Revolutionizing Rural Oncology: Innovative Models and Global Perspectives.

For individuals living in rural areas, access to cancer care can be difficult. Barriers to access cross international boundaries and have a negative impact on treatment outcomes. Current models to increase rural access in the United States are reviewed, as is a system-wide approach to this problem in Australia. Ongoing efforts to increase access to clinical trials for patients in rural areas are also discussed.

Improving access to cancer clinical research in Brazil: recent advances and new opportunities. Expert opinions from the 4th CURA meeting, São Paulo, 2023.

Clinical research is the cornerstone of improvements in cancer care. However, it has been conducted predominantly in high-income countries with few clinical trials available in Brazil and other low-and-middle-income countries (LMIC). Of note, less than one-third of registered clinical trials addressing some of the most commonly diagnosed cancers (breast, lung and cervical) recruited patients from LMIC in the last years. The Institute Project CURA promoted the fourth CURA meeting, discussing barriers to cancer clinical research and proposing potential solutions. A meeting was held in São Paulo, Brazil, in June 2023 with representatives from different sectors: Brazilian Health Regulatory Agency (Anvisa), National Commission of Ethics in Research (CONEP), non-governmental organisations, such as the Latin American Cooperative Oncology Group, the Brazilian Society of Clinical Oncology (SBOC), Contract Research Organisations, pharmaceutical companies and investigators. A total of 16 experts pointed out achievements as shortening the time of regulatory processes involving Anvisa and CONEP, development of staff training programs, maintenance of the National Program of Oncological Attention (PRONON), and the foundation of qualified centres in North and Northeast Brazilian regions. Participants also highlighted the need to be more competitive in the field, which requires optimising ongoing policies and implementing new strategies as decentralisation of clinical research centres, public awareness campaigns, community-centered approaches, collaborations and partnerships, expansion of physicians-directed policies, exploring the role of the steering committee. Active and consistent reporting of the initiatives might help to propagate ongoing advances, increasing Brazilian participation in clinical cancer research. Engagement of all players is crucial to maintain continuous progress with further improvements in critical points including regulatory timelines and increments in qualified human resources which aligned with new educational initiatives focused on physicians and the general population will expand access to cancer clinical trials in Brazil.

Challenges and opportunities for sarcoma care and research in Latin America: a position paper from the LACOG sarcoma group.

As a developing region, Latin America faces unique cancer control and prevention challenges, which are intensified when considering rare cancers, including sarcomas. Sarcomas are a group of malignancies that arise in the connective tissues of the body-such as muscle, fat, nerves, blood vessels, and bones-accounting for a diverse range of tumours that, although rare, require specialized attention. Sarcoma care and research in Latin America require a comprehensive approach that includes deeper epidemiologic knowledge, diagnostic capacity building, access to innovative treatments, increased patient advocacy, and strengthening of clinical research capacity. This article will review current challenges and opportunities for treating patients with sarcoma in Latin America and outline a pathway toward improvement for regional collaborative groups.

Factors influencing COVID-19 mortality among cancer patients: A Brazilian multi-institutional study.

PURPOSE: This study aimed to describe the demographic and clinical characteristics of cancer patients with COVID-19, exploring factors associated with adverse outcomes. PATIENTS AND METHODS: This retrospective cohort study methodically extracted and curated data from electronic medical records (EMRs) of numerous healthcare institutions on cancer patients diagnosed with a confirmed SARS-CoV-2 infection between May 2020 and August 2021, to identify risk factors linked to extended hospitalization and mortality. The retrieved information encompassed the patients' demographic and clinical characteristics, including the incidence of prolonged hospitalization, acute complications, and COVID-19-related mortality. RESULTS: A total of 1446 cancer patients with COVID-19 were identified (mean [Standard deviation] age, 59.2 [14.3] years). Most patients were female (913 [63.1%]), non-white (646 [44.7%]), with non-metastatic (818 [56.6%]) solid tumors (1318 [91.1%]), and undergoing chemotherapy (647 [44.7%]). The rate of extended hospitalization due to COVID-19 was 46% (n = 665), which was significantly impacted by age (p = 0.012), sex (p = 0.003), race and ethnicity (p = 0.049), the presence of two or more comorbidities (p = 0.006), hematologic malignancies (p = 0.013), metastatic disease (p = 0.002), and a performance status ≥ 2 (p = 0.001). The COVID-19-related mortality rate was 18.9% (n = 273), and metastatic disease (<0.001), performance status ≥2 (<0.001), extended hospitalization (p = 0.028), renal failure (p = 0.029), respiratory failure (p < 0.001), sepsis (p = 0.004), and shock (p = 0.040) significantly and negatively influenced survival. CONCLUSION: The rate of extended hospitalization and COVID-19-specific death in cancer patients was notably high and could be influenced by comorbidities, cancer treatment status, and clinical fragility. These observations may aid in developing risk counseling strategies regarding COVID-19 in individuals diagnosed with cancer.

