Major cardiovascular adverse events in older adults with early-stage triple-negative breast cancer treated with adjuvant taxane + anthracycline versus taxane-based chemotherapy regimens: A SEER-medicare study.

BACKGROUND: Triple-negative breast cancer (TNBC) is more aggressive as compared to other subtypes of breast cancer with characteristic metastatic patterns and a poor prognosis. The standard of care for early-stage TNBC is historically anthracycline and taxane-based chemotherapy (ATAX). Despite the effectiveness of this regimen, anthracyclines carry a small but important risk of cardiotoxicity, which is specifically a concern in the older population. This study evaluates major adverse cardiovascular events (MACE) in older women with TNBC treated with ATAX compared to taxane-based chemotherapy (TAX). METHODS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we identified women aged 66 and older with TNBC diagnosed between 2010 and 2015 (N = 2215). We compared patient and clinical characteristics according to adjuvant chemotherapy regimen (chemotherapy versus no chemotherapy and ATAX versus TAX). Logistic regression was performed to estimate the odds ratios (OR) and 95% confidence intervals (CIs), Kaplan-Meier survival curves were generated to estimate three-year overall survival (OS) and cancer specific survival (CSS). Cox proportional hazards models were used to analyze OS and CSS while controlling for patient and tumor characteristics. MACE was defined as acute myocardial infarction, heart failure, potentially fatal arrhythmia, and cerebral vascular incidence. Few patients experienced a cardiac death and therefore this was excluded in the analysis. RESULTS: Of the 2215 patients in our cohort, most patients (n = 1334; 60.26%) received TAX compared to ATAX (n = 881; 39.78%). Patients who received ATAX were not statistically significantly more likely than those who received TAX to experience acute myocardial infarction, cerebral vascular accident (CVA), or potentially fatal arrhythmia when controlling for traditional risk factors. Among patients who experienced MACE, there was no difference in OS or CSS in patients who received TAX vs ATAX. Patients who received ATAX were less likely to develop heart failure than those who received TAX (OR 0.63, 95% CI [0.45-0.88], p < 0.01). Patients who developed MACE and who were > 76 years old had worse OS compared to those who experienced MACE and were age 66-75 years old (HR 1.67, 95% CI [1.07-2.62], p = 0.02). CONCLUSION: Among older women with TNBC, receipt of adjuvant chemotherapy with ATAX was not associated with increased risk of major adverse cardiac events. For those who experienced a cardiac event, there was no difference in survival amongst those who received TAX vs ATAX. Other factors including additional chemotherapy toxicities should be investigated as a potential etiology for the inferior OS previously observed with ATAX vs TAX in older women with node negative or 1-3 positive lymph nodes.

Economic Evaluation of Neoadjuvant Versus Adjuvant Chemotherapy in Cancer Treatment: A Systematic Review and Meta-Analysis.

OBJECTIVES: In the absence of evidence on whether neoadjuvant (NAC) or adjuvant chemotherapy (AC) is more beneficial for various tumor treatments, economic evaluation (EE) can assist medical decision making. There is limited evidence on their cost-effectiveness and their prospective evaluation is less likely in the future. Therefore, a systematic review and meta-analysis about EE for NAC versus AC in solid tumor help compare these therapies from various perspectives. METHODS: Various databases were searched for studies published from inception to 2021. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines and economic-specific guidelines. The data were pooled using a random effects model when possible. RESULTS: The retrieval identified 15 EE studies of NAC versus AC in 8 types of cancer. NAC is the dominant strategy for pancreatic, head and neck, rectal, prostate cancers and colorectal liver metastases. For ovarian cancer, NAC is cost-effective with a lower cost and higher or similar quality-adjusted life-year. There were no significant differences in cost and outcomes for lung cancer. For stage IV or high-risk patients with ovarian or prostate cancer, NAC was cost-effective but not for patients who were not high risk. CONCLUSIONS: The EEs results for NAC versus AC were inconsistent because of their different model structures, assumptions, cost inclusions, and a shortage of studies. There are multiple sources of heterogeneity across EEs evidence synthesis. More high-quality EE studies on NAC versus AC in initial cancer treatment are necessary.

Neo-adjuvant chemotherapy does not reduce surgical complexity nor the accuracy of intra-operative visual assessment of disease in advanced ovarian cancer.

