Randomised, Phase II study of selumetinib, an oral inhibitor of MEK, in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer.

INTRODUCTION: Cisplatin and gemcitabine (CisGem) are standard chemotherapy for advanced biliary tract cancer (BTC). The MEK inhibitor selumetinib showed synergy with gemcitabine when administered sequentially in BTC. This randomised Phase 2 trial aimed to assess the efficacy of sequential or continuous selumetinib with CisGem. METHODS: Patients with advanced BTC received CisGem; arm A included selumetinib every day, arm B: selumetinib, days 1-5, 8-19 each cycle. Arm C received CisGem alone. Selumetinib was dosed at 75 mg BID but amended to 50 mg BID due to toxicity. RESULTS: In all, 51 participants were evaluable for response. No significant difference was seen in mean change in tumour size at 10 weeks between arms A and C (-7.8% vs -12.8%, P = 0.54) or arms B and C (-15% vs -12.8%, P = 0.78). There was no difference in median progression-free survival (6.0, 7.0, 6.3 months, P > 0.95) or overall survival (11.7, 11.7, 12.8 months, P = 0.70) for arms A, B and C, respectively. More participants experienced grade 3-4 toxicities in selumetinib-containing arms. More participants in arm A required chemotherapy dose reductions (P = 0.01) with lower chemotherapy dose intensity during the first 10 weeks. CONCLUSION: Adding sequential or continuous selumetinib to CisGem failed to improve efficacy and increased toxicity in patients with advanced BTC.

The financial impact of cancer care on renal cancer patients.

INTRODUCTION Advances in novel treatment options may render renal cell cancer (RCC) patients susceptible to the financial toxicity (FT) of cancer treatment, and the factors associated with FT are unknown. MATERIALS AND METHODS: Eligible patients were ≥ 18 years old and had a diagnosis of stage IV RCC for at least 3 months. Patients were recruited from Princess Margaret Cancer Centre and Sunnybrook Odette Cancer Centre (Toronto, Canada). FT was assessed using the validated Comprehensive Score for Financial Toxicity (COST) instrument, a 12-question survey scored from 0-44, with lower scores reflecting worse FT. Patient and treatment characteristics, out-of-pocket costs (OOP) and private insurance coverage (PIC) were collected. Factors associated with worse FT (COST score < 21) were determined. RESULTS: Sixty-five patients were approached and 80% agreed to participate (n = 52). The median age was 62 (44-88); 20% were female (n = 10); 43% were age ≥ 65 (n = 22); 63% were Caucasian (n = 31). Median COST score was 20.5 (3-44). Factors associated with worse FT were age < 65 (OR 9.5, p = 0.007), high OOP (OR 4.4, p = 0.04) and receiving treatment off clinical trial (in comparison to being on surveillance or on clinical trial) (OR 5.9, p = 0.03), when adjusting for other factors in multivariable logistic regression. However, there was no correlation between annual income or PIC and FT. CONCLUSION: Financial toxicity in the RCC population is more significant in younger patients and those on treatment outside of a clinical trial. Financial aid should be offered to these at-risk patients to optimize adherence to life prolonging RCC treatments.

The Impact of Brain Metastases and Associated Neurocognitive Aspects on Health Utility Scores in EGFR Mutated and ALK Rearranged NSCLC: A Real World Evidence Analysis.

