Keeping an Eye Out for Immunotherapy Toxicity: A Case of Unilateral Ptosis Caused by Ipilimumab/Nivolumab Therapy.

Despite ocular adverse events from immune checkpoint inhibitors being uncommon, they are still important complications to be aware of. We present the case of metastatic melanoma on ipilimumab/nivolumab in a patient who developed immunotherapy complications with delayed diagnosis because the only presenting symptom was unilateral ptosis. We reviewed the literature for relevant and important ocular and neurological complications of immune checkpoint inhibitors.

Advances in Immunotherapy in Esophagogastric Cancer.

Immune checkpoint inhibitors are rapidly transforming the care of patients with esophagogastric cancer. Particularly, anti-PD-1 therapy has demonstrated promising efficacy in metastatic and resectable disease. In this review, the authors discuss landmark clinical trials, highlight challenges and opportunities in this field, and propose potential directions for future work.

Novel imaging biomarkers predict outcomes in stage III unresectable non-small cell lung cancer treated with chemoradiation and durvalumab.

BACKGROUND: The landmark study of durvalumab as consolidation therapy in NSCLC patients (PACIFIC trial) demonstrated significantly longer progression-free survival (PFS) in patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) treated with durvalumab (immunotherapy, IO) therapy after chemoradiotherapy (CRT). In clinical practice in the USA, durvalumab continues to be used in patients across all levels of programmed cell death ligand-1 (PD-L1) expression. While immune therapies have shown promise in several cancers, some patients either do not respond to the therapy or have cancer recurrence after an initial response. It is not clear so far who will benefit of this therapy or what the mechanisms behind treatment failure are. METHODS: A total of 133 patients with unresectable stage III NSCLC who underwent durvalumab after CRT or CRT alone were included. Patients treated with durvalumab IO after CRT were randomly split into training (D1=59) and test (D2=59) sets and the remaining 15 patients treated with CRT alone were grouped in D3. Radiomic textural patterns from within and around the target nodules were extracted. A radiomic risk score (RRS) was built and was used to predict PFS and overall survival (OS). Patients were divided into high-risk and low-risk groups based on median RRS. RESULTS: RRS was found to be significantly associated with PFS in D1 (HR=2.67, 95% CI 1.85 to 4.13, p<0.05, C-index=0.78) and D2 (HR=2.56, 95% CI 1.63 to 4, p<0.05, C-index=0.73). Similarly, RRS was associated with OS in D1 (HR=1.89, 95% CI 1.3 to 2.75, p<0.05, C-index=0.67) and D2 (HR=2.14, 95% CI 1.28 to 3.6, p<0.05, C-index=0.69), respectively. RRS was found to be significantly associated with PFS in high PD-L1 (HR=3.01, 95% CI 1.41 to 6.45, p=0.0044) and low PD-L1 (HR=2.74, 95% CI 1.8 to 4.14, p=1.77e-06) groups. Moreover, RRS was not significantly associated with OS in the high PD-L1 group (HR=2.08, 95% CI 0.98 to 4.4, p=0.054) but was significantly associated with OS in the low PD-L1 group (HR=1.61, 95% CI 1.14 to 2.28, p=0.0062). In addition, RRS was significantly associated with PFS (HR=2.77, 95% CI 1.17 to 6.52, p=0.019, C-index=0.77) and OS (HR=2.62, 95% CI 1.25 to 5.51, p=0.01, C-index=0.77) in D3, respectively. CONCLUSIONS: Tumor radiomics of pretreatment CT images from patients with stage III unresectable NSCLC were prognostic of PFS and OS to CRT followed by durvalumab IO and CRT alone.

A Review of Treatment-Induced Pulmonary Toxicity in Breast Cancer.

This article reviews the available literature that describes the incidence, diagnosis, mechanism, symptoms, and management of pulmonary toxicity induced by radiation therapy and current systemic medications used to treat breast cancer. An extensive literature search was conducted via Ovid Medline to identify all potentially relevant articles written in English from 2010 through January 2020. Additional relevant articles outside the time frame were included as needed. Although the risk of pulmonary toxicity from various breast cancer treatments is small in most instances, it can be fatal. Due to the high prevalence of breast cancer and the range of treatment options, healthcare providers should be aware of the risk of pulmonary toxicity from those treatments and how to prevent or manage complications.

Studying the association between breast cancer and renal cell carcinoma.