AIM: Compare the surgical complexity and histological accuracy of visual inspection of disease in patients undergoing primary debulking (PDS) versus delayed debulking surgery (DDS) following neo-adjuvant chemotherapy (NACT) for advanced ovarian cancer (AOC). MATERIALS AND METHODS: All patients undergoing PDS or DDS for stage III / IV AOC at a UK cancer centre between January 2014-October 2021 were included. Retrospective data was collected accessing an electronic gynaecological oncology database, operation and histology records. Comparative frequencies of surgical procedures performed were calculated for primary versus delayed cohorts; and correlation between intra-operative suspicion of disease and specimen histology at PDS and DDS compared. RESULTS: N=232. PDS was performed in 45.3% and DDS in 54.7% of patients; achieving complete cytoreduction in 77.2%. Appendicectomy, pelvic and para-aortic nodal dissection were undertaken significantly more often at primary surgery; whilst right diaphragm stripping, pelvic peritonectomy, splenectomy and cholecystectomy were more likely following NACT. We found no variation in bowel resection rates between cohorts. For the majority of specimens, there was no difference in correlation between intra-operative suspicion of disease and final histopathology - with a significantly lower positive predictive value for visual assessment demonstrated only for liver capsule and pelvic peritoneum at DDS. CONCLUSION: NACT does not appear to reduce the complexity of surgery, including rates of bowel resection; nor accuracy of intra-operative visual assessment of disease. We therefore caution against both deferring to NACT to facilitate less radical delayed debulking; and any presumption that macroscopically abnormal tissue at DDS may represent inert post-NACT 'burn-out', mitigating indication for excision. We instead suggest reservation of the neo-adjuvant pathway for patients with poor PS and radiologically-confirmed surgical stopping points; and advocate equivalent and maximal cytoreductive effort to remove all visibly abnormal tissue in both the upfront and delayed surgical settings.

Imaging advances in efficacy assessment of gastric cancer neoadjuvant chemotherapy.

Effective neoadjuvant chemotherapy (NAC) can improve the survival of patients with locally progressive gastric cancer, but chemotherapeutics do not always exhibit good efficacy in all patients. Therefore, accurate preoperative evaluation of the effect of neoadjuvant therapy and the appropriate selection of surgery time to minimize toxicity and complications while prolonging patient survival are key issues that need to be addressed. This paper reviews the role of three imaging methods, morphological, functional, radiomics, and artificial intelligence (AI)-based imaging, in evaluating NAC pathological reactions for gastric cancer. In addition, the advantages and disadvantages of each method and the future application prospects are discussed.

Survival benefits associated with being adherent and having longer persistence to adjuvant hormone therapy across up to five years among U.S. Medicare population with breast cancer.

PURPOSE: To assess associations between adherence to and persistence with adjuvant hormone therapy and mortality among older women with breast cancer. METHODS: The surveillance, epidemiology, and end results data linked with U.S. Medicare claims was used. This study included older women diagnosed with stage I-III hormone receptor-positive breast cancer from 2009 through 2017. Adherence was defined as having proportion of days covered (PDC) ≥ 0.80. Persistence was defined as having no discontinuation, i.e., no break of ≥ 180 continuous days. Length of persistence was calculated as time from therapy initiation to discontinuation. Cox models with time-dependent covariates were used to assess associations between adherence and persistence with mortality. RESULTS: This study included 25,796 women. Adherence rates were 78.1 percent, 75.2 percent, 72.4 percent, 70.0 percent, and 61.5 percent from year 1 to year 5 after hormone therapy initiation. Persistence rates were 87.5 percent, 81.7 percent, 77.1 percent, 72.9 percent, and 68.9 percent through cumulative intervals of 1 year up to 5 years. Adherence was associated with all-cause mortality but not associated with breast cancer-specific mortality. Persistent women had lower risk of all-cause mortality and breast cancer-specific mortality. Each additional year of persistence had additional contributions to survival benefits (11% decreased risk of all-cause mortality and 37% decreased risk of breast cancer-specific mortality). CONCLUSION: This study confirms the detrimental effect of nonadherence to adjuvant hormone therapy across up to 5 years on all-cause survival in older U.S. women. It also reveals the survival benefits associated with having longer persistence across up to 5 years.

Circulating Tumor DNA as a Minimal Residual Disease Assessment and Recurrence Risk in Patients Undergoing Curative-Intent Resection with or without Adjuvant Chemotherapy in Colorectal Cancer: A Systematic Review and Meta-Analysis.

