Predicting Real-World Effectiveness of Cancer Therapies Using Overall Survival and Progression-Free Survival from Clinical Trials: Empirical Evidence for the ASCO Value Framework

Objectives

To measure the relationship between randomized controlled trial (RCT) efficacy and real-world effectiveness for oncology treatments as well as how this relationship varies depending on an RCT’s use of surrogate versus overall survival (OS) endpoints.

吉西他滨联合卡培他滨治疗晚期乳腺癌疗效评价

目的评价吉西他滨联合卡培他滨治疗晚期乳腺癌的疗效和不良反应。方法25例晚期乳腺癌患者接受吉西他滨联合卡培他滨治疗,其中吉西他滨1000 mg/m2静脉滴注半小时,于第1天和第8天;卡培他滨2500mg/m2分早、晚两次口服,连用14天,休息7天,每21天为1个周期。每例患者至少接受3~5个周期化疗。结果25例晚期乳腺癌患者入组本临床研究,疗效可评价,其中完全缓解3例,部分缓解10例,稳定5例,进展7例。总缓解率为52.0%(13/25),完全缓解率为12.0%(3/25),部分缓解率为40.0%(10/25),稳定率为20.0%(5/25),进展率为28.0%(7/25)。主要毒性反应为骨髓抑制和手足综合征。全组平均随访16个月,有效者中位疾病进展时间为7个月,至随访结束,中位总生存时间未达到。结论吉西他滨联合卡培他滨治疗晚期乳腺癌,有效率高,毒性反应轻。     

Non-Pharmacological Self-Management Strategies for Chemotherapy-Induced Peripheral Neuropathy in People with Advanced Cancer: A Systematic Review and Meta-Analysis

Non-pharmacological self-management interventions for chemotherapy-induced peripheral neurotherapy (CIPN) are of clinical interest; however, no systematic review has synthesized the evidence for their use in people with advanced cancer. Five databases were searched from inception to February 2022 for randomized controlled trials assessing the effect of non-pharmacological self-management interventions in people with advanced cancer on the incidence and severity of CIPN symptoms and related outcomes compared to any control condition. Data were pooled with meta-analysis. Quality of evidence was appraised using the Revised Cochrane Risk of Bias Tool for Randomized Trials (RoB2), with data synthesized narratively. Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was applied to assess the certainty of the evidence. Thirteen studies were included, which had a high (69%) or unclear (31%) risk of bias. Greatest confidence was found for physical exercise decreasing CIPN severity (SMD: −0.89, 95% CI: −1.37 to −0.41; p = 0.0003; I² = 0%; n = 2 studies, n = 76 participants; GRADE level: moderate) and increasing physical function (SMD: 0.51, 95% CI: 0.02 to 1.00; p = 0.04; I² = 42%; n = 3 studies, n = 120; GRADE level: moderate). One study per intervention provided preliminary evidence for the positive effects of glutamine supplementation, an Omega-3 PUFA-enriched drink, and education for symptom self-management via a mobile phone game on CIPN symptoms and related outcomes (GRADE: very low). No serious adverse events were reported. The strongest evidence with the most certainty was found for physical exercise as a safe and viable adjuvant to chemotherapy treatment for the prevention and management of CIPN and related physical function in people with advanced cancer. However, the confidence in the evidence to inform conclusions was mostly very low to moderate. Future well-powered and appropriately designed interventions for clinical trials using validated outcome measures and clearly defined populations and strategies are warranted.     

Relationship Between Physician Supply and Breast Cancer Survival: A Geographic Approach

Breast cancer is the most common cancer in women, accounting for nearly 30% of all female cancers. Breast cancer is the second leading cause of cancer mortality in women in the US. During the last two decades, the benefits of early detection, early intervention, and postoperative treatment have resulted in decreased breast cancer mortality in the US general population. However, the distribution of breast cancer mortality varies among geographic regions of the US. The reasons for this variation remain largely unknown. We choose to look for a possible association between the numbers of physicians in each city within the State of Florida and breast cancer survival among women aged 40+ residing in that particular city. Using Cox Proportionate Hazard Modeling, we found a direct association between the number of physicians practicing in a particular city and breast cancer survival in that particular city (P=0.0153), while controlling for other known risk factors affecting survival. To our knowledge, this is the first study to report an association between physician supply and cancer survival within defined geographic areas. This association shows as physician density consistently dropped in a defined geographic area so did time of survival among women with breast cancer.     