BACKGROUND: In lung cancer, brain metastases (BM) and their treatment are associated with high economic burden and inferior health-related quality of life. In the era of targeted therapy, real world evidence through health utility scores (HUS) is critical for economic analyses. MATERIALS AND METHODS: In a prospective observational cohort study (2014-2016), outpatients with stage IV lung cancer completed demographic and EQ-5D-3L surveys (to derive HUS). Health states and clinicopathologic variables were obtained from chart abstraction. Patients were categorized by the presence or absence of BM; regression analyses identified factors that were associated with HUS. A subset of patients prospectively completed neurocognitive function (NCF) tests and/or the FACT-brain (FACT-Br) questionnaire, which were then correlated with HUS (Spearman coefficients; regression analyses). RESULTS: Of 519 patients with 1,686 EQ-5D-3L-derived HUS, 94 (18%) completed NCF tests and 107 (21%) completed FACT-Br; 301 (58%) never developed BM, 24 (5%) developed first BM during study period, and 194 (37%) had BM at study entry. The sample was enriched (46%) for EGFR mutations (EGFRm) and ALK-rearrangements (ALKr). There were no HUS differences by BM status overall and in subsets by demographics. In multivariable analyses, superior HUS was associated with having EGFRm/ALKr (p < .0001), no prior radiation for extracranial disease (p < .001), and both intracranial (p = .002) and extracranial disease control (p < .01). HUS correlated with multiple elements of the FACT-Br and tests of NCF. CONCLUSION: Having BM in lung cancer is not associated with inferior HUS in a population enriched for EGFRm and ALKr. Patients exhibiting disease control and those with oncogene-addicted tumors have superior HUS. IMPLICATIONS FOR PRACTICE: In the setting of EGFR mutations or ALK rearrangement non-small cell lung cancer (NSCLC), a diagnosis of brain metastases no longer consigns the patient to an inferior health state suggesting that new economic analyses in NSCLC are needed in the era of targeted therapies. Additionally, the EQ-5D questionnaire is associated with measures of health-related quality of life and neurocognitive scores suggesting this tool should be further explored in prospective clinical studies.

Monitoring and Management of Immune-Related Adverse Events Associated With Programmed Cell Death Protein-1 Axis Inhibitors in Lung Cancer.

Monoclonal antibodies targeting programmed cell death protein-1 (PD-1) represent a new treatment paradigm in non-small cell lung cancer. Three phase III trials have demonstrated a survival benefit and improved tolerability of nivolumab and pembrolizumab when compared with standard second-line chemotherapy. Nevertheless, the adverse events associated with PD-1 inhibitors are unique; early recognition and treatment are essential. This review summarizes the required monitoring and appropriate management of immune-related adverse events in lung cancer patients receiving these agents. THE ONCOLOGIST: 2017;22:70-80 IMPLICATIONS FOR PRACTICE: : The potential adverse events of immune checkpoint inhibitors differ from conventional chemotherapy and can require a multidisciplinary approach. Continued education is important for all physicians to ensure optimal care for patients.

Pembrolizumab alone or with chemotherapy for metastatic non-small-cell lung cancer: A systematic review and network meta-analysis.

Pembrolizumab monotherapy has replaced chemotherapy as first-line treatment for patients with metastatic non-small-cell lung cancer with tumor programmed death-ligand 1 expression ≥ 50%. The benefit of chemotherapy combined with pembrolizumab, as compared to pembrolizumab monotherapy, remains uncertain. This systematic review and network meta-analysis aimed to compare these therapies through a network of randomized controlled trials. Endpoints evaluated were progression-free survival (PFS) and overall survival (OS) expressed as hazard ratio (HR) and restricted mean survival time (RMST) through reconstruction of individual patient data from Kaplan-Meier curves, and objective response rate and adverse events. Four trials were included. Through HR and RMST, combination therapy demonstrated longer PFS and similar OS as compared to pembrolizumab monotherapy. Combination therapy was associated with an increase in response rate and adverse events. Thus, combination therapy can be considered when rapid response or prevention of rapid progression is needed. Further evidence to directly compare these therapies is required.

Absence of thyroid transcription factor-1 expression is associated with poor survival in patients with advanced pulmonary adenocarcinoma treated with pemetrexed-based chemotherapy.