Emerging data have suggested that circulating tumor DNA (ctDNA) can be a reliable biomarker for minimal residual disease (MRD) in CRC patients. Recent studies have shown that the ability to detect MRD using ctDNA assay after curative-intent surgery will change how to assess the recurrence risk and patient selection for adjuvant chemotherapy. We performed a meta-analysis of post-operative ctDNA in stage I-IV (oligometastatic) CRC patients after curative-intent resection. We included 23 studies representing 3568 patients with evaluable ctDNA in CRC patient post-curative-intent surgery. Data were extracted from each study to perform a meta-analysis using RevMan 5.4. software. Subsequent subgroup analysis was performed for stages I-III and oligometastatic stage IV CRC patients. Results showed that the pooled hazard ratio (HR) for recurrence-free survival (RFS) in post-surgical ctDNA-positive versus -negative patients in all stages was 7.27 (95% CI 5.49-9.62), p < 0.00001. Subgroup analysis revealed pooled HRs of 8.14 (95% CI 5.60-11.82) and 4.83 (95% CI 3.64-6.39) for stages I-III and IV CRC, respectively. The pooled HR for RFS in post-adjuvant chemotherapy ctDNA-positive versus -negative patients in all stages was 10.59 (95% CI 5.59-20.06), p < 0.00001. Circulating tumor DNA (ctDNA) analysis has revolutionized non-invasive cancer diagnostics and monitoring, with two primary forms of analysis emerging: tumor-informed techniques and tumor-agnostic or tumor-naive techniques. Tumor-informed methods involve the initial identification of somatic mutations in tumor tissue, followed by the targeted sequencing of plasma DNA using a personalized assay. In contrast, the tumor-agnostic approach performs ctDNA analysis without prior knowledge of the patient's tumor tissue molecular profile. This review highlights the distinctive features and implications of each approach. Tumor-informed techniques enable the precise monitoring of known tumor-specific mutations, leveraging the sensitivity and specificity of ctDNA detection. Conversely, the tumor-agnostic approach allows for a broader genetic and epigenetic analysis, potentially revealing novel alterations and enhancing our understanding of tumor heterogeneity. Both approaches have significant implications for personalized medicine and improved patient outcomes in the field of oncology. The subgroup analysis based on the ctDNA method showed pooled HRs of 8.66 (95% CI 6.38-11.75) and 3.76 (95% CI 2.58-5.48) for tumor-informed and tumor-agnostic, respectively. Our analysis emphasizes that post-operative ctDNA is a strong prognostic marker of RFS. Based on our results, ctDNA can be a significant and independent predictor of RFS. This real-time assessment of treatment benefits using ctDNA can be used as a surrogate endpoint for the development of novel drugs in the adjuvant setting.

Comparing survival outcomes between neoadjuvant and adjuvant chemotherapy within breast cancer subtypes and stages among older women: a SEER-Medicare analysis.

BACKGROUND: This study aimed to compare survival outcomes of neoadjuvant (NAC) and adjuvant chemotherapy (AdC) within each breast cancer subtype and stage among older women. METHODS: Older (≥ 66 years) women newly diagnosed with stage I-III invasive ductal breast cancer during 2010-2017 and treated with both chemotherapy and surgery within one year were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Analyses were performed within each of six groups, jointly defined based on subtype (hormone receptor [HR]-positive/human epidermal growth factor receptor 2 [HER2]-negative, HER2 + , and triple-negative) and stage (I-II and III). Kaplan-Meier curves and multivariable Cox models were used to compare overall and recurrence-free survival between NAC and AdC, with optimal full matching performed for confounding adjustment. RESULTS: Among 8,495 included patients, 8,329 (20.6% received NAC) remained after matching. Before multiple testing adjustment, Cox models showed that NAC was associated with a lower hazard for death among stage III HER2 + patients (hazard ratio = 0.347, 95% confidence interval CI 0.161-0.745) but a higher hazard for death among triple-negative patients (stage I-II: hazard ratio = 1.558, 95% CI 1.024-2.370; stage III: hazard ratio = 2.453; 95% CI 1.254-4.797). A higher hazard for death/recurrence was associated with NAC among stage I-II HR + /HER2- patients (hazard ratio = 1.305, 95% CI 1.007-1.693). No significant difference remained after multiple testing adjustment. CONCLUSIONS: The opposite trends (before multiple testing adjustment) of survival comparisons for advanced HER2 + and triple-negative disease warrant further research. Caution is needed due to study limitations such as cancer stage validity.

