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ABSTRACT: Background: Clinical trial units are integral to the functioning of a medical oncology department with patient access to clinical trials an important component in patient care. There has been a paucity of potential key performance indicators in medical oncology and clinical trial information may be utilised for this purpose. The aim of this study was to record retrospectively and collate prospectively collected information regarding basic demographics, response rate, progression and survival plus grade 3 or 4 toxicity in patients enrolled in clinical trials for metastatic colorectal cancer at the Sydney Cancer Centre between 1999 and 2007.Methods: Baseline patient demographics, clinical response, progression dates, grade 3 or 4 toxicities plus treatment-related fatalities were collected from individual clinical trials. Outcome measures were clinical response, progression-free survival and overall survival.Results: There was a total of 14 trials undertaken during the defined period for patients with metastatic colorectal cancer. There was available information for 243 patient trials with sufficient information regarding response rates, toxicity, progression and survival. Tumour response rates ranged from 27% to 66% for first line chemotherapy trials and 0% to 20% for non-first line chemotherapy trials. The overall progression-free survival was 6.4 months and overall survival 14.0 months for all trials. There was one treatment-related fatality on clinical trial during this period.Conclusions: Results of our clinical database have been used here to illustrate the concept and value of reporting clinical trial information in medical oncology. Public reporting of such information may allow for comparisons between units and for quality improvement.
Internal Medicine Journal 04/2012; 42(4):416 - 421. · 1.54 Impact Factor
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ABSTRACT: The selection criteria for phase III trials are often stringent. We aimed to determine how many advanced non-small-cell lung cancer (NSCLC) patients would have been eligible for phase III targeted therapy trials and the proportion receiving anticancer treatment.
From March 2007 to May 2008, all advanced NSCLC patients presented at our lung cancer multidisciplinary team meeting were included to assess eligibility for the targeted therapy trials: ECOG-4599, AVAiL, FLEX, TALENT, INTACT-1, INTACT-2, ESCAPE, NEXUS and MONET1. Medical records were examined to determine treatment utilisation and overall survival.
A total of 62 patients were registered: 63% male; median age 71 years; 61% stage IIIB disease. Percentages that met criteria were: ECOG-4599 31%, AVAiL 24%, FLEX 69%, TALENT 27%, INTACT-1 50%, INTACT-2 42%, ESCAPE 39%, NEXUS 63% and MONET1 34%. Common reasons for ineligibility were insufficient life expectancy, poor performance status, abnormal bloods, proteinuria and associated cancer problems. Systemic therapies were received by 66% of patients and median survival was 10.3 months.
Only 24%-69% were eligible for targeted therapy trials but 66% received anticancer treatment. Clinical trials in patients with advanced NSCLC need to be more representative of the majority of patients.
Annals of Oncology 10/2011; 23(5):1229-33. · 6.43 Impact Factor
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ABSTRACT: Advances in the treatment of metastatic colorectal cancer (mCRC) in the last decade have significantly improved survival; however, simple biomarkers to predict response or toxicity have not been identified, which are applicable to all community oncology settings worldwide. The use of inflammatory markers based on differential white-cell counts, such as the neutrophil/lymphocyte ratio (NLR), may be simple and readily available biomarkers.
Clinical information and baseline laboratory parameters were available for 349 patients, from two independent cohorts, with unresectable mCRC receiving first-line palliative chemotherapy. Associations between baseline prognostic variables, including inflammatory markers such as the NLR and tumour response, progression and survival were investigated.
In the training cohort, combination-agent chemotherapy (P=0.001) and NLR ≤ 5 (P=0.003) were associated with improved clinical benefit. The ECOG performance status 1 (P=0.002), NLR>5 (P=0.01), hypoalbuminaemia (P=0.03) and single-agent chemotherapy (P<0.0001) were associated with increased risk of progression. The ECOG performance status ≥ 1 (P=0.004) and NLR>5 (P=0.002) predicted worse overall survival (OS). The NLR was confirmed to independently predict OS in the validation cohort (P<0.0001). Normalisation of the NLR after one cycle of chemotherapy in a subset of patients resulted in improved progression-free survival (P=0.012).