Brazilian Expert Consensus for NTRK Gene Fusion Testing in Solid Tumors.

Oncogenic neurotrophic tropomyosin receptor kinase gene fusions occur in less than 1% of common cancers. These mutations have emerged as new biomarkers in cancer genomic profiling with the approval of selective drugs against tropomyosin receptor kinase fusion proteins. Nevertheless, the optimal pathways and diagnostic platforms for this biomarker's screening and genomic profiling have not been defined and remain a subject of debate. A panel of national experts in molecular cancer diagnosis and treatment was convened by videoconference and suggested topics to be addressed in the literature review. The authors proposed a testing algorithm for oncogenic neurotrophic tropomyosin receptor kinase gene fusion screening and diagnosis for the Brazilian health system. This review aims to discuss the latest literature evidence and international consensus on neurotrophic tropomyosin receptor kinase gene fusion diagnosis to devise clinical guidelines for testing this biomarker. We propose an algorithm in which testing for this biomarker should be requested to diagnose advanced metastatic tumors without known driver mutations. In this strategy, Immunohistochemistry should be used as a screening test followed by confirmatory next-generation sequencing in immunohistochemistry-positive cases.

A phase 2 study of first-line nivolumab in patients with locally advanced or metastatic cutaneous squamous-cell carcinoma.

BACKGROUND: Cutaneous squamous-cell carcinoma (CSCC) is among the most frequent malignancies worldwide. For those not amenable to treatment with curative intent, immune checkpoint inhibition (ICI) with anti-programmed death receptor 1 (PD-1) antibodies has emerged as a novel therapeutic option. In this study, the authors sought to investigate the activity of the anti-PD-1 agent nivolumab in patients with advanced CSCC (aCSCC). METHODS: CA209-9JC was an open-label, single-arm, phase 2 study to evaluate the safety and/or efficacy of nivolumab in systemic treatment-naive patients with aCSCC. Nivolumab (3 mg/kg) was administered every 2 weeks until disease progression, unacceptable toxicity, or 12 months of treatment. The primary end point was the best objective response rate (BORR) as per RECIST 1.1 criteria. Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). RESULTS: Twenty-four patients with aCSCC were enrolled with a median age of 74 years (range, 48-93). Among the 24 patients evaluable for response, the BORR was 58.3% (14/24); there were no complete responses. With a median follow-up of 17.6 months, median duration of response has not been reached, and the estimated median PFS and OS were 12.7 and 20.7 months, respectively. Prior exposure to radiotherapy was associated with worse outcomes (p = .035, univariate analysis). Treatment-related adverse events of any grade and grade ≥ 3 occurred in 21 (87.5%) and six (25%) patients, respectively, and one patient discontinued nivolumab due to toxicities. CONCLUSIONS: Nivolumab resulted in robust antitumor activity, sustained responses, and good tolerability in systemic treatment-naive patients with aCSCC. These data provide further evidence to support the use of ICI as the standard treatment of aCSCC.

Exacerbated Renal and Hematologic Toxicities to Ifosfamide and Doxorubicin-Based Chemotherapy in a Patient with Retroperitoneal Liposarcoma Harboring a Germline Mutation in the WRN Gene.

Werner's syndrome is caused by the inactivation of both WRN alleles and is characterized by premature aging and increased risk of neoplasms, especially those of mesenchymal origins, such as sarcomas. Given the characteristic genomic instability, patients with this syndrome are more susceptible to develop toxicities when exposed to cytotoxic agents, such as alkylators and anthracyclines. The impact of the monoallelic WRN mutation on treatment-associated toxicities is poorly understood. Here, we report a patient with locally advanced dedifferentiated liposarcoma of the retroperitoneum harboring a heterozygous germline inactivation mutation in the WRN gene, who was treated with a classic regimen of ifosfamide and doxorubicin and developed exacerbated and prolonged hematological and renal toxicities.

Management of In-Transit Metastases.