PURPOSE: There are case reports of patients with both primary breast cancer (BC) and renal cell carcinoma (RCC). We explore the association between these two malignancies using SEER population data and our institutional records. METHODS: We studied the association between BC and RCC in the 2000-2016 Surveillance, Epidemiology, and End Results (SEER) database. We then reviewed our hospital records of patients with both BC and RCC and collected information including personal and family history of cancers, genetic testing, and patient outcomes. RESULTS: Of the 813,477 females diagnosed with BC in the SEER database, 1914 later developed RCC. The risk of developing RCC was significantly increased within the first 6 months, 7-12 months, and 1-5 years following BC diagnosis with standardized incidence ratios (SIRs) of 5.08 (95% CI 4.62-5.57), 2.09 (95% CI 1.8-2.42), and 1.15 (95% CI 1.06-1.24), respectively. Of 56,200 females with RCC, 1087 later developed BC. The risk of developing BC following RCC was elevated within the first 6 months (SIR of 1.45 [95% CI 1.20-1.73]). For our hospital patients, 437 had both BC and RCC. 427 (97.71%) were female, and 358 (81.92%) were white, and breast cancer was diagnosed before RCC in 246 (56.3%) patients. There were 15 germline mutations in those with genetic testing. CONCLUSION: Our findings suggest that BC patients are at higher risk of developing RCC and vice versa. BC tended to precede RCC, and patients frequently had personal histories of other malignancies and a family history of cancer, particularly, BC.

Tumor PD-L1 expression is associated with outcomes in stage III non-small cell lung cancer (NSCLC) patients treated with consolidation durvalumab.

BACKGROUND: Durvalumab is an anti-PD-L1 immune checkpoint inhibitor approved for consolidation therapy for patients with stage III non-small cell lung cancer (NSCLC) after chemoradiation. The purpose of our study was to evaluate the association between the degree of tumor PD-L1 expression and outcomes of stage III NSCLC patients treated with durvalumab. METHODS: We conducted a retrospective analysis of all the patients who received durvalumab between July 2017 and July 2019 at our facilities and were diagnosed with or progressed to stage III NSCLC before durvalumab consolidation. Patients were divided into groups based on the degree of PD-L1 expression: <1%, 1-49%, and 50-100%. Overall survival and progression-free survival were estimated by the Kaplan-Meier method and the Multivariate Cox proportional hazard model was used to assess the effect of PD-L1 expression level on OS and PFS, adjusting for age and gender. RESULTS: We identified 121 patients with stage III NSCLC that underwent durvalumab consolidation. Of them, 29.8% had PD-L1 expression of 50-100%, 24.8% had PD-L1 expression of 1-49%, and 27.3% had PD-L1 expression of <1%, while 18.2% were not tested for PD-L1 expression. The rate of cancer progression in the group with 50-100% PD-L1 expression was 16.7% compared to 60% in the 1-49% expression group and 54.6% in the <1% expression group, and the 1-year survival rates were higher in the 50-100% group (97%) compared to the 1-49% group and the <1% group (73% and 78%, respectively; P=0.028). Survival analysis via Kaplan-Meier revealed a significant difference in both PFS (P<0.0001) and OS (P<0.028) based on the extent of PD-L1 expression. Multivariate analysis revealed that a PD-L1 expression >50% was the only factor that was significantly associated with improved PFS (HR =0.205, P=0.0004) and OS (HR =0.339, P=0.04). CONCLUSIONS: Our study demonstrated that patients whose tumors had >50% PD-L1 expression had significantly longer progression-free survival and overall survival than those with lower PD-L1 expression. This suggests that the degree of tumor PD-L1 expression may play a role in predicting benefit from durvalumab for these patients.

Novel targeted therapies for metastatic breast cancer.

Metastatic breast cancer (mBC) continues to be a leading cause of cancer-related death in women. Even though mortality rates have improved over recent years, the 5-year survival rate of advanced BC is still at only 27%. As researchers and clinicians attempt to tackle this challenge, there has been extensive research and many trials studying treatment options for BC patients with metastatic disease, with numerous new therapies being discovered as a result. We review the most pertinent novel agents to enter the scope of BC treatment, including CDK4/6 inhibitors, PI3K inhibitors, mTOR inhibitors, immunotherapy, PARP inhibitors, and more.

ADAM10 and ADAM17 cleave PD-L1 to mediate PD-(L)1 inhibitor resistance.

