Publications by authors named "Geoffrey Chong"

22 Publications

  • Page 1 of 1

Evolution of eligibility criteria for diffuse large B-cell lymphoma randomised controlled trials over 30 years.

Br J Haematol 2021 May 14;193(4):741-749. Epub 2021 Apr 14.

Department of Medical Oncology and Clinical Haematology, Olivia Newton John Cancer Research and Wellness Centre at Austin Health, Heidelberg, Vic., Australia.

Eligibility criteria for randomised control trials (RCT) in diffuse large B-cell lymphoma (DLBCL) may be becoming increasingly strict. In this analysis, 42 first-line phase III RCTs enrolling DLBCL patients since 1990 were identified from PubMed and clinicaltrials.gov. Changes in 31 individual eligibility criteria were assessed using three pre-defined eras [(1) 1993-2005; (2) 2006-2013; and (3) 2014-2020]. The presence of 15/31 criteria increased significantly over time, and the total number of criteria per study also increased over time [median Era 1: 14·5, interquartile range (IQR) 12·6-16·4; Era 2: 21, 18·8-23·3; Era 3: 23, 21-25; P < 0·001]. When each trial's eligibility criteria were applied to 215 consecutive patients from an institutional database treated between 2010 and 2020, a median of 57% (IQR 47-70) of patients were hypothetically eligible for trial enrolment. The median percentage of patients eligible was 68% (56-91), 54% (37-81) and 47% (38-82) for Era 1, 2 and 3 respectively (P = 0·004). Phase III front-line DLBCL trial criteria have become increasingly restrictive over the last three decades, resulting in a diminishing proportion of trial-eligible patients, with less than 50% of our patients eligible for modern-era studies. This potentially impacts generalisability of recent trial results and will likely limit recruitment to ongoing studies.
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http://dx.doi.org/10.1111/bjh.17436DOI Listing
May 2021

Use of Ultrasonography Facilitates Noninvasive Evaluation of Lymphadenopathy in a Lymph Node Diagnostic Clinic.

Clin Lymphoma Myeloma Leuk 2021 Feb 2;21(2):e179-e184. Epub 2020 Oct 2.

Department of Medical Oncology, Olivia Newton-John Cancer Research and Wellness Center, Austin Hospital, Heidelberg, Australia; University of Melbourne, Melbourne, Australia. Electronic address:

Background: Prompt and accurate diagnosis of lymphadenopathy is important, yet there is wide variability in clinical approach and referral patterns, leading to unnecessary investigations and delays in diagnosis. To address this, a lymph node diagnostic clinic (LNDC) was established at our tertiary referral center.

Patients And Methods: We retrospectively analyzed data from 320 consecutive patients referred to the LNDC from March 2008 to March 2020, to describe their management and outcomes.

Results: The most common diagnoses were reactive (57%) and malignant lymphadenopathy (28%). In those with reactive lymphadenopathy, 33% did not undergo further investigations, 37% underwent imaging only, and 29% underwent biopsy. For malignant lymphadenopathy, diagnosis was made at a median (interquartile range) of 9 (6-16) days from first LNDC review, with the decision to biopsy made at the first LNDC review in 95% of cases. Clinical features significantly associated with malignancy included age > 45, B symptoms, history of malignancy, and lymphadenopathy that was ≥ 2 cm, in multiple regions, bilateral, multiple nodes, or supraclavicular. At least 3 of these features were present in 88% of patients with malignant lymphadenopathy. Ultrasound had a sensitivity of 98% and negative predictive value of 97% for detecting malignant lymphadenopathy.

Conclusion: A dedicated LNDC in a tertiary referral center facilitates rapid assessment and diagnosis of lymphadenopathy through a risk-stratified model of management. Ultrasonography, as well as the presence of defined clinical risk factors, were most useful to differentiate benign from malignant lymphadenopathy.
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http://dx.doi.org/10.1016/j.clml.2020.09.012DOI Listing
February 2021

Dual Antiangiogenesis Agents Bevacizumab Plus Trebananib, without Chemotherapy, in First-line Treatment of Metastatic Colorectal Cancer: Results of a Phase II Study.

Clin Cancer Res 2021 Apr 29;27(8):2159-2167. Epub 2021 Jan 29.

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

Purpose: To assess the efficacy and safety of dual antiangiogenesis agents, bevacizumab plus trebananib, without chemotherapy, in first-line treatment of metastatic colorectal cancer (mCRC).

Patients And Methods: This open-label phase II study enrolled patients with unresectable mCRC with no prior systemic treatment. All patients received bevacizumab 7.5 mg/kg 3-weekly and trebananib 15 mg/kg weekly. The primary endpoint was disease control [stable disease, partial response (PR), or complete response (CR)] at 6 months (DC6m). Secondary endpoints included toxicity, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Exploratory biomarkers in plasma angiogenesis-related proteins, tumor gene expression, and plasma antibodies to tumor antigens were examined.

