Adrian Lee

HER2 insertion YVMA mutant lung cancer: Long natural history and response to afatinib

Human epidermal growth factor 2 (HER2, ERBB2) mutations in lung cancers are oncogenic drivers that respond to HER2 targeted therapies. Little is known about the sensitivity of subtypes of HER2 mutant lung cancers to targeted agents. We present a patient with HER2 mutant lung cancer with a 12 base pair insertion YVMA (p.A775_G776insYVMA), who had a long natural history and durable partial response to afatinib. We demonstrate that afatinib has activity in patients with HER2 mutant lung cancers with exon 20 YVMA insertions, the most common variant.

Screening for ROS1 gene rearrangements in non-small-cell lung cancers using immunohistochemistry with FISH confirmation is an effective method to identify this rare target

To assess the prevalence of ROS1 rearrangements in a retrospective and prospective diagnostic Australian cohort and evaluate the effectiveness of immunohistochemical screening.

Systematic Review and Meta-Analysis on the Role of Chemotherapy in Advanced and Metastatic Neuroendocrine Tumor (NET).

Background/Objectives In the era of somatostatin analogues and targeted therapies, the role of chemotherapy in NET remains largely undefined. This systematic review aimed to assess the effect of chemotherapy on response rates (RR), progression-free survival (PFS), overall survival (OS) and toxicity compared to other chemotherapies/systemic therapies or best supportive care in patients with advanced or metastatic NET. Methods Randomised controlled trials (RCTs) from 1946 to 2015 were identified from MEDLINE, EMBASE, other databases and conference proceedings. Review of abstracts, quality assessment and data abstraction were performed independently by two investigators. Meta-analyses were conducted using Mantel-Haenszel analysis with random-effects modelling. Results Six RCTs comparing standard streptozotocin plus 5-fluorouacil (STZ/5FU) chemotherapy to other chemotherapy regimens, and 2 comparing this to interferon (IFN) were included. Only 1 study was considered at low risk of bias. STZ/5-FU was no different to other chemotherapies in response rate [RR 0.96; 95% confidence interval (CI) 0.72–1.27], PFS (RR 0.95; CI 0.81–1.13), or OS (RR 1.03; CI 0.77–1.39). IFN may produce higher response than STZ/5FU (RR 0.20; CI 0.04–1.13), but event rates were small and survival was no different. Interferon was associated with higher overall haematological (RR 0.47; CI 0.27–0.82) and lower overall renal toxicity (RR 3.61; CI 1.24–10.51). Conclusion Strong evidence is lacking in the area of chemotherapy in neuroendocrine tumors. There is currently no evidence that one chemotherapeutic regimen is significantly better than the other, nor is interferon better than chemotherapy. There is an urgent need to design RCTs comparing modern chemotherapy to other agents in NET.

Intensity-modulated radiotherapy using simultaneous-integrated boost for definitive treatment of locally advanced mucosal head and neck cancer: Outcomes from a single-institution series

The study aims to report outcomes for patients treated using intensity‐modulated radiotherapy (IMRT) with simultaneous‐integrated boost and weekly cisplatin for American Joint Committee on Cancer stage III/IV mucosal head and neck squamous cell carcinomas (HNSCCs).

The addition of anti-angiogenic tyrosine kinase inhibitors to chemotherapy for patients with advanced non-small-cell lung cancers: A meta-analysis of randomized trials

OBJECTIVES The role of anti-angiogenic tyrosine kinase inhibitors (AATKI) for patients with non-small-cell lung cancers (NSCLC) is uncertain. We conducted a comprehensive meta-analysis to assess the overall utility of adding AATKI to chemotherapy. MATERIALS AND METHODS We included 15 randomized controlled trials (RCTs) of AATKI plus chemotherapy versus chemotherapy involving 7997 patients with advanced NSCLC. Meta-analysis was performed to obtain pooled hazard ratios (HR) for OS and PFS, and pooled odds ratios (OR) for objective response rate (ORR) and grade 3 or greater toxicity. Pre-specified subgroup analyses were performed according to line of chemotherapy, chemotherapeutic regimen and histology. RESULTS The addition of AATKI to chemotherapy significantly increased progression-free survival (PFS) (HR 0.83, 95% CI 0.79, 0.87; P<0.00001) and ORR [OR 1.63, 95% CI 1.45, 1.84; P<0.00001], but not overall survival (OS) (HR 0.96, 95% CI 0.91, 1.01; P=0.14). OS benefit was seen in the subset of patients with adenocarcinomas (HR 0.86; 95% CI 0.79, 0.95; P=0.002), especially in the second line setting (HR 0.85; 95% CI 0.76, 0.96; P=0.008). However, both grade ≥3 toxicity (HR 2.08, 95% CI 1.59, 2.73; P<0.00001) and treatment-related deaths (OR 2.37, 95% CI 1.58, 3.56; P<0.0001) were significantly higher with the addition of AATKI. CONCLUSION The addition of AATKI to chemotherapy in patients with advanced NSCLC significantly increased PFS and ORR but not OS, and did so at the expense of increased toxicity and treatment-related deaths. Preclinical and translational research in predictive biomarkers are essential for the clinical development of this class of drugs.

