Publications by authors named "Nick Pavlakis"

164 Publications

EGFR Exon 20 Insertion Mutations: Clinicopathological Characteristics and Treatment Outcomes in Advanced Non-Small Cell Lung Cancer.

Clin Lung Cancer 2021 May 16. Epub 2021 May 16.

Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. Electronic address:

Background: Epidermal growth factor receptor gene (EGFR) exon 20 insertion (ex20-ins) mutations are an uncommon and heterogeneous group of non-small cell lung cancers (NSCLCs), resistant to conventional EGFR tyrosine kinase inhibitors (TKIs). Characteristics and outcomes of patients with EGFR ex20-ins have not been fully established; we sought to clarify them using a multinational patient database.

Patients And Methods: Patients with NSCLC from six Australian institutions with EGFR exon 20 mutations (ex20-mut), excluding T790M, were retrospectively reviewed. Clinical characteristics and outcomes with systemic treatments were collected and analyzed using comparative statistics.

Results: Among 109 patients with ex20-mut, 61% were females and 75% were Caucasians. More males presented with de novo metastatic disease (84% vs. 51%; P = .002). Central nervous system (48%) and liver (24%) metastases were common within metastatic patients (n = 86). Thirty-nine patients received platinum-based chemotherapy (PBC) and achieved a 43% objective response rate (ORR), median progression-free survival (mPFS) of 6.9 months, and median overall survival (mOS) of 31.0 months. Twenty-three of the patients with ex20-ins received conventional TKIs, resulting in an ORR of 13%, mPFS of 3.4 months (95% confidence interval [CI], 1.91-6.25), and mOS of 31.0 months (95% CI, 15.09-not reached). Nine patients with S786I mutations received TKIs, resulting in an ORR of 50%, mPFS of 18.2 months (2.79-not reached), and mOS of 33.4 months (95% CI, 16.14-not reached). Twenty-three patients received immune checkpoint inhibitor monotherapy (ICIm), resulting in an ORR of 4%, mPFS of 2.6 months (95% CI, 1.91-4.83), and mOS of 30.8 months (95% CI, 17.62-41.62).

Conclusion: Although phenotypically similar to patients with common EGFR mutations, patients with EGFR ex20-mut had worse survival, perhaps due to the lack of targeted therapies. Chemotherapy was superior to conventional EGFR TKIs in patients with EGFR ex20-ins, although there was moderate activity of TKIs in S768I mutations. ICIm was ineffective.
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http://dx.doi.org/10.1016/j.cllc.2021.04.009DOI Listing
May 2021

Efficacy of immunotherapy in -mutant non-small-cell lung cancer with comutations.

Immunotherapy 2021 Jun 11. Epub 2021 Jun 11.

Department of Medical Oncology, Chris O'Brien Lifehouse, 119-143 Missenden Road, Camperdown, NSW 2050, Australia.

-mutant non-small-cell lung cancer is the most common molecular driver of lung adenocarcinoma in western populations. No  specific therapy has been approved by the FDA until 2021. Despite significant heterogeneity in comutations, patients typically receive single-agent immunotherapy or chemoimmunotherapy as standard first-line therapy. It is unclear whether mutations predict outcomes with immunotherapy; however, there is emerging data suggesting improved outcomes in patients with a  comutation and worse outcomes in patients with a /LKB1 or  comutation.
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http://dx.doi.org/10.2217/imt-2021-0090DOI Listing
June 2021

Neoadjuvant immunotherapy for non-small cell lung cancer: right drugs, right patient, right time?

J Immunother Cancer 2021 Jun;9(6)

Medical Oncology, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.

Standard curative treatment of early-stage non-small cell lung cancer (NSCLC) involves surgery in combination with postoperative (adjuvant) platinum-based chemotherapy where indicated. Preoperative (neoadjuvant) therapies offer certain theoretical benefits compared with adjuvant approaches, including the ability to assess on-treatment response, reduce the tumor bulk prior to surgery, and enhance tolerability in the preoperative setting. Indeed, the use of neoadjuvant therapies are well established in other cancers such as breast and rectal cancers to debulk the tumor and guide ongoing therapy, and neoadjuvant chemotherapy has similar efficacy but less toxicity in NSCLC. More recently, immune checkpoint inhibitors (ICI) targeting programmed death-1 (PD1)/PD1-ligand 1 (PD-L1) have transformed the treatment of advanced NSCLC; the unique mechanisms of action of ICI offer additional rationale for assessment in the neoadjuvant setting. Preclinical studies in mouse cancer models support the proof of concept of neoadjuvant ICI (NAICI) through improvement of T-cell effector function and long-term memory induction. Preliminary early-phase human trial data support the proposition that NAICI in NSCLC may provide an feasible and potentially efficacious future treatment strategy and large, randomized phase III trials are currently recruiting to assess this approach. However, outstanding issues include defining optimal treatment combinations which balance high efficacy with acceptable toxicity, validating biomarkers to aid in patient selection, and avoiding potential pitfalls such as missing a window for successful surgery, that is, choosing the right drugs, for the right patient, at the right time. Predictive biomarkers to direct selection of therapy are required, and the validation of major pathological response (MPR) as a surrogate for survival will be important in the uptake of the neoadjuvant approach.
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http://dx.doi.org/10.1136/jitc-2020-002248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183290PMC
June 2021

The unmet supportive care needs, quality of life, and care experiences of patients with functioning and non-functioning Neuroendocrine tumours (NETs) at early diagnosis.

Patient Educ Couns 2021 May 11. Epub 2021 May 11.

Department of Health Services Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department on Oncology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia; Department of Psychology and Iverson Health Innovation Research Institute, Swinburne University, Melbourne, Australia. Electronic address:

Objective: Healthcare experiences, quality of life and psychosocial needs of patients with Neuroendocrine tumours (NETs) will be assessed to identify differences between NET sub-groups and inform the design of supportive care services.

Methods: This study constitutes phase one of a three-phase mixed-methods multi-site study with NET patients (n = 123). Demographic, clinical and patient reported outcome questionnaire data was collected.

Results: No differences in patient reported outcomes were found beyond symptoms of diarrhoea and flushing between NET sub-groups. For combined NET patients, the majority reported negative experiences in their understanding of the explanation of what was wrong with them (67%); receiving written information about their cancer (69%), their family/carer receiving all the information required to care for them (61%); and the usefulness of information about NETs online (66%). NET patients reported at least one moderate-to-high need for disease specific information (63%). Medium- to large-sized differences in quality of life subscales were also observed with the functioning group reporting more anxiety compared to population norms.

