Cost-effectiveness of FOLFOX6+Bevacizumab Versus FOLFOX6+Cetuximab in Stage IV Colorectal Cancer Patients in Shiraz, Iran.

BACKGROUND: Colorectal cancer is one of the most common cancers in the world, with about one million cases diagnosed annually. Various treatment methods can be used to treat colorectal cancer, including chemotherapy with different drug regimens. Considering the need to opt for more effective and less expensive drugs in the treatment of this disease, the present study aimed to compare the cost-effectiveness of FOLFOX6+Bevacizumab with FOLFOX6+Cetuximab in patients with stage IV colorectal cancer referred to medical centers in Shiraz, Iran, in 2021. MATERIALS AND METHODS: Using a decision tree, the cost-effectiveness and cost-utility of the 2 drug regimens were compared in all studied patients through the census method. Having a societal perspective, this study considered direct medical costs, direct non-medical costs, and indirect costs. The effectiveness indicators included the rate of major response to the drug combination used and the Quality-adjusted Life Year (QALY). The data were analyzed using Treeage 2011 and Excel 2016 software. In order to ensure the robustness of the results, one-way and probabilistic sensitivity analyses were performed as well. RESULTS: The results showed that the expected costs, the effectiveness (major response rate), and the QALYs of the FOLFOX6+Bevacizumab drug regimen were $16746.13(USD), .49, and .19, respectively, and those of the FOLFOX6+Cetuximab regimen were, respectively, $15191.05 (USD), .68, and .22. Therefore, FOLFOX6+Cetuximab compared to FOLFOX6+Bevacizumab was less costly and more effective and had a greater QALY, thus being considered as the dominant option. Also, the results of the sensitivity analyses showed that there was a bit of uncertainty. CONCLUSION: Considering that the FOLFOX6+Cetuximab regimen was more cost-effective, it is suggested to be prioritized in preparing clinical guidelines for Iranian colorectal cancer patients. In addition, increasing the basic and supplementary insurance coverage for this drug combination as well as the use of remote technology to guide patients by oncologists can be solutions to reduce direct and indirect costs of the patients.

Standard threshold laser versus subthreshold micropulse laser for adults with diabetic macular oedema: the DIAMONDS non-inferiority RCT.

BACKGROUND: The National Institute for Health and Care Excellence recommends macular laser to treat diabetic macular oedema with a central retinal subfield thickness of < 400 µm on optical coherence tomography. The DIAMONDS (DIAbetic Macular Oedema aNd Diode Subthreshold micropulse laser) trial compared standard threshold macular laser with subthreshold micropulse laser to treat diabetic macular oedema suitable for macular laser. OBJECTIVES: Determining the clinical effectiveness, safety and cost-effectiveness of subthreshold micropulse laser compared with standard threshold macular laser to treat diabetic macular oedema with a central retinal subfield thickness of < 400 µm. DESIGN: A pragmatic, multicentre, allocation-concealed, double-masked, randomised, non-inferiority, clinical trial. SETTING: Hospital eye services in the UK. PARTICIPANTS: Adults with diabetes and centre-involving diabetic macular oedema with a central retinal subfield thickness of < 400 µm, and a visual acuity of > 24 Early Treatment Diabetic Retinopathy Study letters (Snellen equivalent > 20/320) in one/both eyes. INTERVENTIONS: Participants were randomised 1 : 1 to receive 577 nm subthreshold micropulse laser or standard threshold macular laser (e.g. argon laser, frequency-doubled neodymium-doped yttrium aluminium garnet 532 nm laser); laser treatments could be repeated as needed. Rescue therapy with intravitreal anti-vascular endothelial growth factor therapies or steroids was allowed if a loss of ≥ 10 Early Treatment Diabetic Retinopathy Study letters between visits occurred and/or central retinal subfield thickness increased to > 400 µm. MAIN OUTCOME MEASURES: The primary outcome was the mean change in best-corrected visual acuity in the study eye at 24 months (non-inferiority margin 5 Early Treatment Diabetic Retinopathy Study letters). Secondary outcomes included the mean change from baseline to 24 months in the following: binocular best-corrected visual acuity; central retinal subfield thickness; the mean deviation of the Humphrey 10-2 visual field in the study eye; the percentage of people meeting driving standards; and the EuroQol-5 Dimensions, five-level version, National Eye Institute Visual Function Questionnaire - 25 and Vision and Quality of Life Index scores. Other secondary outcomes were the cost per quality-adjusted life-years gained, adverse effects, number of laser treatments and additional rescue treatments. RESULTS: The DIAMONDS trial recruited fully (n = 266); 87% of participants in the subthreshold micropulse laser group and 86% of participants in the standard threshold macular laser group had primary outcome data. Groups were balanced regarding baseline characteristics. Mean best-corrected visual acuity change in the study eye from baseline to month 24 was -2.43 letters (standard deviation 8.20 letters) in the subthreshold micropulse laser group and -0.45 letters (standard deviation 6.72 letters) in the standard threshold macular laser group. Subthreshold micropulse laser was deemed to be not only non-inferior but also equivalent to standard threshold macular laser as the 95% confidence interval (-3.9 to -0.04 letters) lay wholly within both the upper and lower margins of the permitted maximum difference (5 Early Treatment Diabetic Retinopathy Study letters). There was no statistically significant difference between groups in any of the secondary outcomes investigated with the exception of the number of laser treatments performed, which was slightly higher in the subthreshold micropulse laser group (mean difference 0.48, 95% confidence interval 0.18 to 0.79; p = 0.002). Base-case analysis indicated no significant difference in the cost per quality-adjusted life-years between groups. FUTURE WORK: A trial in people with ≥ 400 µm diabetic macular oedema comparing anti-vascular endothelial growth factor therapy alone with anti-vascular endothelial growth factor therapy and macular laser applied at the time when central retinal subfield thickness has decreased to < 400 µm following anti-vascular endothelial growth factor injections would be of value because it could reduce the number of injections and, subsequently, costs and risks and inconvenience to patients. LIMITATIONS: The majority of participants enrolled had poorly controlled diabetes. CONCLUSIONS: Subthreshold micropulse laser was equivalent to standard threshold macular laser but required a slightly higher number of laser treatments. TRIAL REGISTRATION: This trial is registered as EudraCT 2015-001940-12, ISRCTN17742985 and NCT03690050. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 50. See the NIHR Journals Library website for further project information.

