Concurrent Chemoradiation With or Without Durvalumab in Elderly Patients With Unresectable Stage III NSCLC: Safety and Efficacy.

INTRODUCTION: The addition of durvalumab after chemoradiation therapy (CRT) in unresectable stage III NSCLC significantly improves survival. The benefit of this approach in elderly patients is controversial given the toxicity associated with CRT and, thus, may be underutilized. We sought to investigate the outcomes of elderly patients treated with CRT without or without durvalumab at our center. METHODS: We reviewed all stage III patients with NSCLC treated with CRT between 2018 and 2020. Patients were analyzed on the basis of age: less than 70 years and 70 years and older. The end points evaluated were treatment patterns, toxicity, progression-free survival, and overall survival. RESULTS: The baseline characteristics including Eastern Cooperative Oncology Group performance status and comorbidities were similar among the 115 patients (44 elderly, 71 young). Completion rates of CRT (100%, 97%) and chemotherapy dose intensity (97%, 97%) were high in elderly and young patients, respectively. There was a trend toward increased hospitalizations in elderly patients because of infections (27% versus 13%, p = 0.08). Of those who did not have primary progression after CRT, 78% of eldery and 81% of young patients received durvalumab. The incidence of grade 3 or higher immune-related adverse events was 9% in elderly and 6% in young patients (p = 0.67). The median progression-free survival was similar (15.6 versus 10.5 mo, p = 0.10), even after adjusting for comorbidities (hazard ratio = 0.6, p = 0.09). The 12-month overall survival rates were 78% in the elderly and 76% in young patients (p = 0.98). CONCLUSIONS: Well-selected elderly patients can be treated safely with CRT followed by durvalumab with similar survival benefits compared with their younger counterparts. We would advocate for the referral of all elderly patients for oncologic assessment to avoid undertreatment.

Durability of CNS disease control in NSCLC patients with brain metastases treated with immune checkpoint inhibitors plus cranial radiotherapy.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have excellent systemic activity and are standard first line treatment in EGFR/ALK wild type metastatic non-small cell lung cancer (NSCLC). However, their role in patients with brain metastases, which affects over 20% of patients and cause significant morbidity, is less clear. METHODS: We reviewed patients with EGFR/ALK wild-type mNSCLC with CNS metastases. Serial MRIs were reviewed to determine the time to intracranial progression (iPFS). Multivariate regression was performed to adjust for the disease-specific graded prognostic score (ds-GPA). RESULTS: We identified 36 ICI- and 33 chemotherapy-treated patients with baseline CNS metastases and available serial MRIs (average frequency:3.5 months). Baseline radiation was given except for 2 chemotherapy-treated patients with asymptomatic solitary metastasis. The CNS burden of disease was higher in the ICI-treated group (ICI:22% vs. chemotherapy:0% had >10 lesions; p = 0.02), but the utilization of WBRT was not (ICI:31% vs. chemotherapy:45%; p = 0.09). At the time of progression, CNS involvement was identified in 30 % of ICI-treated patients compared to 64 % of chemotherapy controls (p = 0.02). ICI-treated patients had superior iPFS (13.5 vs 8.4 months) that remained significant in multivariate analysis (HR 1.9; 95%CI 1.1--3.4). Superior CNS outcomes in ICI-treated patients were driven by the PD-L1 high subgroup where the 12-month cumulative incidence rate of CNS progression was 19% in ICI-treated PD-L1 ≥ 50%, 50% in ICI-treated PD-L1 < 50% and 58% in chemotherapy-treated patients (p = 0.03). CONCLUSIONS: Remarkable CNS disease control is seen with baseline RT plus ICIs in patients with PD-L1 ≥ 50%. Strategies for delaying WBRT should be investigated in this subgroup of patients.

Subtypes of EGFR- and HER2-Mutant Metastatic NSCLC Influence Response to Immune Checkpoint Inhibitors.

