Sir Peter MacCallum Department of Oncology - Research Publications
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ItemTreatment of ALK-rearranged non- small cell lung cancer: A review of the landscape and approach to emerging patterns of treatment resistance in the Australian context(WILEY, 2017-08)Since the identification of anaplastic lymphoma kinase (ALK) gene rearrangements in non-small cell lung cancer (NSCLC) in 2005, the treatment of ALK-rearranged NSCLC (ALK+ NSCLC) has evolved at a rapid pace. This molecularly distinct subset of NSCLC has uniquely important biology, clinicopathologic features and mechanisms of drug resistance which impact on the choice of treatment for a patient with this disease. There are multiple ALK tyrosine kinase inhibitors now available in clinical practice with efficacy data continuing to emerge and guide the optimal treatment algorithm. A detailed search of medical databases and clinical trial registries was conducted to capture all relevant articles on this topic enabling an updated detailed overview of the landscape of management of ALK-rearranged NSCLC.
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ItemImpact of sex on prognostic host factors in surgical patients with lung cancer(WILEY, 2017-12)BACKGROUND: Lung cancer has markedly poorer survival in men. Recognized important prognostic factors are divided into host, tumour and environmental factors. Traditional staging systems that use only tumour factors to predict prognosis are of limited accuracy. By examining sex-based patterns of disease-specific survival in non-small cell lung cancer patients, we determined the effect of sex on the prognostic value of additional host factors. METHODS: Two cohorts of patients treated surgically with curative intent between 2000 and 2009 were utilized. The primary cohort was from Melbourne, Australia, with an independent validation set from the American Surveillance, Epidemiology and End Results (SEER) database. Univariate and multivariate analyses of validated host-related prognostic factors were performed in both cohorts to investigate the differences in survival between men and women. RESULTS: The Melbourne cohort had 605 patients (61% men) and SEER cohort comprised 55 681 patients (51% men). Disease-specific 5-year survival showed men had statistically significant poorer survival in both cohorts (P < 0.001); Melbourne men at 53.2% compared with women at 68.3%, and SEER 53.3% men and 62.0% women were alive at 5 years. Being male was independently prognostic for disease-specific mortality in the Melbourne cohort after adjustment for ethnicity, smoking history, performance status, age, pathological stage and histology (hazard ratio = 1.54, 95% confidence interval: 1.10-2.16, P = 0.012). CONCLUSIONS: Sex differences in non-small cell lung cancer are important irrespective of age, ethnicity, smoking, performance status and tumour, node and metastasis stage. Epidemiological findings such as these should be translated into research and clinical paradigms to determine the factors that influence the survival disadvantage experienced by men.
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Itemp16-positive lymph node metastases from cutaneous head and neck squamous cell carcinoma: No association with high-risk human papillomavirus or prognosis and implications for the workup of the unknown primary(WILEY-BLACKWELL, 2016-04-15)BACKGROUND: The incidence of p16 overexpression and the role of human papillomavirus (HPV) in cutaneous head and neck squamous cell carcinoma (cHNSCC) are unclear. METHODS: One hundred forty-three patients with cHNSCC lymph node metastases involving the parotid gland were evaluated for p16 expression by immunohistochemistry. The detection of 18 high-risk HPV subtypes was performed with HPV RNA in situ hybridization for a subset of 59 patients. The results were correlated with clinicopathological features and outcomes. RESULTS: The median follow-up time was 5.3 years. No differences were observed in clinicopathological factors with respect to the p16 status. p16 was positive, weak, and negative in 45 (31%), 21 (15%), and 77 cases (54%), respectively. No high-risk HPV subtypes were identified, regardless of the p16 status. The p16 status was not prognostic for overall (hazard ratio, 1.08; 95% confidence interval [CI], 0.85-1.36; P = .528), cancer-specific (hazard ratio, 1.12; 95% CI, 0.77-1.64; P = .542), or progression-free survival (hazard ratio, 1.03; 95% CI, 0.83-1.29; P = .783). Distant metastasis-free survival, freedom from locoregional failure, and freedom from local failure were also not significantly associated with the p16 status. CONCLUSIONS: p16 positivity is common but not prognostic in cHNSCC lymph node metastases. High-risk HPV subtypes are not associated with p16 positivity and do not appear to play a role in this disease. HPV testing, in addition to the p16 status in the unknown primary setting, may provide additional information for determining a putative primary site.