Effects of Serum Triglycerides on Prostate Cancer and Breast Cancer Risk: A Meta-Analysis of Prospective Studies

Epidemiological studies show conflicting results regarding the link between serum triglyceride and the risk of prostate cancer and breast cancer. Therefore, we performed a meta-analysis of prospective studies to clarify this association. We searched PubMed, EMBASE, the Chinese Biomedical Database (CBM), and the China National Knowledge Infrastructure (CNKI) database to identify relevant prospective studies of the relationship between serum triglyceride and prostate cancer and breast cancer risk. Study-specific estimates adjusting for potential confounders were combined to evaluate a summary relative risks (RRs) and 95% confidence intervals (95% CIs) using a fixed- or random-effects model. A total of 11 prospective studies (619,410 subjects and 15,691 incident prostate cancer patients) and 8 prospective studies (590,878 subjects and 12,177 incident breast cancer patients) were respectively included in our meta-analysis to assess the associations of serum triglyceride with prostate cancer and breast cancer risk. The pooled adjusted RR estimates for prostate cancer and breast cancer for the highest versus the lowest exposure levels of serum triglycerides were 0.95 (95% CI: 0.87–1.04) and 0.94 (95% CI: 0.87–1.00), respectively. Additionally, a dose–response analysis revealed that serum levels of triglycerides were not associated with the risk of prostate cancer and breast cancer. We found that serum triglyceride was not related to the risk of prostate cancer and breast cancer.     

Direct Medical Costs of Advanced Breast Cancer Treatment: A Real-World Study in the Southeast of The Netherlands

ObjectivesPolicy makers increasingly seek to complement data from clinical trials with information from routine care. This study aims to provide a detailed account of the hospital resource use and associated costs of patients with advanced breast cancer in The Netherlands.MethodsData from 597 patients with advanced breast cancer, diagnosed between 2010 and 2014, were retrieved from the Southeast Netherlands Advanced Breast Cancer Registry. Database lock for this study was in October 2017. We report the observed hospital costs for different resource categories and the lifetime costs per patient, adjusted for censoring using Lin’s method. The relationship between patients’ characteristics and costs was studied using multivariable regression.ResultsThe average (SE) lifetime hospital costs of patients with advanced breast cancer were €52 709 (405). Costs differed considerably between patient subgroups, ranging from €29 803 for patients with a triple-negative subtype to €92 272 for patients with hormone receptor positive and human epidermal growth factor receptor 2 positive cancer. Apart from the cancer subtype, several other factors, including age and survival time, were independently associated with patient lifetime costs. Overall, a large share of costs was attributed to systemic therapies (56%), predominantly to a few expensive agents, such as trastuzumab (15%), everolimus (10%), and bevacizumab (9%), as well as to inpatient hospital days (20%).ConclusionsThis real-world study shows the high degree of variability in hospital resource use and associated costs in advanced breast cancer care. The presented resource use and costs data provide researchers and policy makers with key figures for economic evaluations and budget impact analyses.     

A Comparison of Alternative Network Meta-Analysis Methods in the Presence of Nonproportional Hazards: A Case Study in First-Line Advanced or Metastatic Renal Cell Carcinoma

ObjectivesNetwork meta-analysis (NMA) of time-to-event outcomes based on constant hazard ratios can result in biased findings when the proportional hazards (PHs) assumption does not hold in a subset of trials. We aimed to summarize the published non-PH NMA methods for time-to-event outcomes, demonstrate their application, and compare their results.MethodsThe following non-PH NMA methods were compared through an illustrative case study in oncology of 4 randomized controlled trials in terms of progression-free survival and overall survival: (1) 1-step or (2) 2-step multivariate NMAs based on traditional survival distributions or fractional polynomials, (3) NMAs with restricted cubic splines for baseline hazard, and (4) restricted mean survival NMA.ResultsFor progression-free survival, the PH assumption did not hold across trials and non-PH NMA methods better reflected the relative treatment effects over time. The most flexible models (fractional polynomials and restricted cubic splines) fit better to the data than the other approaches. Estimated hazard ratios obtained with different non-PH NMA methods were similar at 5 years of follow-up but differed thereafter in the extrapolations. Although there was no strong evidence of PH violation for overall survival, non-PH NMA methods captured this uncertainty in the relative treatment effects over time.ConclusionsWhen the PH assumption is questionable in a subset of the randomized controlled trials, we recommend assessing alternative non-PH NMA methods to estimate relative treatment effects for time-to-event outcomes. We propose a transparent and explicit stepwise model selection process considering model fit, external constraints, and clinical validity. Given inherent uncertainty, sensitivity analyses are suggested.     