Conclusions: There is a need to improve the current provision of information for people with NETs.

Practice Implications: These findings will inform the design and development of an informational resource to facilitate improved understanding for patients with NETs.
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http://dx.doi.org/10.1016/j.pec.2021.05.006DOI Listing
May 2021

Computed tomography (CT)-defined sarcopenia and myosteatosis are prevalent in patients with neuroendocrine neoplasms (NENs) treated with peptide receptor radionuclide therapy (PRRT).

Eur J Clin Nutr 2021 May 13. Epub 2021 May 13.

Cancer Services, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.

Background/objectives: Neuroendocrine neoplasms (NEN) may predispose patients to malnutrition. CT-defined sarcopenia and myosteatosis are common in other tumour types and recognized adverse prognostic factors. However, the prevalence and prognostic impact of sarcopenia and myosteatosis remain undetermined in NEN patients to date.

Methods: A retrospective study of NEN patients treated with peptide receptor radionuclide therapy (PRRT) at a tertiary institution from 2012 to 2017. Patients with PET/CT imaging at baseline and follow-up were included. The L3 slice of the co-localizing CT was analysed using the Alberta Protocol. Skeletal muscle cross-sectional area and muscle attenuation were measured and compared with pre-defined cut-offs. The primary endpoint was the prevalence of sarcopenia and myosteatosis according to previously published cut-offs.

Results: Fourty-nine patients (median age 64 (range 26-80) years) were included. The most common primary sites of tumour were the small bowel (51%) and pancreas (26%). Baseline sarcopenia was prevalent in 67% of patients and myosteatosis in 71%. Forty-five percent of patients gained weight over the course of PRRT. The presence of baseline sarcopenia was not associated with progression-free survival (20.8 mo vs. 20.7 mo, HR 0.86, p = 0.70) nor overall survival. Similarly, baseline myosteatosis (PFS 19.5 mo vs. 20.8 mo, HR 0.77, p = 0.47) was not significantly associated with survival outcomes. The mean (SD) age of those with myosteatosis was 60.8 ± 11.6 years compared to 49.7 ± 12.7 years for those without (p = 0.003).

Conclusions: Body composition analysis is feasible using routinely acquired PET/CT data for patients with NEN. CT-defined sarcopenia and myosteatosis are prevalent in NEN patients, although myosteatosis is more common with increasing age. These findings were not associated with worsened overall or progression-free survival in the current study.
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http://dx.doi.org/10.1038/s41430-021-00915-4DOI Listing
May 2021

Survival in borderline resectable and locally advanced pancreatic cancer is determined by the duration and response of neoadjuvant therapy.

Eur J Surg Oncol 2021 Apr 30. Epub 2021 Apr 30.

Sydney Medical School, The University of Sydney, Sydney, Australia; Australian Pancreatic Centre, St Leonards, Sydney, NSW, Australia; Upper Gastrointestinal Surgical Unit, Royal North Shore Hospital, Sydney, NSW, Australia.

Background: Pancreatic cancer is the 8th commonest cancer and the 5th commonest cause of cancer-related death in Australia, with a 9% average 5-year survival. This study aims to investigate the effects of neoadjuvant treatment on overall survival (OS) and recurrence-free survival (RFS) in borderline resectable (BRPC) and locally advanced (LAPC) pancreatic adenocarcinoma followed by curative resection.

Materials And Methods: Prospectively-collected demographic, medical, surgical and pathological data of patients with BRPC and LAPC treated with both neoadjuvant therapy (NAT) and surgery at a single tertiary referral centre in Australia were reviewed and analysed.

Results: Between 2012 and 2018, 60 patients, 34 with BRPC and 26 with LAPC, were treated with NAT followed by curative resection. The commonest neoadjuvant chemotherapy regimens were Gemcitabine + Abraxane (51.7%) and FOLFIRINOX (35.0%), with 48.3% of patients additionally receiving neoadjuvant radiotherapy. Median RFS was 30 months and median OS was 35 months. On multivariable analysis, inferior OS was predicted by enlarged loco-regional lymph nodes on initial computed tomography (p = 0.032), larger tumour size post-NAT (p = 0.006) and Common Terminology Criteria for Adverse Events post-NAT toxicity greater than grade 2 (p = 0.015). LAPC patients received more neoadjuvant chemotherapy (p = 0.008) and radiotherapy (p = 0.021) than BRPC and achieved a superior pathological response (p = 0.010).

Conclusion: Patients who respond to NAT likely have a favourable disease biology and will progress well following resection. It is these patients who should be selected for more aggressive upfront management, and those with resistant disease should be spared from high-risk surgery.
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http://dx.doi.org/10.1016/j.ejso.2021.04.005DOI Listing
April 2021

Emerging biological therapies for the treatment of malignant pleural mesothelioma.

Expert Opin Emerg Drugs 2021 Jun 17;26(2):179-192. Epub 2021 May 17.

Sydney Medical School, The University of Sydney, Sydney, Australia.

: Malignant pleural mesothelioma (MPM) has limited treatment options with minimal new therapy approvals for unresectable disease in the past 15 years. However, considerable work has occurred to develop immunotherapies and biomarker driven therapy to improve patient outcomes over this period.: This review examines current standard of care systemic therapy in the first- and second line setting. The last 12 months has seen 2 significant trials (Checkmate 743 and CONFIRM) which provide evidence supporting the role of immunotherapy in the management of MPM. Further trials are underway to assess the role of combination chemoimmunotherapy and personalized therapy. Additionally, a large number of clinical trials are ongoing to assess the efficacy of oncoviral, dendritic cell, anti-mesothelin and chimeric antigen receptor T cell therapy in the treatment of MPM.: Recent Phase III trial results have established a role for immunotherapy in the management of MPM. The optimal sequencing and combination of chemotherapy and immunotherapy remains to be determined. Novel therapies for MPM are promising however efficacy remains to be determined and issues remain regarding access to and delivery of these therapies.
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http://dx.doi.org/10.1080/14728214.2021.1924670DOI Listing
June 2021

Vigilance for carcinoid heart disease is still required in the era of somatostatin analogues: Lessons from a case series.