INTRODUCTION: The efficacy of immune checkpoint inhibitors (ICIs) is low among EGFR-mutated non-small-cell lung cancer (NSCLC), although prolonged responses have occasionally been reported. We investigated the association between mutation subtypes and ICI outcomes among HER2- and EGFR-mutated NSCLC. PATIENTS AND METHODS: This retrospective single-center study analyzed patients with EGFR- and HER2-mutated advanced NSCLC who received at least 1 cycle of ICI between 2013 and 2019. Patient characteristics, mutation subtype, and ICI outcomes. RESULTS: Among 48 patients with advanced NSCLC, 14 (29%) had HER2 mutations and 34 (71%) had EGFR mutations. EGFR mutations included 16 (47%) exon 19 deletion, 7 (21%) L858R, 5 (15%) uncommon, and 6 (18%) exon 20 insertion. Compared to EGFR-sensitizing mutations (ESMs), HER2 and EGFR exon 20 mutations were associated with a trend toward better response (respectively, ESM, HER2, and EGFR exon 20: 11%, 29%, and 50%; P = .07) and significantly better disease control rates (respectively, 18%, 57%, and 67%; P = .008). Compared to ESM, HER2 mutations (adjusted hazard ratio, 0.35; P = .02) and EGFR exon 20 mutations (adjusted hazard ratio, 0.37; P = .10 trend) were also associated with improved PFS. Programmed death ligand 1 (PD-L1) expression remained an independent predictor of PFS (adjusted hazard ratio, 0.42; 95% confidence interval, 0.23-0.76; P = .004). The 6-month PFS rates were 29% (HER2), 33% (EGFR exon 20), and 4% (ESM). ICIs were generally well tolerated in this population. Importantly, no immune-related toxicity was observed in 10 patients who received a tyrosine kinase inhibitor (TKI) as the immediate next line treatment after ICI. CONCLUSION: HER2 and EGFR exon 20 mutations derive greater benefit from ICIs with comparable PFS to wild-type historical second/third-line unselected cohorts. ICIs remain a treatment option for this genomic subgroup, given the absence of approved targeted therapies for these rare mutations.

Value assessment of oncology drugs using a weighted criterion-based approach.

BACKGROUND: Globally, the rising cost of anticancer therapy has motivated efforts to quantify the overall value of new cancer treatments. Multicriteria decision analysis offers a novel approach to incorporate multiple criteria and perspectives into value assessment. METHODS: The authors recruited a diverse, multistakeholder group who identified and weighted key criteria to establish the drug assessment framework (DAF). Construct validity assessed the degree to which DAF scores were associated with past pan-Canadian Oncology Drug Review (pCODR) funding recommendations and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS; version 1.1) scores. RESULTS: The final DAF included 10 criteria: overall survival, progression-free survival, response rate, quality of life, toxicity, unmet need, equity, feasibility, disease severity, and caregiver well-being. The first 5 clinical benefit criteria represent approximately 64% of the total weight. DAF scores ranged from 0 to 300, reflecting both the expected impact of the drug and the quality of supporting evidence. When the DAF was applied to the last 60 drugs (with reviewers blinded) reviewed by pCODR (2015-2018), those drugs with positive pCODR funding recommendations were found to have higher DAF scores compared with drugs not recommended (103 vs 63; Student t test P = .0007). DAF clinical benefit criteria mildly correlated with ESMO-MCBS scores (correlation coefficient, 0.33; 95% CI, 0.009-0.59). Sensitivity analyses that varied the criteria scores did not change the results. CONCLUSIONS: Using a structured and explicit approach, a criterion-based valuation framework was designed to provide a transparent and consistent method with which to value and prioritize cancer drugs to facilitate the delivery of affordable cancer care.

Loss of BAP1 expression in metastatic tumor tissue is an event of poor prognosis in patients with metastatic clear cell renal cell carcinoma.