These results have highlighted NLR as a potentially useful clinical biomarker of systemic inflammatory response in predicting clinically meaningful outcomes in two independent cohorts. Results of this study have also confirmed the importance of a chronic systemic inflammatory response influencing clinical outcomes in patients with mCRC.
British Journal of Cancer 03/2011; 104(8):1288-95. · 5.04 Impact Factor
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ABSTRACT: The link between chronic inflammation and increased risk of developing some cancers is well established. The molecular mechanisms that underlie this process (cause) as well as the chronic inflammation that accompanies cancer (consequence) continue to be elucidated. Cancer-associated inflammation has effects on the ability of cancers to metastasize, on the clinical manifestations of cancer, and on the ability of the patient to tolerate anticancer therapy. The identification of biomarkers of cancer-associated inflammation will assist in identifying patients at risk of its consequences.
Clinical Pharmacology & Therapeutics 02/2010; 87(4):504-8. · 6.04 Impact Factor
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ABSTRACT: To investigate three genetic alterations (TP53 mutation, Kras mutation and microsatellite instability (MSI)) and three polymorphisms (methylene tetrahydrofolate reductase (MTHFR) C677T, excision repair cross complementing group 1 (ERCC1)-118 and X-ray repair cross complementing group 1 (XRCC1)-399) for their ability to predict response, survival and toxicity to FOLFOX first line chemotherapy in the treatment of metastatic colorectal cancer (mCRC).
Tumour tissues from 118 mCRC patients who underwent FOLFOX treatment from three successive phase II trials were evaluated for mutations in TP53 (exons 5-8) and Kras (codons 12 and 13) and for MSI using PCR-based analysis. Genotyping for common single nucleotide polymorphisms in the MTHFR (codon 677), ERCC1 (codon 118) and XRCC1 (codon 399) genes was also carried out using PCR techniques. These genetic markers were correlated with clinical response, survival and toxicity to treatment.
Patients with the T allele of ERCC1-118 showed significantly worse progression-free survival in univariate analysis (HR=2.62; 95% CI=1.14-6.02; P=0.02). None of the genetic alterations or polymorphisms showed significant association with clinical response to FOLFOX. The MTHFR, ERCC1 and XRCC1 polymorphisms showed no associations with overall haematological, gastrointestinal or neurological toxicity to FOLFOX, although MTHFR 677 TT genotype patients showed a significantly higher incidence of grade 3 or 4 diarrhoea (26%) compared with CC or CT genotype patients (6%, P=0.02).
The ERCC1-118 and MTHFR C677T polymorphisms were associated with progression and severe diarrhoea, respectively, after FOLFOX treatment in mCRC. Although our findings require confirmation in large prospective studies, they reinforce the concept that individual genetic variation may allow personalized selection of chemotherapy to optimize clinical outcomes.
British Journal of Cancer 09/2009; 101(6):998-1004. · 5.04 Impact Factor
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ABSTRACT: There is increasing evidence of a systemic inflammatory response associated with malignancy, which may have an impact on both drug disposition and resistance to cytotoxic therapy. The impact of inflammation on drug disposition was studied in mice bearing a number of common tumour xenografts. C57BL/6 mice were inoculated with tumour xenografts. Hepatic expressions of Cyp3a and drug transporters were analysed at the mRNA, protein and functional levels (Cyp3a only). Circulating serum cytokines and the hepatic expression of acute phase proteins (APPs) were measured. Intratumoral levels of multidrug resistance genes were determined. Tumour xenografts elicited an inflammatory response that coincided with repression in hepatic Cyp3a11 activity and the expression of a number of hepatic drug transporters. With tumour growth, a progressive reduction in hepatic Cyp3a11 mRNA expression was seen. Conversely, an increase in the hepatic APP expression and circulating interleukin (IL)-6 levels was observed. Furthermore, a correlation was seen between increased intratumoral expression of the multidrug resistance gene, Mdr1a, and levels of circulating IL-6. Malignancy results in reduced hepatic drug disposition that correlates with an associated inflammatory response. Reduction of inflammation may improve the clinical outcome for patients receiving chemotherapeutic agents that undergo hepatic metabolism.