Results: Forty-five patients were enrolled from four Australian sites. DC6m was 63% [95% confidence interval (CI), 47-77]. ORR was 17% (95% CI, 7-32), comprising of seven PRs. Median duration of response was 20 months (range, 10-48 months). Median PFS was 8.4 months and median OS 31.4 months. Grade 1-2 peripheral edema and joint-related symptoms were common. Overall incidence of grade 3-4 adverse events (AE) of any type was 33% ( = 15). Expected AEs of bevacizumab treatment did not appear to be increased by the addition of trebananib.

Conclusions: In a first-line mCRC population, the dual antiangiogenic combination, bevacizumab plus trebananib, without chemotherapy, was efficacious with durable responses. The toxicity profile of the combination was manageable and did not exceed that expected with bevacizumab +/- chemotherapy. Exploratory biomarker results raise the hypothesis that the antiangiogenic combination may enable the antitumor immune response in immunotolerant colorectal cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2714DOI Listing
April 2021

Single-agent activity of phosphatidylinositol 3-kinase inhibition with copanlisib in patients with molecularly defined relapsed or refractory diffuse large B-cell lymphoma.

Leukemia 2020 08 14;34(8):2184-2197. Epub 2020 Feb 14.

Hospices Civils de Lyon, Université de Lyon, Centre Hospitalier Lyon-Sud, Service d'hématologie, Lyon, France.

Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) have adverse outcomes. We evaluated the efficacy and safety of the phosphatidylinositol 3-kinase inhibitor copanlisib in patients with relapsed/refractory DLBCL and assessed the relationship between efficacy and DLBCL cell of origin (COO; activated B-cell like [ABC] and germinal center B-cell like [GCB]) and other biomarkers. The primary endpoint was objective response rate (ORR) in DLBCL COO subgroups (ABC, GCB, and unclassifiable) and by CD79B mutational status (NCT02391116). Sixty-seven patients received copanlisib (ABC DLBCL, n = 19; GCB DLBCL, n = 30; unclassifiable, n = 3; missing, n = 15). The ORR was 19.4%; 31.6% and 13.3% in ABC and GCB DLBCL patients, respectively. ORR was 22.2%/20.0% for patients with/without CD79B mutations (wild type, n = 45; mutant, n = 9; missing, n = 13). Overall median progression-free survival and duration of response were 1.8 and 4.3 months, respectively. Adverse events included hypertension (40.3%), diarrhea (37.3%), and hyperglycemia (32.8%). Aberrations were detected in 338 genes, including BCL2 (53.7%) and MLL2 (53.7%). A 16-gene signature separating responders from nonresponders was identified. Copanlisib treatment demonstrated a manageable safety profile in patients with relapsed/refractory DLBCL and a numerically higher response rate in ABC vs. GCB DLBCL patients.
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http://dx.doi.org/10.1038/s41375-020-0743-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387311PMC
August 2020

Patient selection and tolerability of high-dose methotrexate as central nervous system prophylaxis in diffuse large B-cell lymphoma.

Cancer Chemother Pharmacol 2020 01 17;85(1):133-140. Epub 2019 Dec 17.

The University of Melbourne, Parkville, VIC, Australia.

Introduction: Central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is usually fatal. Risk stratification of patients has historically been poorly defined, and CNS prophylaxis with high-dose methotrexate (HDMTX) can be associated with multiple toxicities. The CNS International Prognostic Index (IPI) defines three patient risk groups for CNS disease. The aims of this study were to evaluate the toxicity of HDMTX and describe outcomes in HDMTX and non-HDMTX patients according to the CNS-IPI.

Methods: 205 patients diagnosed with DLBCL between 2004 and 2014, initially treated with RCHOP-like chemotherapy and considered for HDMTX CNS prophylaxis were identified by pharmacy records at two teaching hospitals. Patient records were retrospectively reviewed for HDMTX toxicity, CNS-IPI calculation and CNS relapse.

Results: 28 patients with DLBCL were selected for two doses of HDMTX. Two of 28 patients received only one dose, and three had their second dose reduced due to renal impairment. 28% of patients experienced nephrotoxicity. 24 HDMTX and 122 non-HDMTX patients were evaluable for the CNS-IPI. No significant difference in the CNS-IPI distribution between the two groups was identified (p = 0.695). Five patients had CNS relapse, two who received HDMTX and three who did not. No significant difference in CNS relapse rate was identified between 24 HDMTX patients propensity-matched to 24 non-HDMTX patients.

Conclusions: HDMTX was well-tolerated by patients. Application of the CNS-IPI identifies a different population of candidates for CNS prophylaxis compared to traditional criteria.
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http://dx.doi.org/10.1007/s00280-019-04007-wDOI Listing
January 2020

Comprehensive geriatric assessment is useful in an elderly Australian population with diffuse large B-cell lymphoma receiving rituximab-chemotherapy combinations.