INTRODUCTION: Adenocarcinoma is the commonest histologic subtype of lung cancer and is often identified by immunohistochemical staining for thyroid transcription factor-1 (TTF-1). However, up to 20% of lung adenocarcinomas do not express TTF-1, and there is uncertainty regarding the significance of this. We aimed to evaluate the prognostic effect of TTF-1 expression status on survival in patients treated with pemetrexed-based chemotherapy for advanced adenocarcinoma of the lung. METHODS: This retrospective study included patients treated with pemetrexed-based chemotherapy for stage IIIB/IV lung adenocarcinoma, who had known TTF-1 expression status. Clinical and demographic data were obtained from medical records. Overall survival (OS) was estimated using the Kaplan-Meier method, and differences in survival between groups assessed using the Cox proportional hazards model. RESULTS: Forty-four patients were identified with documented TTF-1 expression: 35 with TTF-1-positive and 9 with TTF-1-negative disease. Patients in the TTF-1-negative group had poorer performance scores than those in the TTF-1-positive group (ECOG 2: 67 vs 20%, p = 0.008), and received less chemotherapy (median cycles 2 vs 4, p = 0.009), and were fewer in treatment with doublet regimens (22 vs 69%, p = 0.013). OS was significantly shorter in the TTF-1-negative group than in the TTF-1-positive group (2.4 vs 11.5 months, HR 8.38, p < 0.0001). CONCLUSIONS: In this group of patients treated with pemetrexed-based chemotherapy for advanced pulmonary adenocarcinoma, absence of TTF-1 expression was associated with an aggressive tumor phenotype, poorer performance status, and poor survival. This subgroup of patients should be recognized as having a distinct clinical course, with limited benefit from standard chemotherapy.

Financial Burden Among Patients With Lung Cancer in a Publically Funded Health Care System.

INTRODUCTION: Financial distress has been established as a clinically relevant patient-reported outcome associated with worse mortality and quality of life. Our goal was to define factors associated with financial burden (FB) in a public health care system. MATERIALS AND METHODS: Patients with advanced lung cancer were recruited from outpatient clinics at the Princess Margaret Cancer Centre (Toronto, Canada). FB was measured with the validated Comprehensive Score for Financial Toxicity (COST) instrument, a 12-item survey scored from 0 to 44, with lower scores reflecting worse financial well-being. Data on patient and treatment characteristics, total out-of-pocket costs (OOP), and private insurance coverage were collected. Multivariable logistic regression models were fit for COST score and each variable, to determine factors associated with greater FB (COST < 21). RESULTS: Of 251 patients approached, 200 (80%) participated. The median age of the cohort was 65 years; 56% were female. The median total OOP ranged between $1000 and $5000 CAD. The median COST score was 21 (range, 0-44). FB was associated with age, with patients < 65 years reporting greater FB than older patients (COST, 18.0 vs. 24.0; P < .0001). In multivariable logistic regression analysis, younger age was associated with greater FB, when adjusting for income, employment status, OOP, and private insurance coverage (odds ratio, 3.6; 95% confidence interval, 1.5-9.1; P < .0001). CONCLUSION: Age is significantly associated with FB in the Canadian (Ontario) public health care system, with younger patients with lung cancer reporting greater financial distress. This study highlights priority patient populations where FB should be routinely assessed and appropriate resources for support offered.

Development and evaluation of screening dysphagia tools for observational studies and routine care in cancer patients.

BACKGROUND AND AIMS: Dysphagia can be associated with significant morbidity in cancer patients. We aimed to develop and evaluate dysphagia screener tools for use in observational studies (phase 1) and for routine symptom monitoring in clinical care (phase 2). METHODS: Various dysphagia or odynophagia screening questions, selected after an expert panel reviewed the content, criterion, and construct validity, were compared with either functional assessment of cancer therapy - esophageal cancer (FACT-E) Swallowing Index Cut-Off Values or to questions adapted from the Patient Reported Outcomes for Common Terminology Criteria for Adverse Events. Sensitivity, specificity, and patient acceptability were assessed. RESULTS: In Phase 1 (n = 178 esophageal cancer patients), the screening question "How are you currently eating?" had the highest sensitivities and specificities against various Swallowing Index Cut-Off Value cut-offs, with the best optimal cutoff associated with weight loss (80% sensitivity and 75% specificity). In phase 2 (255 head and neck, gastro-esophageal, and thoracic cancer patients), a single question screener ("Do you experience any difficulty or pain upon swallowing?") versus a Patient Reported Outcomes for Common Terminology Criteria for Adverse Events-like gold standard generated sensitivities between 86% and 94% and specificities between 93% and 100%. This screening question (+/- follow-up questions) had a median completion time of under 2 minutes, and >90% of patients were willing to complete the survey electronically, did not feel that survey made clinic visit more difficult, and did not find the questions upsetting or distressful. CONCLUSION: Our results demonstrate that these screener tools ("How are you currently eating?", "Do you experience any difficulty or pain upon swallowing?") can effectively screen dysphagia symptoms without increasing cancer outpatient clinic burden, both in observational studies and for routine clinical monitoring.