Asia Pac J Clin Oncol 2021 Apr 14. Epub 2021 Apr 14.

Department of Endocrine Oncology, University Hospital, Uppsala, Sweden.

Aim: Carcinoid heart disease (CHD) is a well-documented complication of neuroendocrine tumors (NETs) due to secreted hormones causing fibrosis. Somatostatin analogues (SSAs) can decrease hormonal secretion and inhibit tumor growth. The reported incidence of CHD has decreased as SSA use has increased. We describe a series of patients who have developed CHD even though they were treated with SSA therapy.

Methods: Nine patients were seen in four centers in Australia and New Zealand. The average duration of follow-up from diagnosis was 39 months.

Results: Three patients had Grade 1 and six Grade 2 disease by World Health Organization 2010 criteria. All patients had no CHD symptoms at baseline and started SSA therapy soon after diagnosis, yet developed significant, symptomatic cardiac dysfunction in their disease course. The median time from NET diagnosis to SSA initiation was 1 month, and median time from NET diagnosis to CHD diagnosis was 23 months (range 4-52). All patients who were tested had persistently increased hormonal levels (chromogranin A, urinary 5-hydroxyindolacetic acid).

Conclusions: The good symptomatic control afforded by SSAs should not lead to reduced vigilance in screening for CHD, especially in patients with persistently elevated hormonal assays. Clinicians should consider regular echocardiographic screening in patients with a secretory syndrome.
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http://dx.doi.org/10.1111/ajco.13577DOI Listing
April 2021

Relationship between PD-L1 expression and outcome in EGFR-mutant lung cancer patients treated with EGFR tyrosine kinase inhibitors.

Lung Cancer 2021 05 9;155:28-33. Epub 2021 Mar 9.

Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Chris O'Brien Lifehouse, Camperdown, NSW, Australia. Electronic address:

Objectives: Predictive biomarkers for poor response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is an area of ongoing research. This multicentre retrospective study sought to determine the impact of programmed death-ligand 1 (PD-L1) tumour proportional score (TPS) on outcome in EGFR TKI treated patients.

Materials And Methods: Patients with Stage IIIB/IV lung adenocarcinoma harbouring a sensitising EGFR mutation treated with first-line TKI at five metropolitan hospitals were included. PD-L1 TPS was determined using the Ventana anti-PD-L1 (SP263) assay. High PD-L1 expression was defined as TPS ≥ 50 %. Determinants of progression and survival hazards were modelled using Cox regression.

Results: A total of 186 patients were included. Mean age was 67 years, 66 % were female and 54 % were Asian. Patients with high PD-L1 expression (n = 23; 12 %) had significantly shorter progression free survival (6.6 vs 13.0 months, hazard ratio (HR) 2.6 95 % CI 1.6-4.2, p < 0.0001) and overall survival (11.5 vs 32.9 months, HR 3.3, 95 % CI 1.9-5.7, p < 0.0001) compared to patients with PD-L1 low/negative tumours. This remained significant in multivariate analyses. High PD-L1 in post-TKI progression biopsies was not associated with poorer survival.

Conclusion: In this large, real-world cohort of EGFR-mutant lung adenocarcinoma patients, high PD-L1 expression was associated with early resistance to 1st generation EGFR TKIs and shorter survival, regardless of ethnicity.
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http://dx.doi.org/10.1016/j.lungcan.2021.03.004DOI Listing
May 2021

Dual Positron Emission Tomography imaging in bronchial neuroendocrine neoplasms (NENs): The NETPET score as a prognostic biomarker.

J Nucl Med 2021 Feb 12. Epub 2021 Feb 12.

Royal North Shore Hospital, Australia.

PET scans using [F]FDG and somatostatin receptor imaging agents are both used in imaging of neuroendocrine neoplasms (NENs). We have suggested the "NETPET score", utilizing uptake of both PET tracers, as a prognostic biomarker in NENs. We previously demonstrated the effectiveness of the NETPET score in gastroenteropancreatic (GEP) NENs. Its prognostic relevance in bronchial NENs remains undetermined. This is a retrospective multicentre study (2011-2018) assessing patients who had advanced bronchial NEN and who underwent both [F]FDG and [Ga]Ga-DOTATATE PET within 60 days of each other. The NETPET score was assigned by experienced nuclear medicine physicians and compared with other clinical data such as WHO grade. The primary outcome was overall survival (OS); NETPET score and other prognostic variables were analysed using univariate and multivariate analyses by the Cox proportional-hazards model. Thirty-eight patients were included for review. The NETPET score and histology were significantly correlated with OS in univariate analyses ( = 0.003, = 0.01). On multivariate analysis, only the NETPET score remained significant ( = 0.03). The NETPET score was significantly associated with histological grade ( = 0.006, chi-squared test). The NETPET score is a prognostic biomarker in bronchial NENs as well as GEPNENs. Whilst it needs to be validated in prospective studies, it holds significant promise as a biomarker for a wide range of NENs.
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http://dx.doi.org/10.2967/jnumed.120.257659DOI Listing
February 2021

Rapid Resistance of FGFR-driven Gastric Cancers to Regorafenib and Targeted FGFR Inhibitors can be Overcome by Parallel Inhibition of MEK.

Mol Cancer Ther 2021 04 9;20(4):704-715. Epub 2021 Feb 9.

Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.

Amplification or overexpression of the FGFR family of receptor tyrosine kinases occurs in a significant proportion of gastric cancers. Regorafenib is a multikinase inhibitor of angiogenic and oncogenic kinases, including FGFR, which showed activity in the randomized phase II INTEGRATE clinical trial in advanced gastric cancer. There are currently no biomarkers that predict response to this agent, and whether regorafenib is preferentially active in FGFR-driven cancers is unknown. Through screening 25 gastric cancer cell lines, we identified five cell lines that were exquisitely sensitive to regorafenib, four of which harbored amplification or overexpression of family members. These four cell lines were also sensitive to the FGFR-specific inhibitors, BGJ398, erdafitinib, and TAS-120. Regorafenib inhibited FGFR-driven MAPK signaling in these cell lines, and knockdown studies confirmed their dependence on specific FGFRs for proliferation. In the INTEGRATE trial cohort, amplification or overexpression of FGFRs 1-4 was detected in 8%-19% of cases, however, this was not associated with improved progression-free survival and no objective responses were observed in these cases. Further preclinical analyses revealed FGFR-driven gastric cancer cell lines rapidly reactivate MAPK/ERK signaling in response to FGFR inhibition, which may underlie the limited clinical response to regorafenib. Importantly, combination treatment with an FGFR and MEK inhibitor delayed MAPK/ERK reactivation and synergistically inhibited proliferation of FGFR-driven gastric cancer cell lines. These findings suggest that upfront combinatorial inhibition of FGFR and MEK may represent a more effective treatment strategy for FGFR-driven gastric cancers.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0836DOI Listing
April 2021

Impact of COVID-19 on cancer service delivery: results from an international survey of oncology clinicians.