Malignant Cardiac Tamponade from Non-Small Cell Lung Cancer: Case Series from the Era of Molecular Targeted Therapy

Cardiac tamponade complicating malignant pericardial effusion from non-small cell lung cancer (NSCLC) is generally associated with extremely poor prognosis. With improved systemic chemotherapy and molecular targeted therapy for NSCLC in recent years, the prognosis of such patients and the value of invasive cardiothoracic surgery in this setting have not been adequately examined. We report outcomes from a contemporary case series of eight patients who presented with malignant cardiac tamponade due to NSCLC to an Australian academic medical institution over an 18 months period. Two cases of cardiac tamponade were de novo presentations of NSCLC and six cases were presentations following previous therapy for NSCLC. The median survival was 4.5 months with a range between 9 days to alive beyond 17 months. The two longest survivors are still receiving active therapy at 17 and 15 months after invasive surgical pericardial window respectively. One survivor had a histological subtype of large cell neuroendocrine carcinoma and the other received targeted therapy for epidermal growth factor receptor mutation. These results support the consideration of active surgical palliation to treating this oncological emergency complicating NSCLC, including the use of urgent drainage, surgical creation of pericardial window followed by appropriate systemic therapy in suitably fit patients.

Complete response in a patient with stage IV adrenocortical carcinoma treated with adjuvant trans-catheter arterial chemo-embolization (TACE)

Adrenocortical carcinoma is a rare cancer, with estimate population incidence of 0.7–2.0 cases per 1 million each year. It also carries poor prognosis with estimated 5‐year survival of less than 15% of those with metastatic disease and has a poor response to cytotoxic treatment. A randomized controlled trial published in 2012 by Fassnacht et al. demonstrated improved progression‐free survival with first‐line etoposide‐doxirubicin‐cisplatin‐mitotane (EDP‐M) compared to first‐line streptozocin–mitotane in patients with stage III–IV disease.

Pembrolizumab-induced auto-immune type-1 diabetes in a patient with metastatic melanoma

Immunotherapy for metastatic melanoma has improved response rates and progression‐free survival significantly compared to traditional chemotherapy. However, our understanding of their unique side‐effect profile remains limited given the novelty of these treatments. Unlike traditional cytotoxic chemotherapy, immunotherapy is often associated with autoimmune‐related toxicities, including colitis, thyroiditis, pneumonitis or hepatitis. However, autoimmune endocrinopathies are much less well described. These experiences are concerning as the use of these agents is becoming more widespread in other cancer subtypes and they require very different approaches in regard to toxicity management. We report a case of pembrolizumab‐induced auto‐immune diabetes and hepatitis in a patient undergoing treatment for metastatic melanoma.

FET PET in the evaluation of indeterminate brain lesions on MRI: Differentiating glioma from other non-neoplastic causes – A pilot study

We aimed to determine the utility of FET PET in the management of indeterminate CNS lesions found on MRI. We performed a retrospective analysis of patients with FET PET at a single tertiary institution from 2011 to 2015. FET PET images were processed using usual methods and measurements taken including SUVmax, TBRmax, and analysis of dynamic series where available (Kipeak, Vdpeak, as well as tumor:background ratio for these variables). Correlation studies were performed using ANOVA between cohorts of high-grade histology, low-grade histology, and benign histology/stable on observation. Thirty-five patients were included, of whom 34 were suitable for analysis with median follow-up of 5 months. The positive predictive value of FET PET in this cohort was 83.3%. FET SUVmax differentiated between patients with high-grade (mean SUV 3.38, 95% CI 2.21-4.55), low-grade (1.88, 95% CI 1.33-2.43) and benign/observation (1.42, 95% CI 1.13-1.71) cohorts (p = 0.0003). Similarly, tumour to brain ratio was significant (p < 0.0001). Kipeak distinguished between high grade and observation cohorts (p = 0.036), as did KiTBR (p = 0.025). Vd peak was not significantly different in these two cohorts (p = 0.057) but Vd TBR was (p = 0.041). In conclusion, FET PET demonstrated a high positive predictive value for glioma in patients with indeterminate brain lesions on MRI. The combination of negative FET and negative FDG PET scans may predict an indolent clinical course. Confirmatory trials are needed to establish the potential value of FET PET in guiding surgical management in this cohort.

ROS1-Rearranged Non–Small-Cell Lung Cancer, Factor V Leiden, and Recurrent Venous Thromboses

Cancer-related venous thromboembolic events are a significant morbidity and mortality burden. The risks of venous thromboembolic events vary with cancer location, stage, preexisting thrombophilia conditions, and possibly with driver mutations. In combination, these risks may be synergistic despite each factor being a minor risk independently. Despite the availability of targeted therapy for ROS1rearranged nonesmall-cell lung cancer, there is increasing evidence of a poorer outcome group with rapid decline and progression of disease; the mechanisms are still unknown, and interaction with coagulation system may be a potential factor. Thromboprophylaxis for increasedor multiple-risk patients needs to be individually tailored and closely monitored.