British Journal of Cancer 02/2008; 98(1):91-7. · 5.04 Impact Factor
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ABSTRACT: The purpose of this study was to investigate the utility of plasma pharmacokinetic and pharmacodynamic measures including plasma deoxynucleosides, homocysteine and methylmalonic acid concentrations in understanding the time course and extent of the inhibition of thymidylate synthase (TS) by pemetrexed in the context of a phase I/II combination study with vinorelbine. Eighteen patients received supplementation with folic acid and Vitamin B(12) 1 week before beginning treatment with pemetrexed and vinorelbine administered in a dose-escalating manner on a 21-day cycle. Heparinised blood samples were collected from consenting patients in the first cycle for pharmacokinetic analyses and in the first two cycles for determination of plasma thymidine, deoxyuridine, homocysteine and methylmalonic acid concentrations. These values were correlated with response and toxicity. Plasma deoxyuridine was used as a measure of TS inhibition, and concentrations of deoxyuridine were significantly elevated relative to baseline on days 1 (P<0.01), 2 (P<0.001) and 3 (P<0.05) after treatment at all pemetrexed dose levels (400-700 mg m(-2)). The magnitude of deoxyuridine elevation correlated with pemetrexed area under the plasma concentration-time curve (AUC) (r(2)=0.23, P<0.05). However, deoxyuridine concentrations returned to baseline between 8 and 15 days after treatment with pemetrexed, suggesting that inhibition of TS was not durable. Pemetrexed AUC correlated with the percentage decline (relative to baseline) in both platelets (r(2)=0.58, P<0.001) and leucocytes (r(2)=0.26, P<0.05) at day 8. Baseline homocysteine was also significantly correlated with these measures of haematological toxicity (r(2)=0.37, P<0.01 and r(2)=0.39, P<0.01, respectively). In addition, there was a significant reduction of plasma homocysteine on days 8 (P<0.005) and 15 (P<0.05) in cycle 1 compared to baseline values. The results suggest that the TS inhibitory effects of pemetrexed are short-lived and make the case for a more frequent schedule of administration such as every 2 weeks. The lack of protracted TS inhibition may be due to concomitant vitamin administration, and this may be the mechanism by which vitamins prevent life-threatening toxicity from pemetrexed. Baseline homocysteine concentration remains a predictive marker for haematological toxicity even following folate supplementation.
British Journal of Cancer 11/2007; 97(8):1071-6. · 5.04 Impact Factor
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ABSTRACT: The purpose of this study was to evaluate the safety and activity of fixed-dose capecitabine in patients with advanced colorectal cancer and to correlate pretreatment plasma concentrations of homocysteine and serum and red cell folate with toxicity. Patients received capecitabine 2000 mg (4 x 500 mg tablets) twice daily on days 1-14 every 3 weeks. They were reviewed weekly during the first cycle and then three weekly for safety assessment. Eligibility criteria were advanced/metastatic colorectal cancer, < or = 2 prior chemotherapy regimens, ECOG performance status 0-2 and life expectancy >12 weeks. A total of 60 patients were enrolled and 55 were evaluable for efficacy. The median age was 72 years and 63% of patients had a performance status of 1 or 2. Confirmed tumour responses were reported in 15 patients (28%; 95% confidence interval (CI), 15.7-40.3%). The median time to disease progression was 4.9 months and median overall survival was 11.2 months. The median ratio of fixed dose to body surface area (BSA)-calculated dose was 88% (range 65-108%). Significant myelosuppression was not observed. Grade 2/3 treatment-related adverse events were diarrhoea (34%), fatigue (27%), stomatitis (15%) and hand-foot syndrome (22%). Dose reduction due to adverse events was required in 16 patients (29%) and multiple reductions in five patients (9%). There was no grade 3/4 haematological toxicity, any grade 4 adverse events or treatment-related deaths. Patients with higher pretreatment levels of serum folate experienced significantly greater toxicity (P = 0.02, CI: 1.0-1.2) during cycle 1 and over the entire treatment period (P = 0.04, CI: 1.0-1.3). Pretreatment homocysteine concentrations did not predict for toxicity. In conclusion, fixed-dose capecitabine appears to have similar efficacy and safety compared to the currently recommended dose schedule based on body surface area and simplifies drug administration. A high pretreatment folate may be predictive of increased toxicity from capecitabine.
