Health Services Access Inequalities in Brazil Result in Poorer Outcomes for Stage III NSCLC-RELANCE/LACOG 0118.

Introduction: Stage III NSCLC is a heterogeneous disease, representing approximately one-third of newly diagnosed lung cancers. Brazil lacks detailed information regarding stage distribution, treatment patterns, survival, and prognostic variables in locally advanced NSCLC. Methods: RELANCE/LACOG 0118 is an observational, retrospective cohort study assessing sociodemographic and clinical data of patients diagnosed with having stage III NSCLC from January 2015 to June 2019, regardless of treatment received. The study was conducted across 13 cancer centers in Brazil. Disease status and survival data were collected up to June 2021. Descriptive statistics, survival analyses, and a multivariable Cox regression model were performed. p values less than 0.05 were considered significant. Results: We recruited 403 patients with stage III NSCLC. Most were male (64.0%), White (31.5%), and smokers or former smokers (86.1%). Most patients had public health insurance (67.5%), had stage IIIA disease (63.2%), and were treated with concurrent chemoradiation (53.1%). The median follow-up time was 33.83 months (95% confidence interval [CI]: 30.43-37.50). Median overall survival (OS) was 27.97 months (95% CI: 21.57-31.73), and median progression-free survival was 11.23 months (95% CI: 10.70-12.77). The type of treatment was independently associated with OS and progression-free survival, whereas the types of health insurance and histology were independent predictors of OS only. Conclusions: Brazilian patients with stage III NSCLC with public health insurance are diagnosed later and have poorer OS. Nevertheless, patients with access to adequate treatment have outcomes similar to those reported in the pivotal trials. Health policy should be improved to make lung cancer diagnosis faster and guarantee prompt access to adequate treatment in Brazil.

Moderately hypofractionated post-operative radiation therapy for breast cancer: preferences amongst radiation oncologists from countries in Latin America and the Caribbean.

Background: The safety and effectiveness of moderately hypofractionated post-operative radiation therapy for breast cancer were demonstrated by several trials. This study aimed to evaluate the current patterns of practice and prescription preference about moderately hypofractionated post-operative radiation therapy to assess possible aspects that affect the decision-making process regarding the use of fractionation in breast cancer patients in Latin America and the Caribbean (LAC). We also aimed to identify factors that can restrain the utilization of moderately hypofractionated post-operative radiation therapy for breast cancer. Materials an methods: Radiation oncologists from LAC were invited to contribute to this study. A 38-question survey was used to evaluate their opinions. Results: A total of 173 radiation oncologists from 13 countries answered the questionnaire. The majority of respondents (84.9%) preferred moderately hypofractionated post-operative radiation therapy as their first choice in cases of whole breast irradiation. Whole breast plus regional nodal irradiation, post-mastectomy (chest wall and regional nodal irradiation) without reconstruction, and post-mastectomy (chest wall and regional node irradiation) with reconstruction hypofractionated post-operative radiation therapy was preferred by 72.2% 71.1%, and 53.7% of respondents, respectively. Breast cancer stage, and flap-based breast reconstruction were the factors associated with absolute contraindications for the use of hypofractionated schedules. Conclusion: Even though moderately hypofractionated post-operative radiation therapy for breast cancer is considered a new standard to the vast majority of the patients, its unrestricted application in clinical practice across LAC still faces reluctance.

Clinical validation and diagnostic accuracy of 99mTc-EDDA/HYNIC-TOC compared to 111In-DTPA-octreotide in patients with neuroendocrine tumours: the LACOG 0214 study.