Assessment of Attitudes Toward Initiation of Immediate Adjuvant Chemotherapy for Colon Cancer.

INTRODUCTION: Early initiation of chemotherapy after surgery for colon cancer has survival benefits. Immediate adjuvant chemotherapy (IAC) involves giving chemotherapy during surgical resection and immediately postoperatively. This novel approach has been shown to be safe, eliminating delays in adjuvant treatment that could increase the risk of micro-metastatic spread. The aim of this study was to assess the willingness of the general public to accept IAC. MATERIALS AND METHODS: Between March and April 2021, 800 telephone interviews were conducted with a sample of adult New York State residents. The Survey Research Institute of Cornell University conducted all surveys. Kruskal-Wallis, chi-squared, and Fisher's tests were conducted using R 4.0.2. RESULTS: Three scenarios were presented: (1) receiving IAC resulting in improved survival and quality of life, (2) finishing chemotherapy earlier without survival impact, and (3) finishing chemotherapy earlier but with possible side effects. Respondents with higher education were more likely to accept (1) & (2), males were more likely to accept (2) & (3), higher income respondents were more likely to accept (1) & (3), and those with more work hours were more likely to accept (2). Lastly, 16% responded they would be very or extremely likely, and 52% respondents would be somewhat likely or likely to accept intraoperative chemotherapy, even if it may not be necessary. CONCLUSIONS: Respondents were likely to accept IAC if offered. Given the known risk of delayed adjuvant chemotherapy (AC) in colon cancer, further research is warranted to determine the survival and quality of life (QOL) benefits of IAC.

CDX2 Biomarker Testing and Adjuvant Therapy for Stage II Colon Cancer: An Exploratory Cost-Effectiveness Analysis.

OBJECTIVES: Adjuvant chemotherapy is not recommended for patients with average-risk stage II (T3N0) colon cancer. Nevertheless, a subgroup of these patients who are CDX2-negative might benefit from adjuvant chemotherapy. We evaluated the cost-effectiveness of testing for the absence of CDX2 expression followed by adjuvant chemotherapy (fluorouracil combined with oxaliplatin [FOLFOX]) for patients with stage II colon cancer. METHODS: We developed a decision model to simulate a hypothetical cohort of 65-year-old patients with average-risk stage II colon cancer with 7.2% of these patients being CDX2-negative under 2 different interventions: (1) test for the absence of CDX2 expression followed by adjuvant chemotherapy for CDX2-negative patients and (2) no CDX2 testing and no adjuvant chemotherapy for any patient. We derived disease progression parameters, adjuvant chemotherapy effectiveness and utilities from published analyses, and cancer care costs from the Surveillance, Epidemiology, and End Results (SEER)-Medicare data. Sensitivity analyses were conducted. RESULTS: Testing for CDX2 followed by FOLFOX for CDX2-negative patients had an incremental cost-effectiveness ratio of $5500/quality-adjusted life-years (QALYs) compared with no CDX2 testing and no FOLFOX (6.874 vs 6.838 discounted QALYs and $89 991 vs $89 797 discounted US dollar lifetime costs). In sensitivity analyses, considering a cost-effectiveness threshold of $100 000/QALY, testing for CDX2 followed by FOLFOX on CDX2-negative patients remains cost-effective for hazard ratios of <0.975 of the effectiveness of FOLFOX in CDX2-negative patients in reducing the rate of developing a metastatic recurrence. CONCLUSIONS: Testing tumors of patients with stage II colon cancer for CDX2 and administration of adjuvant treatment to the subgroup found CDX2-negative is a cost-effective and high-value management strategy across a broad range of plausible assumptions.

Perioperative chemotherapy versus adjuvant chemotherapy strategies in resectable gastric and gastroesophageal cancer: A Markov decision analysis.