The retina is a layer at the back of the eye. Its centre is called the macula and is responsible for central vision. Some people with diabetes develop diabetic macular oedema. In diabetic macular oedema fluid leaks from retinal blood vessels and builds up at the macula, resulting in sight loss. Diabetic macular oedema can be mild or severe; this can be determined measuring the thickness of the macula, which is measured in micrometres (µm). One micrometre is one thousandth of a millimetre. In mild diabetic macular oedema, the thickness of the macula increases, but is less than 400 µm. Patients with mild diabetic macular oedema can be treated with a laser and there are two laser types. The standard threshold macular laser has been available for many years. It clears the diabetic macular oedema but produces a 'burn' in the retina. The subthreshold micropulse laser is newer. It does not produce a burn but also clears the diabetic macular oedema. The lack of a burn, however, has led to doubts about whether or not this laser works as well as the standard threshold macular laser because 'no burn' was taken to mean 'less benefit'. These doubts led to our establishing the DIAMONDS (DIAbetic Macular Oedema aNd Diode Subthreshold micropulse laser) trial, which compared these two lasers for people with mild diabetic macular oedema. A total of 266 people suitable for either laser joined the study at 16 NHS hospitals across the UK; 133 received standard threshold macular laser and 133 received subthreshold micropulse laser. The choice of laser was determined by chance. The DIAMONDS trial found that the subthreshold micropulse laser was as good as the standard threshold macular laser (i.e. 'clinically equivalent') in terms of improving people's vision, reducing macula thickness, allowing people to meet driving standards and maintaining their quality of life, both in general terms and for vision in particular. There was a small increase (less than one session on average per person) in the number of laser treatment sessions needed with subthreshold micropulse laser. The costs of both laser treatments were about the same.

Safety Assessment on Serious Adverse Events of Targeted Therapeutic Agents Prescribed for RAS Wild-Type Metastatic Colorectal Cancer: Systematic Review and Network Meta-Analysis.

Despite substantially elevated risk of serious adverse events (SAEs) from targeted therapy in combination with chemotherapy, comprehensive pharmacovigilance research is limited. This study aims to systematically assess SAE risks of commonly prescribed targeted agents (bevacizumab, cetuximab, and panitumumab) in patients with rat sarcoma viral oncogene homolog (RAS) wild-type metastatic colon cancer. Keyword searches of Cochrane Library, Clinical Key and MEDLINE were conducted per PRISMA-NMA guidelines. Frequentist network meta-analysis was performed with eight randomized controlled trials to compare relative risk (RR) of 21 SAE profiles. The risks of hematological, gastrointestinal, neurological SAE were insignificant among targeted agents (p > 0.05). The risk of serious hypertension was substantially elevated in bevacizumab-based chemotherapy (p < 0.05), whereas panitumumab-based chemotherapy had markedly elevated risk of serious thromboembolism (RR 3.65; 95% CI 1.30−10.26). Although both cetuximab and panitumumab demonstrated increased risk of serious dermatological and renal toxicities, panitumumab-based chemotherapy has relatively higher risk of skin toxicity (RR 15.22; 95% CI 7.17−32.35), mucositis (RR 3.18; 95% CI 1.52−6.65), hypomagnesemia (RR 20.10; 95% CI 5.92−68.21), and dehydration (RR 2.81; 95% CI 1.03−7.67) than cetuximab-based chemotherapy. Thus, further studies on risk stratification and SAE management are warranted for safe administration of targeted agents.

Assessment of Capecitabine and Bevacizumab With or Without Atezolizumab for the Treatment of Refractory Metastatic Colorectal Cancer: A Randomized Clinical Trial.

Importance: Cotargeting vascular endothelial growth factor and programmed cell death 1 or programmed cell death ligand 1 may produce anticancer activity in refractory metastatic colorectal cancer (mCRC). The clinical benefit of atezolizumab combined with chemotherapy and bevacizumab remains unclear for the treatment of mCRC. Objectives: To assess whether the addition of atezolizumab to capecitabine and bevacizumab therapy improves progression-free survival (PFS) among patients with refractory mCRC and to perform exploratory analyses among patients with microsatellite-stable (MSS) disease and liver metastasis. Design, Setting, and Participants: This double-blind phase 2 randomized clinical trial enrolled 133 patients between September 25, 2017, and June 28, 2018 (median duration of follow-up for PFS, 20.9 months), with data cutoff on May 4, 2020. The study was conducted at multiple centers through the Academic and Community Cancer Research United network. Adult patients with mCRC who experienced disease progression while receiving fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and anti-epidermal growth factor receptor antibody therapy (if the patient had a RAS wild-type tumor) were included. Interventions: Patients were randomized (2:1) to receive capecitabine (850 or 1000 mg/m2) twice daily on days 1 to 14 and bevacizumab (7.5 mg/kg) on day 1 plus either atezolizumab (1200 mg; investigational group) or placebo (placebo group) on day 1 of each 21-day cycle. Main Outcomes and Measures: The primary end point was PFS; 110 events were required to detect a hazard ratio (HR) of 0.65 with 80% power (1-sided α = .10). Secondary end points were objective response rate, overall survival (OS), and toxic effects. Results: Of 133 randomized patients, 128 individuals (median age, 58.0 years [IQR, 51.0-65.0 years]; 77 men [60.2%]) were assessed for efficacy (82 in the investigational group and 46 in the placebo group). Overall, 15 patients (11.7%) self-identified as African American or Black, 8 (6.3%) as Asian, 1 (0.8%) as Pacific Islander, 101 (78.9%) as White, 1 (0.8%) as multiple races (Asian, Native Hawaiian/Pacific Islander, and White), and 2 (1.6%) as unknown race or unsure of race. Microsatellite-stable disease was present in 110 patients (69 in the investigational group and 41 in the placebo group). Median PFS was 4.4 months (95% CI, 4.1-6.4 months) in the investigational group and 3.6 months (95% CI, 2.2-6.2 months) in the placebo group (1-sided log-rank P = .07, a statistically significant result; HR, 0.75; 95% CI, 0.52-1.09). Among patients with MSS and proficient mismatch repair, the HR for PFS was 0.66 (95% CI, 0.44-0.99). The most common grade 3 or higher treatment-related adverse events in the investigational vs placebo groups were hypertension (6 patients [7.0%] vs 2 patients [4.3%]), diarrhea (6 patients [7.0%] vs 2 patients [4.3%]), and hand-foot syndrome (6 patients [7.0%] vs 2 patients [4.3%]). One treatment-related death occurred in the investigational group. In the investigational group, the response rate was higher among patients without liver metastasis (3 of 13 individuals [23.1%]) vs with liver metastasis (4 of 69 individuals [5.8%]). The benefit of atezolizumab for PFS and OS was greater among patients without vs with liver metastasis (primary analysis of PFS: HR, 0.63 [95% CI, 0.27-1.47] vs 0.77 [95% CI, 0.51-1.17]; OS: HR, 0.33 [95% CI, 0.11-1.02] vs 1.14 [95% CI, 0.72-1.81]). Conclusions and Relevance: In this randomized clinical trial, the addition of atezolizumab to capecitabine and bevacizumab therapy provided limited (ie, not clinically meaningful) clinical benefit. Patients with MSS and proficient mismatch repair tumors and those without liver metastasis benefited more from dual inhibition of the vascular endothelial growth factor and programmed cell death 1 or programmed cell death ligand 1 pathways. Trial Registration: ClinicalTrials.gov Identifier: NCT02873195.