ESMO Open 2020 12;5(6):e001090

Sir Peter MacCallum Department of Oncology, University of Melbourne Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia; Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Electronic address:

Objectives: To report clinician-perceived changes to cancer service delivery in response to COVID-19.

Design: Multidisciplinary Australasian cancer clinician survey in collaboration with the European Society of Medical Oncology.

Setting: Between May and June 2020 clinicians from 70 countries were surveyed; majority from Europe (n=196; 39%) with 1846 COVID-19 cases per million people, Australia (AUS)/New Zealand (NZ) (n=188; 38%) with 267/236 per million and Asia (n=75; 15%) with 121 per million at time of survey distribution.

Participants: Medical oncologists (n=372; 74%), radiation oncologists (n=91; 18%) and surgical oncologists (n=38; 8%).

Results: Eighty-nine per cent of clinicians reported altering clinical practices; more commonly among those with versus without patients diagnosed with COVID-19 (n=142; 93% vs n=225; 86%, p=0.03) but regardless of community transmission levels (p=0.26). More European clinicians (n=111; 66.1%) had treated patients diagnosed with COVID-19 compared with Asia (n=20; 27.8%) and AUS/NZ (n=8; 4.8%), p<0.001. Many clinicians (n=307; 71.4%) reported concerns that reduced access to standard treatments during the pandemic would negatively impact patient survival. The reported proportion of consultations using telehealth increased by 7.7-fold, with 25.1% (n=108) of clinicians concerned that patient survival would be worse due to this increase. Clinicians reviewed a median of 10 fewer outpatients/week (including non-face to face) compared with prior to the pandemic, translating to 5010 fewer specialist oncology visits per week among the surveyed group. Mental health was negatively impacted for 52.6% (n=190) of clinicians.

Conclusion: Clinicians reported widespread changes to oncology services, in regions of both high and low COVID-19 case numbers. Clinician concerns of potential negative impacts on patient outcomes warrant objective assessment, with system and policy implications for healthcare delivery at large.
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http://dx.doi.org/10.1136/esmoopen-2020-001090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709494PMC
December 2020

A Critical Assessment of Postneoadjuvant Therapy Pancreatic Cancer Regression Grading Schemes With a Proposal for a Novel Approach.

Am J Surg Pathol 2021 03;45(3):394-404

Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research.

Currently, there is no consensus on the optimal tumor response score (TRS) system to assess regression in pancreatic cancers resected after neoadjuvant therapy. We developed a novel TRS (Royal North Shore [RNS] system) based on estimating the percentage of tumor bed occupied by viable cancer and categorized into 3 tiers: grade 1 (≤10%), grade 2 (11% to 75%), and grade 3 (>75%). We assessed 147 resected carcinomas with this and other TRS systems (College of American Pathologists [CAP], MD Anderson Cancer Center [MDACC], and Evans). The 3-tiered RNS system predicted median survival after surgery for grades 1, 2, and 3 of 54, 23, and 9 months, respectively (P<0.05). The CAP, MDACC, and Evans systems also predicted survival (P<0.05) but less consistently. The median survival for MDACC and CAP grade 0 (complete regression) was less than MDACC grade 1 and CAP grades 1 and 2. There was no difference in survival between CAP grades 2 and 3 (P=0.960), Evans grades 1 and 2a (P=0.395), and Evans grades 2a and 2b (P=0.587). Interobserver concordance was weak for CAP (κ=0.431), moderate for MDACC (κ=0.691), minimal for Evans (κ=0.307), and moderate to strong for RNS (κ=0.632 to 0.84). Of age, sex, size, stage, grade, perineural and vascular invasion, extrapancreatic extension, margin status, and RNS score, only RNS score, vascular invasion, and extrapancreatic extension predicted survival in univariate analysis. Only extrapancreatic extension (P=0.034) and RNS score (P<0.0001) remained significant in multivariate analysis. We conclude that the RNS system is a reproducible and powerful predictor of survival after resection for pancreatic cancers treated with neoadjuvant therapy and should be investigated in larger cohorts.
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http://dx.doi.org/10.1097/PAS.0000000000001601DOI Listing
March 2021

Increased rates of cetuximab reactions in tick prevalent regions and a proposed protocol for risk mitigation.

Asia Pac J Clin Oncol 2020 Sep 24. Epub 2020 Sep 24.

Northern Cancer Institute, Sydney, New South Wales, Australia.

Background: Cetuximab is an anti-epidermal growth factor receptor mouse-human chimeric monoclonal antibody used to treat advanced colorectal cancers. Initial data suggest that severe infusion reactions occurred in 4.5%, many on first exposure. The majority of those with anaphylactic reactions possess predeveloped IgE antibodies to galactose-alpha-1,3-galactose. It is thought that the vector for preexposure to alpha-gal is antigen inoculation via tick bites. This retrospective study reviews the experience of two community cancer centers in high tick exposure areas in Sydney with cetuximab anaphylaxis and proposes a protocol to avoid this.

Method: Severe cetuximab infusion reactions occurring in the Northern Cancer Institute Frenchs Forest and St Leonards clinics, Sydney, from May 2014 to February 2019 were recorded. Area of residence was then compared to areas of known high tick prevalence.

Results: A total of 87 patients received cetuximab in this period. Six patients (6.9%) experienced at least a grade 3 reaction, three females, age range 41-72 years (median 57.5 years). All were receiving cetuximab for metastatic colorectal cancer and their anaphylaxis occurred with the first infusion in all cases.

Conclusion: These cases support the existing theory of increased rates of cetuximab anaphylaxis in areas of high tick prevalence. Given this, we recommend the following protocol for patients being considered for cetuximab therapy: known mammalian meat allergy as an absolute contraindication; all patients receiving cetuximab should have RAST (ImmunoCAP ) testing for alpha-gal specific-IgE-specific antibodies before first infusion and those who test positive to be considered alternate therapy.
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http://dx.doi.org/10.1111/ajco.13465DOI Listing
September 2020

Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety run-in.