Long term responders to palliative chemotherapy for advanced biliary tract cancer.

BACKGROUND: Patients with advanced biliary tract cancer (BTC) are often treated with palliative chemotherapy (PC). Standard PC since 2010 is a cisplatin/gemcitabine doublet, with median overall survival (OS) of 11.7 months from the ABC-02 trial. Prior to this, our institutional standard was gemcitabine and fluoropyrimidine. The ABC-02 study used 8 cycles of PC as standard with treatment stopped even in the absence of disease progression, but some patients may benefit from continuing PC longer than 8 cycles. METHODS: Patients treated with at least 2 cycles of PC for advanced BTC in Princess Margaret Cancer Centre between 1987 and 2015 were included, and divided into 2 groups for analysis-long-term responders (LTR) who received 9 or more cycles, and controls (2-8 cycles). Data was collected on demographics, clinicopathological features, PC regimen, toxicities, and survival. The primary outcome measure was OS, with secondary analyses including progression-free survival (PFS) and toxicity rates between groups. RESULTS: A total of 382 patients were identified, 123 who met the criteria for LTR and 259 who were included as controls. The baseline demographic and clinical characteristics were similar, although more patients in the control group had gallbladder cancer or extrahepatic cholangiocarcinoma than LTR (P=0.024), and more patients in the LTR group were treated with combination chemotherapy regimens (93% vs. 82% in controls, P=0.003). The LTR patients had significantly longer PFS (median 13.3 vs. 4.1 months, P<0.001) and longer OS than controls (median 22.1 vs. 9.2 months, P<0.001). In LTR patients, 15% had a break from chemotherapy of 3 months or more and restarted the same regimen. The LTR patients reported higher rates of nausea, cutaneous and hematologic toxicity, but also more frequently went on to receive second-line chemotherapy (47% vs. 33%, P=0.007). In multivariable analysis of OS, LTR, good performance status and intrahepatic site of cancer were associated with better survival. CONCLUSIONS: From this institutional dataset, a significant proportion of patients continued chemotherapy past 8 cycles, and appeared to derive benefit from longer duration of treatment. Toxicity rates were higher in this group, but manageable as evidenced by second-line treatment rates. Discontinuation of chemotherapy for reasons other than toxicity or progression may result in loss of disease control and impact survival in this population; these data suggest the use of continued chemotherapy to disease progression in patients with advanced BTC is a favorable option.

Prognostic and predictive effects of TP53 co-mutation in patients with EGFR-mutated non-small cell lung cancer (NSCLC).

INTRODUCTION: TP53 mutations are common in non-small cell lung cancer (NSCLC) and have been reported as prognostic of poor outcome. The impact of TP53 co-mutations in epidermal growth factor receptor (EGFR)-mutated NSCLC is unclear. MATERIALS AND METHODS: Tissue from 105 patients with EGFR-mutated NSCLC at Princess Margaret Cancer Centre was analyzed by next-generation or Sanger sequencing to determine TP53 mutational status. Associations between TP53 status and baseline patient and tumor characteristics, treatments and outcomes (relapse-free survival [RFS] after surgical resection, overall survival [OS], overall response rate [ORR] and progression-free survival [PFS] on EGFR tyrosine kinase inhibitors [TKIs]), were investigated. RESULTS: Dual TP53/EGFR mutations were found in 43/105 patients (41%). Among 76 patients who underwent surgical resection, neither RFS (HR 0.99, CI 0.56-1.75, p=0.96) nor OS (HR 1.39, CI 0.70-2.77; p=0.35) was associated with TP53 status. Sixty patients (24 TP53 MUT; 36 TP53 WT) received first-generation EGFR TKIs for advanced disease. ORR was not significantly different (TP53 MUT 54%, WT 66%, p=0.42). There was a non-significant trend towards shorter PFS on EGFR TKIs with TP53 mutation (HR 1.74, CI 0.98-3.10, p=0.06). When limited to TP53 missense mutations (n=17), PFS was significantly shorter (HR 1.91, CI 1.01-3.60, p=0.04). Among 11 evaluable patients treated with T790M inhibitors, ORR was not significantly different (TP53 MUT 3/3 [100%], WT 7/8 [88%]). CONCLUSIONS: Patients with dual TP53/EGFR mutations, especially missense mutations, had marginally lower response rates and shorter PFS when treated with EGFR TKI therapy. Larger datasets are required to validate these observations.

