A real-world study of pneumonitis in non-small cell lung cancer patients receiving durvalumab following concurrent chemoradiation.

Background: Locally advanced non-small cell lung cancer (LA-NSCLC) treated with the programmed death-ligand 1 inhibitor durvalumab has been associated with significant rates of pneumonitis, which has led to higher rates of discontinuation of therapy in real-world populations. Thus far there has been no consensus in the literature on the impact of pneumonitis on survival. Methods: This is a retrospective cohort study of veterans receiving durvalumab between 12/5/2017 and 4/15/2020. Participants were identified using VINCI data services. Patients were followed through 9/14/2021. Development of clinical pneumonitis was assessed through review of documentation and graded using CTCAE 4.0 criteria. Univariate logistic regression analysis evaluated for associations between body mass index (BMI), age, race, co-morbidity index, chemotherapy regimen, chronic obstructive pulmonary disease (COPD) severity, and development of clinical pneumonitis. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier methods. Cox proportional hazards models were utilized to evaluate the association between risk of death at 1 and 2 years and candidate predictor variables. Results: A total of 284 patients were included in this study. Sixty-one patients developed clinically significant pneumonitis, 7 patients developed grade 5 pneumonitis (death from pneumonitis). The median OS in patients that developed pneumonitis was 27.8 vs. 36.9 months in patients that did not develop pneumonitis (P=0.22). BMI was found to be a clinical predictor of pneumonitis (P=0.04). COPD severity, race, age at durvalumab start date, chemotherapy regimen, and Romano comorbidity index were not significant predictors of pneumonitis. Cox proportional hazards analysis failed to demonstrate an association between the development of pneumonitis and risk of death in this population. Conclusions: The incidence of clinically significant pneumonitis is higher than noted in the PACIFIC trial in this cohort, however this high rate of pneumonitis does not have an impact on OS or PFS. Obesity was found to be a significant predictor of pneumonitis in this patient population.

Advancing age and the risk of bleomycin pulmonary toxicity in a largely older cohort of patients with newly diagnosed Hodgkin Lymphoma.

OBJECTIVES: In patients with Hodgkin Lymphoma (HL), the relationship between increasing age and bleomycin pulmonary toxicity (BPT) remains unclear. This study explores associations between age and BPT in a real-world cohort of largely older patients with HL. MATERIAL AND METHODS: This study retrospectively evaluated a nationwide patient cohort of United States Veterans diagnosed with HL in VA medical centers between October 1, 2002 and December 31, 2013 (follow up through April 15, 2016). The primary outcome was the development BPT, defined as: ambient air oxygen saturations <92% with pulmonary infiltrates on chest radiograph and no other etiologies OR clinician documentation of BPT. Multivariable logistic regression was used to evaluate variables associated with development of BPT. Cox proportional hazards analysis was performed to evaluate the risk of death up-to 5-years from diagnosis. RESULTS: Overall, 847 patients received chemotherapy and 739 of these patients received bleomycin. Sixty-six patients (9.3%) developed BPT. The incidence of BPT per age category: 0.03 (9/262), 0.07 (13/188), 0.13 (23/171), and 0.24 (21/88) for age categories: ≤ 49, 50-59, 60-69 and ≥ 70 years. Odds of BPT steadily increased with advancing age (compared to patients age ≤ 49 years) with odds ratios of 1.65 (95% CI 0.68-4.03), 3.24 (1.43-7.34), 6.01(2.52-7.34) for age categories 50-59, 60-69 and ≥ 70 years, respectively. The was no association between bleomycin and risk of death up-to 5-years [HR: 0.87; 95% CI (0.61-1.23)]. CONCLUSION: This study demonstrates a direct relationship between age >60 years and odds of developing clinically significant BPT.

Systemic Therapy for Combined Hepatocellular-Cholangiocarcinoma: A Single-Institution Experience.

Background: Combined hepatocellular-cholangiocarcinoma tumors (cHCC-CCA) are a heterogeneous group of rare malignancies that have no established optimal treatment. Patients and Methods: We identified patients with cHCC-CCA treated at a tertiary center and retrospectively examined their histology, interventions, and outcomes. We calculated disease control rate (DCR), disease progression, overall survival, and progression-free survival (PFS) between treatment subgroups. Results: A total of 123 patients were evaluable. Interventions included resection, locoregional therapy, transplant, chemotherapy, and targeted agents. Ultimately, 68 patients received systemic treatment-57 with gemcitabine plus either 5-fluoropyrimidine (5-FU) or a platinum combination. Disease progression was more common in the gemcitabine/5-FU group versus gemcitabine/platinum (P=.028), whereas DCR favored gemcitabine/platinum (78.4% vs 38.5%; P=.0143). Median PFS from time of initial diagnosis favored the gemcitabine/platinum group, but the difference did not reach statistical significance. Targeted agents had minimal to no effect on survival metrics. Conclusions: Gemcitabine/platinum seems to be a superior regimen for patients with cHCC-CCA who require systemic treatment. Further studies are needed to clarify the regimen's efficacy and applicability in patient subgroups.

Stereotactic radiosurgery and immunotherapy in melanoma brain metastases: Patterns of care and treatment outcomes.

