Medicine (St Vincent's) - Research Publications
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ItemAustralian experience of a modified schedule of FOLFOX with high activity and tolerability and improved convenience in untreated metastatic colorectal cancer patients(NATURE PUBLISHING GROUP, 2005-03-14)This study determined the efficacy and safety of a modified FOLFOX regimen that improved patient convenience without compromising oxaliplatin dose intensity. A total of 62 patients with previously untreated metastatic colorectal cancer were enrolled to receive, entirely as outpatients, 2-weekly cycles of oxaliplatin 100 mg m(-2) i.v. over 2 h, together with leucovorin 400 mg m(-2) over 2 h, 5-fluorouracil (5-FU) 400 mg m(-2), bolus, followed by a 46-h infusion of 5-FU at 2.4 g m(-2). Treatment was given until progression or unmanageable toxicity. In all, 61 patients received > or =one oxaliplatin dose and a median of 11 treatment cycles (range 1-20 cycles); 22 (36%) reported grade 3/4 neutropenia and 13 patients (21%) experienced grade 3 neurotoxicity; 16 patients (26%) discontinued treatment due to disease progression or death, 15 (25%) due to neurotoxicity and six (10%) due to haematological toxicity. Of the 56 eligible patients, complete or partial responses were observed in 29 or 52% (95% confidence interval 38-65%). Median progression-free survival was 8.2 months (7.1-9.9) and median overall survival was 18.7 months (14.0-23.4). In our experience, a modified schedule of FOLFOX improves convenience without compromising efficacy or toxicity.
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ItemA phase I trial of Capecitabine plus Gemcitabine with radical radiation for locally advanced pancreatic cancer(NATURE PUBLISHING GROUP, 2009-01-13)Standard chemoradiotherapy with infusional 5FU for locally advanced pancreatic cancer (LAPC) has limited efficacy in this disease. The combination of Capecitabine (Cap) and Gemcitabine (Gem) are synergistic and are potent radiosensitisers. The aim of this phase I trial was thus to determine the highest administered dose of the Cap plus Gem combination with radical radiotherapy (RT) for LAPC. Patients had LAPC, adequate organ function, ECOG PS 0-1. During RT, Gem was escalated from 20-50 mg m(-2) day(-1) (twice per week), and Cap 800-2000 mg m(-2) day(-1) (b.i.d, days 1-5 of each week). Radiotherapy 50.4 Gy/28 fractions/5.5 weeks, using 3D-conformal techniques. Three patients were entered to each dose level (DL). Dose-limiting toxicity(s) (DLTs) were based on treatment-related toxicities. Twenty patients were accrued. Dose level (DL) 1: Cap/Gem; 800/20 mg m(-2) day(-1) (3 patients), DL2: 1000/20 (12 patients), DL3: 1300/30 (5 patients). Dose-limiting toxicities were observed in DL3; grade 3 dehydration (1 patient) and grade 3 diarrhoea and dehydration (1 patient). Dose level 2 was the recommend phase 2 dose. Disease control rate was 75%: PR=15%, SD=60%. Median overall survival was 11.2 months. The addition of Cap and Gem to radical RT was feasible and active and achieved at relatively low doses.
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ItemThe multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study(NATURE PUBLISHING GROUP, 2006-10-09)Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCalpha), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases. In mice, midostaurin slows growth and delays lung metastasis of melanoma cell lines. We aimed to test midostaurin's safety, efficacy and biologic activity in a Phase IIA clinical trial in patients with metastatic melanoma. Seventeen patients with advanced metastatic melanoma received midostaurin 75 mg p.o. t.i.d., unless toxicity or disease progression supervened. Patient safety was assessed weekly, and tumour response was assessed clinically or by CT. Tumour biopsies and plasma samples obtained at entry and after 4 weeks were analysed for midostaurin concentration, PKC activity and multidrug resistance. No tumour responses were seen. Two (12%) patients had stable disease for 50 and 85 days, with minor response in one. The median overall survival was 43 days. Seven (41%) discontinued treatment with potential toxicity, including nausea, vomiting, diarrhoea and/or fatigue. One patient had >50% reduction in PKC activity. Tumour biopsies showed two PKC isoforms relatively insensitive to midostaurin, out of three patients tested. No modulation of multidrug resistance was demonstrated. At this dose schedule, midostaurin did not show clinical or biologic activity against metastatic melanoma. This negative trial reinforces the importance of correlating biologic and clinical responses in early clinical trials of targeted therapies.