Zinc and Breast Cancer Survival: A Prospective Cohort Study of Dietary Intake and Serum Levels

Zinc has been suggested to play a role in breast cancer progression; however, no previous study on zinc levels and the potential effect on breast cancer survival has been conducted. This study investigates recurrence-free survival (RFS), breast cancer-specific survival (BCSS) and overall survival (OS) in relation to zinc levels, in serum and diet, overall and stratified for phosphorus and selenium levels. The Malmö Diet and Cancer Study, a prospective population-based cohort in Sweden including 17,035 women, was used to identify breast cancer patients diagnosed in the period 1991–2013. Diet was assessed by a validated modified diet history method. A Cox regression analysis yielded hazard ratios (HRs) with 95% confidence intervals adjusted for potential confounders. Out of 1062 patients with invasive breast cancer, 268 recurrences, 205 breast cancer deaths and 228 deaths from other causes were recorded. No overall associations were seen between zinc and RFS, BCSS or OS. However, in women with a high phosphorus intake, a higher BCSS and OS were seen in zinc intake Q2 to Q4 versus Q1; the adjusted HR was 0.41 (0.23–0.73) and 0.64 (0.41–1.00), respectively. The results indicate that the combination of intermediate/high zinc intake and high phosphorus intake may lead to a better breast cancer survival.     

Patient-Reported Outcomes as Independent Prognostic Factors for Survival in Oncology: Systematic Review and Meta-Analysis

ObjectivesAssessment of patient-reported outcomes (PROs) in oncology is of critical importance because it provides unique information that may also predict clinical outcomes.MethodsWe conducted a systematic review of prognostic factor studies to examine the prognostic value of PROs for survival in cancer. A systematic literature search was performed in PubMed for studies published between 2013 and 2018. We considered any study, regardless of the research design, that included at least 1 PRO domain in the final multivariable prognostic model. The protocol (EPIPHANY) was published and registered in the International Prospective Register of Systematic Reviews (CRD42018099160).ResultsEligibility criteria selected 138 studies including 158 127 patients, of which 43 studies were randomized, controlled trials. Overall, 120 (87%) studies reported at least 1 PRO to be statistically significantly prognostic for overall survival. Lung (n = 41, 29.7%) and genitourinary (n = 27, 19.6%) cancers were most commonly investigated. The prognostic value of PROs was investigated in secondary data analyses in 101 (73.2%) studies. The EORTC QLQ-C30 questionnaire was the most frequently used measure, and its physical functioning scale (range 0-100) the most frequent independent prognostic PRO, with a pooled hazard ratio estimate of 0.88 per 10-point increase (95% CI 0.84-0.92).ConclusionsThere is convincing evidence that PROs provide independent prognostic information for overall survival across cancer populations and disease stages. Further research is needed to translate current evidence-based data into prognostic tools to aid in clinical decision making.     

Medical Treatments for Acromegaly: A Systematic Review and Network Meta-Analysis

Background

Acromegaly results from the hypersecretion of growth hormone. Because of the low incidence rates of this disease worldwide, few clinical trials evaluating drug treatments have been conducted.

Physical Activity and Risk of Breast Cancer: A Meta-Analysis of 38 Cohort Studies in 45 Study Reports

Objectives

To evaluate and quantify the association between physical activity (PA) and risk of breast cancer.