British Journal of Cancer 04/2006; 94(7):964-8. · 5.04 Impact Factor
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ABSTRACT: People affected by cancer want information about their prognosis but clinicians have trouble estimating and talking about it. We sought to determine the nature and accuracy of medical oncologists' estimates of life expectancy in newly referred patients with incurable cancer. With reference to each patient, medical oncologists estimated how long they thought 90, 50, and 10% of similar patients would live. These proportions were chosen to reflect worst case, predicted, and best case scenarios suitable for discussions. After a median follow-up of 35 months, 86 of the 102 patients had died with an observed median survival of 12 months. Oncologists' estimates of each patient's worst case, predicted and best case scenarios were well-calibrated: 10% of patients lived for fewer months than estimated for the worst 10% of similar patients; 50% lived for at least as long as estimated for 50% of similar patients (predicted survival), and 17% lived for more months than estimated for the best 10% of similar patients. Oncologists' estimates of each patient's predicted survival were imprecise: 29% were within 0.67-1.33 times the patient's actual survival, 35% were too optimistic (>1.33 times the actual survival), and 39% were too pessimistic (<0.67 times the actual survival). The proportions of patients with actual survival times bounded by simple multiples of their predicted survival were as follows: 61% between half to double their predicted, 6% at least three to four times their predicted, and 4% no more than 1/6 of their predicted; similar to the proportions in an exponential distribution (about 50%, 10% and 10% respectively). Ranges based on simple multiples of the predicted survival time appropriately convey prognosis and its uncertainty in newly referred people with incurable cancer.
British Journal of Cancer 01/2006; 94(2):208-12. · 5.04 Impact Factor
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ABSTRACT: There is irrefutable evidence of the association between lung cancer and smoking. The effects of public health campaigns to reduce population-smoking rates on the incidence and the histological distribution of lung cancer were examined.
The data held in the New South Wales Cancer Registry from 1972 to 2001 was accessed.
The data revealed a decreasing incidence of lung cancer amongst males and a rate that continued to increase amongst females. Interestingly, there was also an effect on the histological distribution of lung cancers, with falling rates of small cell lung cancer and squamous cell cancer, both of which have a high association with smoking; and an increasing incidence of adenocarcinomas.
These trends reveal patterns seen worldwide. The increasing proportion of adenocarcinomas in particular may be related to the changing composition of cigarettes and filters.
Respirology 04/2005; 10(2):233-8. · 2.42 Impact Factor
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Journal of Clinical Oncology 03/2005; 23(4):910-2. · 18.37 Impact Factor
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Journal of Clinical Oncology 03/2005; 23(4):912-3. · 18.37 Impact Factor
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Journal of Clinical Oncology 03/2005; 23(4):914-5. · 18.37 Impact Factor
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J Vardy,
K Engelhardt,
K Cox,
J Jacquet,
A McDade,
M Boyer,
P Beale,
M Stockler,
R Loneragan,
B Dennien,
R Waugh, S J Clarke
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ABSTRACT: Central venous access port devices (CVAPD) are necessary for delivery of prolonged infusional chemotherapy or in patients with poor peripheral venous access. Previous studies of Hickman catheters report complication rates in about 45% of patients. Our aim was to assess the early and late complication rate, and duration that the CVAPD remained functional, following insertion by interventional radiologists in patients with solid tumours. A prospective study was undertaken in 110 consecutive patients who had insertion of 111 subclavian CVAPD. The median age of patients was 57 years (range 17-83), 64 were females; 68 patients (61%) had gastrointestinal tumours and 25 (23%) had breast cancer. CVAPD were successfully implanted in all but one patient. There were four (4%) immediate major complications: thrombosis 2 and pneumothorax 2. Nine patients (8%) had bruising or pain. Four devices (4%) became infected. In total, 100 CVAPD (90%) were either removed as planned at the end of treatment (n=23) after a median 203 days, or remained in situ for a median of 237 days (7-1133). Premature removal occurred in eight patients due to infection (n=4), thrombosis (n=3) or faulty device (n=1). Four patients were lost to follow-up. Radiological insertion of CVAPD is safe and convenient with low rates of complications.