PURPOSE: To evaluate the prognostic impact of the protein expression of both PBRM1 and BAP1 in metastatic tissue of patients with metastatic clear cell renal cell carcinoma (ccRCC). PATIENTS AND METHODS: In all 124 consecutive cases of metastatic ccRCC, who underwent metastasectomy or biopsy of metastatic tumor tissue between 2007 and 2016 were selected from the medical records of our institution. Additionally, 38 paired cases with tissue from the primary tumor involving radical or partial nephrectomy for ccRCC were also selected. All cases were reviewed for uniform reclassification and the most representative tumor areas were selected for the construction of a tissue microarray. RESULTS: PBRM1 nuclear staining of the 124-immunostained metastases of ccRCC specimens showed that 98 (79.0%) had negative expression and 26 (21.0%) positive expression of PBRM1. Regarding BAP1 expression, we observed that 77 (62.1%) specimens were negative and 47 (37.9%) showed positive nuclear staining. When we compared the expression of both markers on primary tumor and tumor metastasis, we found disagreement in half of the cases. Five-year overall survival rates in patients with positive expression and negative expression of BAP1 were 53.2% and 35.1%, respectively (P = 0.004). Five-year progression-free survival rates in patients with positive expression and negative expression of BAP1 were 14.9% and 3.9%, respectively (P = 0.003). Conversely, PBRM1 expression did not significantly influence either overall survival or progression-free survival rates. In multivariate analysis, negative expression of BAP1 tumors also presented higher risks of death (hazard ratio (HR) = 1.913, P = 0.041) and disease progression (HR = 1.656, P = 0.021). CONCLUSION: The use of prognostic biomarkers identified in the primary tumor tissue might be not reliable in the metastatic disease scenario. Patients with metastatic ccRCC that present loss of BAP1 expression in metastatic tissue demonstrated poor survival rates and represent a relevant risk group for tumor recurrence and death.

Prognostic impact of concomitant loss of PBRM1 and BAP1 protein expression in early stages of clear cell renal cell carcinoma.

PURPOSE: To evaluate the prognostic impact of immunohistochemical expression of BAP1 and PBRM1 in patients with early stage (pT1-pT2N0M0) clear cell renal cell carcinoma (ccRCC). PATIENTS AND METHODS: A total of 441 consecutive patients treated surgically for stages I and II (TNM-AJCC 2010) ccRCC between 1990 and 2016 were selected. All cases were reviewed for uniform reclassification and the most representative tumor areas were selected for the construction of a tissue microarray. Sixty-two patients had frozen tumoral tissue available in the tumor bank of our institution for quantitative real-time reverse transcriptase polymerase chain reaction analysis. RESULTS: Of the 441-immunostained ccRCC specimens, 91 (20.6%) and 107 (24.3%) showed negative-expression of PBRM1 and BAP1, respectively. Fifty-eight (13.2%) showed negative-expression of both markers (PBRM1-/BAP-). There was an association between both markers expression pattern and classical parameters, such as pT stage (P<0.001), tumor size (P<0.001), and tumor grade (P<0.001). Both independent PBRM1 and BAP1 negative-expression were associated with lower rates of disease-specific survival and recurrence-free survival. When patients were grouped into presence of positive expression of one or both markers vs. PBRM1-/BAP1- patients, disease-specific survival and rates were 95.3% vs. 77.6%, respectively (P<0.001). PBRM1-/BAP1-group presented a higher risk of cancer specific death (hazard ratio = 2.722, P = 0.007) and disease recurrence (hazard ratio = 2.467, P = 0.004) in multivariate analysis. CONCLUSION: Patients with early stage tumors that present concomitant loss of both PBRM1 and BAP1 demonstrated worse survival rates and represent a relevant risk group for tumor recurrence and death.

