Lithium Intercalation into the Excitonic Insulator Candidate Ta2NiSe5.

A new reduced phase derived from the excitonic insulator candidate Ta2NiSe5 has been synthesized via the intercalation of lithium. LiTa2NiSe5 crystallizes in the orthorhombic space group Pmnb (no. 62) with lattice parameters a = 3.50247(3) Å, b = 13.4053(4) Å, c = 15.7396(2) Å, and Z = 4, with an increase of the unit cell volume by 5.44(1)% compared with Ta2NiSe5. Significant rearrangement of the Ta-Ni-Se layers is observed, in particular a very significant relative displacement of the layers compared to the parent phase, similar to that which occurs under hydrostatic pressure. Neutron powder diffraction experiments and computational analysis confirm that Li occupies a distorted triangular prismatic site formed by Se atoms of adjacent Ta2NiSe5 layers with an average Li-Se bond length of 2.724(2) Å. Li-NMR experiments show a single Li environment at ambient temperature. Intercalation suppresses the distortion to monoclinic symmetry that occurs in Ta2NiSe5 at 328 K and that is believed to be driven by the formation of an excitonic insulating state. Magnetometry data show that the reduced phase has a smaller net diamagnetic susceptibility than Ta2NiSe5 due to the enhancement of the temperature-independent Pauli paramagnetism caused by the increased density of states at the Fermi level evident also from the calculations, consistent with the injection of electrons during intercalation and formation of a metallic phase.

Cost of treating metastatic colorectal cancer: a systematic review.

OBJECTIVE: The cost of treating metastatic colorectal cancer places a significant economic burden on individuals, populations, and health care. However, there is a paucity of information on the costs of the contemporary management of metastatic colorectal cancer. This systematic review aims to review the literature to estimate the direct cost of treating metastatic colorectal cancer. STUDY DESIGN: Systematic review. METHODS: MEDLINE, Embase, Web of Science, Evidence-Based Medicine Reviews: National Health Service Economic Evaluation Database Guide, EconLit, and grey literature from the 1st of January 2000 to the 1st of February 2020 were all searched for studies reporting the direct costs of treating metastatic colorectal cancer. The methodological quality of the included studies was assessed using the Evers' Consensus on Health Economic Criteria checklist. RESULTS: In total, 39,489 records were retrieved, and 29 studies were included. Costs of treating metastatic colorectal cancer varied because of the heterogeneity of treatment. Studies reported average costs ranged from $12,346 to $293,461. Studies that included the cost of systemic therapy reported an estimated cost of almost $300,000. CONCLUSION: The existing evidence indicates that the cost of treating metastatic colorectal cancer places a significant economic burden on healthcare systems despite differences in methodology and treatment heterogeneity. Future research needs to define the cost components of treating metastatic colorectal cancer to improve comparability and examine the relationship between spending, overall survival, and quality of life. Identifying these costs and their impact on health care budgets can help policymakers plan health system expenditure.

Impact of physical activity on fatigue and quality of life in people with advanced lung cancer: a randomized controlled trial.

BACKGROUND: Physical activity (PA) improves fatigue and quality of life (QOL) in cancer survivors. Our aim was to assess whether a 2-month PA intervention improves fatigue and QOL for people with advanced lung cancer. METHODS: Participants with advanced lung cancer, Eastern Cooperative Oncology Group performance status (PS) ≤2, >6 months life expectancy, and ability to complete six-min walk test, were stratified (disease stage, PS 0-1 versus 2, centre) and randomized (1:1) in an open-label study to usual care (UC) (nutrition and PA education materials) or experimental intervention (EX): UC plus 2-month supervised weekly PA and behaviour change sessions. Assessments occurred at baseline, 2, 4, and 6 months. The primary endpoint was fatigue [Functional Assessment of Cancer Therapy-Fatigue (FACT-F) questionnaire] at 2 months. The study was designed to detect a difference in mean FACT-F subscale score of 6. Analysis was intention-to-treat using linear mixed models. RESULTS: We recruited 112 patients: 56 (50.4%) were randomized to EX, 55(49.5%) to UC; 1 ineligible. Male 55%; median age 64 years (34-80); 106 (96%) non-small cell lung cancer; 106 (95.5%) stage IV. At 2, 4 and 6 months, 90, 73 and 62 participants were assessed, respectively, with no difference in attrition between groups. There were no significant differences in fatigue between the groups at 2, 4 or 6 months: mean scores at 2 months EX 37.5, UC 36.4 (difference 1.2, 95% CI - 3.5, 5.8, P = 0.62). There were no significant differences in QOL, symptoms, physical or functional status, or survival. CONCLUSIONS: Adherence to the intervention was good but the intervention group did not increase their PA enough compared to the control group, and no difference was seen in fatigue or QOL. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry No. ACTRN12609000971235.

