisplatin alone . Renal toxicity from cisplatin was not increased by epinephrine .  No haematological or neurological toxicity was recorded . The other grade 3–4 adverse events [ thromboembolism ( 5 ) , peritonitis ( 1 ) , abdominal bleeding ( 1 ) , bowel fistula ( 1 ) ] occurred as often as usually reported for this heavy surgical procedure . Conclusion The combination of i.p . epinephrine with cisplatin as intraoperative chemotherapy after optimal cytoreductive surgery is feasible . The recommended concentration for further studies is 2 mg/l for i.p . epinephrine BACKGROUND Despite the progress that has been achieved in the last years , recurrence rates in ovarian cancer patients are still considerably high and the majority of patients ultimately become c and i date s for second-line treatment . Carboplatin reinduction is a broadly adopted regimen in patients with recurrences occurring six months or later after first-line treatment .  Gemcitabine is among the c and i date s as combination partner in second-line regimens . PATIENTS AND METHODS We performed a study with escalating doses of gemcitabine combined with carboplatin in 26 platinum-pretreated patients with recurrent ovarian cancer and a treatment-free interval of 6 + months .  Dose-limiting toxicity ( DLT ) and a maximum tolerable dose ( MTD ) recommendable for further trials was evaluated . RESULTS The DLT was myelosuppression , mainly thrombocytopenia . No dose limiting non-hematological toxicities were observed . The MTD of gemcitabine was 1,000 mg/m2 given on days 1 + 8 of a three-week schedule combined with carboplatin AUC 4 given on day 1 . The majority of evaluable patients showed an objective response ( 62.5 % ) , and median progression-free and overall survival were 10 and 18 + months , respectively . CONCLUSION Gemcitabine-carboplatin given according to the MTD is well tolerated and active against recurrent platinum-sensitive disease . A r and omized trial comparing carboplatin with or without gemcitabine in platinum-sensitive ovarian cancer has already been initiated β-blockers are a class of drugs that are widely used in treating cardiac , respiratory and other ailments . They act by blocking β-adrenergic receptor-mediated signaling . Studies in various cancers have shown that patients taking a β-blocker have higher survival and lower recurrence and metastasis rates . This is supported by several pre clinical and in vitro studies showing that adrenergic activation modulates apoptosis , promotes angiogenesis and other cancer hallmarks , and these effects can be abrogated by β-blockers . These studies provide a rationale for the use of β-blockers as adjuvants with cancer chemotherapy . However , all published studies so far are retrospective and most do not take into account the specific β-blocker used or address which is most likely to benefit cancer patients . The published epidemiological studies are correlative and have not examined the adrenergic receptor status of the tumors . Knowledge of the β-adrenergic receptor status of tumor cells is essential in choosing the best β-blocker for adjuvant therapy . A comprehensive , prospect i ve study is necessary to definitively prove the utility of using β-blockers with chemotherapy and to identify the specific β-blocker most likely to benefit patients with cancer Recent clinical evidence revealed that the use of beta-blockers such as propranolol , prior to diagnosis or concurrently with chemotherapy , could increase relapse-free and overall survival in breast cancer patients . We therefore hypothesized that propranolol may be able to increase the efficacy of chemotherapy either through direct effects on cancer cells or via anti-angiogenic mechanisms . In vitro proliferation assay showed that propranolol ( from 50 - 100 μM ) induces dose-dependent anti-proliferative effects in a panel of 9 human cancer and “ normal ” cell lines . Matrigel assays revealed that propranolol displays potent anti-angiogenic properties at non-toxic concentrations ( < 50 μM ) but exert no vascular-disrupting activity . Combining chemotherapeutic drugs , such as 5-fluorouracil ( 5-FU ) or paclitaxel , with propranolol at the lowest effective concentration result ed in synergistic , additive or antagonistic effects on cell proliferation in vitro depending on the cell type and the dose of chemotherapy used . Interestingly , breast cancer and vascular endothelial cells were among the most responsive to these combinations . Furthermore , Matrigel assays indicated that low concentrations of propranolol ( 10 – 50 μM ) potentiated the anti-angiogenic effects of 5-FU and  paclitaxel  . Using an orthotopic xenograft model of triple-negative breast cancer , based on injection of luciferase-expressing MDA-MB-231 cells in the mammary fat pad of nude mice , we showed that propranolol , when used alone , induced only transient anti-tumor effects , if at all , and did not increase median survival . However , the combination of propranolol with chemotherapy result ed in more profound and sustained anti-tumor effects and significantly increased the survival benefits induced by chemotherapy alone ( + 19 % and + 79 % in median survival for the combination as compared with 5-FU alone and paclitaxel alone , respectively ; p<0.05 ) . Collectively our results show that propranolol can potentiate the anti-angiogenic effects and anti-tumor efficacy of chemotherapy . The current study , together with retrospective clinical data , strongly suggests that the use of propranolol concurrently with chemotherapy may improve the outcome of breast cancer patients , thus providing a strong rationale for the evaluation of this drug combination in prospect i ve clinical studies OBJECTIVE To verify preliminary studies on patients with melanoma exposed to β-blockers  that suggested