Discrepâncias clínico-patológicas e achados cardiovasculares em 409 autópsias consecutivas / Clinical and pathological discrepancies and cardiovascular findings in 409 consecutive autopsies

FUNDAMENTO: As discrepâncias entre os diagnósticos clínicos e em autópsia persistem em todo o mundo. OBJETIVO: Avaliamos as autópsias em um hospital-escola para analisar a precisão dos diagnósticos cardiovasculares clínicos em comparação aos achados post-mortem. MÉTODOS: As 409 autópsias consecutivas entre 2003 e 2006 foram analisadas em um hospital terciário de São José do Rio Preto, São Paulo (SP), Brasil. A comparação dos achados cardiovasculares clínicos e patológicos foi realizada por meio da classificação de discrepâncias de Goldman. RESULTADOS: A taxa de autópsia no hospital foi de 8 por cento. As causas cardiovasculares de óbito representavam 42,8 por cento (175 de 409 pacientes) dos diagnósticos de autópsia. Em 98 pacientes (56 por cento), houve discrepâncias significativas (classes I e II), o que representa uma grande proporção de diagnósticos equivocados de infarto mesentérico (84,6 por cento), infarto agudo do miocárdio (64,7 por cento), dissecção da aorta (64,2 por cento) e embolia pulmonar (62,5 por cento). Foram observadas maiores taxas de concordância para a insuficiência cardíaca congestiva (59 por cento) e para o acidente vascular cerebral isquêmico agudo (58,8 por cento). A idade, o sexo, o tempo de permanência e a última unidade de admissão no hospital não foram associados aos critérios de Goldman. CONCLUSÃO: As discrepâncias dos diagnósticos clínicos e em autópsia relativos à morte cardiovascular permanecem elevados no Brasil, a despeito dos recursos tecnológicos disponíveis. Além disso, nossos achados reforçam a importância do exame post-mortem como uma contribuição para a melhoria da assistência médica.

BACKGROUND: Discrepancies between clinical and autopsy diagnoses persists worldwide. OBJECTIVE: We evaluated autopsies in a university hospital in order to assess the accuracy of clinical cardiovascular diagnosis compared to postmortem findings. METHODS: Four hundred nine consecutive autopsies between 2003 and 2006 were analyzed in a tertiary-care hospital in São José do Rio Preto, SP, Brazil. The comparison of clinic-pathological cardiovascular findings was performed using Goldman's discrepancies classification. RESULTS: Autopsy rate at the hospital was 8 percent. Cardiovascular causes of death represented 42.8 percent (175 out of 409 patients) of autopsy diagnoses. In 98 (56 percent) patients, there were major discrepancies (class I and II), representing a large proportion of misdiagnoses for mesenteric infarction (84.6 percent), acute myocardial infarction (64.7 percent), aorta dissection (64.2 percent), and pulmonary embolism (62.5 percent). Highest concordance rates were observed in congestive heart failure (59 percent) and acute ischemic stroke (58.8 percent). Age, sex, length of stay and the last admission unit at the hospital were not associated with Goldman criteria. CONCLUSION: Clinic-autopsy discrepancies concerning cardiovascular death remain high in Brazil, despite technological resources available. Moreover, our findings reinforce the importance of postmortem examination in contributing to medical care improvement.

Discrepâncias clínico-patológicas em pacientes graves com difícil diagnóstico pre-mortem / Clinical-pathological discrepancies in critically ill patients with difficult premortem diagnoses

INTRODUÇÃO: A importância das autópsias é um tema comum de discussão tanto no Brasil como em todo o mundo, já que pode elucidar as causas de óbito e tem um valor social muito amplo. Entretanto, esta prática vem sendo gradualmente considerada desnecessária, tendo ocorrido um declínio no número de exames post-mortem. OBJETIVOS: Comparar o diagnóstico clínico e patológico em pacientes com difícil diagnóstico pre-mortem. MÉTODOS: Foram analisados todos os casos de autópsias (em um total de 98) de pacientes oriundos de três unidades de terapia intensiva médico-cirúrgicas (total de 78 leitos) pertencentes a uma faculdade de medicina, realizadas no período de janeiro de 2003 a dezembro de 2006. Analisamos os diagnósticos clínicos e patológicos segundo os critérios de Goldman. RESULTADOS: Em 49 casos (50 por cento) foram encontradas discordâncias classes I e II de Goldman. Por outro lado, apenas 30 (30,6 por cento) dos casos tiveram uma concordância completa entre os diagnósticos pre-mortem e post-mortem sendo classificados como classe V. As infecções tiveram uma taxa de concordância significantemente maior do que as doenças cardiovasculares. CONCLUSÃO: Encontramos discrepâncias significantes entre os achados clínicos e patológicos, o que reforça o valor dos exames post-mortem.