Br J Haematol 2019 10 17;187(1):73-81. Epub 2019 Jun 17.

Department of Haematology and Medical Oncology, Olivia Newton-John Cancer Research and Wellness Centre, Austin Health, Melbourne, Australia.

Elderly patients may be heterogeneous in their abilities to tolerate immunochemotherapy-associated toxicities. We describe the morbidity of rituximab-chemotherapy combinations among 205 newly-diagnosed diffuse large B-cell lymphoma (DLBCL) patients aged ≥60 years from 3 tertiary hospitals between 2009 and 2016, and explore the utility of retrospectively-assigned baseline Comprehensive Geriatric Assessment (CGA) in predicting these toxicities. Seventy-three percent (146/201) experienced grade ≥3 toxicities, 81% (163/201) needed admission, 52% (107/205) had ≥2 unplanned admissions, 82/201 (41%) required dose reductions (DR) subsequent to Cycle 1, 39/166 (23%) had chemotherapy delays and 26/198 (13%) ceased therapy early. CGA was associated with pre-emptive baseline DR and perhaps because of this, did not predict grade ≥3 toxicities, ≥2 unplanned admissions or subsequent DR. Three-year overall survival (OS) of CGA-fit, CGA-unfit and CGA-frail patients was 82%, 60% and 53%, respectively. Three-year progression-free survival (PFS) of CGA-fit, CGA-unfit and CGA-frail patients was 66%, 58% and 46%, respectively. OS of CGA-fit patients was not statistically different from CGA-unfit patients, but was superior to CGA-frail patients (hazard ratio 2·892, 95% confidence interval 1·275-6·559, P = 0·011). PFS differences were not statistically significant. Baseline DR and early therapy cessation were associated with inferior OS and PFS independent of CGA. Prospective studies are needed to confirm if CGA-adapted treatment strategies minimize morbidity and improves survival.
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http://dx.doi.org/10.1111/bjh.16049DOI Listing
October 2019

Prognostication of diffuse large B-cell lymphoma in the molecular era: moving beyond the IPI.

Blood Rev 2018 09 26;32(5):400-415. Epub 2018 Mar 26.

Olivia Newton John Cancer Research and Wellness Centre, Austin Health, Heidelberg, Australia; University of Melbourne, Melbourne, Australia; Eastern Health, Box Hill, Australia. Electronic address:

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with variable outcomes. Despite the majority of patients being cured with combination chemoimmunotherapy, up to 30% eventually succumb to the disease. Until recently, baseline prognostic assessment has centred on the International Prognostic Index (IPI), although this index is yet to impact strongly on treatment choice. Molecular features such as cell of origin, MYC and BCL-2 genetic alterations and protein overexpression were identified over a decade ago, yet their prognostic value is still not fully elucidated. Adding complexity are the plethora of new clinical, biological and molecular prognostic markers described in the recent literature, most of which lack independent validation, likely act as surrogate markers for those already in common use and have yet to substantially impact on therapeutic decision making. This review comprehensively assesses the value of individual prognostic markers in the clinical setting and their potential to predict response to novel agents, and ways to optimise their use in future research.
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http://dx.doi.org/10.1016/j.blre.2018.03.005DOI Listing
September 2018

Novel Indications for Bruton's Tyrosine Kinase Inhibitors, beyond Hematological Malignancies.

J Clin Med 2018 Mar 21;7(4). Epub 2018 Mar 21.

Department of Medical Oncology and Clinical Haematology, Olivia Newton-John Cancer Research Institute, Austin Health, Heidelberg, VIC 3084, Australia.

Bruton's tyrosine kinase (BTK) is a critical terminal enzyme in the B-cell antigen receptor (BCR) pathway. BTK activation has been implicated in the pathogenesis of certain B-cell malignancies. Targeting this pathway has emerged as a novel target in B-cell malignancies, of which ibrutinib is the first-in-class agent. A few other BTK inhibitors (BTKi) are also under development (e.g., acalabrutinib). While the predominant action of BTKi is the blockade of B-cell receptor pathway within malignant B-cells, increasing the knowledge of off-target effects as well as a potential role for B-cells in proliferation of solid malignancies is expanding the indication of BTKi into non-hematological malignancies. In addition to the expansion of the role of BTKi monotherapy, combination therapy strategies utilizing ibrutinib with established regimens and combination with modern immunotherapy compounds are being explored.
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http://dx.doi.org/10.3390/jcm7040062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920436PMC
March 2018

Is Upfront Escalated BEACOPP for Advanced Hodgkin Lymphoma Becoming a Distant Memory?

J Clin Oncol 2017 01 28;35(3):371-372. Epub 2016 Oct 28.