Smoking as a Risk Factor for Prostate Cancer: A Meta-Analysis of 24 Prospective Cohort Studies

Objectives. We evaluated the relationship between smoking and adenocarcinoma of the prostate.Methods. We pooled data from 24 cohort studies enrolling 21 579 prostate cancer case participants for a general variance-based meta-analysis. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated separately for mortality and incidence studies. We tested the robustness of effect measures and evaluated statistical heterogeneity with sensitivity analyses.Results. In the pooled data, current smokers had no increased risk of incident prostate cancer (RR = 1.04; 95% CI = 0.87, 1.24), but in data stratified by amount smoked they had statistically significant elevated risk (cigarettes per day or years: RR = 1.22; 95% CI = 1.01, 1.46; pack years of smoking: RR = 1.11; 95% CI = 1.01, 1.22). Former smokers had an increased risk (RR = 1.09; 95% CI = 1.02, 1.16). Current smokers had an increased risk of fatal prostate cancer (RR = 1.14; 95% CI = 1.06, 1.19). The heaviest smokers had a 24% to 30% greater risk of death from prostate cancer than did nonsmokers.Conclusions. Observational cohort studies show an association of smoking with prostate cancer incidence and mortality. Ill-defined exposure categories in many cohort studies suggest that pooled data underestimate risk.Prostate cancer is the most common solid tumor diagnosed among men in the United States, with an estimate of more than 186 000 new cases and 28 000 deaths in 2008.¹ Unfortunately, few risk factors have been identified, other than advanced age and family history.² That environmental factors may play a role in its etiology is suggested by data demonstrating wide international variation in incidence. Migrant studies document increased occurrence among those moving from low- to high-incidence countries, as was observed among Japanese men who immigrated to the United States.³ Autopsy studies have documented a consistent prevalence (15%–30%) of histologic or latent prostate cancer across populations.⁴ These findings suggest that initiating events for prostate cancer may differ from those contributing to progression and the occurrence of clinically evident disease.Despite the demonstrated links between smoking and several solid tumors, the association between cigarette smoking and prostate cancer remains a matter of debate. Although this disease is not considered to be tobacco related,⁵ cigarette smoke is known to contain multiple carcinogens, including N-nitroso compounds (recognized animal carcinogens).^6,7 An association with smoking could also have a hormonal basis: male smokers were found to have elevated levels of circulating androsterone and testosterone, which may increase prostate cancer risk or contribute to cancer progression.⁸Unfortunately, results from human observational studies are inconsistent across study types, with case–control analyses showing particular heterogeneity.⁵ In addition, epidemiological analyses suggest that the outcomes of studies examining the influence of smoking on prostate cancer incidence may differ from the results in studies of prostate cancer mortality.⁹ This may further complicate analysis of a causal association. Because this topic had not previously been subjected to meta-analysis and results from epidemiological studies were inconsistent, we pooled data from the available cohort studies to elucidate the possible relationship between smoking and the etiology and progression of adenocarcinoma of the prostate.     

Survivor Dragon Boating: A Vehicle to Reclaim and Enhance Life After Treatment for Breast Cancer

The authors investigated the psychosocial impact of dragon boat participation on women who have been treated for breast cancer. Open-ended qualitative interviews were completed by 10 new members recruited from two breast cancer survivor dragon boat teams. Our findings indicate that the women's experience of survivor dragon boating surpassed their expectations and offered them hope and increased strength and the ability to regain control of their lives. Key themes emerging from the in-depth interviews that encapsulate the experiences of women in their first season of dragon boating follow: awakening of the self, common bond, regaining control, being uplifted, and transcending the fear of death. The interview data support the emerging hypothesis that dragon boating is a vehicle for improving women's wellness and post-treatment qualityof life.     

贝伐单抗联合化疗治疗晚期非小细胞肺癌的有效性评价

目的评价贝伐单抗(15mg/kg)联合化疗治疗晚期非小细胞肺癌患者的有效性。方法通过检索PubMed和Cochrane Library数据库,收集了四个随机对照临床试验进行meta分析,有效性的评价指标包括疾病无进展生存时间(PFS)和总生存时间(OS)。结果与对照组相比,贝伐单抗组的患者的疾病进展风险比为0.709(P<0.001),死亡风险比为0.804(P=0.002)。结论对于晚期非小细胞肺癌,采用贝伐单抗(15mg/kg)联合化疗的治疗方法会显著提高患者的PFS和OS。