a reduced risk of disease recurrence and death . PATIENTS AND METHODS Data were obtained from all consecutive patients diagnosed as having melanoma between January 1 , 1993 , and December 31 , 2009 , at the Department of Dermatology of the University of Florence , Azienda Sanitaria di Firenze . Participants were excluded if at baseline they reported a previous diagnosis of cutaneous malignant melanoma or another malignant disease . We also excluded participants with evidence of visceral , lymph nodal , and in-transit metastasis at the time of the diagnosis . RESULTS Of 741 consecutive patients with melanoma , 79 ( 11 % ) were prescribed β-blockers ( for hypertension in most cases ) for 1 or more years ( treated ) and 662 ( 89 % ) were not ( untreated ) . The multivariate Cox model indicated that the treated group had improved overall survival after a median follow-up of 4 years ( P=.005 ) . For each year of β-blocker use , the risk of death was reduced by 38 % . The presence of hypertension , the use of antihypertensive agents for 1 or more years , or the use of other commonly used medicines were not associated with a better outcome for patients with melanoma . CONCLUSION The results confirm and strengthen previous findings that β-blocker use is associated with a reduced risk of melanoma recurrence and death . The results also indicate the strong need for a r and omized clinical trial to conclusively assess whether β-blockers afford protection against melanoma recurrence and death OBJECTIVE Retrospective analyses suggest that the treatment with beta blocker improves survival in patients with breast cancer and melanoma . The aim of this study was to investigate the impact of medication with beta blocker in patients with recurrent ovarian cancer . METHODS Included patients received treatment within two prospect i ve clinical trials : AGO-OVAR 2.4 phase I trial ( carboplatin/gemcitabine ; N=25 , protocol AGO-OVAR 2.4 ) and AGO led intergroup phase III trial ( carboplatin vs carboplatin/gemcitabine ; N=356 , protocol AGO-OVAR 2.5 , EORTC-GCG , NCIC CTG ) . Concurrent medication was documented after every cycle and thorough monitoring was conducted . RESULTS During the studies 38 patients ( 9.97 % ) received a beta blocker as co-medication . Patients treated with beta blockers  were significantly older than patients not treated with beta blockers .  Response rates to chemotherapy were not different between patients treated with beta blockers and those who were not . After a median follow-up of 17 months , 349 ( 91.6 % ) patients had progressive disease and 267 ( 70.1 % ) patients had died . No difference in median progression-free survival ( 7.79 vs 7.62 months ( p=0.95 ) ) and overall survival ( 21.2 vs 17.3 months ( p=0.18 ) ) was recorded for patients treated with and without beta blocker . In multivariate analyses including age , platinum free-interval , study treatment and ECOG performance status beta blocker treatment was not associated with a significant impact on progression-free survival ( HR : 0.92 ; 95 % CI : 0.65 - 1.31 ; p=0.65 ) and overall survival ( HR:0.74 ; 95%CI : 0.49 - 1.11 ; p=0.15 ) . CONCLUSIONS In this series of recurrent platinum-sensitive ovarian cancer patients it could not be confirmed whether beta blocker treatment was associated with better or worse outcome Primary surgery followed by platinum‐taxane based chemotherapy has been the st and ard therapy in advanced ovarian cancer . However , the prognostic role of complete and so‐called optimal and suboptimal debulking and its interaction with biological factors has not been not fully defined PURPOSE Most patients with advanced ovarian cancer develop recurrent disease . For those patients who recur at least 6 months after initial therapy , paclitaxel platinum has shown a modest survival advantage over platinum without paclitaxel ; however , many patients develop clinical ly relevant neurotoxicity , frequently result ing in treatment discontinuation . Thus , an alternative regimen without significant neurotoxicity was evaluated by comparing gemcitabine plus carboplatin with single-agent carboplatin in platinum-sensitive recurrent ovarian cancer patients . METHODS Patients with platinum-sensitive recurrent ovarian cancer were r and omly assigned to receive either gemcitabine plus carboplatin or carboplatin alone , every 21 days . The primary objective was to compare progression-free survival ( PFS ) . RESULTS Three hundred fifty-six patients ( 178 gemcitabine plus carboplatin ; 178 carboplatin )  were r and omly assigned . Patients received a median of six cycles in both arms . With a median follow-up of 17 months , median PFS was 8.6 months ( 95 % CI , 7.9 to 9.7 months ) for gemcitabine plus carboplatin and 5.8 months ( 95 % CI , 5.2 to 7.1 months ) for carboplatin . The hazard ration ( HR ) for PFS was 0.72 ( 95 % CI , 0.58 to 0.90 ; P = .0031 ) . Response rate was 47.2 % ( 95 % CI , 39.9 % to 54.5 % ) for gemcitabine plus carboplatin and 30.9 % ( 95 % CI , 24.1 % to 37.7 % ) for carboplatin ( P = .0016 ) . The HR for overall survival was 0.96 ( 95 % CI , 0.75 to1.23 ; P = .7349 ) . While myelosuppression was significantly more common in the combination , sequelae such as febrile neutropenia or infections were uncommon . No statistically significant differences in quality of life scores between arms were noted . CONCLUSION Gemcitabine plus carboplatin significantly improves PFS and response rate without worsening quality of life for patients with platinum-sensitive recurrent ovarian cancer
The last ten years have seen hardly any improvement in the prognosis of ovarian carcinoma .
There is a great need for new treatment strategies , and a recent retrospective study showing a survival advantage with the use of beta blockers met with a very positive response .