Eliza A. Hawkes, Olivia Newton-John Cancer Wellness & Research Centre, Austin Hospital; and Eastern Health, Melbourne, Victoria, Australia; and Geoffrey Chong and Andrew Grigg, Olivia Newton-John Cancer Wellness & Research Centre, Austin Hospital, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1200/JCO.2016.68.2047DOI Listing
January 2017

A Randomized Controlled Trial of a Nurse-Led Supportive Care Package (SurvivorCare) for Survivors of Colorectal Cancer.

Oncologist 2016 08 15;21(8):1014-23. Epub 2016 Jun 15.

Department of Cancer Experiences Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia Department of Psychology, Swinburne University of Technology, Melbourne, Victoria, Australia.

Introduction: Colorectal cancer (CRC) and its treatments can cause distressing sequelae. We conducted a multicenter randomized controlled trial aiming to improve psychological distress, supportive care needs (SCNs), and quality of life (QOL) of patients with CRC. The intervention, called SurvivorCare (SC), comprised educational materials, needs assessment, survivorship care plan, end-of-treatment session, and three follow-up telephone calls.

Methods: At the end of treatment for stage I-III CRC, eligible patients were randomized 1:1 to usual care (UC) or to UC plus SC. Distress (Brief Symptom Inventory 18), SCNs (Cancer Survivors' Unmet Needs measure), and QOL (European Organization for Research and Treatment of Cancer [EORTC] QOL questionnaires C30 and EORTC CRC module CR29) were assessed at baseline and at 2 and 6 months (follow-up 1 [FU1] and FU2, respectively). The primary hypothesis was that SC would have a beneficial effect on distress at FU1. The secondary hypotheses were that SC would have a beneficial effect on (a) SCN and QOL at FU1 and on (b) distress, SCNs, and QOL at FU2. A total of 15 items assessed experience of care.

Results: Of 221 patients randomly assigned, 4 were ineligible for the study and 1 was lost to FU, leaving 110 in the UC group and 106 in the SC group. Patients' characteristics included the following: median age, 64 years; men, 52%; colon cancer, 56%; rectal cancer, 35%; overlapping sites of disease, 10%; stage I disease, 7%; stage II, 22%; stage III, 71%. Baseline distress and QOL scores were similar to population norms. Between-group differences in distress at FU1 (primary outcome) and at FU2, and SCNs and QOL at FU1 and FU2 were small and nonsignificant. Patients in the SC group were more satisfied with survivorship care than those in the UC group (significant differences on 10 of 15 items).

Conclusion: The addition of SC to UC did not have a beneficial effect on distress, SCNs, or QOL outcomes, but patients in the SC group were more satisfied with care.

Implications For Practice: Some survivors of colorectal cancer report distressing effects after completing treatment. Strategies to identify and respond to survivors' issues are needed. In a randomized controlled trial, the addition of a nurse-led supportive care package (SurvivorCare) to usual post-treatment care did not impact survivors' distress, quality of life, or unmet needs. However, patients receiving the SurvivorCare intervention were more satisfied with survivorship care. Factors for consideration in the design of subsequent studies are discussed.
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http://dx.doi.org/10.1634/theoncologist.2015-0533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4978555PMC
August 2016

Phase I Imaging and Pharmacodynamic Trial of CS-1008 in Patients With Metastatic Colorectal Cancer.

J Clin Oncol 2015 Aug 29;33(24):2609-16. Epub 2015 Jun 29.

Marika Ciprotti, Niall C. Tebbutt, Fook-Thean Lee, Sze-Ting Lee, Hui K. Gan, Wendie Hopkins, Fiona E. Scott, Andrew M. Scott, Ludwig Institute for Cancer Research; David C. McKee, Graeme J. O'Keefe, Sylvia J. Gong, Geoffrey Chong, Bridget Chappell, Andrew M. Scott, Austin Health, Melbourne, Australia; Martin W. Brechbiel, National Cancer Institute, Bethesda, MD; Archie N. Tse, Jonathan Greenberg, Daiichi Sankyo Co., Ltd, Parsippany, NJ; Mendel Jansen, Daiichi Sankyo Development Ltd, Gerrards Cross, Buckinghamshire, United Kingdom; Manabu Matsumura, Masakatsu Kotsuma, Rira Watanabe, Daiichi Sankyo Co., Ltd, Tokyo, Japan; Robert A. Beckman, Georgetown University Medical Center and Ralph Venhaus, Ludwig Institute for Cancer Research, New York, NY.

Purpose: CS-1008 (tigatuzumab) is a humanized, monoclonal immunoglobulin G1 (IgG1) agonistic antibody to human death receptor 5. The purpose of this study was to investigate the impact of CS-1008 dose on the biodistribution, quantitative tumor uptake, and antitumor response in patients with metastatic colorectal cancer (mCRC).

Patients And Methods: Patients with mCRC who had received at least one course of chemotherapy were assigned to one of five dosage cohorts and infused with a weekly dose of CS-1008. Day 1 and day 36 doses were trace-labeled with indium-111 ((111)In), followed by whole-body planar and regional single-photon emission computed tomography (SPECT) imaging at several time points over the course of 10 days.