Treatment options for patients with brain metastases from EGFR/ALK-driven lung cancer.

INTRODUCTION: Brain metastases in EGFR/ALK-driven NSCLC frequently pose treatment dilemmas. Tyrosine kinase inhibitors (TKIs) can control extracranial disease, but radiotherapy is often required for intracranial control. We aimed to evaluate the impact of first-line whole brain radiotherapy (WBRT), stereotactic radiotherapy (SRS) or TKI alone on outcomes of patients with brain metastases from EGFR/ALK-driven NSCLC. METHODS: This single center retrospective review included 184 patients with brain metastases from EGFR/ALK-driven NSCLC, and analyzed effect of treatment choice on time to intracranial progression (TTIP) and overall survival (OS). RESULTS: First-line treatment for brain metastases consisted of WBRT in 120 patients, SRS in 37 and TKI alone in 27. WBRT-treated patients had more brain metastases, and more baseline symptoms. Median TTIP was longer in the WBRT group at 50.5months than SRS or TKI groups at 12 and 15months (p=0.0038). No significant difference was seen in median OS: 21.6months in the WBRT group, 23.9months in the SRS group and 22.6months in the TKI group (p=0.67). In multivariable analysis, age>65years (HR 2.2, p=0.0014), greater number of brain metastases (HR 2.48, p=0.0002) and greater number of extracranial metastatic sites (2 vs 0-1 HR=2.05, p=0.014 and 3+ vs 0-1 HR=2.95, p=0.0001 were associated with shorter OS. No independent effect was seen from first-line CNS treatment choice. CONCLUSIONS: First-line WBRT for brain metastases from EGFR/ALK-driven NSCLC was associated with longer TTIP than SRS or TKI alone, with no difference in OS. These results could support deferral of WBRT until intracranial progression in selected patients who are closely monitored.

Adjuvant therapy for resected biliary tract cancer: a review.

Surgical resection remains the most important treatment for patients with biliary tract cancer (BTC), but despite radical surgical techniques many patients ultimately develop recurrent disease. BTC encompasses several distinct disease entities-intrahepatic, perihilar and distal bile duct cholangiocarcinoma as well as gallbladder cancer. These tumors are histologically similar, but have different etiologies and recent information regarding their genomic footprint has questioned their biological similarity. Surgical approaches are also necessarily varied based on the site of the tumor. Due to the poor survival rates seen in this disease, there has been significant effort to investigate chemotherapy and radiotherapy as adjuvants in patients whose disease has been successfully resected. The majority of the published evidence supporting this treatment relies on retrospective series or limited prospective studies, making interpretation difficult and complicating treatment decisions. This review summarizes the data regarding these adjunctive therapies.

Eribulin for the treatment of metastatic breast cancer: an update on its safety and efficacy.

Breast cancer remains a leading cause of cancer-related death internationally. Treatment approaches for metastatic breast cancer have evolved in recent years; however chemotherapy remains a core component for the majority of patients. Agents such as anthracyclines and taxanes have been extensively studied and form standard treatment. Eribulin mesylate is a novel synthetic microtubule-directed chemotherapy, based on a naturally-occurring compound. Through phase I studies, eribulin was found to be tolerable and activity was seen in patients with metastatic breast cancer. Phase II studies in metastatic breast cancer further demonstrated its efficacy, with responses and survival which compare favorably with other studied chemotherapy agents. The phase III EMBRACE study showed superior survival for patients treated with eribulin compared with those who received a physician's choice control. This led to its approval for use in many countries in this setting. Its toxicity profile is well established and manageable for the most part, with the commonest reported toxicities being alopecia, fatigue, neutropenia and peripheral neuropathy. A second reported phase III study comparing eribulin to capecitabine failed to show an improvement in survival in pretreated patients. This article reviews the clinical pharmacology and mechanism of action of eribulin, and summarizes the results of the major preclinical and clinical studies of eribulin in metastatic breast cancer.