ADAM10 and ADAM17 expression and soluble PD-L1 (sPD-L1) predict poor prognosis in many malignancies, including in patients treated with PD-(L)1 inhibitors. The mechanism of soluble PD-L1 production and its effects are unknown. Here we uncover a novel mechanism of ADAM10- and ADAM17-mediated resistance to PD-(L)1 inhibitors. ADAM10 and ADAM17 cleave PD-L1 from the surface of malignant cells and extracellular vesicles. This cleavage produces an active sPD-L1 fragment that induces apoptosis in CD8 + T cells and compromises the killing of tumor cells by CD8 + T cells. Reduced tumor site PD-L1 protein-to-mRNA ratios predict poor outcomes and are correlated with elevated ADAM10 and ADAM17 expression in multiple cancers. These results may explain the discordance between PD-L1 immunohistochemistry and PD-(L)1 inhibitor response. Thus, including ADAM10 and ADAM17 tissue staining may improve therapy selection. Furthermore, treatment with an ADAM10/ADAM17 inhibitor may abrogate PD-(L)1 inhibitor resistance and improve clinical responses to PD-(L)1 immunotherapy.

Epidemiology of Cholangiocarcinoma; United States Incidence and Mortality Trends.

BACKGROUND: Cholangiocarcinoma is an aggressive malignancy with few available studies assessing incidence and mortality. In this study, we aim to investigate trends of incidence and mortality in a large nation-wide epidemiologic study. METHODS: We used SEER 18 database to study cholangiocarcinoma cases in the US during 2000-2015. Incidence and mortality rates of cholangiocarcinoma were calculated by race and were expressed by 1,000,000 person-years. Annual percent change (APC) was calculated using joinpoint regression software. RESULTS: We reviewed 16,189 patients with cholangiocarcinoma, of which 64.4% were intrahepatic. Most patients were whites (78.4%), males (51.3%), and older than 65 years (63%). A total of 13,121 patients died of cholangiocarcinoma during the study period. Cholangiocarcinoma incidence and mortality were 11.977 and 10.295 and were both higher among Asians, males, and individuals older than 65 years. Incidence rates have significantly increased over the study period (APC=5.063%, P<.001), while mortality increased significantly over the study period (APC=5.964%, P<.001), but decreased after 2013 (APC=-25.029, P<.001). CONCLUSION: The incidence and mortality of cholangiocarcinoma were increasing in the study period with significant observed disparities based on race and gender.

Impact of an Electronic Medical Record Alert on Code Status Documentation for Hospitalized Patients With Advanced Cancer.

PURPOSE: Cardiopulmonary resuscitation in hospitalized patients with advanced cancer is associated with high rates of morbidity and mortality. Although advance care planning (ACP) in this population improves quality, patient satisfaction, hospice use, rates of harm, and health care costs, ACP documentation rates remain low. We observed changes in ACP documentation by internal medicine residents within a tertiary hospital's inpatient oncology service after a mandatory training module and enterprise-wide modification in electronic health medical records (EHMR). METHODS: For patients admitted to the Cleveland Clinic oncology service, this 16-week retrospective review observed resident code status (CS) documentation through admission notes and direct EHMR orders before and after implementation of an ACP training module and CS best practice alert (BPA). In addition, residents were surveyed on perceived barriers to CS documentation. RESULTS: In 535 unique admissions (244 before BPA, 291 after BPA), residents exhibited a 14.4% increase (from 47.1% to 61.5%) in admission note CS documentation and an 18.2% increase (from 12.7% to 30.9%) in CS orders at time of discharge. The most common self-reported barrier to ACP documentation was forgetting to discuss, with first-, second-, and third-year residents admitting to feeling uncomfortable in orchestrating ACP conversations at rates of 58%, 6%, and 5%, respectively. CONCLUSION: Resident ACP documentation remains suboptimal in the high-risk cohort of hospitalized patients with advanced cancer. However, rates seem to be positively influenced by online modules and EHMR-based interventions. Additional efforts to improve the current practice and culture of ACP remain a crucial aspect in the quality and safety of our approach to patient care.

Outcome disparities in colorectal cancer: a SEER-based comparative analysis of racial subgroups.