PURPOSE: Preclinical studies have suggested that radiation therapy (RT) enhances antitumor immune response and can act synergistically when administered with immunotherapy. However, this effect in melanoma brain metastasis is not well studied. We aim to explore the clinical effect of combining RT and immunotherapy in patients with melanoma brain metastasis (MBM). MATERIALS AND METHODS: Patients with MBM between 2011 and 2013 were obtained from the National Cancer Database. Patients who did not have identifiable sites of metastasis and who did not receive RT for the treatment of their MBM were excluded. Patients were separated into cohorts that received immunotherapy versus patients who did not. Univariable and multivariable analyses were performed using Cox model to determine predictors of OS. Kaplan-Meier method was used to compare OS. Univariable and multivariable analyses using logistic regression model were used to determine the factors predictive for the use of immunotherapy. Propensity score analysis was used to account for differences in baseline patient characteristics between the RT and RT + immunotherapy groups. Significance was defined as a P value ≤ 0.05. RESULTS: A total of 1104 patients were identified: 912 received RT alone and 192 received RT plus immunotherapy. The median follow-up time was 6.4 (0.1-56.8) months. Patients with extracranial disease (OR 1.603, 95% CI 1.146-2.243, P = 0.006), and patients receiving SRS (OR 1.955, 95% CI 1.410-2.711, P < 0.001) as compared to WBRT, had a higher likelihood of being treated with immunotherapy. The utilization of immunotherapy had nearly doubled between 2011 and 2013 (12.9-22.8%). On multivariable analysis, factors associated with superior OS were younger age, lower medical comorbidities, lack of extracranial disease, and treatment with immunotherapy and SRS. The median OS was 11.1 (8.9-13.4) months in RT plus immunotherapy vs. 6.2 (5.6-6.8) months in RT alone (P < 0.001), which remained significant after propensity score matching. CONCLUSIONS: An increase in trend for the use of immunotherapy was noted, however, an overwhelming majority of the patients with this disease are still treated without immunotherapy. Addition of immunotherapy to RT is associated with improved OS in MBM. Given the selection biases that are inherent in this analysis, prospective trials investigating the combination of RT, especially SRS and immunotherapy are warranted.

Hematopoietic cell transplantation comorbidity index (HCT-CI) is predictive of adverse events and overall survival in older allogeneic transplant recipients.

OBJECTIVES: Our goal was to evaluate the ability of the hematopoietic cell transplantation comorbidity index (HCT-CI) to predict outcomes after allogeneic stem cell transplant (SCT) within the context of an older patient population, where multiple comorbidities are common. MATERIALS AND METHODS: We performed a retrospective cohort study of SCT patients ≥50years of age at our institution, identifying 59 patients with complete HCT-CI data collected prospectively. RESULTS: HCT-CI category distribution in our sample was disproportionate, with almost half of patients having scores ≥3. High HCT-CI score (≥3 vs <3) was associated with significantly inferior OS (median OS not reached for HCT-CI <3 vs 14months for HCT-CI ≥3; hazard ratio (HR) 2.2, p=0.02). HCT-CI score was a better predictor of OS than age, performance status or conditioning intensity. When adjusted for disease relapse risk, HCT-CI score conferred a worse prognosis in the low risk group (HR 1.43, p=0.03) but not in the intermediate/high risk group (HR 1.08, p=0.65). NRM was low in the total sample (6% at one year) and was not associated with HCT-CI score. Grade 3-4 non-hematologic adverse events within the first 100days after SCT were significantly more common in the higher HCT-CI groups (p=0.02). CONCLUSIONS: In our older patient cohort with a high incidence of multiple comorbidities, HCT-CI score ≥3 was significantly associated with OS, particularly in the subset of patients with a low disease relapse risk.

Integrin alpha2 mediates selective metastasis to the liver.

Cancers display distinct patterns of organ-specific metastasis. Comparative analysis of a broad array of cell membrane molecules on a liver-metastasizing subline of B16 melanoma versus the parental B16-F0 revealed unique up-regulation of integrin alpha2. The direct role of integrin alpha2 in hepatic metastasis was shown by comparison of high versus low-expressing populations, antibody blockade, and ectopic expression. Integrin alpha2-mediated binding to collagen type IV (highly exposed in the liver sinusoids) and collagen type IV-dependent activation of focal adhesion kinase are both known to be important in the metastatic process. Analysis of primary colorectal cancers as well as coexisting liver and lung metastases from individual patients suggests that integrin alpha2 expression contributes to liver metastasis in human colorectal cancer. These findings define integrin alpha2 as a molecule conferring selective potential for formation of hepatic metastasis, as well as a possible target to prevent their formation.

DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer.

PURPOSE: Contrary to the extensive data accumulated regarding pancreatic carcinogenesis, the clinical and molecular features characteristic of advanced stage (stage III and IV) disease are unknown. A comprehensive study of pancreatic cancers from patients who have succumbed to their disease has the potential to greatly expand our understanding of the most lethal stage of this disease and identify novel areas for intervention. MATERIALS AND METHODS: Rapid autopsies were performed on 76 patients with documented pancreatic cancer. The histologic features of end stage disease were determined and correlated to the stage at initial diagnosis, patterns of failure (locally destructive v metastatic disease) and the status of the KRAS2, TP53, and DPC4 genes. RESULTS: At autopsy, 30% of patients died with locally destructive pancreatic cancer, and 70% died with widespread metastatic disease. These divergent patterns of failure found at autopsy (locally destructive v metastatic) were unrelated to clinical stage at initial presentation, treatment history, or histopathologic features. However, Dpc4 immunolabeling status of carcinoma tissues harvested at autopsy, a sensitive marker of DPC4 genetic status, was highly correlated with the presence of widespread metastasis but not with locally destructive tumors (P = .007). CONCLUSION: Pancreatic cancers are represented by distinct genetic subtypes with significantly different patterns of failure. Determinations of DPC4 status at initial diagnosis may be of value in stratifying patients into treatment regimens related to local control versus systemic therapy.