Fatigue in people with localized colorectal cancer who do and do not receive chemotherapy: a longitudinal prospective study.

BACKGROUND: Fatigue is associated with cancer and chemotherapy and may be sustained. Here, we describe a prospective longitudinal study evaluating fatigue and putative mechanisms in people with colorectal cancer (CRC). PATIENTS AND METHODS: People with localized CRC completed the Functional Assessment of Cancer Treatment-Fatigue (FACT-F) questionnaire at baseline (before chemotherapy, if given), 6, 12, and 24 months. Healthy controls (HCs) were assessed at the first three time points. Fatigue was defined by standardized FACT-F scores ≤68/100. Quality-of-life (QoL, assessed by the FACT-G questionnaire), affective, and cognitive symptoms were evaluated. Associations were sought between fatigue, baseline factors, and blood tests (including hemoglobin, cytokines, and sex hormones). Regression analyses, Fisher's exact tests, and Wilcoxon rank-sum tests assessed levels of fatigue at each time point and change in fatigue from baseline. A repeated-measures analysis investigated prognostic factors of fatigue across all time points. RESULTS: A total of 289 subjects with localized CRC (173 received chemotherapy) and 72 HCs were assessed. More CRC patients had fatigue than HCs at baseline (52% versus 26%, P < 0.001). Fatigue was increased in the chemotherapy (CTh) group at 6 months [CTh+ 70% versus CTh- 31% (P < 0.001), HCs 22%] and remained more common at 12 [CTh+ 44% versus CTh- 31% (P = 0.079)] and 24 months [CTh+ 39% versus CTh- 24% (P = 0.047)]. There was no significant difference between those not receiving chemotherapy and HCs at follow-up assessments. Fatigue was associated with poor QoL, affective and cognitive symptoms, but not consistently with cytokine levels. Predictors for sustained fatigue were baseline fatigue, treatment group, cognitive and affective symptoms, poorer QoL, and comorbidities. CONCLUSIONS: CRC patients have more fatigue than HCs at baseline. Fatigue peaks immediately after adjuvant chemotherapy, but remains common for 2 years in those who receive chemotherapy. Cognitive and affective symptoms, QoL, comorbidities, chemotherapy, and baseline fatigue predict for longer term fatigue.

Cognitive function and fatigue after diagnosis of colorectal cancer.

BACKGROUND: Cognitive impairment and fatigue have been associated with cancer and its treatment. We present baseline data from a large longitudinal study that evaluates cognitive function, fatigue, and potential underlying mechanisms following diagnosis of colorectal cancer (CRC). PATIENTS AND METHODS: We evaluated CRC patients with stage I-III disease before or after surgery, participants with limited metastatic disease and healthy controls (HC). Neuropsychological evaluation included clinical and computerised tests. Participants completed questionnaires for fatigue and quality of life (QOL)-(FACT-F), anxiety/depression, and cognitive symptoms (FACT-Cog). Ten cytokines, clotting factors, sex hormones, carcinoembryonic antigen (CEA), and apolipoprotein E genotype were evaluated. Primary end points were cognitive function on clinical tests evaluated by a Global Deficit score (GDS) and fatigue. Associations between test results, demographic, and disease related factors were explored. RESULTS: We assessed 291 participants with early-stage disease [median age 59 (23-75) years, 63% men], 72 with metastatic disease, and 72 HC. Using GDS, 45% (126/281) of participants with early-stage CRC had cognitive impairment versus 15% (11/72) of HC (odds ratio 4.51, 95% confidence interval 2.28-8.93; P < 0.001), with complex processing speed, attention/working memory, and verbal learning efficiency being most affected. Women with early-stage CRC had greater cognitive impairment than men [55/105 (52%) versus 71/176 (40%), P < 0.050]. Cognitive symptoms were self-reported by 21% (59/286) of early-stage patients versus 17% (12/72) of HC; fatigue by 52% (149/287) of early-stage patients and 26% (19/72) of HC (P < 0.0001). Women reported more fatigue than men (P = 0.003). Fatigue, QOL, anxiety/depression, and cognitive symptoms were associated with each other (r = 0.43-0.71), but not with neuropsychological performance. Most cytokines were elevated in cancer patients. Cognitive function was not associated with cytokines, sex hormones, clotting factors, CEA, or apolipoprotein E genotype. CONCLUSIONS: The incidence of cognitive impairment was three to five times higher in CRC patients than HC, with women having higher impairment rates than men. The cognitive impairment profile suggests dysfunction primarily in fronto-subcortical brain systems. TRIAL REGISTRATION: NCT00188331.

Single-centre experience with peptide receptor radionuclide therapy for neuroendocrine tumours (NETs): results using a theranostic molecular imaging-guided approach.