99mTc-EDDA/HYNIC-TOC is an easily available and cheaper radionuclide that could be used for somatostatin-receptor-based imaging of neuroendocrine tumours (NETs). We aimed to evaluate the diagnostic performance of 99mTc-EDDA/HYNIC-TOC compared to111In-DTPA-octreotide in patients (pts) with NETs. We performed a prospective diagnostic study including pts with biopsy-confirmed NET and at least one visible lesion at conventional imaging. Two independent nuclear medicine physicians evaluated pts who underwent 99mTc and 111In scans and images. The primary outcome was comparative diagnostic accuracy of 99mTc and 111In. Secondary outcomes include safety. Nine pts were included and performed 14 paired scans. Overall, 126 lesions were identified. 99mTc demonstrated superior sensitivity both when all images were analysed (93.7, 95% CI 88.1% - 96.8% versus 74.8%, 95% CI 66.6 - 81.6%, p < 0.001) and when liver-specific images were analysed (97.8%, 95% CI 92.7% - 99.5% versus 85.1%, 95% CI 76.6% - 91.0%, p < 0.001). 99mTc was also associated with a lower negative likelihood ratio (LR) (0.002, 95% CI 0.009 - 0.1 versus 0.19, 95% CI 0.12 - 0.42, p = 0.009) when evaluating hepatic lesions. Adverse events happened in 3 pts after 111In and in 2 pts after 99mTc, all grade 1. The 99mTc demonstrated a higher sensitivity overall and a better negative LR in liver-specific images compared to 111In in pts with NETs. Our findings suggest that 99mTc is an alternative to 111In and is especially useful in ruling out liver metastases. NCT02691078.

Results of a survey study on health professionals' perceptions of tumor boards in Brazil.

Background: Tumor boards (TB) are synonymous with quality of care but have been occasionally misunderstood and underutilized. This survey aimed to evaluate health professionals' perceptions of TBs in Brazil. Materials & methods: The survey was sent electronically. Results: Of 206 respondents, 67.8% attended TBs at least once and 82.4% dedicated at least 1 h weekly to them; 64.2% preferred a more &educational' model over case discussions only; 63.1% had institutional leadership capable of promoting multidisciplinarity; 21.1 and 32.7% of the physicians and nonphysicians, respectively, felt intimidated to express their opinions; 91.6% believed that TBs improve cancer outcomes. Postpandemic, 52.7% preferred a hybrid (virtual/face-to-face) model. Conclusion: This study provides a glimpse of the reality of TBs in Brazil, with potential implications for clinical practice.

Current Scenario of Clinical Cancer Research in Latin America and the Caribbean.

In Latin America and the Caribbean (LAC), progress has been made in some national and regional cancer control initiatives, which have proved useful in reducing diagnostic and treatment initiation delays. However, there are still significant gaps, including a lack of oncology clinical trials. In this article, we will introduce the current status of the region's clinical research in cancer, with a special focus on academic cancer research groups and investigator-initiated research (IIR) initiatives. Investigators in LAC have strived to improve cancer research despite drawbacks and difficulties in funding, regulatory timelines, and a skilled workforce. Progress has been observed in the representation of this region in clinical trial development and conduct, as well as in scientific productivity. However, most oncology trials in the region have been sponsored by pharmaceutical companies, highlighting the need for increased funding from governments and private foundations. Improvements in obtaining and/or strengthening the LAC cancer research group's financing will provide opportunities to address cancer therapies and management shortcomings specific to the region. Furthermore, by including this large, ethnic, and genetically diverse population in the world's research agenda, one may bridge the gap in knowledge regarding the applicability of results of clinical trials now mainly conducted in populations from the Northern Hemisphere.

Current scenario and future perspectives of clinical research in Brazil: a national survey.