Results: Nineteen patients were enrolled. (111)In-CS-1008 uptake in tumor was observed in only 12 patients (63%). (111)In-CS-1008 uptake and pharmacokinetics were not affected by dose or repeated drug administration. (111)In-CS-1008 biodistribution showed gradual blood-pool clearance and no abnormal uptake in normal tissue. No anti-CS-1008 antibody development was detected. One patient achieved partial response (3.7 months duration), eight patients had stable disease, and 10 patients had progressive disease. Clinical benefit rate (stable disease + partial response) in patients with (111)In-CS-1008 uptake in tumor was 58% versus 28% in patients with no uptake. An analysis of individual lesions showed that lesions with antibody uptake were one third as likely to progress as those without antibody uptake (P = .07). Death-receptor-5 expression in archived tumor samples did not correlate with (111)In-CS-1008 uptake (P = .5) or tumor response (P = .6).

Conclusion: Death-receptor-5 imaging with (111)In-CS-1008 reveals interpatient and intrapatient heterogeneity of uptake in tumor, is not dose dependent, and is predictive of clinical benefit in the treatment of patients who have mCRC.
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http://dx.doi.org/10.1200/JCO.2014.60.4256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881374PMC
August 2015

Quantitative intratumoural microdistribution and kinetics of (131)I-huA33 antibody in patients with colorectal carcinoma.

EJNMMI Res 2014 30;4:22. Epub 2014 May 30.

Ludwig Institute for Cancer Research, Austin Health, Melbourne 3084, Australia ; Department of Nuclear Medicine and Centre for PET, Austin Health, Melbourne 3084, Australia.

Background: The ability of recombinant antibodies to adequately penetrate into tumours is a key factor in achieving therapeutic effect; however, the behaviour of antibodies at a cellular level in tumours is poorly understood. The purpose of this study was to investigate those factors that influence the macroscopic and microscopic intratumoural distribution of an IgG1-humanized antibody, huA33, in colorectal tumours.

Methods: Twelve patients were infused with radiolabelled huA33 at 7 days prior to elective surgery for colorectal carcinoma. Macroscopic huA33 uptake was determined by both gamma well counter and autoradiography measurements of the resected tumour specimens. Microscopic uptake was then quantitated at a cellular level and compared to vascular penetrance. The impact of variation in tumour antigen (GPA33) expression, tumour size, specimen type (primary vs metastatic), presence of macroscopic necrosis, and tumour vasculature on huA33 uptake were examined.

Results: The I-huA33 uptake in whole tumour sections was (mean ± SD) 5.13 ± 2.71 × 10(-3)% injected dose per gram (ID/g). GPA33 was expressed in all viable tumour cells, and huA33 uptake was excellent regardless of tumour size and specimen type. In tumours with macroscopically evident central necrosis (n = 5), huA33 uptake in tumour necrotic centres was lower than in viable peripheries (0.606 ± 0.493 vs 2.98 ± 2.17 × 10(-3)%ID, p = 0.06). However, when corrected for low cell viability in necrotic centres, uptake of huA33 at the cellular level was highly comparable to that in the more viable tumour periphery (7.10 ± 5.10 × 10(-9) vs 3.82 ± 3.67 × 10(-9)%ID/cell, p = 0.4). In the five patients who exhibited macroscopic necrosis in their tumours, huA33 showed excellent tissue penetration, with a maximum penetration distance of 26 μm in peripheral tumour regions and 118 μm in central regions. No correlation was observed between (131)I-huA33 uptake in tumour on a cellular basis and tumour vascularity.

Conclusions: In patients with colorectal carcinoma, monoclonal antibody huA33 effectively targets viable tumour cells in all cellular milieus examined, including effective penetration into necrotic tumour centres, a novel and therapeutically important finding.
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http://dx.doi.org/10.1186/s13550-014-0022-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070025PMC
July 2014

Interstitial lung disease in a patient treated with oxaliplatin, 5-fluorouracil and leucovorin (FOLFOX) for metastatic colorectal cancer.

Radiol Oncol 2012 Dec 9;46(4):360-2. Epub 2012 Nov 9.

Department of Respiratory and Sleep Medicine, Austin Health, Heidelberg, Victoria, Australia ; Institute for Breathing and Sleep, Austin Hospital, Heidelberg, Victoria, Australia.

Background: Oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (FOLFOX) is a common chemotherapeutic regimen for advanced colorectal cancer. Here, we present a case of interstitial lung disease associated with FOLFOX therapy.