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ItemOxaliplatin combined with infusional 5-fluorouracil and concomitant radiotherapy in inoperable and metastatic rectal cancer: a phase I trial(NATURE PUBLISHING GROUP, 2005-02-28)The aim of this study was to define the recommended dose of oxaliplatin when combined with infusional 5-fluorouracil (5-FU) and concurrent pelvic radiotherapy. Eligible patients had inoperable rectal cancer, or symptomatic primary rectal cancer with metastasis. Oxaliplatin was given on day 1 of weeks 1, 3 and 5 of radiotherapy. Dose level 1 was oxaliplatin 70 mg m(-2) with 5-FU 200 mg m(-2) day(-1) continuous infusion 96 h week(-1). On dose level 2, the oxaliplatin dose was increased to 85 mg m(-2). On dose level 3, the duration of the 5-FU was increased to 168 h per week. Pelvic radiotherapy was 45 Gray (Gy) in 25 fractions over 5 weeks with a boost of 5.4 Gy. Fluorine-18 fluoro deoxyglucose and Fluorine-18 fluoro misonidazole positron emission tomography (FDG-PET and FMISO-PET) were used to assess metabolic tumour response and hypoxia. In all, 16 patients were accrued. Dose-limiting toxicities occurred in one patient at level 2 (grade 3 chest infection), and two patients at level 3 (grade 3 diarrhoea). Dose level 2 was declared the recommended dose level. FDG-PET imaging showed metabolic responses in 11 of the 12 primary tumours assessed. Four of six tumours had detectable hypoxia on FMISO-PET scans. The addition of oxaliplatin to infusional 5-FU chemoradiotherapy was feasible and generally well tolerated. For future trials, oxaliplatin 85 mg m(-2) and 5-FU 200 mg m(-2) day(-1) continuous infusion 96 h week(-1) is the recommended dose when combined with 50.4 Gy of pelvic radiotherapy.
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ItemRapid screening for depression - validation of the Brief Case-Find for Depression (BCD) in medical oncology and palliative care patients(SPRINGERNATURE, 2004-08-31)Depression in oncology patients is under-recognised and associated with poor outcomes. Screening can increase case recognition. The Brief Case-Find for Depression (BCD) is a four-question, interviewer-administered instrument that has been previously validated in a general medical setting. The primary aim of this study was to validate the BCD in a medical oncology/palliative care setting, primarily by comparing its association with physical illness measures and with the Primary Care Evaluation of Mental Disorders (PRIME-MD), the Beck Depression Inventory (BDI) and the Hospital Anxiety and Depression Scale (HADS). Eligible adult oncology patients gave informed consent and completed the above measures and a pain scale. Agreement between the BCD and other instruments was assessed. Construct validity was determined by comparing depressed/nondepressed patients with respect to performance status, symptoms, pain score and functional impairment. A total of 100 patients had a median age of 58 (range 21-90) and ECOG performance status (PS) 2 (0-4). In all, 60% had metastatic disease. The therapeutic goal was curative/adjuvant in 39% and palliative in 61%. Prevalence of depression according to the various measures was: BCD 34%, PRIME-MD 12%, BDI 19% and HADS 14%. In total, 45% of patients responded positively to a single-item screening question. The BCD showed fair agreement with the PRIME-MD (kappa=0.21), moderate agreement with the BDI (kappa=0.43) and fair agreement with the HADS (kappa=0.27). Against the PRIME-MD diagnosis of depression, the BCD had greater sensitivity, but lesser specificity and overall agreement, compared with the BDI and depression scale of the HADS. Patients with probable depression (according to BCD) had inferior PS (P=0.0064), increased pain (P=0.045) and greater impairment of functioning (PRIME-MD: P=0.0003). There was no association with gender, age, disease status or therapeutic goal. Depression is common in oncology patients. The BCD is a quick, easy-to-administer screen for depression, which has reasonable psychometric properties in this population.