Lancet Oncol 2020 09;21(9):1213-1223

National Health and Medical Research Council, Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia.

Background: There is a strong unmet need to improve systemic therapy in mesothelioma. Chemotherapy with cisplatin and pemetrexed improves survival in malignant pleural mesothelioma, and immune checkpoint inhibitors are an emerging treatment in this disease. We aimed to evaluate the activity of durvalumab, an anti-PD-L1 antibody, given during and after first-line chemotherapy with cisplatin and pemetrexed in patients with advanced malignant pleural mesothelioma.

Methods: DREAM was a multicentre, single-arm, open-label, phase 2 trial done in nine hospitals in Australia. Eligible patients were aged 18 years or older and had histologically confirmed malignant pleural mesothelioma considered unsuitable for cancer-directed surgery, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease as per the modified Response Evaluation Criteria in Solid Tumors version 1.0 (mRECIST) for mesothelioma that was previously untreated with systemic therapy. All histological subtypes were eligible. The first six participants were treated for two cycles in a safety run-in. All participants received cisplatin 75 mg/m, pemetrexed 500 mg/m, and durvalumab 1125 mg intravenously on day 1 of a 3-weekly schedule for a maximum of six cycles. Change from cisplatin to carboplatin with an area under the curve of 5 was permitted. Durvalumab was continued for a maximum of 12 months. The primary endpoint was progression-free survival at 6 months, measured according to mRECIST for malignant pleural mesothelioma and analysed in the intention-to-treat population. Safety analyses included all participants who receive at least one dose of any study drug. This study is registered with the Australia New Zealand Clinical Trials Registry, ACTRN12616001170415.

Findings: Between Dec 28, 2016, and Sept 27, 2017, 55 participants were enrolled. 54 patients were eligible and were followed up for a median of 28·2 months (IQR 26·5-30·2). 31 (57%; 95% CI 44-70) of 54 patients were alive and progression-free at 6 months. The most common grade 3-4 adverse events were neutropenia (seven [13%] patients), nausea (six [11%]), and anaemia (four [7%]). A total of 60 serious adverse events occurred in 29 participants, five of which were considered possibly related to durvalumab. Five patients died during the study treatment; none of these five deaths were attributed to study treatment.

Interpretation: The combination of durvalumab, cisplatin, and pemetrexed has promising activity and an acceptable safety profile that warrants further investigation in a randomised phase 3 trial.

Funding: AstraZeneca.
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http://dx.doi.org/10.1016/S1470-2045(20)30462-9DOI Listing
September 2020

Australian experience of peptide receptor radionuclide therapy in lung neuroendocrine tumours.

Oncotarget 2020 Jul 7;11(27):2636-2646. Epub 2020 Jul 7.

Department of Medical Oncology, Monash Health, Melbourne, Australia.

Background: Peptide receptor radionuclide therapy (PRRT) is an approved treatment modality for gastroenteropancreatic neuroendocrine tumours (GEP NETs), Although Phase III randomised clinical trial data is not available for NETs of other site of origin, in practice, PRRT is used more widely in clinical practice, based on its mechanism of targeting the somatostatin receptor. Use of PRRT for lung (bronchial) NET, specifically typical and atypical carcinoid (TC, AC), has been reported only in small retrospective case series. This multicentre study adds to the evidence regarding utility of PRRT for lung NETs.

Materials And Methods: A retrospective chart review of patients with TC and AC who received Lu-dotatate PRRT between January 2002 and June 2019 in six hospitals across Australia was undertaken. Data regarding demographics, efficacy and toxicity was evaluated at each site by the treating clinician.

Results: Forty-eight patients (32 AC, 15 TC, 1 unclassified) received a median of four Lu-dotatate treatments. There was a median of one prior line of systemic treatment (range: 0-3). The response rate to Lu-dotatate was 33%, with a median overall survival of 49 months (range of 3-91), at a median follow up of 33 months. This compares favourably with GEP NET. Overall toxicity was recorded as modest.

Conclusions: Lu-dotatate PRRT in patients with lung NETs is used in real world practice, where it appears well-tolerated with some efficacy. Further evidence could be obtained through a global prospective clinical or registry trial.
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http://dx.doi.org/10.18632/oncotarget.27659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343632PMC
July 2020

Routine Early 68Ga-DOTATATE Positron Emission Tomography Has Low Yield After Resection of Appendiceal Neuroendocrine Neoplasms.

Pancreas 2020 08;49(7):891-896

From the Departments of Nuclear Medicine.

Objectives: Appendiceal neuroendocrine neoplasms (appNEN) generally carry a low recurrence risk. Ga-DOTATATE positron emission tomography (DOTA PET) is increasingly used as it is more sensitive than cross-sectional imaging. We hypothesize that early DOTA PET is unlikely to detect recurrent disease in patients with low-risk resected appNEN because of the delayed pattern of recurrence.

Methods: Retrospective study (dual review) of patients undergoing DOTA PET 0 to 18 months after resected appNEN. The primary outcome was the proportion of scans demonstrating residual disease.

Results: Forty-one patients were included (median age, 29 years; 63% female), most with small, low-grade appNEN. No scans (0%) showed residual/distant disease. Eight (20%) of 41 scans showed indeterminate findings requiring follow-up. Five (12%) scans were recommended for follow-up with modalities other than DOTA PET (vertebra, 3; thyroid; bone, 1 each). Three (7%) were recommended for follow-up with DOTA PET (all with indeterminate abdominal uptake). These 3 patients had no recurrent disease on follow-up.

Conclusions: The Ga-DOTATATE PET is of no value when performed in the first 18 months after resected appNEN. Although 20% of scans showed indeterminate findings, more than half did not require repeat DOTA PET. Despite advantages over cross-sectional imaging, DOTA PET is not recommended in staging after completely resected appNEN.
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http://dx.doi.org/10.1097/MPA.0000000000001589DOI Listing
August 2020

ALK-Rearranged Non-Small Cell Lung Cancer in 2020: Real-World Triumphs in an Era of Multigeneration ALK-Inhibitor Sequencing Informed by Drug Resistance Profiling.