Case Report: A 74-year-old man with a history of metastatic colorectal cancer was admitted with a four week history of progressive dyspnoea and evidence of severe respiratory failure. He had recently completed six cycles of FOLFOX chemotherapy in the months prior to presentation. Investigations did not reveal convincing evidence of infection or pulmonary embolism. CT chest demonstrated widespread pulmonary infiltrates and interlobular septal thickening. The patient was commenced on both broad spectrum antibiotic therapy and high dose corticosteroid treatment however his respiratory failure continued to progress. The patient died four days after admission due to progressive respiratory failure. Subsequent post-mortem examination demonstrated evidence of diffuse alveolar damage without evidence of tumour infiltration, infection or pulmonary embolism.

Conclusions: Although infrequent, pulmonary toxicity can occur in association with FOLFOX therapy. Cessation of therapy and prompt initiation of corticosteroids may improve outcomes.
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http://dx.doi.org/10.2478/v10019-012-0006-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572892PMC
December 2012

Mortality within 30 days of receiving systemic anti-cancer therapy at a regional oncology unit: what have we learned?

Asia Pac J Clin Oncol 2012 Dec 12;8(4):325-9. Epub 2012 Mar 12.

Ballarat Base Hospital, Ballarat Health Services, Ballarat, Victoria 3350, Australia.

Aims: Benefits to patients from systemic anti-cancer therapies (SACT) occur at a cost of significant toxicities that can be life threatening. Published data of SACT mortality outside clinical trials is limited with no published Australia data. We aim to establish local outcomes at a regional Victorian oncology center to allow comparison with limited international data.

Methods: An audit was undertaken at Ballarat Health Services to analyze all deaths occurring within 30 and 60 days of receiving SACT (cytotoxic chemotherapy and targeted therapy) for epithelial malignancies and hematological malignancies (excluding acute leukemia), over a 12-month period. Hormonal therapy was excluded.

Results: Between 1 January and 31 December 2008, 378 patients received SACT. In total 13 deaths (3.4%) occurred within 30 days following SACT. Three deaths (23%) were definitely treatment-related - neutropenic sepsis, pneumocystis pneumonia and bowel perforation, respectively. Eight deaths (62%) were definitely unrelated to treatment. Most deaths were due to disease progression (six patients) For two patients (15%), the cause of death was unknown. Most patients were treated with palliative intent. Most patients were receiving first-line treatment (seven patients, 50%). A further five deaths (1.3%) occurred 31-60 days after SACT, four of which were due to disease progression.

Conclusion: Our local outcome data are comparable to limited current international data. This type of audit reviews local outcomes and identifies factors contributing to mortality in order to improve standards of care. We encourage similar audits to establish national benchmarks of 30-day mortality rate.
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http://dx.doi.org/10.1111/j.1743-7563.2011.01498.xDOI Listing
December 2012

Bilateral papilledema on sunitinib therapy for advanced renal cell carcinoma.

Med Oncol 2011 Dec 4;28 Suppl 1:S395-7. Epub 2010 Nov 4.

Ballarat Base Hospital, Drummond Street North, Ballarat, VIC 3350, Australia.

We report the case of a 59-year-old man with advanced renal cell carcinoma who developed bilateral papilledema while on therapy with sunitinib, a multi-targeted tyrosine kinase inhibitor (TKI). While papilledema has been reported in association with another TKI (imatinib), the association between sunitinib and papilledema has not previously been reported in the literature.
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http://dx.doi.org/10.1007/s12032-010-9719-5DOI Listing
December 2011

Longitudinal assessment of quality of life in rectal cancer patients with or without stomas following primary resection.

Dis Colon Rectum 2009 Apr;52(4):669-77

Royal Marsden Hospital, London and Surrey, United Kingdom.

Purpose: The purpose of this study was to assess the longitudinal impact of stoma formation on the health-related quality of life of rectal cancer patients treated with adjuvant chemotherapy.

Methods: Health-related quality of life data was prospectively collected in a randomized trial designed to compare 24 weeks of bolus 5-fluorouracil/leucovorin with 12 weeks of continuous 5-fluorouracil in patients with resected Dukes B and C colorectal cancer. Health-related quality of life data was collected at baseline, during adjuvant treatment, and at one and three years after completion of chemotherapy.

Results: Between 1993 and 2003, 186 rectal cancer patients were enrolled. One hundred thirty-nine patients had anterior resection, of whom 46 had a temporary defunctioning colostomy. Forty-seven patients had abdominoperineal resection with formation of a permanent colostomy. There was no significant difference in global health-related quality of life between patients with and patients without a stoma at any time point. However, during adjuvant treatment, role (P = 0.04) and social (P = 0.005) functioning were significantly worse in stoma patients than in nonstoma patients. Moreover, the impairment in social functioning persisted at one (P = 0.03) and three years (P = 0.04) after adjuvant chemotherapy.

Conclusion: Our results demonstrate important adverse effects of either temporary or permanent stoma formation on subsequent health-related quality of life in patients with rectal cancer.
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http://dx.doi.org/10.1007/DCR.0b013e31819eb970DOI Listing
April 2009

A pilot study of monoclonal antibody cG250 and low dose subcutaneous IL-2 in patients with advanced renal cell carcinoma.