PURPOSE OF REVIEW: The purpose of this study is to discuss the current knowledge and future perspectives regarding the treatment options for in-transit metastases (ITM), along with the optimal algorithms for patients presenting with this adverse manifestation of melanoma. RECENT FINDINGS: In addition to procedures historically accepted for the management of ITM, encompassing surgery and regional techniques, novel medications in the form of immune checkpoint inhibitors (ICI) and targeted therapies now represent standard options, allowing for the possibility of combined approaches, with an expanding role of systemic therapies. Melanoma in-transit metastases consist of intralymphatic neoplastic implants distributed between the primary site and the regional nodal basin, within the subepidermal and dermal lymphatics. Distinct risk factors may influence the development of ITM, and the clinical presentation can be highly heterogeneous, enhancing the complexity of the management of ITM. Surgical resection, when feasible, continues to represent a standard approach for patients with curative intent. Patients with extensive or unresectable disease may also benefit from regional approaches that include isolated limb perfusion or infusion, electrochemotherapy, and a wide variety of intralesional therapies. Over the past decade, regimens with ICI and BRAF/MEK inhibitors dramatically expanded the benefit of systemic treatments for patients with melanoma, both in the adjuvant setting and for those with advanced disease, and the combination of these modalities with regional treatments, as well as neoadjuvant approaches, may represent the future for the treatment of patients with ITM.

Identification of the TP53 p.R337H Variant in Tumor Genomic Profiling Should Prompt Consideration of Germline Testing for Li-Fraumeni Syndrome.

PURPOSE: Li-Fraumeni syndrome (LFS) is rare in the worldwide population, but it is highly prevalent in the Brazilian population because of a founder mutation, TP53 p.R337H, accounting for 0.3% of south and southeastern population. Clinical criteria for LFS may not identify all individuals at risk of carrying the Brazilian founder mutation because of its lower penetrance and variable expressivity. This variant is rarely described in databases of somatic mutations. Somatic findings in tumor molecular profiling may give insight to identify individuals who might be carriers of LFS and allow the adoption of risk reduction strategies for cancer. MATERIALS AND METHODS: We determined the frequency of the TP53 p.R337H variant in tumor genomic profiling from 755 consecutive Brazilian patients with pan-cancer. This is a retrospective cohort from January 2013 to March 2020 at a tertiary care center in Brazil. RESULTS: The TP53 p.R337H variant was found in 2% (15 of 755) of the samples. The mutation allele frequency ranged from 30% to 91.7%. A total of seven patients were referred for genetic counseling and germline testing after tumor genomic profiling results were disclosed. All the patients who proceeded with germline testing (6 of 6) confirmed the diagnosis of LFS. Family history was available in 12 cases. Nine patients (9 of 12) did not meet LFS clinical criteria. CONCLUSION: The identification of the TP53 p.R337H variant in tumor genomic profiling should be a predictive finding of LFS in the Brazilian population and should prompt testing for germline status confirmation.

Ganglionar tuberculosis infection evolving to hemophagocytic lymphohistiocytosis after anti-programmed cell death 1 treatment for high-risk melanoma: a case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis is a rare, potentially fatal syndrome of immune hyperactivation. Here we describe a ganglionar tuberculosis evolving to hemophagocytic lymphohistiocytosis following adjuvant immunotherapy in a melanoma patient. CASE PRESENTATION: A 76-year-old Caucasian male with melanoma started with fever, diffuse petechiae, splenomegaly, anemia, thrombocytopenia, hypofibrinogenemia, and hyperferritinemia 2 months following completion of adjuvant treatment with nivolumab. Positron emission tomography scan showed significant hypermetabolism in cervical, supraclavicular, mediastinal, and abdominal lymph nodes. Bone marrow aspiration demonstrated no alterations, except for a hypercellular pattern. Dexamethasone and intravenous immunoglobulin were started owing to suspicion of hemophagocytic lymphohistiocytosis. Core biopsy of the infracarinal lymph node revealed a chronic granulomatous inflammation and caseous necrosis, with positivity for Mycobacterium tuberculosis by polymerase chain reaction, and treatment for ganglionar tuberculosis was started. CONCLUSION: This case highlights the challenges involving programmed cell death 1 blockade in high-risk melanoma, in which infections, lymphoproliferative disorders, and sarcoidosis can mimic disease progression and trigger immune-related adverse events.

Neoadjuvant stereotactic ablative radiotherapy (SABR) for soft tissue sarcomas of the extremities.