Background: Epidemiological and clinical cancer research is essential to understanding tumour behaviour and developing new therapies in oncology. However, several countries including Brazil as well as many other regions of the world have limited participation in cancer research. Despite 625,000 new cancer cases recorded in Brazil in 2022, only 2.2% of ongoing cancer clinical trials are available in the country. We conducted an online survey to describe physician engagement with research and to identify the main barriers precluding participation in and conduct of clinical cancer research in the country. Methods: An anonymous online survey of 23 objective questions was sent by e-mail to Brazilian members of the Latin American Cooperative Oncology Group and the Brazilian Society of Clinical Oncology. The first 13 questions addressed demographic information, medical training and previous research participation. In the second part, the main barriers to engagement and participation in clinical trials in Brazil were addressed. Continuous variables were measured by median and range. Analyses were performed using SAS statistical software (version 9.4; SAS Institute, Inc. Cary, NC). Results: 109 physicians answered the survey. Most participants were oncologists (N = 98, 89.9%), living in capital cities (N = 84, 77.1%), were from the Southeast region of Brazil (N = 63, 57.8%) and worked at institutions providing exclusively private healthcare (N = 59, 54.1%). Of the 109 respondents, 83 (76.1%) reported working in research centres (as investigators or sub-investigators). Surprisingly, 31.2% of physicians recognised they invite less than 1% of their patients to participate in clinical trials, even though 98 (89.9%) considered the participation of patients in clinical trials extremely relevant. The main barriers compromising the conduct of research in the country were the low number of available trials (48.2%) and the lack of qualified human resources to staff research sites (22.9%). Other reported barriers were the lengthy regulatory approval process (42.2%), followed by a lack of awareness of clinical research by patients resulting in low recruitment rates (24.1%). Of the 26 (23.8%) respondents not working with research, 25 (96.1%) reported interest in being involved, 31.8% have tried participating in research and 62.4% reported limited knowledge of trial procedures. Conclusion: These results suggest a clear need to further engage physicians in clinical research activities in Brazil. Patient education strategies should improve the low recruitment rates and secondarily increase the number of proposed trials in the country.

Real-world data on triple-negative breast cancer in Latin America and the Caribbean.

Breast cancer (BC) is the most prevalent cancer in women in Latin America and the Caribbean. We compiled real-world data (RWD) on the epidemiology, diagnosis, treatment, and patient outcomes of triple-negative breast cancer (TNBC), addressing the main barriers to optimal care in Latin America. The prevalence of TNBC varies between 11% and 38.5% of all BC cases diagnosed in the region, and TNBC primarily affects young patients. Delays in BC diagnosis, with consequent advanced disease stages and barriers to access efficient therapies, particularly due to high costs, negatively impact patient outcomes. Cancer clinical trials are an opportunity to access standard and novel therapies for patients with this aggressive BC subtype and thus must be prioritised. Finally, generating RWD and cost-effectiveness studies in a region with limited resources is critical for decision-makers to define the incorporation of new technologies for the treatment of BC.

Socioeconomic Impact of Cancer in Latin America and The Caribbean.

The incidence of cancer in Latin America and the Caribbean (LAC) is increasing yearly and is expected to reach 2.4 million new cases by 2040, with a more pronounced effect in Central America and South America. In addition, cancer is already the most frequent cause of premature death for most countries in LAC, and the second cause of death independent of country socioeconomic status, clearly demonstrating that the cancer burden in LAC should be addressed now rather than considered as an issue to be dealt with in the future. LAC countries performed in a mid-range zone in terms of income and mortality-to-incidence ratio compared to other countries globally. The LAC continent has, in general, a median income per capita and a median availability of radiotherapy (RDT) machines per capita. Patients that have private health coverage are more likely to receive preventive care such as pap smears and mammography in many countries of the LAC. The human development index was negatively related to mortality from oral cancer in the LAC countries with medium and low Human Development Index (HDI). Cancer treatment adverse events can negatively affect survivors' workability compromising their return to work after diagnosis. In conclusion, the cancer burden can be a major public health issue with a considerable socioeconomic impact in LAC countries. It is demonstrated in several studies that unequal access to optimal care is frequent in LAC and that health insurance type may impact patients' diagnosis and outcome.

Combination immunotherapy for pancreatic cancer: challenges and future considerations.

INTRODUCTION: Immune checkpoint inhibitors (ICI) have not yielded significant efficacy in pancreatic ductal adenocarcinoma (PDA), despite the role of the innate and adaptive immune systems on progression and survival. However, recently identified pathways have identified new targets and generated promising clinical investigations into promoting an effective immune-mediated antitumor response in PDA. AREAS COVERED: We review biological mechanisms associated with immunotherapy resistance and outline strategies for therapeutic combinations with established and novel therapies in PDA. EXPERT OPINION: Pancreatic cancers rarely benefit from treatment with ICI due to an immunosuppressive tumor microenvironment (TME). New understandings of factors associated with the suppressive TME include low- and poor-quality neoantigens, constrained effector T cells infiltration, and the presence of a dense, suppressive myeloid cell population. These findings have been translated into new clinical investigations evaluating novel therapies in combination with ICI and/or standard systemic chemotherapy and radiotherapy. The epithelial, immune, and stromal compartments are intricately related in PDA, and the framework for successful targeting of this disease requires a comprehensive and personalized approach.