INTRODUCTION: The importance of autopsies is a common theme of discussions both in Brazil and around the world as it elucidates causes of death and has wide ranging social value. However this is a practice that is gradually being considered unnecessary and there have been a decline in the number of postmortems examinations. OBJECTIVES: To compare clinical and pathological diagnosis in critically ill patients with difficult premortem diagnosis. METHODS: All autopsy cases (total of 98) from any of the three general medical/surgical intensive care units (78 beds in total) affiliated to the medical school from January 2003 to December 2006 were analyzed. We analyzed the clinical and pathological diagnosis based on the Goldman criteria. RESULTS: In 49 (50 percent) cases, there were class I and II of Goldman. In contrast, only 30 (30.6 percent) had a complete agreement between premortem and postmortem diagnosis and were classified as class V. Infections had a significantly greater rate of concordant diagnosis than cardiovascular diseases. CONCLUSION: We found significant discrepancies between clinical and pathological findings, reinforcing the value of postmortem examination.

Clinical and pathological discrepancies and cardiovascular findings in 409 consecutive autopsies.

BACKGROUND: Discrepancies between clinical and autopsy diagnoses persists worldwide. OBJECTIVE: We evaluated autopsies in a university hospital in order to assess the accuracy of clinical cardiovascular diagnosis compared to postmortem findings. METHODS: Four hundred nine consecutive autopsies between 2003 and 2006 were analyzed in a tertiary-care hospital in São José do Rio Preto, SP, Brazil. The comparison of clinic-pathological cardiovascular findings was performed using Goldman's discrepancies classification. RESULTS: Autopsy rate at the hospital was 8%. Cardiovascular causes of death represented 42.8% (175 out of 409 patients) of autopsy diagnoses. In 98 (56%) patients, there were major discrepancies (class I and II), representing a large proportion of misdiagnoses for mesenteric infarction (84.6%), acute myocardial infarction (64.7%), aorta dissection (64.2%), and pulmonary embolism (62.5%). Highest concordance rates were observed in congestive heart failure (59%) and acute ischemic stroke (58.8%). Age, sex, length of stay and the last admission unit at the hospital were not associated with Goldman criteria. CONCLUSION: Clinic-autopsy discrepancies concerning cardiovascular death remain high in Brazil, despite technological resources available. Moreover, our findings reinforce the importance of postmortem examination in contributing to medical care improvement.

Clinical-pathological discrepancies in critically ill patients with difficult premortem diagnoses. / Discrepâncias clínico-patológicas em pacientes graves com difícil diagnóstico pre-mortem.

INTRODUCTION: The importance of autopsies is a common theme of discussions both in Brazil and around the world as it elucidates causes of death and has wide ranging social value. However this is a practice that is gradually being considered unnecessary and there have been a decline in the number of postmortems examinations. OBJECTIVES: To compare clinical and pathological diagnosis in critically ill patients with difficult premortem diagnosis. METHODS: All autopsy cases (total of 98) from any of the three general medical/surgical intensive care units (78 beds in total) affiliated to the medical school from January 2003 to December 2006 were analyzed. We analyzed the clinical and pathological diagnosis based on the Goldman criteria. RESULTS: In 49 (50%) cases, there were class I and II of Goldman. In contrast, only 30 (30.6%) had a complete agreement between premortem and postmortem diagnosis and were classified as class V. Infections had a significantly greater rate of concordant diagnosis than cardiovascular diseases. CONCLUSION: We found significant discrepancies between clinical and pathological findings, reinforcing the value of postmortem examination.