BACKGROUND: Soft tissue sarcomas (STS) comprise a diverse group of mesenchymal malignancies that require multidisciplinary care. Although surgery remains the primary form of treatment for those with localized disease, radiation therapy (RT) is often incorporated either in the neo- or adjuvant setting. Given the development of modern RT techniques and alternative dosing schedules, stereotactic ablative radiotherapy (SABR) has emerged as a promising technique. However, the current role of SABR in the treatment of STS of the extremities remains uncertain. METHODS AND MATERIALS: This was a single-center, prospective, single-arm phase II trial. Patients with localized STS who were candidates for limb-preservation surgery were included. Experimental treatment consisted of SABR with 40 Gy in 5 fractions, administered on alternate days, followed by surgery after a minimum interval of 4 weeks. The primary outcome was the rate of wound complication. Secondary outcomes included 2-year local control (LC), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS) rates (and other toxicities). RESULTS: Twenty-five patients were enrolled between October 2015 and November 2019 and completed the treatment protocol. The median rate of histopathologic regression was 65% (range 0-100) and 20.8% of tumors presented pathologic complete response (pCR). Wound complications were observed in 7/25 patients (28%). Three patients underwent disarticulation by vascular occlusion after plastic reconstruction and one patient was amputated by grade 3 limb dysfunction. After a median follow up of 20.7 months, the 2-year estimated risk of local recurrence, distant metastasis and cause-specific death were 0%, 44.7% and 10.6% respectively. CONCLUSIONS: Neoadjuvant SABR appears to improve the pCR for patients with eSTS, with acceptable rate of wound complications. Nevertheless, this benefit should be weighed against the risk of late of vascular toxicity with SABR regimen since, even in a short median follow-up, a higher rate of amputation than expected was observed. A larger sample size with longer follow-up is necessary to conclude the overall safety of this strategy.

Combinatorial Approaches to the Treatment of Advanced Melanoma.

The treatment landscape for patients with advanced melanoma has dramatically improved over the past decade, leading to unprecedented survival. Despite the robust activity of single-agent immune-checkpoint blockade with anti-CTLA-4 or anti-PD-1 agents, and the efficacy of targeted therapies capable of interrupting aberrant signaling resulting from BRAF mutations, the benefit from these therapies is not universal. Advanced understanding of immune and molecular processes underlying melanoma tumorigenesis has demonstrated the promise of combined, multidrug regimens. We discuss the currently available evidence that supports using combinatorial approaches in advanced melanoma treatment and provide insights into promising new combination strategies under investigation.

Merkel cell carcinoma in Latin America: a contribution from an expanded access program for avelumab to address issues from experts' recommendations.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive malignancy, associated with poor outcomes in patients with metastatic disease (mMCC). Management has been dramatically altered as a result of incorporating immune checkpoint blockade agents. MCC data from Latin America (LATAM) come from case-series or individual records. Regional registries are lacking. A need for better registries to improve current knowledge about MCC is highlighted. Our objectives were to describe a real-world experience with avelumab as a second-line (or first-line in unfit patients) treatment in a subset of LATAM participants enrolled in a global Expanded Access Program (EAP) for patients with mMCC, and to evaluate its contribution to the resolution of the concerns described in a recent regional experts review. MATERIALS AND METHODS: We reviewed data of LATAM participants in an avelumab EAP for mMCC treatment (NCT03089658). EAP patient had unresectable or mMCC with progressive disease after one line of chemotherapy, and were ineligible for clinical trials or unfit for chemotherapy. RESULTS: 46 patients (median age: 71.6 years; 60.9% males; median treatment duration: 7.9 months) were included in the LATAM EAP. Physician-assessed objective responses were available for 19 patients. Complete response rate was 15.8% and partial response rate reached 42.1%, summarizing an objective response rate of 57.9%. Stable disease rate was 10.5%, with a disease control response of 68.4%. CONCLUSION: Avelumab showed robust efficacy and a safety profile consistent with global EAP data. Results are aimed to improve current knowledge about mMCC treatment and access to immunooncologic strategies for treating LATAM patients.

Trends in Melanoma Mortality in Brazil: A Registry-Based Study.