Oncologist 2020 08 2;25(8):641-649. Epub 2020 Jul 2.

Department of Medical Oncology, Royal North Shore Hospital, St Leonards, New South Wales, Australia.

Since its discovery in 2007, we have seen the lives of patients diagnosed with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancers (NSCLC) transform with the advent of molecular therapies with first-, second-, and third-generation ALK inhibitors now available in the clinic. Despite great gains in patient survival now measured in years and preserved quality of life with targeted therapies, drug resistance is unfortunately inevitably encountered in this rare and unique molecular subset of lung cancer, and patients will eventually succumb to the disease. As these patients are often young, fit, and never smokers, the clinical and scientific communities have aligned to expedite drug development and access. Drug resistance profiling and further strategies are being explored through clinical trials, including the evaluation of specific drug sequencing and combinations to overcome such resistance and promote patient longevity. The cases of this report focus on precision medicine and aim to portray the pertinent aspects to consider when treating ALK-rearranged NSCLC in 2020, an ever-shifting space. By way of case examples, this report offers valuable information to the treating clinician, including the evolution of systemic treatments and the management of oligo-progression and multisite drug resistance. With the maturation of real-world data, we are fortunate to be experiencing quality and length of life for patients with this disease surpassing prior expectations in advanced lung cancer. KEY POINTS: This report focuses on the importance of genetic analysis of serial biopsies to capture the dynamic therapeutic vulnerabilities of a patient's tumor, providing a perspective on the complexity of ALK tyrosine kinase inhibitor (ALKi) treatment sequencing. These case examples contribute to the literature on ALK-rearranged and oncogene addicted non-small cell lung cancer (NSCLC), providing a framework for care in the clinic. In oligo-progressive disease, local ablative therapy and continuation of ALKi postprogression should be considered with potential for sustained disease control. ALK G1202R kinase domain mutations (KDM), highly prevalent at resistance to second-generation ALKi resistances, may emerge in non-EML4-ALK variant 3 cases and is sensitive to third-generation lorlatinib. When in compound with one or more ALK KDMs, resistance to lorlatinib is expected. In the case of rampantly progressive disease, rebiopsy and redefining biology in a timely manner may be informative.
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http://dx.doi.org/10.1634/theoncologist.2020-0075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418351PMC
August 2020

Small Molecule KRAS Inhibitors: The Future for Targeted Pancreatic Cancer Therapy?

Cancers (Basel) 2020 May 24;12(5). Epub 2020 May 24.

Northern Clinical School, Faculty of Medicine and Health, University of Sydney, St Leonards 2065, NSW, Australia.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid tumors in the world. Currently, there are no approved targeted therapies for PDAC. Mutations in () are known to be a major driver of PDAC progression, but it was considered an undruggable target until recently. Moreover, PDAC also suffers from drug delivery issues due to the highly fibrotic tumor microenvironment. In this perspective, we provide an overview of recent developments in targeting mutant KRAS and strategies to overcome drug delivery issues (e.g., nanoparticle delivery). Overall, we propose that the antitumor effects from novel KRAS inhibitors along with strategies to overcome drug delivery issues could be a new therapeutic way forward in PDAC.
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http://dx.doi.org/10.3390/cancers12051341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281596PMC
May 2020

Practical Considerations for Treating Patients With Cancer in the COVID-19 Pandemic.

JCO Oncol Pract 2020 08 13;16(8):467-482. Epub 2020 May 13.

Biosecurity Program, Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia.

Cancer has become a prevalent disease, affecting millions of new patients globally each year. The COVID-19 pandemic is having far-reaching impacts around the world, causing substantial disruptions to health and health care systems that are likely to last for a prolonged period. Early data have suggested that having cancer is a significant risk factor for mortality from severe COVID-19. A diverse group of medical oncologists met to formulate detailed practical advice on systemic anticancer treatments during this crisis. In the context of broad principles, issues including risks of treatment, principles of prioritizing resources, treatment of elderly patients, and psychosocial impact are discussed. Detailed treatment advice and options are given at a tumor stream level. We must maintain care for patients with cancer as best we can and recognize that COVID-19 poses a significant competing risk for death that changes conventional treatment paradigms.
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http://dx.doi.org/10.1200/OP.20.00229DOI Listing
August 2020

Trifluridine/tipiracil: A practical guide to its use in the management of refractory metastatic colorectal cancer in Australia.

Asia Pac J Clin Oncol 2020 Apr;16 Suppl 1:3-12

NHMRC Clinical Trials Centre, University of Sydney, NSW, Australia.

Trifluridine/tipiracil is available on the Australian Pharmaceutical Benefits Scheme for the treatment of patients with metastatic colorectal cancer (mCRC) previously treated with, or not considered candidates for, fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-vascular endothelial growth factor agents and anti-epidermal growth factor receptor agents. This article reviews trifluridine/tipiracil clinical data and presents practical information on its use in the management of refractory mCRC in Australia. Whereas the primary mechanism of action of fluoropyrimidines such as fluorouracil (5-FU) and capecitabine is enzyme inhibition of nucleotide synthesis, trifluridine/tipiracil primarily acts by incorporation into DNA, resulting in DNA dysfunction. Trifluridine/tipiracil has activity in patients with 5-FU-resistant tumors and can be considered in patients with prior intolerance or toxicity to 5-FU. In the pivotal phase III RECOURSE trial evaluating trifluridine/tipiracil in chemotherapy-refractory mCRC, efficacy benefits were observed across all a priori prognostic subgroups including those defined by age (≥65 and ≥75 years), geographical origin, primary tumor site or KRAS status. Trifluridine/tipiracil therapy benefits appropriately selected patients who have an ECOG performance status of 0 or 1, with no more than mild hepatic impairment or mild-to-moderate renal impairment, and who are capable of adhering to oral therapy safely. Appropriate dosing, monitoring for adverse events and effective management of side effects are essential.
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http://dx.doi.org/10.1111/ajco.13336DOI Listing
April 2020

Management of early-stage gastro-esophageal cancers: expert perspectives from the Australasian Gastrointestinal Trials Group (AGITG) with invited international faculty.

Expert Rev Anticancer Ther 2020 04 12;20(4):305-324. Epub 2020 Apr 12.

Queen Elizabeth Hospital, University of Adelaide, Adelaide, Australia.