BACKGROUND: Perioperative chemotherapy has been shown to improve overall survival (OS) for operable gastric and gastroesophageal cancer. However, optimal sequence of surgery and chemotherapy has not been clearly identified. Markov models are useful for analyzing the outcomes of different treatment strategies in the absence of adequately powered randomized clinical trials. In this study, we use Markov decision analysis models to compare median OS (mOS), quality-adjusted mOS, life expectancy (LE), and quality-adjusted life expectancy (QALE) of perioperative chemotherapy with adjuvant chemotherapy strategies in resectable gastric and gastroesophageal cancer patients. METHODS: Markov models are constructed to compare two strategies: adjuvant chemotherapy after surgery and preoperative chemotherapy followed by cancer resection and postoperative chemotherapy. LE and QALE are calculated analytically, and mOS are obtained by simulation. Parameters used in the models are computed from prospective clinical trial data published in PUBMED from January 2000 to July 2020. RESULTS: Total of 8088 patients from 25 prospective studies were included in this analysis. Regardless of R0 resection ratio, the analyses of the models show a higher mOS for patients in the perioperative therapy arm compared to adjuvant chemotherapy. For R0 resected patients, the perioperative therapy arm provided an additional 11.0 mOS months (61.3 months vs. 50.3 months). For R1 resected patients, the perioperative therapy arm had mOS of 17.0 months vs. 10.7 months in adjuvant therapy. CONCLUSIONS: The Markov models indicate that perioperative chemotherapy improves mOS, quality-adjusted mOS, LE, and QALE for resectable gastric and gastroesophageal cancer patients compared to adjuvant chemotherapy strategies.

A digital health platform for assisting the diagnosis and monitoring of COVID-19 progression: An adjuvant approach for augmenting the antiviral response and mitigating the immune-mediated target organ damage.

Coronavirus disease 2019 (COVID-19), which is a respiratory illness associated with high mortality, has been classified as a pandemic. The major obstacles for the clinicians to contain the disease are limited information availability, difficulty in disease diagnosis, predicting disease prognosis, and lack of disease monitoring tools. Additionally, the lack of valid therapies has further contributed to the difficulties in containing the pandemic. Recent studies have reported that the dysregulation of the immune system leads to an ineffective antiviral response and promotes pathological immune response, which manifests as ARDS, myocarditis, and hepatitis. In this study, a novel platform has been described for disseminating information to physicians for the diagnosis and monitoring of patients with COVID-19. An adjuvant approach using compounds that can potentiate antiviral immune response and mitigate COVID-19-induced immune-mediated target organ damage has been presented. A prolonged beneficial effect is achieved by implementing algorithm-based individualized variability measures in the treatment regimen.

Cost-effectiveness of ipilimumab versus high-dose interferon as an adjuvant therapy in resected high-risk melanoma.

BACKGROUND: Adjuvant ipilimumab was found to improve the overall survival and reduce toxicity compared to high-dose interferon (HDI) in patients with resected, high-risk melanoma. However, the cost of ipilimumab is substantially higher than HDI. This study evaluates the cost-effectiveness of ipilimumab as an adjuvant treatment in melanoma from a healthcare perspective. METHODS: We designed a Markov model simulating resected, high-risk melanoma patients receiving either ipilimumab or HDI. Transition probabilities, including risks of survival, disease progression, and toxicity, were ascertained from clinical trial data. Costs and quality of life measurements (health utilities) were extracted from the literature. Incremental cost-effectiveness ratios (ICERs), defined as incremental costs divided by incremental quality-adjusted life-years (QALYs), assessed cost-effectiveness. ICERs <$100,000/QALY were deemed cost-effective. We measured model uncertainty with one-way and probabilistic sensitivity analyses. RESULTS: In our base case model, ipilimumab increased costs by $107,100 and increased effectiveness by 0.43 QALY, yielding an ICER of $392,600/QALY. Our model was moderately sensitive to the costs of ipilimumab, though the cost of ipilimumab would need to decrease by 44% for ipilimumab to become cost-effective compared to HDI. The model was not sensitive to survival, toxicity, or other costs. Probabilistic sensitivity analysis showed that HDI would remain the cost-effective treatment option 96.2% of the time at a willingness-to-pay threshold of $100,000/QALY. CONCLUSIONS: Adjuvant ipilimumab increases the survival and decreases the toxicity compared to HDI in resected, high-risk melanoma patients, though this would not be considered cost-effective due to the high price of ipilimumab.

Early Cost-effectiveness Analysis of Risk-Based Selection Strategies for Adjuvant Treatment in Stage II Colon Cancer: The Potential Value of Prognostic Molecular Markers.