British Journal of Cancer 10/2004; 91(6):1045-9. · 5.04 Impact Factor
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ABSTRACT: Inflammatory disease states (infection, arthritis) are associated with reduced drug oxidation by the cytochrome P450 3A system. Many chemotherapy agents are metabolised through this pathway, and disease may therefore influence inter-individual differences in drug pharmacokinetics. The purpose of this study was to assess cytochrome P450 3A function in patients with advanced cancer, and its relation to the acute-phase response. We evaluated hepatic cytochrome P450 3A function in 40 patients with advanced cancer using the erythromycin breath test. Both the traditional C(20min) measure and the recently proposed 1/T(MAX) values were estimated. The marker of acute-phase response, C-reactive protein and the pro-inflammatory cytokines IL-6, IL-1beta, TNFalpha and IL-8 were measured in serum or plasma at baseline. Cancer patients with an acute phase response (C-reactive protein >10 mg x l(-1), n=26) had reduced metabolism as measured with the erythromycin breath test 1/T(MAX) (Kruskal-Wallis Anova, P=0.0062) as compared to controls (C-reactive protein < or =10 mg x l(-1), n=14) Indeed, metabolism was significantly associated with C-reactive protein over the whole concentration range of this acute-phase marker (r=-0.64, Spearman Rank Correlation, P<0.00001). C-reactive protein serum levels were significantly correlated with those of IL-6 (Spearman coefficient=0.58, P<0.0003). The reduction in cytochrome P450 3A function with acute-phase reaction was independent of the tumour type and C-reactive protein elevation was associated with poor performance status. This indicates that the sub-group of cancer patients with significant acute-phase response have compromised drug metabolism, which may have implications for the safety of chemotherapy in this population.
British Journal of Cancer 07/2002; 87(3):277-80. · 5.04 Impact Factor
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ABSTRACT: To evaluate the efficacy and safety of pemetrexed therapy for chemotherapy-naïve patients with surgically incurable non-small-cell lung cancer (NSCLC).
Eligible patients received pemetrexed 600 mg/m2 every 3 weeks. Restaging was performed after every two cycles of therapy and toxicity was assessed at each cycle of pemetrexed. In the absence of disease progression or undue toxicity, treatment was continued for a maximum of 12 cycles.
Fifty-nine patients (median age 59 years; range 39-74 years) received a median of four cycles of pemetrexed. Nineteen patients (32%) had a ECOG performance status (PS) of two and 39 patients (66%) had stage IV disease. The most common histological sub-types were adenocarcinoma (20 patients, 34%) and large cell (18 patients, 31%). Sixteen patients (27%) had received prior radiotherapy. Nine patients achieved a partial response for an overall response rate of 15.8% (95% confidence interval CI 7% to 28%). The median duration of response was 4.9 months, and the median survival was 7.2 months. The principal toxicities were myelosuppression and rash. While grade 3 or 4 neutropenia was seen in 25 patients (42%), only two patients (3%) developed grade 3 infection. Eighteen patients (31%) developed grade 3 or 4 cutaneous toxicity, which improved with prophylactic oral dexamethasone administered for 3 days beginning the day before pemetrexed treatment. Asymptomatic elevations in hepatic biochemistry (especially alanine transaminase and aspartate transaminase) were seen in 47 patients (80%); however, these did not interfere with the dose or schedule of pemetrexed and returned to normal levels throughout the study.
This is the largest study confirming the encouraging single-agent activity of pemetrexed in chemotherapy-naïve patients with NSCLC. In addition, this study demonstrates that a dose of 600 mg/m2 can be delivered safely; however, treatment should be restricted to patients with a PS of 0 or 1. The results of combination studies are awaited with interest.