Assessment of extended urine protein monitoring frequency in patients receiving bevacizumab.

PURPOSE: Proteinuria monitoring is required for patients receiving bevacizumab. Nonetheless, the frequency of monitoring is not specified in the package insert. A 2014 quality improvement study performed at Yale New Haven Health System (YNHHS) found that proteinuria occurred in 15% (all grade) of the 162 patients evaluated. These results led to decreasing the frequency of proteinuria monitoring from every treatment to every other treatment. The objective of this study is to assess the safety of the extended interval for urine protein (UP) monitoring. METHODS: Patients receiving at least four bevacizumab treatments at YNHHS from January to June 2017 were randomly selected and retrospectively reviewed. The following data were collected: baseline patient characteristics, comorbidities, medication history, and proteinuria monitoring. The grade, prevalence and management of proteinuria were evaluated. The minimum necessary sample size was determined to be 384 treatments to achieve a 95% confidence interval. RESULTS: Fifty-five patients and 388 bevacizumab treatments were evaluated. Urine protein was assessed in 52.5% of treatments. The incidence of proteinuria among patients was 7.2% (grade 2) and 0% (grade 3). Cumulative dose and the number of total bevacizumab doses did not affect the timing for onset or severity of proteinuria. Two patients with UP ≥ 2+ were further monitored using a 24-h urine collection test with negative results. No treatments were held due to proteinuria. CONCLUSION: Monitoring proteinuria every other treatment does not increase the frequency of adverse events. Urine protein is now monitored prior to every third bevacizumab treatment, reducing unnecessary labs and chair time.

Patient preferences and predicted relative uptake for targeted therapies in metastatic colorectal cancer: a discrete choice experiment.

OBJECTIVE: Ras wild-type metastatic colorectal cancers (mCRC) may be treated with anti-vascular endothelial growth factor (VEGF) or anti-epidermal growth factor receptor (EGFR) agents. We aim to estimate patients' preferences for mCRC treatment and relative importance of cost, efficacy improvement, avoidance of side effects and therapy convenience, and relative uptake between profiles that resemble Bevacizumab (anti-VEGF) and Cetuximab (anti-EGFR), two commonly prescribed mCRC targeted therapies. METHODS: Discrete choice experiment (DCE) was administered to English- or Chinese-speaking Stage 2 or 3 colon cancer patients at the National Cancer Centre Singapore. DCE attributes comprise progression-free survival (PFS), severity of acne-like skin rashes, severity of bleeding, out-of-pocket cost per month and frequency of drug administration. Mixed logit model was used to calculate preference weights for all attribute levels. Subgroup analyses were conducted by interacting attribute levels with selected respondent characteristics. Relative uptake rates for various medication scenarios were studied. RESULTS: 169 respondents aged 61.5 ± 10.5 years completed the survey. They placed the greatest weight on cost, followed by bleeding and skin rashes, then PFS and finally frequency of drug administration. This was similarly observed in the subgroup analyses. A scenario with shorter PFS but less severe side effects has a slightly higher relative uptake at 55%. One quarter of respondents reported that they would not take the treatment they preferred in the choice task. CONCLUSION: Patients were willing to trade off some degree of efficacy to avoid certain severity of side effects. It is therefore crucial for patients and physicians to discuss patients' preferences and circumstances to understand which attributes are more important, as well as patients' views on the trade-offs between treatment benefits and risks.

Chemotherapy-induced nausea in a sample of gynaecological cancer patients: assessment issues and personal risk factors evaluation.

PURPOSE: Chemotherapy-induced nausea (CIN) is a relevant problem for gynaecological cancer patients. The evaluation of CIN is a key aspect in its management, along with the identification of associated risk factors. The objective of the study was to compare different measurements of nausea and to investigate personal risk factors in CIN development. METHOD: Eighty-one women treated for gynaecological cancers took part. The presence of CIN was evaluated using the MASCC Antiemesis Tool (MAT) and a patient's report to clinicians at the subsequent chemotherapy cycle. Personal risk factors were assessed using the State-Trait Anxiety Inventory and a self-report questionnaire. RESULTS: The study shows that the agreement between patients' assessment of CIN with MAT and what they referred to clinicians was only moderate for acute nausea (Cohen's Kappa = 0.55; p < 0.001), while good for delayed nausea (Cohen's Kappa = 0.68; p < 0.001). At multiple logistic regression analysis, younger age, anticipatory nausea, patient medium-high expectations of CIN, and parity emerged as risk factors for the development of acute nausea (p = 0.0087, 0.0080, 0.0122 and 0.0021, respectively). Patient medium-high expectations of CIN and being single resulted to be risk factors for delayed nausea (p = 0.0397 and 0.0024, respectively). CONCLUSIONS: Our findings confirm that personal factors contribute to individual differences in the development of CIN; moreover, we highlight the importance of CIN evaluation by clinicians, underlining the need to use reliable instruments.