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ItemA phase I trial of preoperative radiotherapy and capecitabine for locally advanced, potentially resectable rectal cancer(NATURE PUBLISHING GROUP, 2004-09-13)The purpose of the study was to determine the maximum-tolerated dose (MTD) of oral capecitabine, combined with concurrent, standard preoperative pelvic radiotherapy, when given twice daily, from Monday to Friday throughout the course of radiotherapy, for locally advanced potentially resectable rectal cancer. Maximum-tolerated dose was defined as the total (given in two equally divided doses) oral dose of capecitabine that caused treatment-related grade 3 or 4 toxicity in one-third or more of the patients treated. Radiotherapy involved 50.4 Gy given in 28 fractions in 5 weeks and 3 days. Eligible patients had a newly diagnosed clinical stage T3-4 N0-2 M0 rectal adenocarcinoma located within 12 cm of the anal verge suitable for curative resection. Surgery was performed 4-6 weeks from completion of preoperative chemoradiotherapy. In all, 28 patients were enrolled in the study at predefined dose levels: 850 mg m(-2) day(-1) (n=3), 1000 mg m(-2) day(-1) (n=6), 1250 mg m(-2) day(-1) (n=3), 1650 mg m(-2) day(-1) (n=3), 1800 mg m(-2) day(-1) (n=8) and 2000 mg m(-2) day(-1) (n=5). The mean age was 62.3 years (range: 33-80 years). Five patients were female and 23 male. The median distance of tumour from the anal verge was 6 cm (range: 1-11 cm). Endorectal ultrasound was performed in 93% of patients. A total of 26 patients (93%) had T3 disease and two patients had resectable T4 disease. Dose-limiting toxicity (DLT) developed in one patient at dose level 1000 mg m(-2) day(-1) (RTOG grade 3 cystitis). Two of the five patients at dose level 2000 mg m(-2) day(-1) had a total of three DLT (grade 3 perineal skin reaction, grade 3 diarrhoea and grade 3 dehydration). Dose escalation of capecitabine was ceased at 2000 mg m(-2) day(-1) after reaching MTD. None of the eight patients at dose level 1800 mg m(-2) day(-1) developed DLT. All except one patient underwent surgery. A total of 15 patients had the clinical T stage reduced by at least one stage in pathologic specimens. Five patients (19%) achieved a pathologic complete response. We conclude that the MTD of capecitabine was reached at a dose level of 2000 mg m(-2) day(-1), given as 1000 mg m(-2) twice daily, from Monday to Friday throughout the course of preoperative pelvic irradiation of 50.4 Gy. For patients with resectable rectal cancer receiving concurrent, full dose radiotherapy, the recommended dose of capecitabine for further study is 1800 mg m(-2) day(-1) when given in this schedule.
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ItemAdjuvant and neoadjuvant therapy for gastric cancer using epirubicin/cisplatin/5-fluorouracil (ECF) and alternative regimens before and after chemoradiation(NATURE PUBLISHING GROUP, 2003-10-20)Chemoradiation is now used more commonly for gastric cancer following publication of the US Intergroup trial results that demonstrate an advantage to adjuvant postoperative chemoradiotherapy. However, there remain concerns regarding the toxicity of this treatment, the optimal chemotherapy regimen and the optimal method of radiotherapy delivery. In this prospective study, we evaluated the toxicity and feasibility of an alternative chemoradiation regimen to that used in the Intergroup trial. A total of 26 patients with adenocarcinoma of the stomach were treated with 3D-conformal radiation therapy to a dose of 45 Gy in 25 fractions with concurrent continuous infusional 5-fluorouracil (5-FU). The majority of patients received epirubicin, cisplatin and 5-FU (ECF) as the systemic component given before and after concurrent chemoradiation. The overall rates of observed grade 3 and 4 toxicities were 38 and 15%, respectively. GIT grade 3 toxicity was observed in 19% of patients, while haematologic grade 3 and 4 toxicities were observed in 23%. Our results suggest that this adjuvant regimen can be delivered safely and with acceptable toxicity. This regimen forms the basis of several new studies being developed for postoperative adjuvant therapy of gastric cancer.