Cancer Immun 2007 Aug 17;7:14. Epub 2007 Aug 17.

Ludwig Institute for Cancer Research, Victoria, Australia.

The chimeric monoclonal antibody cG250 recognizes the CAIX/MN antigen. cG250 induces antibody-dependent cellular cytotoxicity (ADCC) responses in vitro that can be enhanced by IL-2. We studied the effects of adding daily low-dose subcutaneous IL-2 to cG250 for treatment of clear cell renal cell carcinoma (RCC). The primary endpoints of the trial were toxicity and immunological effects (human anti-chimeric antibodies [HACA], ADCC, natural killer [NK] and lymphokine-activated killer cell [LAK] activity); secondary endpoints were cG250 biodistribution and pharmacokinetics (PK) and tumour response rates. Eligible patients had unresectable metastatic or locally advanced clear cell RCC with measurable or evaluable disease. Nine patients were treated with six doses of cG250 (10 mg/m(2)/week, first and fifth doses trace-labelled with (131)I), and 1.25 x 10(6) IU/m(2)/day IL-2 for six weeks. Treatment was generally well tolerated with no adverse events attributable to cG250. Two patients required a 50% dose reduction of IL-2 due to toxicity. No HACA was detected. (131)I-labeled cG250 showed excellent targeting of tumour deposits. (131)I cG250 PK: T(1/2)alpha 20.16 +/- 6.59 h, T(1/2)beta 126.21 +/- 34.04 h, CL 39.67 +/- 23.06 mL/h, Cmax 5.12 +/- 0.86 microg/mL, V(1) 3.88 +/- 1.05 L. IL-2 did not affect cG250 PK. A trend for increased percentage of circulating CD3-/CD16+CD56+ NK cells was observed. Some patients showed enhanced ADCC or LAK activity. No antitumour responses were observed. In conclusion, weekly cG250 with daily low-dose subcutaneous IL-2 is well tolerated. IL-2 does not influence cG250 biodistribution or increase HACA.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935743PMC
August 2007

A phase I biodistribution and pharmacokinetic trial of humanized monoclonal antibody Hu3s193 in patients with advanced epithelial cancers that express the Lewis-Y antigen.

Clin Cancer Res 2007 Jun;13(11):3286-92

Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, Austin Hospital, Australia.

Purpose: We report a first-in-man trial of a humanized antibody (hu3S193) against the Le(y) antigen.

Experimental Design: Patients with advanced Le(y)-positive cancers received four infusions of hu3S193 at weekly intervals, with four dose levels (5, 10, 20, and 40 mg/m(2)). The first infusion of hu3S193 was trace labeled with Indium-111, and biodistribution, pharmacokinetics, tumor uptake, and immune response were evaluated in all patients.

Results: A total of 15 patients (7 male/8 female; age range, 42-76 years; 6 breast, 8 colorectal cancer, and 1 non-small-cell lung cancer) were entered into the study. Transient grade 1 to 2 nausea and vomiting was observed following infusion of hu3S193 at the 40 mg/m(2) dose level only. There was one episode of dose-limiting toxicity with self-limiting Common Toxicity Criteria grade 3 elevated alkaline phosphatase observed in one patient with extensive liver metastases. The biodistribution of (111)In-hu3S193 showed no evidence of any consistent normal tissue uptake, and (111)In-hu3S193 uptake was observed in cutaneous, lymph node, and hepatic metastases. Hu3S193 displayed a long serum half-life (T(1/2)beta = 189.63 +/- 62.17 h). Clinical responses consisted of 4 patients with stable disease and 11 patients with progressive disease, although one patient experienced a 89% decrease in a lymph node mass, and one patient experienced inflammatory symptoms in cutaneous metastases, suggestive of a biological effect of hu3S193. No immune responses (human anti-human antibody) to hu3S193 were observed.

Conclusion: Hu3S193 is well tolerated and selectively targets tumors, and the long half-life and biological function in vivo of this antibody makes it an attractive potential therapy for patients with Le(y)-expressing cancers.
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http://dx.doi.org/10.1158/1078-0432.CCR-07-0284DOI Listing
June 2007

Gemcitabine, cisplatin and methylprednisolone (GEM-P) with or without Rituximab in relapsed and refractory patients with diffuse large B cell lymphoma (DLBCL).

Hematology 2007 Apr;12(2):149-53

Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK.