Cost-effectiveness of niraparib, rucaparib, and olaparib for treatment of platinum-resistant, recurrent ovarian carcinoma.

BACKGROUND: Olaparib was approved on December 19, 2014 by the US FDA as 4th-line therapy (and beyond) for patients with germline BRCA1/2 mutations; rucaparib was approved on December 19, 2016 as 3rd-line therapy (and beyond) for germline or somatic BRCA1/2-mutated recurrent disease. On October 23, 2019, niraparib was approved for treatment of women with damaging mutations in BRCA1/2 or other homologous recombination repair genes who had been treated with three or more prior regimens. We compared the cost-effectiveness of PARPi(s) with intravenous regimens for platinum-resistant disease. METHODS: Median progression-free survival (PFS) and toxicity data from regulatory trials were incorporated in a model which transitioned patients through response, hematologic complications, non-hematologic complications, progression, and death. Using TreeAge Pro 2017, each PARPi(s) was compared separately to non­platinum-based and bevacizumab-containing regimens. Costs of IV drugs, managing toxicities, infusions, and supportive care were estimated using 2017 Medicare data. Incremental cost-effectiveness ratios (ICERs) were calculated and PFS was reported in quality adjusted life months for platinum-resistant populations. RESULTS: Non­platinum-based intravenous chemotherapy was most cost effective ($6,412/PFS-month) compared with bevacizumab-containing regimens ($12,187/PFS-month), niraparib ($18,970/PFS-month), olaparib ($16,327/PFS-month), and rucaparib ($16,637/PFS-month). ICERs for PARPi(s) were 3-3.5× times greater than intravenous non­platinum-based regimens. CONCLUSION: High costs of orally administered PARPi(s) were not mitigated or balanced by costs of infusion and managing toxicities of intravenous regimens typically associated with lower response and shorter median PFS. Balancing modest clinical benefit with costs of novel therapies remains problematic and could widen disparities among those with limited access to care.

Randomized Phase III Study of Continuation Maintenance Bevacizumab With or Without Pemetrexed in Advanced Nonsquamous Non-Small-Cell Lung Cancer: COMPASS (WJOG5610L).

PURPOSE: Patients with non-small-cell lung cancer (NSCLC) have been shown to benefit from maintenance therapy. COMPASS evaluated the efficacy and safety of bevacizumab with or without pemetrexed as continuation maintenance therapy after carboplatin, pemetrexed, and bevacizumab induction therapy. PATIENTS AND METHODS: Patients with untreated advanced nonsquamous NSCLC without confirmed EGFR 19 deletion or L858R mutation received first-line therapy with carboplatin area under the curve 6, pemetrexed 500 mg/m2, and bevacizumab 15 mg/kg once every 3 weeks for 4 cycles. Patients without disease progression during the induction therapy were randomly assigned 1:1 for maintenance therapy with pemetrexed 500 mg/m2 plus bevacizumab 15 mg/kg or bevacizumab 15 mg/kg once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was overall survival (OS) after random assignment. RESULTS: Between September 2010 and September 2015, 907 patients received induction therapy. Of those, 599 were randomly assigned: 298 received pemetrexed plus bevacizumab, and 301 received bevacizumab. The median OS was 23.3 v 19.6 months (hazard ratio [HR], 0.87; 95% CI, 0.73 to 1.05; 1-sided stratified log-rank P = .069). In the wild-type EGFR subset, the OS HR was 0.82 (95% CI, 0.68 to 0.99; 1-sided unstratified log-rank P = .020). The median progression-free survival (PFS) was 5.7 v 4.0 months (HR, 0.67; 95% CI, 0.57 to 0.79; 2-sided log-rank P < .001). The safety data were consistent with previous reports of treatment regimens. CONCLUSION: In terms of the primary end point of OS, no statistically significant benefit was observed; however, PFS in the total patient population and OS in patients with wild-type EGFR was prolonged with the addition of pemetrexed to bevacizumab maintenance therapy.

Assessment of neurocognitive decline in cancer patients, except brain cancer, under long-term treatment with bevacizumab.

PURPOSE: We performed a cross-sectional study of neurocognitive function in non-brain cancer patients treated with long-term bevacizumab. METHODS/PATIENTS: From 2015 to 2017, we included patients with different types of cancer treated with bevacizumab with or without chemotherapy (BEV; N = 20) or only chemotherapy (ChT; N = 19) for at least 34 weeks, patients who received non-brain radiotherapy (RxT; N = 19), and healthy controls (HC; N = 19) were assessed once at week 34 of treatment (BEV and ChT) or at completion of radiotherapy. Neurocognition was evaluated with the Hopkins Verbal Learning Test-Revised (HVLT-R) total and delayed recall, the Trail Making Test A and B, and the Controlled Oral Word Association Test in the four groups. Non-parametric tests were used to assess differences between groups. RESULTS: The BEV, ChT, and RxT groups scored significantly lower than the HC group on all tests and especially on the HVLT-R total recall. In no case were the mean scores of the BEV group significantly lower than those of the ChT or RxT groups. CONCLUSIONS: Neurocognitive impairment was seen even in patients treated with local non-brain radiotherapy. Treatment with bevacizumab for a long period of time does not seem to worsen neurocognitive function to a greater extent than chemotherapy.

Assessment of Combined Nivolumab and Bevacizumab in Relapsed Ovarian Cancer: A Phase 2 Clinical Trial.