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ItemClinical Management of Adverse Events Associated with Lorlatinib(OXFORD UNIV PRESS, 2019-08)Lorlatinib is a novel, highly potent, brain-penetrant, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI), which has broad-spectrum potency against most known resistance mutations that can develop during treatment with crizotinib and second-generation ALK TKIs. The safety profile of lorlatinib was established based on 295 patients who had received the recommended dose of lorlatinib 100 mg once daily. Adverse events associated with lorlatinib are primarily mild to moderate in severity, with hypercholesterolemia (82.4%), hypertriglyceridemia (60.7%), edema (51.2%), peripheral neuropathy (43.7%), and central nervous system effects (39.7%) among the most frequently reported. These can be effectively managed with dose modification and/or standard supportive medical therapy, as indicated by a low incidence of permanent discontinuations due to adverse reactions. Most patients (81.0%) received at least one lipid-lowering agent. Prescription of supportive therapy should also consider the potential for drug-drug interactions with lorlatinib via engagement of specific CYP450 enzymes. This article summarizes the clinical experience from lorlatinib phase I investigators and was generated from discussion and review of the clinical study protocol and database to provide an expert consensus opinion on the management of the key adverse reactions reported with lorlatinib, including hyperlipidemia, central nervous system effects, weight increase, edema, peripheral neuropathy, and gastrointestinal effects. Overall, lorlatinib 100 mg once daily has a unique safety profile to be considered when prescribed, based on the recent U.S. Food and Drug Administration approval, for the treatment of patients with ALK-positive metastatic non-small cell lung cancer previously treated with a second-generation ALK TKI. IMPLICATIONS FOR PRACTICE: Despite the advancement of second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs), the emergence of resistance and progression of central nervous system metastases remain clinically significant problems in ALK-positive non-small cell lung cancer. Lorlatinib is a potent, brain-penetrant, third-generation, macrocyclic ALK/ROS1 TKI, with broad-spectrum potency against most known resistance mutations that can develop during treatment with existing first- and second-generation ALK TKIs. This article provides recommendations for the clinical management of key adverse reactions reported with lorlatinib.
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ItemRadiotherapy and immunotherapy: a synergistic effect in cancer care(WILEY, 2019-01-14)Radiotherapy is an effective treatment modality commonly used in efforts to cure many localised cancers and in the palliation of symptoms in metastatic cancers. Immunotherapy has revolutionised cancer care by increasing the disease control and overall survival of patients in several cancer types; however, the majority of patients do not respond to currently available therapies based on immune checkpoint inhibitors (ICIs). The benefit of those agents is limited to patients who have a pre-existing active immune microenvironment that can be reactivated by ICIs. It is now recognised that radiotherapy does not only directly kill tumour cells but it also changes the tumour microenvironment, enhancing tumour cell recognition by the immune system and, therefore, acting as an in situ vaccine. Radiotherapy increases expression of tumour-associated antigens, causes the release of cytokines, stimulates recruitment of dendritic cells and, most importantly, stimulates the proliferation and priming of cytotoxic CD8+ T cells in the tumour microenvironment. This immunological cascade specifically generates activated T cells able to induce immunogenic cell death directed against cancer cells bearing those antigens. By its ability to overcome some tumour immune escape mechanisms, radiation provides a non-pharmacological and cost-effective approach to potentially improve the systemic response to immune checkpoints inhibitors.
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ItemUnilateral Radiotherapy Treatment for p16/Human Papillomavirus-Positive Squamous Cell Carcinoma of Unknown Primary in the Head and Neck(WILEY, 2018-09)OBJECTIVES/HYPOTHESIS: The outcomes of unilateral radiotherapy treatment for patients with p16/HPV-positive squamous cell carcinomas of unknown primary (SCCUP) affecting cervical lymph nodes are under-reported. Compared to radiating large volumes of the pharyngeal axis (the more common approach), this is potentially a much less toxic treatment for a good prognosis group. STUDY DESIGN: Retrospective cohort study. METHODS: We identified patients with SCCUP who were treated radically at our center and did not have parotid or isolated level IV or V nodal involvement. Failure-free and overall survivals were calculated using Kaplan-Meier methods. RESULTS: From 2004 to 2012, there were 49 radically treated patients with SCCUP. Fourteen patients had bilateral neck treatment (they had bilateral nodal disease or suspected lesions in the base of tongue, though not proven with biopsy), two had surgery alone, whereas 33 had unilateral radiotherapy (after neck dissection, excisional biopsy, or definitively with concurrent chemotherapy). Of the 33 patients, 21 tested positive to p16/HPV and had median follow-up of 57 months. In this group, no isolated contralateral neck failures or putative primaries emerged. There was 1/21 (4.3%) ipsilateral neck failure, 1/21 (4.3%) concurrent contralateral neck and distant failure, and 1/21 (4.3%) patient with distant failure. The 5-year freedom from failure was 78% (95% confidence interval [CI]: 56%-100%) and overall survival was 90% (95% CI: 79%-100%). CONCLUSIONS: With no emergence of putative primaries and no isolated contralateral neck failures, this single-institution experience in p16/HPV-positive SCCUP patients suggests that unilateral radiotherapy may be an underutilized management strategy. LEVELS OF EVIDENCE: 4 Laryngoscope, 128:2076-2083, 2018.