Outcomes and Prognostic Factors of Patients with Metastatic Colorectal Cancer Who Underwent Pulmonary Metastasectomy with Curative Intent: A Brazilian Experience.

BACKGROUND: We aimed to identify clinicopathological and molecular features associated with progression-free survival (PFS) and overall survival (OS) after pulmonary metastasectomy for metastatic colorectal cancer in a retrospective cohort in Brazil. MATERIALS AND METHODS: We did a retrospective review of thoracic surgeries performed in a single large academic hospital in Brazil from January 1985 to September 2019. Demographics, previously described prognostic factors, and clinicopathological and molecular characteristics were abstracted. Univariate Cox regression was performed for each variable, and, when significant, data were dichotomized to provide clinically meaningful thresholds. RESULTS: Records from 698 patients were reviewed. Fifty-eight patients underwent pulmonary metastasectomy with curative intent. Of those, 53.4% had a single metastatic lesion. The median size of the largest lesion was 1.5 cm. Results of RAS, RAF, and mismatch repair testing and of cytokeratin 20 (CK20) and CDX2 testing were available for 13.8% and 58.6% of the sample, respectively. Median PFS was 14 months, median OS was 58 months, and 5-year survival was 49.8%. Unfavorable prognostic factors for OS included disease-free interval (DFI) <24 months, synchronous presentation, size of the largest lesion ≥2 cm, and loss of CK20 expression. Presenting with more than one lesion was prognostic for PFS but not for OS. CONCLUSION: In this Brazilian cohort, our findings corroborate existing data supporting DFI, synchronous presentation, and number and size of lesions as prognostic factors. Furthermore, we found that loss of CK20 expression may be associated with more aggressive disease and shorter OS. Additional molecular prognostic factors after pulmonary metastasectomy for colorectal cancer should be further explored. IMPLICATIONS FOR PRACTICE: This study consolidates disease-free interval, synchronous presentation, and number and size of lesions as clinically relevant data that may help guide therapy for patients with colorectal cancer and lung metastases who are candidates for curative-intent metastasectomy. Additionally, in this sample, lack of cytokeratin 20 expression in metastases was associated with shorter progression-free survival and overall survival, suggesting that biomarkers also may have a role in guiding therapy in this setting and that additional biomarkers should be further explored.

Evaluation of dried blood spots as an alternative matrix for therapeutic drug monitoring of abiraterone and delta(4)-abiraterone in prostate cancer patients.

Therapeutic drug monitoring (TDM) approaches may benefit patients treated with abiraterone acetate (AA) as drug efficacy is imprecise and important pharmacokinetic variability is known. Current methods based on the analysis of plasma present the disadvantage of the fast degradation of the analytes in the liquid sample. Dried blood spots (DBS) consist of a minimally invasive and unexplored sampling strategy to monitor the levels of abiraterone (ABI) and delta(4)-abiraterone (D4A) in patients. This study presents the development and validation of a precise and accurate method to monitor ABI and D4A in DBS samples by UPLC-MS/MS. Bioanalytical method validation was carried out according to current guidelines, evaluating the impact of DBS-specific parameters such as hematocrit and spot volume on accuracy. Based on the analysis of quality control samples prepared at low, medium and high concentrations, the method was precise with CV ≤ 6.97 % and 10.26 % for ABI and D4A, respectively. The method was also highly accurate, between 93.6-106.8 % for ABI and 96.0-108.5 % for D4A. The DBS method is compatible with the analysis of samples of unknown volume and hematocrit range of the studied population. In addition, ABI and D4A were stable for 7 days in DBS at room temperature, which is feasible for sample transportation in postal service and analysis in the laboratory. Method application to 16 clinical samples revealed good correlation between measured plasma concentrations and estimated plasma concentrations for ABI (r = 0.884, P < 0.05) and D4A (r = 0.920, P < 0.05). Passing-Bablok regression analysis and Bland-Altmann plots indicated correlation between the results obtained from DBS and plasma, with a slight overestimation of the concentrations of ABI in DBS, which could be related to the small study cohort. Therefore, the results of this first work indicate that DBS consist of a promising alternative sampling strategy in TDM studies of AA.