: A multimodal approach in operable early-stage oesophago-gastric (OG) cancer has evolved in the last decade, leading to improvement in overall outcomes.: A review of the published literature and conference abstracts was undertaken on the topic of optimal adjunctive chemotherapy or chemoradiotherapy in early-stage OG cancers. This review article focuses on the current evidence pertaining to neoadjuvant and perioperative strategies in curable OG cancers including the evolving landscape of immunotherapy and targeted drugs in this setting.: Adjunctive therapies in the form of preoperative chemo-radiotherapy (CRT) or chemotherapy and perioperative chemotherapy over surgery alone improve outcomes in patients with operable OG cancer. Although there are variations in practice around the world, a multi-disciplinary approach to patient care is of paramount importance. Immunotherapy and on treatment functional imaging are two examples of emerging strategies to improve the outcome for early-stage patients. A better understanding of the molecular biology of this disease may help overcome the problem of tumor heterogeneity and enable more rationally designed and targeted therapeutic interventions in the future.
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http://dx.doi.org/10.1080/14737140.2020.1746185DOI Listing
April 2020

Evolving role of regorafenib for the treatment of advanced cancers.

Cancer Treat Rev 2020 Jun 20;86:101993. Epub 2020 Feb 20.

BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBEREHD, Barcelona, Spain.

Regorafenib is an oral tyrosine kinase inhibitor (TKI) approved for the treatment of refractory metastatic colorectal cancer (mCRC), advanced gastrointestinal stromal tumors (GIST) previously treated with imatinib and sunitinib, and unresectable hepatocellular carcinoma (HCC) following progression on sorafenib. Regorafenib was initially approved for mCRC based on improved overall survival (OS) in the randomized, placebo-controlled, phase 3 CORRECT trial, which was confirmed in an expanded population of Asian patients in the randomized, placebo-controlled phase 3 CONCUR trial. Approvals in GIST, and more recently in HCC, were based on the results from the randomized, placebo-controlled, phase 3 GRID and RESORCE trials, respectively. In this review, we provide a comprehensive summary of the clinical evidence for approval of regorafenib in mCRC, GIST, and HCC, present emerging evidence of regorafenib activity in other tumor types (namely, gastroesophageal cancer, sarcomas, biliary tract cancer, and glioblastoma), and discuss trials in progress within the context of regorafenib's mechanism of action. We describe recent advances and key lessons learned with regorafenib, including the importance of managing common drug-related toxicities using dose-optimization strategies, the search for biomarkers to predict response to treatment, and highlight some of the unaddressed questions and future directions for regorafenib across tumors.
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http://dx.doi.org/10.1016/j.ctrv.2020.101993DOI Listing
June 2020

Identification of Novel Biomarkers in Pancreatic Tumor Tissue to Predict Response to Neoadjuvant Chemotherapy.

Front Oncol 2020 4;10:237. Epub 2020 Mar 4.

Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia.

Neoadjuvant chemotherapy (NAC) has been of recent interest as an alternative to upfront surgery followed by adjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC). However, a subset of patients does not respond to NAC and may have been better managed by upfront surgery. Hence, there is an unmet need for accurate biomarkers for predicting NAC response in PDAC. We aimed to identify upregulated proteins in tumor tissue from poor- and good-NAC responders. Tumor and adjacent pancreas tissue samples were obtained following surgical resection from NAC-treated PDAC patients. SWATH-MS proteomic analysis was performed to identify and quantify proteins in tissue samples. Statistical analysis was performed to identify biomarkers for NAC response. Pathway analysis was performed to characterize affected canonical pathways in good- and poor-NAC responders. A total of 3,156 proteins were identified, with 19 being were significantly upregulated in poor-responders compared to good-responders (log ratio > 2, < 0.05). Those with the greatest ability to predict poor-NAC response were GRP78, CADM1, PGES2, and RUXF. Notably, canonical pathways that were significantly upregulated in good-responders included acute phase signaling and macrophage activation, indicating a heightened immune response in these patients. A novel biomarker signature for poor-NAC response in PDAC was identified.
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http://dx.doi.org/10.3389/fonc.2020.00237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064619PMC
March 2020

Update on optimal treatment for metastatic colorectal cancer from the AGITG expert meeting: ESMO congress 2019.

Expert Rev Anticancer Ther 2020 04 6;20(4):251-270. Epub 2020 Apr 6.

Medical Oncology, The Queen Elizabeth Hospital, Woodville, Australia.

: Outcomes in metastatic colorectal cancer are improving, due to the tailoring of therapy enabled by better understanding of clinical behavior according to molecular subtype.: A review of the literature and recent conference presentations was undertaken on the topic of systemic treatment of metastatic colorectal cancer. This review summarizes expert discussion of the current evidence for therapies in metastatic colorectal cancer (mCRC) based on molecular subgrouping.: EGFR-targeted and VEGF-targeted antibodies are now routinely incorporated into treatment strategies for mCRC. EGFR-targeted antibodies are restricted to patients with extended wild-type profiles, with evidence that they should be further restricted to patients with left-sided tumors. Clinically distinct treatment pathways based on tumor and MMR status, are now clinically applicable. Evidence suggests therapy for additional subgroups will soon be defined; the most advanced being for patients with G12 C mutation and gene fusion defects.
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http://dx.doi.org/10.1080/14737140.2020.1744439DOI Listing
April 2020

A multicenter study of thromboembolic events among patients diagnosed with ROS1-rearranged non-small cell lung cancer.

Lung Cancer 2020 04 22;142:34-40. Epub 2020 Jan 22.

Bill Walsh Translational Research Laboratory, Kolling Institute Medical Institute of Research, Royal North Shore Hospital, St Leonards, New South Wales, Australia; Northern Clinical School, University of Sydney, St Leonards, New South Wales, Australia; Northern Cancer Institute, St Leonards, New South Wales, Australia; Department of Medical Oncology, Royal North Shore Hospital, St Leonards, New South Wales, Australia.

Objectives: This study aimed to describe the longitudinal thromboembolism (TE) risk relative to the natural history of disease and clinical course of ROS1 rearranged non-small cell lung cancer (NSCLC).

Materials And Methods: Cases of ROS1-rearranged NSCLC from six Australian hospitals were pooled and evaluated for incidence, timing, predictors and outcomes of venous or arterial TE, as well as objective response rate (ORR) to active therapy and overall survival (OS).