PURPOSE: Previous studies of ethnic disparities in colorectal cancer (CRC) have focused mainly on patients of Caucasian and African-American descent. We aimed to evaluate outcomes for a range of races, representing a broader demographic of the US population. METHODS: The Surveillance, Epidemiology, and End Results database was queried to identify patients with CRC diagnosed between 1994 and 2014. We performed unadjusted Kaplan-Meier test and multivariable covariate-adjusted Cox models to calculate the overall and CRC-specific survival of patients according to their race. RESULTS: We identified 401,723 patients diagnosed with CRC between 1994 and 2014. Overall survival (OS) and CRC-specific survival were compared across different races stratified by age, sex, marital status, disease stage and grade, and undergoing surgery as a treatment. Overall, Asian/Pacific Islanders and Hispanics had improved CRC-specific survival compared to Whites (HR = 0.873, 95%CI 0.853-0.893, P < .001, and HR = 0.958, 95%CI 0.937-0.979, P < .001, respectively). Blacks had the worst CRC-specific survival outcomes when compared to Whites (HR = 1.215, 95%CI 1.192-1.238, P < .001). Racial disparity persisted when looking at two different time periods (1994-2003 and 2004-2014). CONCLUSIONS: Asians/Pacific Islanders have improved outcomes from CRC compared to other races. Multifactorial, including genetic, environmental, and socioeconomic factors appear to influence outcomes and need to be addressed separately in order to reduce racial disparities among patients with CRC.

A phase I study of the farnesyltransferase inhibitor Tipifarnib in combination with the epidermal growth factor tyrosine kinase inhibitor Erlotinib in patients with advanced solid tumors.

Introduction Based on preclinical cytotoxic synergy between tipifarnib and erlotinib, a phase I study of this combination was conducted in patients with advanced solid tumors to evaluate safety, tolerability, maximum tolerated dose (MTD) and preliminary evidence of efficacy. Methods Patient enrollment followed the traditional "3 + 3" dose escalation scheme, through 4 dose levels, ranging from tipifarnib 200 mg twice daily plus erlotinib 75 mg once daily to tipifarnib 300 mg twice daily plus erlotinib 150 mg once daily. After the MTD of the combination was identified, 12 additional patients were treated to better define the pharmacokinetics and pharmacodynamics of these agents. Results A total of 27 patients were enrolled in the study (dose escalation, 15; dose expansion, 12). Dose limiting toxicity was seen in one patient at dose level 4 (grade 3 diarrhea). The MTD was reached at erlotinib 150 mg once daily combined with tipifarnib 300 mg twice daily. The most common side effects of the combination of all grades were diarrhea (85.2%), fatigue (77.8%), rash (70.4%), and anorexia (59.3%). Overall, 2 patients (7.4%; with liver cancer and melanoma, respectively) had partial responses, 10 (37%) had stable disease, 11 had progressive disease (40.7%) and 4 stopped treatment prematurely for assessment. Conclusion The combination of tipifarnib and erlotinib was well tolerated. Erlotinib 150 mg once daily for 28 days combined with tipifarnib 300 mg twice daily for 21 days was identified as the recommended phase 2 dose. Tipifarnib is currently being evaluated in HRAS mutant tumors, providing a potential opportunity to further test this combination.

Transarterial therapy: an evolving treatment modality of hepatocellular carcinoma.

Liver cancer is the fifth most common cancer in men, the seventh most common in women, and the third most common cause of death from cancer worldwide. Only 30-40% of liver cancer patients present early enough to undergo curative treatments such as surgery or liver transplantation. Local treatment with radiofrequency ablation or ethanol injection is often reserved for non-surgical candidates with early stages of disease. Transarterial embolization has become a widely accepted treatment for asymptomatic patients with unresectable lesions. This review discusses in details the three major forms of transarterial therapies: Bland embolization, chemoembolization, and radioembolization.

The clinical utility of biomarkers in the management of pancreatic adenocarcinoma.

Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States and survival rates have seen minimal improvement over the past few decades. Although results are poor, surgical resection is considered the only curative therapeutic intervention for pancreatic cancer, thereby emphasizing the significance of effective diagnostic and prognostic tools to improve outcomes. As such, biomarkers play a promising role in the development of personalized treatments for patients with pancreatic cancer. Prognostic biomarkers, such as serum carbohydrate antigen 19-9 in particular, as well as cancer stem cell markers, provide valuable insight into the biological processes of an individual and their likely course of disease. This, consequently, allows for the assessment of optimal therapeutic intervention. Furthermore, current efforts target putative predictive biomarkers such as BRCA2, PALB2, and SPARC so as to determine their influence on tumor response on targeted therapies. As research progresses, more evidence will provide clinicians with guidelines on the utilization of biomarkers to accurately stage and tailor personalized treatment to the needs of specific patients with pancreatic cancer.