Importance: To date, single-agent programmed cell death 1 protein 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint blockade has shown limited activity in recurrent epithelial ovarian cancer. Combination strategies of PD-1/PD-L1 inhibition with antiangiogenic therapy have the potential for synergistic activity through modulation of the microenvironment and represent a potential therapeutic opportunity in this disease. Objective: To evaluate the activity of combined nivolumab and bevacizumab in women with relapsed ovarian cancer. Design, Setting, and Participants: A single-arm, phase 2 study enrolled patients between February 8, 2017, and December 29, 2017, at 2 sites in the United States; the primary data analysis was completed July 27, 2018. Thirty-eight women with relapsed epithelial ovarian cancer were enrolled in this study. Participants had disease recurrence within 12 months of their last platinum-based therapy and had received between 1 and 3 lines of prior therapy. Interventions: Participants received intravenous nivolumab and intravenous bevacizumab once every 2 weeks. Main Outcome and Measures: The primary end point was objective response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors 1.1. Secondary end points included evaluation of the ORR by platinum sensitivity, assessment of progression-free survival, assessment of safety data, and investigation of the association of tumor PD-L1 with response to therapy. Results: Of the 38 women enrolled, 18 had platinum-resistant and 20 had platinum-sensitive disease; mean (SD) age was 63.0 (9.1) years. Eleven patients experienced a confirmed response to nivolumab with bevacizumab (ORR, 28.9%; 95% exact binomial CI, 15.4%-45.9%), with 1 additional unconfirmed response. The ORR was 40.0% (19.1%-64.0%) in platinum-sensitive and 16.7% (95% CI 3.6%-41.4%) in platinum-resistant participants. Thirty-four participants (89.5%) experienced at least 1 treatment-related adverse event; 9 participants (23.7%) experienced a grade 3 or higher treatment-related adverse event. Median progression-free survival was 8.1 months (95% CI, 6.3-14.7 months). In 36 histologic samples for which PD-L1 testing could be performed, 22 samples (61.1%) had a PD-L1 tumoral percentage less than 1, and 14 samples (38.9%) had a PD-L1 tumoral percentage of 1 or greater. Ten responses occurred in patients with PD-L1 tumor percentage less than 1, and 2 in patients with PD-L1 tumor percentages of 1 or greater. Conclusions and Relevance: The nivolumab with bevacizumab combination appeared to show activity in patients with relapsed ovarian cancer, with greater activity in the platinum-sensitive setting. Alternative combinational strategies may be necessary in the platinum-resistant setting.

Real-World Clinical and Economic Outcomes and the Role of Bevacizumab in Patients With Non-Small-Cell Lung Cancer With Liver Metastases.

PURPOSE: Liver metastases are associated with poor outcomes in patients with advanced non-small-cell lung cancer (aNSCLC). Nevertheless, the vasculature in the liver microenvironment may be conducive to the use of antiangiogenesis inhibitors to potentially improve outcomes. Limited real-world clinical and economic data are currently available for this patient subpopulation. METHODS: Two retrospective cohort analyses were conducted using data from an electronic health record (n = 14,209) and a claims database (n = 9,017). Patients with aNSCLC with and without liver metastases were identified in each database. Patients with baseline liver metastases in the electronic health record database were further categorized into two subgroups-those who had or had not received bevacizumab-containing regimens. Multivariable Cox proportional hazards regression models were used to adjust for baseline characteristics to evaluate the effect of treatment of bevacizumab. RESULTS: Liver metastases were associated with significantly poorer survival (median overall survival, 6.3 months v 10.1 months) and higher costs and health care resource utilization-total per-patient-per-month costs of $27,589 versus $19,607. Cost differences were primarily driven by inpatient costs, including a two-fold increase in hospitalizations and a 1.7-fold higher mean length of stay. Treatment with bevacizumab was associated with improved survival. Whereas overall survival improved in patients with and without baseline liver metastases who received bevacizumab, the relative survival benefit was greater in patients with liver metastases (hazard ratio, 0.63 [95% CI, 0.50 to 0.81] v hazard ratio, 0.80 [95% CI, 0.74 to 0.86]). CONCLUSION: Patients with aNSCLC with liver metastases have poorer survival and a higher cost and health care resource utilization burden. Bevacizumab was associated with a survival benefit in patients with aNSCLC with liver metastases.

Bevacizumab Use and the Risk of Arterial and Venous Thromboembolism in Patients with High-Grade Gliomas: A Nested Case-Control Study.

STUDY OBJECTIVE: Bevacizumab is used in the treatment of recurrent glioblastoma, but evidence is limited on the incidence of thromboembolic complications regarding the use of this drug in real-world settings. We evaluated the risk of arterial thromboembolism (ATE) and venous thromboembolism (VTE) associated with the use of bevacizumab among adults diagnosed with high-grade gliomas in a commercially insured U.S. DESIGN: Nested case-control study. DATA SOURCE: Truven Health MarketScan Commercial and Medicare Supplemental health claims databases (2009-2015). PATIENTS: A total of 2157 patients with high-grade gliomas who underwent incident (first-time) craniotomy, radiation, and concurrent temozolomide treatment between 2009 and 2015 were identified. Overall, 25 cases of ATE and 99 cases of VTE were each identified in this cohort, and each case was matched to up to 10 controls (170 for ATE and 819 for VTE) based on sex, age, quarter year of index time, and follow-up duration by using incidence density sampling without replacement from the overall cohort. Controls were at risk for the outcome of interest (ATE or VTE) at the time of case occurrence and survived at least as long as their referent case. MEASUREMENTS AND MAIN RESULTS: Exposure to bevacizumab was determined during inpatient or outpatient encounters between the index date (date of the incident craniotomy) and the ATE or VTE event or corresponding matched control date. Multivariable conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of ATE and VTE separately. A higher proportion of patients with ATE received bevacizumab compared with controls (28% vs 17%; adjusted OR 1.51, 95% CI 0.54-4.24), but this excess in odds was not statistically significant. Similarly, bevacizumab was not significantly associated with VTE (13% vs 9%; adjusted OR 1.40, 95% CI 0.71-2.75). CONCLUSION: We found no significant association between the use of bevacizumab and the occurrence of thromboembolic events in patients with high-grade gliomas, although our study was limited by the small number of ATE events. Because the potential for complications from arterial thrombosis cannot be completely ruled out, further research is needed to confirm the thromboembolic safety of bevacizumab in a larger sample of patients with high-grade gliomas.