Results: Of 42 patients recruited, 20 (48%) experienced TE; one (2%) arterial, 13 (31%) a pulmonary emboli (PE), and 12 (29%) a deep vein thrombosis. Among those with TE, six (30%) experienced multiple events, three as concurrent and three as recurrent diagnoses. The cumulative incidence of TE over time, adjusted for death as a competing risk factor, approached 50%. TE occurred prior to, during and post the peri-diagnostic period and occurred irrespective of treatment strategy. A thrombophilia was identified in n = 3/10 (30%) cases screened: in two factor V Leiden and in one anti-thrombin III (ATIII) deficiency. Median OS was 21.3 months in those with TE vs. 28.8 months in those without; hazard ratio 1.16 (95%CI 0.43-3.15). Respective ORR to first-line therapy with TE was 50% vs. 44% without TE in the chemotherapy arm and 67% vs. 50% in the targeted therapy arm.

Conclusion: In the rare cancer subtype, ROS1, these real-world data demonstrate sustained TE risk beyond the diagnostic period irrespective of therapeutic strategy. High incidence of PE, concurrent TE, and recurrent TE warrant validation in larger cohorts. Consideration of primary thromboprophylaxis in ROS1 populations is recommended.
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http://dx.doi.org/10.1016/j.lungcan.2020.01.017DOI Listing
April 2020

The Economic Impact on Australian Patients with Neuroendocrine Tumours.

Patient 2020 06;13(3):363-373

School of Nursing and Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Brisbane, QLD, 4059, Australia.

Background And Objective: Little is known about the economic burden to patients and families with neuroendocrine tumours (NETs) for medical out-of-pocket expenses and employment decisions. This study was performed to determine the extent and factors influencing the financial consequences of living with NETs and their effect on quality of life.

Methods: We undertook an online cross-sectional survey using a targeted approach and collected Australian Medicare claims data. Validated surveys measured health-related quality of life (EuroQol 5-dimension 5-level [EuroQol-5D-5L]) and financial toxicity (COmprehenSive Financial Toxicity [COST]), supplemented with questions on employment and retirement, insurance and out-of-pocket medical expenses. Generalised linear models were performed to assess determinants of quality of life and out-of-pocket expenses recorded by Medicare.

Results: The survey was answered by 204 patients with a mean age of 59 years who were diagnosed on average 5.2 years ago. Self-reported mean costs were 1698 Australian dollars ($A) (standard deviation [SD] $A2132) over 3 months (median $A877) and were highest for medical tests (mean $A376 [17% of total costs], SD $A722), travel-related expenses (mean $A289 [13%], SD $A559), and specialist visits (mean $A225 [10%], SD $A342) ($A1 = $US0.69). Imaging scans, surgery and travel expenses were the most common cost burdens reported by patients. Having private health insurance was the key determinant of higher out-of-pocket costs. Poorer quality of life was significantly associated with higher financial toxicity, not working due to cancer, nausea/diarrhoea, two or more co-morbidities and younger age.

Conclusions: Medical expenses are substantial for some patients with NETs. Quality of life is adversely affected for patients experiencing financial toxicity and avoiding early retirement is an important issue for supportive care services.
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http://dx.doi.org/10.1007/s40271-020-00412-zDOI Listing
June 2020

Tissue biomarker panel as a surrogate marker for squamous subtype of pancreatic cancer.

Eur J Surg Oncol 2020 08 6;46(8):1539-1542. Epub 2020 Feb 6.

Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; Australian Pancreatic Centre, St Leonards, Sydney, Australia; Upper GI Surgical Unit, Royal North Shore Hospital and North Shore Private Hospital, Australia. Electronic address:

Background: Pancreatic ductal adenocarcinoma (PDAC) has been recently classified into four subtypes based on the gene expression levels, with squamous subtype having worst prognostic outcomes. However, gene expression analysis for each individual patient is not clinically feasible due to very high associated cost. We previously reported that levels of three biomarkers (S100A4, Ca-125 and Mesothelin) can be used to classify PDAC patients based on their survival outcomes. This project aimed to determine if this novel biomarker panel can be used as a surrogate to identify squamous PDAC subtype.

Methods: Using the Nanostring gene expression platform, tumor tissue from 24 PDAC patients were analysed for our novel biomarkers and markers associated with four PDAC subtypes.

Results: Gene expression of our biomarker panel (S100A4, Ca-125 and Mesothelin) closely clustered together with markers for squamous PDAC subtype.

Conclusion: These results highlight the potential of our biomarkers to be utilized for identification of squamous PDAC subtype.
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http://dx.doi.org/10.1016/j.ejso.2020.02.001DOI Listing
August 2020

The INTERNET STUDY: A phase II study of everolimus in patients with fluorodeoxyglucose ( F) positron-emission tomography positive intermediate grade pancreatic neuroendocrine tumors.

Asia Pac J Clin Oncol 2020 Jun 7;16(3):150-157. Epub 2020 Feb 7.

Neuroendocrine Unit, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Aims: This multicenter phase II trial evaluates the efficacy of everolimus in poor prognosis grade 2 (G2) pancreatic neuroendocrine tumors (PNETs), defined by 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET) avidity. FDG-PET avidity in NETs is associated with a significantly higher risk of death, outperforming Ki-67 index or liver metastases as a poor prognostic factor. We hypothesized that everolimus has efficacy in patients with FDG-PET-avid G2 PNETs and prospectively evaluated progression-free survival (PFS) and response in the first-line setting.

Methods: Patients with FDG-PET-avid G2 advanced PNET received everolimus 10 mg daily until disease progression. Patients were staged every 12 weeks with CT/MRI and FDG-PET and every 24 weeks with Gallium 68 (68Ga) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotate (DOTATATE, GaTate) PET. The primary endpoint was PFS at 6 months. Overall survival rate, PET/structural imaging response and toxicity were also measured.

Results: Nine patients were accrued from December 2012 to February 2015. Median treatment duration was 13.8 months. The estimated PFS rate at 6 months was 78%. The best response on CT/MRI was stable disease in nine patients (100%) and partial response on FDG-PET in five patients (55.5%). Treatment-related adverse effects were consistent with previous studies of everolimus.

Conclusion: Everolimus is active with prolonged disease control in poor prognosis FDG-avid G2 PNETs. Treatment individualization based on functional imaging warrants further evaluation.
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http://dx.doi.org/10.1111/ajco.13307DOI Listing
June 2020