PURPOSE: A substantial increase in melanoma incidence has been consistently observed worldwide over the past decades. However, melanoma mortality rates have remained stable or declined over the past years in most regions. Given the paucity of melanoma mortality data for different Brazilian regions, we sought to describe melanoma mortality trends in southeastern Brazil and their relationship with demographic variables. MATERIALS AND METHODS: A cross-sectional registry-based analysis was conducted to describe melanoma mortality trends in the state of São Paulo, Brazil, from 1996 to 2016. Demographic information from melanoma-related death records, including sex and age, was collected from the Fundação Sistema Estadual de Análise de Dados database. The annual percentage change (APC) was calculated to identify mortality trends over the period. RESULTS: An increasing melanoma mortality trend was detected among males, regardless of age (APC, 1.72%; P < .001), and was more pronounced for men ≥ 60 years old (APC, 2.63%; P < .001). Melanoma mortality rates have also increased for patients ≥ 60 years old, regardless of sex (APC, 1.11%; P < .001). A non-statistically significant increase in the overall melanoma mortality rate was observed over the 20-year period analyzed (APC, 0.36%; P = .4). CONCLUSION: Our data suggest a stable melanoma mortality over the past two decades for the overall population studied; however, a significant increase in melanoma mortality rates has been demonstrated among males and in the population ≥ 60 years old, emphasizing the need to implement prevention strategies and expand access to effective therapies for this population.

SARS-CoV-2 testing for asymptomatic adult cancer patients before initiating systemic treatments: a systematic review.

INTRODUCTION: Cancer patients may have a higher risk of severe events and unfavourable outcomes in the setting of COVID-19. This review addresses the question of whether to test asymptomatic cancer patients before initiating systemic cancer treatments. METHODS: This systematic review was conducted based on the PRISMA framework. Pubmed, Embase, Web of Science and Cochrane Central Register of Controlled Trials were systematically searched, as well as guidelines from international institutions involved in cancer care and COVID-19 research. Studies published in English, from 1 December 2019 to 27 May 2020 were considered eligible. We included studies which mentioned testing strategies for SARS-CoV-2 of asymptomatic cancer patients before starting immunosuppressive treatments. RESULTS: We identified 1,163 studies and 4 guidelines through the literature search. A total of 18 articles were considered eligible and were included in the final analysis. Two articles were cohort studies, and the remaining were expert consensuses and published guidelines. The most common recommendation among the studies in this systematic review was to test asymptomatic patients for SARS-CoV-2 prior to treatment. CONCLUSION: There is a lack of studies which directly address COVID-19 testing of asymptomatic patients before treatment. Our systematic review showed that most of the published data favours routine test for SARS-CoV-2 before initiating systemic treatment but failed to identify a good level of evidence to support these recommendations. Based upon this review, we proposed local recommendations at our centre. Each institution should consider the pros and cons of testing asymptomatic patients, evaluating accessibility to testing resources and local epidemiology.

Surgical resection, intraoperative radiotherapy and immediate plastic reconstruction: A good option for the treatment of distal extremity soft tissue sarcomas.

AIM: To show three patients with soft tissue sarcomas of distal extremities conservatively treated after tumor-board discussion, involving margin-free surgery, exclusive intraoperative radiotherapy, and immediate reconstruction. BACKGROUND: Current guidelines show clear and robust recommendations regarding the composition of the treatment of sarcomas of extremities. However, little evidence exists regarding the application of these treatments depending on the location of the primary neoplasia. Tumors that affect the distal extremities present different challenges and make multidisciplinary discussions desirable. METHODS/RESULTS: We reported 3 patients who were approached with a conservative intention, after tumor board recomendation. The goals from the treatment performed were aesthetic and functional preservation, while enruring locoregional control. We had wound healing complications in 2 of the cases, requiring additional reconstruction measures. Patients are followed up for 24, 20 and 10 months; local control is 100%, and functional preservation is 100%. CONCLUSIONS: Despite being a small series, it was sufficient to illustrate successful multidisciplinary planning, generating a therapeutic result with improved quality of life for patients who had an initial indication for extremity amputation.

COVID-19 in a patient with advanced Merkel cell carcinoma receiving immunotherapy.

Background: Little is known about the 2019 novel coronavirus disease (COVID-19) course and outcomes in patients receiving immunotherapy. Here we describe a metastatic Merkel cell carcinoma patient with a severe acute respiratory syndrome coronavirus 2 infection while receiving pembrolizumab. Case presentation: A 66-year-old man, with a metastatic Merkel cell carcinoma receiving pembrolizumab, presented with fever. Chest computed tomography (CT) showed pulmonary ground-glass opacities, suggesting viral or immuno-related etiology. On day 7, the patient was hospitalized due to dyspnea and worsening of the radiological findings. Real time polymerase chain reaction (RT-PCR) testing confirmed COVID-19. The patient developed acute respiratory distress syndrome and acute kidney injury. Hydroxychloroquine was administered for 5 days, but discontinued after supraventricular extrasystoles. Clinical improvement allowed the patient's discharge after 81 days of hospitalization. Conclusion: A careful evaluation of oncologic patients receiving immunotherapy during the COVID-19 pandemic is of utmost importance.