Off-label use of bevacizumab in the treatment of retinal disease: ethical implications.

Anti-vascular endothelial growth factor (anti-VEGF) therapy has revolutionised the treatment of a variety of ophthalmic conditions and has become the first-line therapy for a range of retinal diseases. Bevacizumab, a VEGF inhibitor first approved for the treatment of colorectal cancer, has been shown to be nearly or virtually as effective and safe as other anti-VEGF therapies in the treatment of certain retinal diseases but is not approved or registered by the Food and Drug Administration or European Medicines Agency. While other anti-VEGF options are approved and registered, they are generally more expensive and less accessible. Accordingly, despite its off-label status, bevacizumab is frequently used for a variety of disabling retinal diseases. Indeed, bevacizumab is included on the World Health Organization's list of essential medicines. However, its use in some parts of the world remains restricted due to its off-label status. How, then, should healthcare authorities approach this situation? What are the ethical and societal implications of adhering to a standard and generally effective evaluation and approval system while restricting access to a potentially cost-saving therapy? In countries where its use is not restricted, how should providers approach off-label treatment with bevacizumab? By examining the evidence behind bevacizumab's efficacy and safety and evaluating the individual and societal implications of off-label use and restriction, this paper illustrates the ethical factors providers and policy makers must consider in the off-label use of bevacizumab and ultimately argues for increased access to bevacizumab in the treatment of retinal disease.

Advocacy for a New Oncology Research Paradigm: The Model of Bevacizumab in Triple-Negative Breast Cancer in a French Cohort Study.

BACKGROUND: Triple-negative breast cancer remains a disease with poor prognosis and few treatment options, due to the lack of therapeutic targets. Bevacizumab, the first anti-VEGF agent approved in the treatment of cancer, has demonstrated efficacy in breast cancer in combination with paclitaxel for the first-line treatment of HER2-negative metastatic breast cancer. Despite the fact that the benefit was particularly significant for triple-negative breast cancer with its approval in 2008 by the FDA, this decision was later reversed as there was no improvement in overall survival in addition to significant costs. OBJECTIVES: The scope of the present study is to focus on the role of bevacizumab in triple-negative breast cancer through the analysis of overall survival, progression-free survival, and cost benefit among 45 patients in a French monocentric study and to discuss new paradigms of endpoints. METHODS: All patients diagnosed with metastatic triple-negative breast cancer, for whom first-line treatment was bevacizumab in combination with paclitaxel between January 2011 and April 2018 were included in this single-center retrospective study, and a chart review of all recruited subjects was performed from medical records. RESULTS: In this real-life study among 45 patients with metastatic triple-negative breast cancer, bevacizumab provided a significant benefit for a category of patients, with longer median progression-free survival and the ability of maintenance therapy associated to limited side effects. CONCLUSIONS: Beyond being the phoenix of breast oncology and a magnet of controversy, the case of bevacizumab in metastatic breast cancer highlights one of the greatest challenges in oncology, namely to balance modest clinical benefits with exponential costs. A balance needs to be found between health care affordability, high price of progress, and the best medical decision for the patients, in order to avoid the "unbreathable tipping point" we are actually dealing with.

Cost-effectiveness of Maintenance Capecitabine and Bevacizumab for Metastatic Colorectal Cancer.

Importance: Unregulated drug prices increase cancer therapy costs. After induction chemotherapy, patients with metastatic colon cancer can receive maintenance capecitabine and bevacizumab therapy based on improved progression-free survival, but whether this treatment's cost justifies its benefits has not been evaluated in the United States. Objective: This study sought to determine the influence of capecitabine and bevacizumab drug prices on cost-effectiveness from a Medicare payer's perspective. Design, Setting, and Participants: The incremental cost-effectiveness of capecitabine and bevacizumab maintenance therapy was determined with a Markov model using a quality-of-life penalty based on outcomes data from the CAIRO phase 3 randomized clinical trial (RCT), which included 558 adults in the Netherlands with unresectable metastatic colorectal cancer who had stable disease or better following induction chemotherapy. The outcomes were modeled using Markov chains to account for patients who had treatment complications or cancer progression. Transition probabilities between patient states were determined, and each state's costs were determined using US Medicare data on payments for capecitabine and bevacizumab treatment. Deterministic and probabilistic sensitivity analyses identified factors affecting cost-effectiveness. Main Outcomes and Measures: Life-years gained were adjusted using CAIRO3 RCT quality-of-life data to determine quality-adjusted life-years (QALYs). The primary end point was the incremental cost-effectiveness ratio, representing incremental costs per QALY gained using a capecitabine and bevacizumab maintenance regimen compared with observation alone. Results: Markov model estimated survival and complication outcomes closely matched those reported in the CAIRO3 RCT, which included 558 adults (n = 197 women, n = 361 men; median age, 64 and 63 years for patients in the observation and maintenance therapy groups, respectively) in the Netherlands with unresectable metastatic colorectal cancer who had stable disease or better following induction chemotherapy. Incremental costs for a 3-week maintenance chemotherapy cycle were $6601 per patient. After 29 model iterations corresponding to 60 months of follow-up, mean per-patient costs were $105 239 for maintenance therapy and $21.10 for observation. Mean QALYs accrued were 1.34 for maintenance therapy and 1.20 for observation. The incremental cost-effectiveness ratio favored maintenance treatment, at an incremental cost of $725 601 per QALY. The unadjusted ratio was $438 394 per life-year. Sensitivity analyses revealed that cost-effectiveness varied with changes in drug costs. To achieve an incremental cost-effectiveness ratio of less than $59 039 (median US household income) per unadjusted life-year would require capecitabine and bevacizumab drug costs to be reduced from $6173 (current cost) to $452 per 3-week chemotherapy cycle. Conclusions and Relevance: Antineoplastic therapy is expensive for payers and society. The price of capecitabine and bevacizumab maintenance therapy would need to be reduced by 93% to make it cost-effective, a finding useful for policy decision making and payment negotiations.