Annals of Oncology 06/2002; 13(5):737-41. · 6.43 Impact Factor
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ABSTRACT: A reversed-phase high-performance liquid chromatography method was developed and validated for the quantitation of pemetrexed (LY231514, ALIMTA) in human urine and plasma. Plasma samples were spiked with the internal standard lometrexol and extracted using Certify II columns. Pemetrexed was assayed in diluted urine by an external calibration method. A C8 column was used for the separation of analytes with a mobile phase composed of sodium formate buffer and acetonitrile. Between- and within-day precision and accuracy were acceptable down to the limit of quantitation of 5 ng/ml in plasma. This method was used successfully for an investigation of the disposition of pemetrexed in patients receiving 500 mg/m2 as a 10-min infusion.
Journal of chromatography. B, Biomedical sciences and applications 01/2002; 765(2):135-40.
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ABSTRACT: Various clinical and laboratory parameters have been investigated for their ability to predict toxicity arising from the use of the anticancer drug, irinotecan (CPT-11). In particular, patients deficient in the conjugation of SN-38, a metabolite of CPT-11, are known to be at greater risk. We describe one case of a patient with metastatic colorectal cancer treated with a single dose of CPT-11 at 125 mg/m(2). Although this patient lacked any known predictive factors for toxicity, he experienced severe side-effects several days later. We hypothesized that the toxicity in this patient was due to compromised SN-38 conjugation. Plasma samples were analyzed by reversed-phase high-performance liquid chromatography assay for CPT-11 and its metabolites at 96, 144, 168, 192 and 288 h post-administration. We observed that the concentrations of both the parent drug and its metabolites were markedly raised (11- to 60-fold expected). Additionally the estimated terminal half-lives were 1.5-7 times those expected (29.5, 101, 39.6 and 41.8 h for CPT-11, APC, SN-38G and SN-38, respectively). We conclude that the toxicity in this patient was not caused by deficient SN-38 conjugation, but by decreased drug excretion through both hepatic and renal routes.
Anti-Cancer Drugs 09/2001; 12(7):619-25. · 2.41 Impact Factor
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ABSTRACT: The combination of paclitaxel and etoposide was evaluated in a phase II study in patients with locally advanced or metastatic non small-cell lung cancer (NSCLC). Thirty-five patients, median age 61, received treatment with paclitaxel 200 mg/m (2) intravenous over 3 h on day 1, and oral etoposide, 100 mg daily on days 1-5. Cycles were repeated every 21 days for a maximum of nine cycles, or until progression occurred. Twenty-eight patients had stage IV disease, and seven patients had stage IIIA or B disease. There was one complete and seven partial responses (overall response rate, 23%). Two of these responses were in patients with stage III disease (29%) and six in patients with stage IV disease (21%). Median survival was 8.7 months, and 36% of patients were alive at 1 year. There were no treatment-related deaths and little grade 3 or 4 non-haematological toxicity although grade 3 or 4 neutropenia occurred in 60% of patients (33% of cycles). There were four episodes of febrile neutropenia. The combination of paclitaxel and oral etoposide is active in advanced NSCLC and can be delivered with acceptable toxicity.
Lung Cancer 05/2001; 32(1):89-94. · 3.43 Impact Factor
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ABSTRACT: The erythromycin breath test (EBT) is a putative probe of cytochrome P450 (CYP) 3A4 activity in vivo. Therefore, the EBT might prove useful for the individualisation of doses of drugs that have a low therapeutic window (for example the immunosuppressants or cytotoxics) and are metabolised by CYP3A4. However, there is a lack of consensus as to how the EBT should be used to predict total body clearance (CL), and the results so far have been largely disappointing. We argue that the required assumption that individuals produce 5 mmol of CO2/min per m2 at rest is one of the problems with the existing EBT, as the literature suggests significant variability and possible gender differences in this parameter. An examination of the EBT with a simple compartment model suggests that alternative parameters could be more useful in the prediction of CL. In particular, there is theoretical support for the use of the time-point at which breath radioactivity is maximal (tmax) as a correlate for CL. This is in agreement with our recent study of the pharmacokinetics of erythromycin in patients with cancer.
Clinical Pharmacokinetics 02/2001; 40(3):151-8. · 5.40 Impact Factor