BACKGROUND: To explore the potential value of consensus molecular subtypes (CMS) in stage II colon cancer treatment selection, we carried out an early cost-effectiveness assessment of a CMS-based strategy for adjuvant chemotherapy. METHODS: We used a Markov cohort model to evaluate three selection strategies: (i) the Dutch guideline strategy (MSS+pT4), (ii) the mutation-based strategy (MSS plus a BRAF and/or KRAS mutation or MSS plus pT4), and (iii) the CMS-based strategy (CMS4 or pT4). Outcomes were number of colon cancer deaths per 1,000 patients, total discounted costs per patient (pp), and quality-adjusted life-years (QALY) pp. The analyses were conducted from a Dutch societal perspective. The robustness of model predictions was assessed in sensitivity analyses. To evaluate the value of future research, we performed a value of information (VOI) analysis. RESULTS: The Dutch guideline strategy resulted in 8.10 QALYs pp and total costs of €23,660 pp. The CMS-based and mutation-based strategies were more effective and more costly, with 8.12 and 8.13 QALYs pp and €24,643 and €24,542 pp, respectively. Assuming a threshold of €50,000/QALY, the mutation-based strategy was considered as the optimal strategy in an incremental analysis. However, the VOI analysis showed substantial decision uncertainty driven by the molecular markers (expected value of partial perfect information: €18M). CONCLUSIONS: On the basis of current evidence, our analyses suggest that the mutation-based selection strategy would be the best use of resources. However, the extensive decision uncertainty for the molecular markers does not allow selection of an optimal strategy at present. IMPACT: Future research is needed to eliminate decision uncertainty driven by molecular markers.

Cost-Effectiveness of Adjuvant Treatment for Ductal Carcinoma In Situ.

PURPOSE: Ductal carcinoma in situ (DCIS) accounts for 20% of breast cancer cases in the United States and is potentially overtreated, leading to high expenditures and low-value care. We conducted a cost-effectiveness analysis evaluating all adjuvant treatment strategies for DCIS. METHODS: A Markov model was created with six competing treatment strategies: observation, tamoxifen (TAM) alone, aromatase inhibitor (AI) alone, radiation treatment (RT) alone, RT + TAM, and RT + AI. Baseline recurrence rates were modeled using the NSABP B17 and RTOG 9804 trials for standard-risk and good-risk DCIS, respectively. Relative risk reductions and adverse event rates for each treatment strategy were derived from meta-analyses of large randomized trials. We used a willingness-to-pay threshold of $100,000 in US dollars/quality-adjusted life-year and a lifetime horizon for two cohorts of women, age 40 and 60 years. Comprehensive sensitivity analyses evaluated the robustness of base-case results. RESULTS: RT alone was cost-effective for patients with standard-risk DCIS, and observation was cost-effective for patients with good-risk DCIS, across both age groups. Strategies including TAM or AI resulted in fewer quality-adjusted life-years than observation, because of the prolonged decrement in quality of life outweighing the modest benefit in ipsilateral risk reduction. In sensitivity analysis, RT alone was cost-effective for age 40, good-risk patients when ipsilateral risk reduction matched that of the RTOG 9804 trial, there was minimal increased risk of contralateral breast secondary malignancy, or there was strong patient willingness to pursue RT. CONCLUSION: Our findings suggest that cost-effective and clinically optimal treatment strategies are RT alone for standard-risk DCIS and observation for good-risk DCIS, with personalization on the basis of patient age and preference for RT. Hormonal therapy is likely suboptimal for most patients with DCIS.

Effect assessment of methotrexate in combination with other chemotherapeutic agents for osteosarcoma in children: A protocol for systematic review and meta-analysis.

BACKGROUND: Osteosarcoma is a primary form of malignant bone tumor. It is commonly prevalent among children. Treating osteosarcoma with chemotherapy has had limited clinical outcomes due to side effects and the formation of drug resistance. Presently, a mixture of doxorubicin, cisplatin, ifosfamide, epirubicin methrotrexate, and other supplementary medications are used in osteosarcoma chemotherapy. Therefore, this study aims to investigate the clinical therapeutic effects of combining methotrexate with other chemotherapeutic agents to treat osteosarcoma in children. METHODS: The search of several electronic databases will lead to source related published studies. The electronic databases include both English (PubMed, EMBASE, Web of Science, and the Cochrane Library) and Chinese (China National Knowledge Infrastructure, WanFang, and China Biomedical Database) databases. All studies published from inception to November 19, 2020 are searched. Study selection, extraction of data, and evaluation of the bias risk in included studies are carried out by two authors independently. The software, RevMan 5.3, is used to analyze the data. RESULTS: This study provides evidence of substantial quality for the clinical therapeutic effects of methotrexate combined with other chemotherapeutic agents for treating osteosarcoma in children. CONCLUSION: The results of this study provide conclusive evidence with regards to the clinical application of methotrexate combined with other chemotherapeutic agents for treating osteosarcoma in children. ETHICS AND DISSEMINATION: Since this study will use published data, ethical approval is not required. SYSTEMATIC REVIEW REGISTRATION NUMBER: This protocol has been registered on INPLASY202110024.