A quick UPLC-MS/MS method for therapeutic drug monitoring of abiraterone and delta(4)-abiraterone in human plasma.

Abiraterone acetate efficacy against prostate cancer is dependent on the circulating levels of abiraterone and its active metabolites, which present significant pharmacokinetic variability among patients. Thus, therapeutic drug monitoring can be performed to improve treatment outcomes. To support such studies, there are only a limited number of bioanalytical methods in current literature. This work presents a fast method to quantify abiraterone and D4A in plasma in 4 min by UPLC-MS/MS. Bioanalytical method validation was performed according to the recommendations of the US Food and Drug Administration. The method was linear within the range of 1-400 ng/ml for abiraterone and 0.2-20 ng/ml for D4A (r2 > 0.99). Based on the analysis of quality control samples at the lower limit of quantification, low, medium and high concentrations, the method was precise (CVabiraterone ≤ 9.72%; CVD4A ≤ 14.64%) and accurate (CVabiraterone 95.51-107.59%; CVD4A 98.04-99.89%). Application of the method to the quantification of abiraterone and D4A in 10 clinical samples revealed important variability in the conversion ratio of abiraterone to D4A (CV 90.85%). Considering the current literature, this is the fastest method to quantify abiraterone and D4A in plasma, allowing for optimization of the analytical routine.

CYP3A4*22 is related to increased plasma levels of 4-hydroxytamoxifen and partially compensates for reduced CYP2D6 activation of tamoxifen.

AIM: To evaluate the impact of CYP3A4*22 in the formation of endoxifen (EDF) and hydroxytamoxifen (HTF), under different CYP2D6 genotypic backgrounds. MATERIALS & METHODS: 178 patients were enrolled in the study. CYP2D6 and CYP3A4 genotyping and tamoxifen (TAM) and metabolites quantification were performed. RESULTS: EDF concentrations were lower in poor (2.77 ng ml(-1)) and CYP2D6 intermediate metabolizers (5.84 ng ml(-1)), comparing to functional group (EM-F) (10.67 ng ml(-1), p < 0.001). HTF and TAM levels were respectively 47 and 53% higher in CYP3A4*22 carriers compared with *1/*1 patients in the whole group. Patients with impaired CYP2D6 metabolism and carriers of CYP3A4*22 had EDF levels comparable to CYP2D6 EM-F group (9.06 and 10.67 ng ml(-1), p = 0.247). CONCLUSION: The presence of CYP3A4*22 might compensate the reduction of EDF concentrations related to CYP2D6 inactivity, especially due to increased HTF concentrations.

Influence of CYP2D6 and CYP3A4 Phenotypes, Drug Interactions, and Vitamin D Status on Tamoxifen Biotransformation.

OBJECTIVE: In view of the large variability on therapeutic response and the multiple factors associated to tamoxifen (TAM) metabolic activation, this study aimed to evaluate the effect of CYP2D6 and CYP3A4 phenotypes, drug interactions, and vitamin D exposure on TAM metabolism in a group of breast cancer patients. METHODS: Trough blood samples were collected from 116 patients. TAM and metabolites endoxifen (EDF), N-desmethyltamoxifen, and 4-hydroxytamoxifen (HTF) were measured in plasma by liquid chromatography-tandem mass spectrometry. CYP2D6 and CYP3A4 phenotyping were obtained according to [dextromethorphan]/[dextrorphan] and [omeprazole]/[omeprazole sulfone] metabolic ratios, measured by high-performance liquid chromatography in plasma collected 3 hours after oral administration of 33 mg of dextromethorphan and 20 mg of omeprazole. Vitamin D3 was measured in plasma by high-performance liquid chromatography-ultraviolet. Data on concomitant use of drug considered as CYP2D6 and CYP3A4 inhibitor or inducer and vitamin D supplementation were recorded. RESULTS: About 20% of patients had reduced CYP2D6 metabolic activity and 7% CYP3A4 impaired metabolism. EDF levels diminished proportionally to the reduction of CYP2D6 metabolic activity (poor metabolizer 2.79 ng·mL, intermediate metabolizer (IM) 5.36 ng·mL, and extensive metabolizer 10.65 ng·mL, P < 0.01). Median plasma levels of TAM (161.50 ng·mL) and HTF (1.32 ng·mL) in CYP2D6 IM/CYP3A4 poor metabolizer patients were higher (P < 0.05) than those from CYP2D6 IM/CYP3A4 extensive metabolizer patients (122.07 ng·mL and 0.61 ng·mL, respectively). Seasons contributed to the interpatient variability of EDF and HTF levels; summer concentrations were 24% and 42% higher compared with winter. Vitamin D3 was not associated to CYP3A4 metabolic activity, indicating that other mechanisms might be involved in the relation between TAM metabolism and vitamin D exposure. CONCLUSIONS: CYP3A4 contributes to the bioactivation of TAM through formation of HTF and becomes increasingly important in case of reduced or absent CYP2D6 activity. EDF and HTF exposure were associated to seasonal variations, with considerable higher plasma concentrations during summer.