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ItemSurvival difference according to mutation status in a prospective cohort study of Australian patients with metastatic non-small-cell lung carcinoma(WILEY, 2018-01)BACKGROUND: Non-small-cell lung cancer (NSCLC) is a heterogeneous disease comprising not only different histological subtypes but also different molecular subtypes. AIM: To describe the frequency of oncogenic drivers in patients with metastatic NSCLC, the proportion of patients tested and survival difference according to mutation status in a single-institution study. METHODS: Metastatic NSCLC patients enrolled in a prospective Thoracic Malignancies Cohort Study between July 2012 and August 2016 were selected. Patients underwent molecular testing for epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) gene rearrangements, Kirsten rat sarcoma (KRAS), B-Raf proto-oncogene (BRAF) mutations and ROS1 gene rearrangements. Survival was calculated using the Kaplan-Meier method for groups of interest, and comparisons were made using the log-rank test. RESULTS: A total of 392 patients were included, 43% of whom were female with median age of 64 years (28-92). Of 296 patients tested, 172 patients (58%) were positive for an oncogenic driver: 81 patients (27%) were EGFR positive, 25 patients (9%) were ALK positive, 57 patients (19%) had KRAS mutation and 9 patients (3%) were ROS1 or BRAF positive. Patients with an actionable mutation (EGFR/ALK) had a survival advantage when compared with patients who were mutation negative (hazard ratio (HR) 0.49; 95% confidence interval (CI) 0.33-0.71; P < 0.01). Survival difference between mutation negative and mutation status unknown was not statistically significant when adjusted for confounding factors in a multivariate analysis (HR 1.29; 95% CI 0.97-1.78, P = 0.08). CONCLUSION: In this prospective cohort, the presence of an actionable mutation was the strongest predictor of overall survival. These results confirm the importance of molecular testing and suggest likely survival benefit of identification and treatment of actionable oncogenes.
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ItemNo Preview AvailableAbsence of a Relationship between Tumor 18F-fluorodeoxyglucose Standardized Uptake Value and Survival in Patients Treated with Definitive Radiotherapy for Non-Small-Cell Lung Cancer(LIPPINCOTT WILLIAMS & WILKINS, 2014-03)INTRODUCTION: A recent meta-analysis suggested that patients with non-small-cell lung cancer (NSCLC) whose primary tumors have a higher standardized uptake value (SUV) derived from F-fluorodeoxyglucose positron emission tomography (PET) have a worse prognosis in comparison with those with tumors with lower values. However, previous analyses have had methodological weaknesses. Furthermore, the prognostic significance over the full range of SUV values in patients treated nonsurgically remains unclear. The aim of this retrospective study was to investigate the relationship between survival and maximum SUV (SUV(max)) analyzed as a continuous variable, in patients with NSCLC, staged using PET/computed tomography (CT) and treated with radiotherapy with or without chemotherapy. METHODS: Eligible patients had a histological diagnosis of NSCLC, were treated with radical radiotherapy with or without chemotherapy as their primary treatment, and had pretreatment PET/CT scans. SUV(max), defined as the maximum pixel SUV value retrieved from the primary tumor, was analyzed primarily as a continuous variable for overall survival. RESULTS: Eighty-eight patients met eligibility criteria: stage I, 19; stage II, 10; and stage III, 59. Median SUV(max) was 15.0 (range, 2.5-56). Higher stage was associated with higher SUV(max) values (p = 0.048). In univariate analysis, there was no evidence of a prognostic effect of SUV(max) (hazard ratio per doubling = 0.83; 95% confidence interval, 0.62-1.11; p = 0.22). Analyzing SUV(max) as a dichotomous variable (median cut point = 15.0), the hazard ratio (high: low) for risk of death was 0.71, with p = 0.18 (95% confidence interval, 0.44-1.15). CONCLUSIONS: In this cohort of patients, increasing SUV(max) derived from F-fluorodeoxyglucose-PET/CT was associated with increasing tumor, node, metastasis (TNM) stage. We found no evidence of an association of increasing SUV(max) with a shorter survival. Previous reports of an association between prognosis and SUV(max) may partly be the result of methodological differences between this study and previous reports and an association between stage and SUV(max).
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ItemA critical re-assessment of DNA repair gene promoter methylation in non-small cell lung carcinoma(NATURE PORTFOLIO, 2014-02-26)DNA repair genes that have been inactivated by promoter methylation offer potential therapeutic targets either by targeting the specific repair deficiency, or by synthetic lethal approaches. This study evaluated promoter methylation status for eight selected DNA repair genes (ATM, BRCA1, ERCC1, MGMT, MLH1, NEIL1, RAD23B and XPC) in 56 non-small cell lung cancer (NSCLC) tumours and 11 lung cell lines using the methylation-sensitive high resolution melting (MS-HRM) methodology. Frequent methylation in NEIL1 (42%) and infrequent methylation in ERCC1 (2%) and RAD23B (2%) are reported for the first time in NSCLC. MGMT methylation was detected in 13% of the NSCLCs. Contrary to previous studies, methylation was not detected in ATM, BRCA1, MLH1 and XPC. Data from The Cancer Genome Atlas (TCGA) was consistent with these findings. The study emphasises the importance of using appropriate methodology for accurate assessment of promoter methylation.