This is the first report of the combination of gemcitabine, cisplatin and methylprednisolone (GEM-P) with Rituximab (GEM-PR) for diffuse large B-cell lymphoma (DLBCL). Thirty-nine patients with relapsed or refractory DLBCL in this study received GEM-P with (n = 24) or without Rituximab (n = 15) 64% patients had Stage III/IV disease. The overall response rate (ORR) was 59% (95% CI 42.1-74.4); 11/39 (28%) patients attained complete response. Patients received a median of two cycles (1-4) of treatment. For GEM-PR group, the ORR was 67% (95% CI 45-84%) compared to 47% (95% CI 21-73%) in GEM-P alone. one-year progression-free survival was 51% (95% CI 28-69%) in GEM-PR group compared to 27% (95% CI 8-49%) in GEM-P alone (P = 0.04). GEM-P is an effective second-line regimen in patients with relapsed or refractory DLBCL and the addition of Rituximab appears to further improve outcomes.
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http://dx.doi.org/10.1080/10245330701214095DOI Listing
April 2007

Phase I trial of 131I-huA33 in patients with advanced colorectal carcinoma.

Clin Cancer Res 2005 Jul;11(13):4818-26

Ludwig Institute for Cancer Research, Melbourne, Australia.

Purpose: Humanized monoclonal antibody A33 (huA33) targets the A33 antigen which is expressed on 95% of colorectal cancers. A previous study has shown excellent tumor-targeting of iodine-131 labeled huA33 (131I-huA33). Therefore, we did a phase I dose escalation trial of 131I-huA33 radioimmunotherapy.

Experimental Designs: Fifteen patients with pretreated metastatic colorectal carcinoma each received two i.v. doses of 131I-huA33. The first was an outpatient trace-labeled "scout" dose for biodistribution assessment, followed by a second "therapy" dose. Three patients were treated at 20, 30, and 40 mCi/m2 dose levels, and six patients at 50 mCi/m2 to define the maximum tolerated dose.

Results: Hematologic toxicity was 131I dose-dependent, with one episode of grade 4 neutropenia and two episodes of grade 3 thrombocytopenia observed at 50 mCi/m2. The maximum tolerated dose was determined to be 40 mCi/m2. There were no acute infusion-related adverse events, and gastrointestinal toxicity was not observed despite uptake of 131I-huA33 in bowel. Seven patients developed pruritus or rash, which was not related to 131I dose. There was excellent tumor-targeting of 131I-huA33 shown in all patients. The serum T1/2beta of 131I-huA33 was (mean +/- SD) 135.2 +/- 46.9 hours. The mean absorbed tumor dose was 6.49 +/- 2.47 Gy/GBq. Four patients developed human anti-human antibodies. At restaging, 4 patients had stable disease, whereas 11 patients had progressive disease.

Conclusion: Radioimmunotherapy using 131I-huA33 shows promise in targeting colorectal tumors, and is deliverable at a maximum tolerated dose of 40 mCi/m2. Further studies of 131I-huA33 in combination with chemotherapy are planned.
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http://dx.doi.org/10.1158/1078-0432.CCR-04-2330DOI Listing
July 2005

A phase I trial of humanized monoclonal antibody A33 in patients with colorectal carcinoma: biodistribution, pharmacokinetics, and quantitative tumor uptake.

Clin Cancer Res 2005 Jul;11(13):4810-7

Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, Melbourne, Victoria, Australia.

Purpose: To determine the in vivo characteristics of huA33, a CDR-grafted humanized antibody against the A33 antigen, we have conducted an open-label, dose escalation, biopsy-based phase I trial of huA33 in patients with colorectal carcinoma.

Experimental Design: Patients with colorectal carcinoma were infused with [131I]huA33 (400 MBq: 10 mCi) and [125I]huA33 (40 MBq: 1 mCi) 1 week before surgery. There were four huA33 dose levels (0.25, 1.0, 5.0, and 10 mg/m2). Adverse events, pharmacokinetics, biodistribution, tumor biopsies, and immune responses to huA33 were evaluated.

Results: There were 12 patients entered into the trial (6 males and 6 females; age range, 39-66 years). No dose-limiting toxicity was observed. The biodistribution of huA33 showed excellent uptake of [131I]huA33 in metastatic colorectal carcinoma. Pharmacokinetic analysis showed no significant difference in terminal half-life (T1/2beta) between dose levels (mean +/- SD, 86.92 +/- 22.12 hours). Modeling of colon uptake of huA33 showed a T1/2 of elimination of 32.4 +/- 8.1 hours. Quantitative tumor uptake ranged from 2.1 x 10(-3) to 11.1 x 10(-3) %ID/g, and tumor/normal tissue and tumor/serum ratios reached as high as 16.3:1 and 4.5:1, respectively. Biosensor analysis detected low-level human anti-human antibody responses in four patients following huA33 infusion.

Conclusions: huA33 shows selective and rapid localization to colorectal carcinoma in vivo and penetrates to the center of large necrotic tumors, and colon elimination half-life of huA33 is equivalent to basal colonocyte turnover. The excellent targeting characteristics of this humanized antibody indicate potential for the targeted therapy of metastatic colorectal cancer in future trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-04-2329DOI Listing
July 2005