Ultra-high performance liquid chromatography tandem mass spectrometric method for the determination of tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen in dried blood spots--development, validation and clinical application during breast cancer adjuvant therapy.

A LC-MSMS method for the simultaneous determination of tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen in dried blood spots samples was developed and validated. The method employs an ultrasound-assisted liquid extraction and a reversed phase separation in an Acquity(®) C18 column (150×2.1 mm, 1.7 µm). Mobile phase was a mixture of formic acid 0.1% (v/v) pH 2.7 and acetonitrile (gradient from 60:40 to 50:50, v/v). Total analytical run time was 8 min. Precision assays showed CV % lower than 10.75% and accuracy in the range 94.5 to 110.3%. Mean analytes recoveries from DBS ranged from 40% to 92%. The method was successfully applied to 91 paired clinical DBS and plasma samples. Dried blood spots concentrations were highly correlated to plasma, with rs>0.83 (P<0.01). Median estimated plasma concentrations after hematocrit and partition factor adjustment were: TAM 123.3 ng mL(-1); NDT 267.9 ng mL(-1), EDF 10.0 ng mL(-1) and HTF 1.3 ng mL(-1,) representing in average 98 to 104% of the actually measured concentrations. The DBS method was able to identify 96% of patients with plasma EDF concentrations below the clinical threshold related to better prognosis (5.9 ng mL(-1)). The procedure has adequate analytical performance and can be an efficient tool to optimize adjuvant breast cancer treatment, especially in resource limited settings.

Development, validation and clinical application of a HPLC-FL method for CYP2D6 phenotyping in South Brazilian breast cancer patients.

OBJECTIVE: To develop and validate a method for determination of dextromethorphan (DMT) and dextrorphan (DTP) in plasma samples using HPLC-FL and to apply it to CYP2D6 phenotyping of a population from the South of Brazil. METHODS: Samples were prepared by hydrolysis and liquid-liquid extraction. Analysis was conducted in a reversed phase column, with isocratic elution and fluorescence detection. One hundred and forty patients being treated with tamoxifen were given 30 mg of dextromethorphan and their CYP2D6 phenotypes were determined on the basis of [DMT]/[DTP] metabolic ratios in plasma samples collected after 3h. RESULTS: Total chromatography running time was 12 min. Precision (CV%) was below 9.7% and accuracy was between 92.1 and 106.9%. The lower limits of quantification were 1 ng mL(-1) for DMT and 10 ng mL(-1) for DTP. Mean extraction yield of analytes was 86.6%. Mean age of patients was 55.7 years. Phenotype frequencies were as follows: 7.1% poor metabolizers, 13.6% intermediate metabolizers, 77.1% extensive metabolizers and 2.1 ultra-rapid metabolizers. Metabolic ratios for patients on strong (n=11) and weak (n=16) CYP2D6 activity inhibitors were different from each other and also different from ratios for patients not taking enzyme inhibitors (n=113). CONCLUSIONS: A sensitive method for determination of dextromethorphan and its metabolite in plasma samples was developed and successfully applied, providing evidence of the impact that CYP2D6 inhibitors have on the enzyme's metabolic capacity.