Quality of life assessment in renal cell carcinoma Phase II and III clinical trials published between 2010 and 2020: a systematic review.

Aims: Quality of life (QoL) assessment is frequently not included among the end points of clinical trials (CTs) on renal cell carcinoma. Herein we aimed to describe the assessment and reporting of QoL in Phase II and Phase III CTs published between 2010 and 2020. Methods: A total of 25 CTs were included; 76% of trials included were conducted in metastatic renal cell carcinoma patients, while 20% of studies evaluated adjuvant systemic treatments. Results: In 13/25 publications, QoL was not listed among the end points, with secondary publications dedicated to QoL present in a minority of cases. Conclusions: QoL was not included among the end points of a large percentage of CTs. Implementing the inclusion of QoL represents an urgent need.

Lay abstract Recent years have seen growing attention toward quality of life (QoL) in medical oncology clinical trials and statistical measurement of this aspect of cancer treatment. Nonetheless, although most clinicians and researchers agree that QoL should represent a fundamental component of clinical trials, the inclusion of QoL results is still inadequate, and our systematic review confirms that implementing the inclusion of QoL remains an urgent need.

Impact and Cost-Effectiveness of Oncotype DX for Guiding Adjuvant Chemotherapy Decisions in Early Breast Cancer.

INTRODUCTION: Oncotype DX is approved in multiple countries but its cost-effectiveness is a matter of considerable health debate. Lebanon is high-middle income country according to the World Bank classification however it is facing a mounting financial and health care burden from cancer. Therefore, we conducted a costeffectiveness analysis of Oncotype DX based Lebanese on real-life data. METHODS: We updated a Canadian cost-effectiveness model of Oncotype DX by incorporating Lebanese data. The patient population was a real-life cohort of 82 women diagnosed with hormone receptor - positive and HER2 - negative early breast cancer. RESULTS: Overall, providing Oncotype DX to only intermediate Adjuvant! Online risk patients costs an additional $83 CAD (93,883 LBP) per additional QALY. From this point, extending provision to also cover high Adjuvant! Online risk patients costs an additional $736 CAD (831,578 LBP) per additional QALY. From this point, extending provision further to also cover low Adjuvant! Online risk patients (such that Oncotype DX is provided to all patients) costs an additional $14,562 CAD (16.46m LBP) per additional QALY. Given that most women in our population-based sample were classified as intermediate Adjuvant! Online risk patients, our study focused on this subset in the second analysis. Providing Oncotype DX to intermediate Adjuvant! Online risk patients has a relatively small additional cost compared to not providing Oncotype DX, and results in a relatively large QALY gain. The incremental cost per QALY is $2,022 CAD (2.29m LBP), implying that Oncotype DX is cost-effective for intermediate Adjuvant! Online risk patients if the willingness-to-pay for a QALY is greater than 2.29m LBP. CONCLUSION: As one of the few economic evaluations to date conducted using Lebanese data, this evaluation provides information to decision makers regarding the cost-effectiveness of providing Oncotype DX to Lebanese patients.

Real-world anticancer medications for reproductive-age women with breast cancer by using a claims database in Japan.

Aim: To describe real-world breast cancer medications among reproductive-age women. Patients & methods: Using data from a Japanese claims database, anticancer prescriptions were classified into seven categories of amenorrhea risk based on fertility preservation guidelines. Results: We identified 2999 women with records of breast cancer and anticancer prescription from 2005 to 2018. The proportions of prescriptions were as follows: high, 4.1-12.9%; intermediate: 6.0-16.3%; low: 0.4-2.3%; very low/no: 0.3-12.2%; unknown: 33.9-45.5%; unlisted combination: 12.2-23.4%; and unlisted drug: 12.5-26.7%. The common drugs in the unknown category were trastuzumab (n = 1527), docetaxel (n = 1014), and paclitaxel (n = 995). For medications unlisted in the guidelines, various drugs and drug combinations were observed. Conclusion: Numerous anticancer drugs are currently being prescribed with insufficient evidence regarding amenorrhea risk.