Cost savings analysis and toxicity audit of a bevacizumab dose rounding policy at a community cancer center.

Purpose To evaluate the potential cost savings incurred from a policy to round doses of bevacizumab to the nearest vial size. Secondarily, to determine differences in rates of adverse events between patients who had their doses rounded up compared with those who had doses rounded down. Methods This study is a retrospective chart review of all patients who received at least one rounded dose of bevacizumab over a period of 22 months. Doses of bevacizumab were calculated based on actual body weight. The calculated dose was then rounded to the nearest 400 or 100 mg vial size. The predicted effect on cost was calculated in US dollars for both the pre-rounded dose and the rounded dose. Adverse events including hypertension, proteinuria, and vascular events were compared between those that received a dose that was rounded up and those with a dose rounded down. Results A total of 55 patients received at least one dose bevacizumab between 1 August 2014 and 31 May 2016. A total of 470 doses were administered. The estimated cost savings by rounding bevacizumab doses to the nearest 100 mg during the study time period was $164,617.92. Patients receiving either a dose that was rounded up or rounded down to the nearest 100 mg experienced similar rates of adverse events. Conclusion Dose rounding of bevacizumab to the nearest vial size resulted in significant cost savings and did not significantly impact the incidence of adverse events.

Public Reimbursement of Prescription Drugs Used For Off-Label Indications in Ontario.

BACKGROUND: A Canadian Agency for Drugs and Technologies in Health (CADTH) therapeutic review concluded that bevacizumab and ranibizumab have similar efficacy and safety in treating retinal conditions and recommended bevacizumab be used as preferred initial therapy based on a cost-saving perspective. Such use would be off-label because bevacizumab is not approved for these conditions and has a serious safety warning (SSW) in its Product Monograph (PM) about intravitreal use. OBJECTIVE: To evaluate whether the Ontario Public Drug Programs (OPDP) reimbursement is provided only for off-label use for serious, life-threatening or severely debilitating conditions and not when the drug's PM contains a SSW against such use. METHODS: OPDP reimbursement criteria for non-palliative drugs from its frequently-requested Exceptional Access Program (EAP) and Limited Use (LU) lists were compared with approved indications and SSWs in the drugs' PMs. RESULTS: Of 125 unique frequently-requested non-palliative EAP drugs, 12 included off-label use for serious conditions for which no alternative treatment exists. Eight of the 12 had SSWs, but only one warning for orally-administered sirolimus related directly to the OPDP-reimbursed off-label use. Of 29 injectable non-palliative LU drugs, one had off-label LU criteria allowing reimbursement for an unapproved indication and a SSW unrelated to the reimbursable indication. CONCLUSION: Presently, OPDP only reimburse drugs for off-label use for the treatment of serious, life-threatening or severely debilitating conditions for which no alternative treatment exists. OPDP should not diverge from this approach by allowing cost-savings to trump appropriate drug use, which would set a unique and unprecedented example.

Eficacia y seguridad de aflibercept para el tratamiento de la vasculopatía coroidea polipoidal refractaria a antiangiogénicos (bevacizumab o ranibizumab) / Efficacy and safety of aflibercept for the treatment of polypoid choroidal vasculopathy refractory to antiangiogenic agents (bevacizumab or ranibizumab)