Lay abstract The ability to have children for breast cancer patients is one of the key issues of cancer survivorship, especially because recent progress in anticancer treatments has enabled patients to achieve longer survival. The fertility preservation guidelines of the American Society of Clinical Oncology (2006) introduce some anticancer treatments that carry potential risks to future fertility. In this study, the anticancer prescriptions of 2999 patients with breast cancer aged between 15 and 49 years were examined. Results showed that several medications are prescribed despite the lack of information on the risk of infertility. This suggests that further research is required to fill the evidence gap, and that decision aid through adequate counseling should be undertaken.

Triple-marker immunohistochemical assessment of muscle-invasive bladder cancer: Is there prognostic significance?

BACKGROUND: Bladder cancer is the ninth most common cancer worldwide, and the third most common cancer in Lebanon. Immunohistochemistry (IHC) has been used to stratify muscle-invasive bladder cancer (MIBC) into different subtypes. However, to our knowledge, there exists no study that investigates the use of this low-cost technique to predict prognosis in bladder cancer patients in our region. AIM: To examine the feasibility of low-cost triple-marker IHC assessment for MIBC subtyping in order to predict patients' survival and cisplatin sensitivity. METHODS AND RESULTS: We collected the specimens of deceased patients diagnosed with MIBC on pathology at our institution. For each case, tumor tissue blocks were retrieved and stained for hematoxylin and eosin in addition to three molecular markers by IHC: cytokeratin 5/6, cytokeratin 14 staining basal BC, and GATA3 staining luminal BC. A cut-off of ≥20% was set as positive. Kaplan-Meier curves were built, factored by BC subtype, to predict overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS). Hazard ratios in Cox regression were also created accounting for oncological factors and BC subtype. We categorized specimens as either luminal (GATA3 positive only) (n = 21; 56.7%) or as double-positive (GATA3 and basal cytokeratin 5/6 or cytokeratin 14 positive) (n = 16; 43.3%). The overall median survival was similar between the two categories (27.0 ± 4.82 months). Numbers favored luminal disease for PFS (Breslow P = .032). After adjusting for covariates, luminal molecular expression predicted PFS (0.28; [0.09-0.94]). Yet, the Cox model was not able to identify any predictors of OS or DSS. CONCLUSION: Specimens enriched with only a luminal molecular profile were more likely to exhibit cisplatin sensitivity. Despite the absence of guidelines recommending the utilization of molecular profiling in clinic practice, triple-marker IHC could serve as a potential low-cost prognostic indicator to identify patients at high risk of progression.

The use of genomic tests in patients with breast cancer in Lombardy: a successful healthcare model.

BACKGROUND: The accurate identification of patients with early breast cancer (eBC) suitable for adjuvant chemotherapy is essential in order to avoid overtreatment or undertreatment. For eBC patients with luminal (HR+/HER2-) intermediate risk disease, multigene assays (MGAs) have been convincingly reported to be useful in guiding treatment decisions. The most recently published data and recommendations from main International Guidelines and Heath Technology Assessment reports confirmed the benefit of MGAs in guiding treatment decisions for clinically intermediate risk patients, and led several countries to test reimbursement. PURPOSE: This article describes the process followed by the Lombardy region in Italy regarding the reimbursement of MGAs for patients with eBC, based on the results of a prospective clinical trial. RESULTS: The study shows that the use of Oncotype DX allowed avoiding the use of unnecessary adjuvant chemotherapy in 50% of patients for whom chemotherapy was initially recommended according to traditional clinical practice. On the basis of these data, a group of oncologists in collaboration with a pathologist regional board formally requested authorization for MGA reimbursement in Lombardy. Acknowledging the strategic importance of the proposal, the Lombardy region approved the reimbursement of MGAs for resident patients with luminal eBC at intermediate clinical risk. It can be assumed that about 1500 patients will be tested in Lombardy per year and this should allow the Regional Health Service to save more than 750 chemotherapies/year. CONCLUSION: The introduction of MGAs in the clinical evaluation of patients with luminal eBC with intermediate risk is economically sustainable and contributes towards preserving quality of life of eligible women.