INTRODUCCIÓN: El presente dictamen expone la evaluación del uso de aflibercept para el tratamiento de la vasculopatía coroidea polipoidal (VCP) refractaria a antiangiogénicos (bevacizumab o ranibizumab). La vasculopatía coroidea polipoidal (VCP) es una afección vascular de la coroides que se caracteriza por el desarrollo de dilataciones aneurismáticas, en forma de pólipos, de los vasos de la coroides. Además, se acompaña de formación anómala de vasos sanguíneos en forma ramificada. El diagnóstico se basa en el hallazgo de dilataciones polipoideas en la angiografía con indocianina verde. Los pólipos coroideos y la neovascularización pueden conducir a episodios recurrentes de desprendimiento de retina con exudados, desprendimiento epitelial con pigmento hemorrágico y hemorragia subretiniana. Inicialmente el tratamiento del VCP consistía en la terapia fotodinámica (PDT, por sus siglas en inglés photodynamic therapy) con verteporfina. Posteriormente, este fue reemplazado por los agentes anti receptor del factor de crecimiento endotelial vascular (anti-VEGF, por sus siglas en inglés vascular endotelial growth factor), como bevacizumab, ranibizumab y aflibercept, en el tratamiento de primera línea en pacientes con VCP. La extensión de su uso en esta población fue a partir de los resultados de ensayos clínicos aleatorizados (ECA) en la degeneración macular asociada a la edad (DMAE), pero que no distinguieron a los pacientes con VCP a pesar de que los efectos de la terapia anti-VEGF para la VCP puede diferir de aquellos con DMAE. TECNOLOGÍAS SANITARIA DE INTERÉS: AFLIBERCEPT: La solución de aflibercept para inyección (Eylea ®, Bayer Pharma) es una proteína de fusión consistente en la porción Fc de la inmunoglobulina IgG humana y de derivados de péptidos del receptor de factor de crecimiento endotelial vascular (VEGF). Esta proteína soluble se une a todas las formas de VEGF-A, VEGF-B y el factor de crecimiento placentario, previniendo que estos factores estimulen el crecimiento de los nuevos y frágiles vasos sanguíneos asociados con la degeneración macular asociado con la edad (FDA 2011). METODOLOGÍA: Se realizó una búsqueda de la literatura con respecto a la eficacia y perfil toxico del uso de aflibercept para el tratamiento de la vasculopatía coroidea polipoidal refractaria a antiangiogénicos (bevacizumab o ranibizumab). Esta búsqueda se efectuó en los meta-buscadores: Translating Research into Practice (TRIPDATABASE), National Library of Medicine (Pubmed-Medline) y Health Systems Evidence. Adicionalmente, se amplió la búsqueda revisando la evidencia generada por grupos internacionales que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), tales como, la Cochrane Group, the National Institute for Health and Care Excellence (NICE), the Agency for Health care Research and Quality (AHRQ), the Canadian Agency for Drugs and Technologies in Health (CADTH) y the Scottish Medicines Consortium (SMC). Esta búsqueda se completó ingresando a la página web www.clinicaltrials.gov, para así poder identificar ensayos clínicos en elaboración o que no hayan sido publicados aún, y así disminuir el riesgo de sesgo de publicación. RESULTADOS: La búsqueda de la literatura científica no identificó ningún ensayo clínico aleatorizado en la población de interés. En su lugar solo se identificaron escasos estudios de series de casos, que representan el nivel más bajo de evidencia. Pero que, además, presentaron importantes limitaciones metodológicas que disminuyen en gran medida la confianza en sus resultados. Los problemas metodológicos se relacionaron con problemas en la definición de los pacientes, los análisis estadísticos, el reporte de los resultados, un periodo corto de seguimiento y muestras pequeñas. La definición de ser refractario al tratamiento con anti-VEGF estaba ausente o no era uniforme entre los estudios. Cada estudio incluyó entre 10 y 30 ojos, un número muy limitado y con alto riesgo de errores tipo I y II. Los autores realizaron múltiples comparaciones sin implementar ningún ajuste. Los resultados se reportaron de manera incompleta sin agregar información de los valores de varianza o valores de significancia. En algunos estudios que incluyeron tanto a pacientes con VCP y DMAE, los resultados no se presentaron de manera diferenciada por diagnóstico. Respecto a los resultados reportados, no había consistencia en los desenlaces evaluados ni en las escalas con las que fueron medidas o los presentaron de manera cualitativa sin definiciones claras. Tampoco hubo uniformidad en el tratamiento con aflibercept. Así, el número de dosis de carga y de mantenimiento fueron inconsistentes, además, de que el tiempo de tratamiento fue corto (entre 3 y 6 meses) y solo un estudio presentó sus resultados a los 12 meses. CONCLUSIONES: La vasculopatía coroidea polipoidal (VCP) es una afección vascular de la coroides que se caracteriza por el desarrollo de dilataciones aneurismáticas, en forma de pólipos, de los vasos de la coroides. Aunque se considera a la VCP como un subtipo de la DMAE, existen controversias acerca de si la VCP forma parte del espectro de presentación de la DMAE. Existen varias marcas distintivas en la patología entre ambas, además de diferencias en el curso clínico, respuesta a los tratamientos, incluso algunos estudios proponen diferentes factores de riesgo genéticos. El reemplazo del uso del PDT por el de los agentes anti-VEGF intra-vítreo en pacientes con VCP como tratamiento de primera línea se derivó de los resultados de los ECA en pacientes con DMAE. Pero estos estudios no distinguieron entre los fenotipos de DMAE, y los efectos de la terapia anti-VEGF para la VCP, que puede diferir de aquellos con DMAE. La información disponible del uso de aflibercept en pacientes con VCP y respuesta inadecuada al tratamiento previo con anti-VEGF proviene de unos escasos estudios de series de casos, en un número limitado de pacientes y por un corto periodo de seguimiento. Estos estudios padecen de limitaciones metodológicas importantes relacionados con la definición de los pacientes, el número de pacientes incluidos, los análisis estadísticos, el reporte de resultados y el tiempo de seguimiento. El nivel de evidencia respecto a los efectos de aflibercept en pacientes con VCP refractarios a un agente anti-VEGF es muy bajo. Pero, además se suman limitaciones metodológicas de los estudios que afectan en gran medida su validez y confiabilidad. Asimismo, está comprometida la validez externa debido a las muestras pequeñas de los pacientes incluidos. No es posible evaluar el perfil de toxicidad de aflibercept en la población de interés del este dictamen. Los estudios de series de casos no reportaron los eventos adversos, o lo hicieron de manera incompleta, situación que no permite saber cuál es el perfil de toxicidad de aflibercept en los pacientes con VCP y uso previo de anti-VEGF. Con la información disponible, la incertidumbre es alta respecto a la potencial eficacia de aflibercept en el tratamiento de segunda línea en pacientes con VCP. Asimismo, la ausencia de datos de toxicidad oculares y sistémicos, no permite evaluar la relación beneficio/riesgo de este medicamento. El Instituto de Evaluación de Tecnologías en Salud e Investigación IETSI no aprueba el uso de aflibercept para el tratamiento de la vasculopatía coroidea polipoidal refractario a anti-angiogénicos (bevacizumab o ranibizumab).

Aflibercept, bevacizumab or ranibizumab for diabetic macular oedema: recent clinically relevant findings from DRCR.net Protocol T.

PURPOSE OF REVIEW: The aim of this study was to provide clinically relevant findings from the DRCR.net Protocol T, a multicentre randomized clinical trial comparing intravitreous aflibercept, repackaged (compounded) bevacizumab and ranibizumab for vision-impairing centre-involved diabetic macular oedema (DME). RECENT FINDINGS: At 1 year, all three antivascular endothelial growth factor (anti-VEGF) drugs, on average, improved visual acuity. There was no difference among drugs in mean change in visual acuity from baseline among eyes with baseline Snellen equivalent visual acuity of 20/32 to 20/40, whereas aflibercept yielded superior vision outcomes among eyes with baseline visual acuity of 20/50 to 20/320. At 2 years, aflibercept remained superior, on average, to bevacizumab, but not ranibizumab, among eyes with baseline visual acuity of 20/50 to 20/320. Over 2 years, in post-hoc area-under-the-curve analysis, aflibercept vision outcomes were superior to bevacizumab or ranibizumab among these eyes. All three drugs had comparable ocular and systemic safety profiles. The substantial cost differential between aflibercept and bevacizumab raises challenges when safety and efficacy are at odds with cost-effectiveness results. SUMMARY: When initial visual acuity loss is mild, there are no apparent differences, on average, among aflibercept, bevacizumab and ranibizumab for treating DME. When visual acuity loss is moderate or worse, aflibercept is more likely to improve visual acuity.