AIM: To summarise our centre's experience managing patients with neuroendocrine tumours (NETs) in the first 5 years after the introduction of peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-octreotate (LUTATE). The report emphasises aspects of the patient management related to functional imaging and use of radionuclide therapy. METHODS: We describe the criteria for treatment with LUTATE at our centre, the methodology for patient selection, and the results of an audit of clinical measures, imaging results and patient-reported outcomes. Subjects are treated initially with four cycles of ~ 8 GBq of LUTATE administered as an outpatient every 8 weeks. RESULTS: In the first 5 years offering LUTATE, we treated 143 individuals with a variety of NETs of which approx. 70% were gastroentero-pancreatic in origin (small bowel: 42%, pancreas: 28%). Males and females were equally represented. Mean age at first treatment with LUTATE was 61 ± 13 years with range 28-87 years. The radiation dose to the organs considered most at risk, the kidneys, averaged 10.6 ± 4.0 Gy in total. Median overall survival (OS) from first receiving LUTATE was 72.5 months with a median progression-free survival (PFS) of 32.3 months. No evidence of renal toxicity was seen. The major long-term complication seen was myelodysplastic syndrome (MDS) with a 5% incidence. CONCLUSIONS: LUTATE treatment for NETs is a safe and effective treatment. Our approach relies heavily on functional and morphological imaging informing the multidisciplinary team of NET specialists to guide appropriate therapy, which we suggest has contributed to the favourable outcomes seen.

A derived neutrophil to lymphocyte ratio predicts survival in patients with cancer.

BACKGROUND: The neutrophil lymphocyte ratio (NLR) has prognostic value in patients with a variety of cancers. Many chemotherapeutic trial databases hold information on white cell and neutrophil counts only. The aim of the present study was to compare the prognostic value of the NLR with a derived score (dNLR), composed of white cell and neutrophil counts. METHODS: Patients (n=27,031) who were sampled incidentally between 2000 and 2007 for neutrophil, lymphocyte and white cell counts, and also had a diagnosis of cancer (Scottish Cancer Registry), were identified. Of this group, 12,118 patients who had been sampled within 2 years of their cancer diagnosis were studied. RESULTS: On follow-up, there were 7366 deaths, of which 6198 (84%) were cancer deaths. The median time from blood sampling to diagnosis was 2.1 months. The area under the receiver-operating characteristic (ROC) curve for cancer-specific survival was 0.650 for the NLR and 0.640 for the dNLR. The NLR and dNLR were independently associated with survival in all cancers studied (all P<0.001). The optimal thresholds, on the basis of hazard ratios and area under the curve, were 4 : 1 for the NLR and 2 : 1 for the dNLR. CONCLUSION: The results of the present study show that the dNLR has similar prognostic value to the NLR. Therefore, the universally available dNLR is to be commended for use in the risk stratification of patients undergoing chemotherapy.

The eligibility of advanced non-small-cell lung cancer patients for targeted therapy clinical trials.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Reporting clinical trial information: colorectal cancer trials at Sydney Cancer Centre.

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.

Neutrophil/lymphocyte ratio predicts chemotherapy outcomes in patients with advanced colorectal cancer.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Molecular markers of response and toxicity to FOLFOX chemotherapy in metastatic colorectal cancer.

BACKGROUND: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

The integration of pharmacology and pathophysiology into locoregional chemotherapy delivery via mass fluid transfer.

The prevailing paradigm of locoregional chemotherapy has been centred around delivering chemotherapy as close to the tumour as possible and in some cases incorporating vascular isolation techniques. Strategically, the development of these techniques has been rudimentary without consideration for the interdependencies between macrovascular manipulation and the microvascular effects. This review focuses on how new capabilities offered by recent advances in vascular access technology could be exploited to facilitate the mass fluid transfer (MFT) of anticancer agents to solid tumours. A haemodynamic model of MFT is proposed using the physical laws of fluid flow, flux, and diffusion that describe the microvascular effects anticancer agents may have upon tumours through the manipulation of macrovascular blood flow control. Finally, the possible applications of this technique for several organs are discussed.

Treatment of ALK-rearranged non-small cell lung cancer: A review of the landscape and approach to emerging patterns of treatment resistance in the Australian context.

Since the identification of anaplastic lymphoma kinase (ALK) gene rearrangements in non-small cell lung cancer (NSCLC) in 2005, the treatment of ALK-rearranged NSCLC (ALK+ NSCLC) has evolved at a rapid pace. This molecularly distinct subset of NSCLC has uniquely important biology, clinicopathologic features and mechanisms of drug resistance which impact on the choice of treatment for a patient with this disease. There are multiple ALK tyrosine kinase inhibitors now available in clinical practice with efficacy data continuing to emerge and guide the optimal treatment algorithm. A detailed search of medical databases and clinical trial registries was conducted to capture all relevant articles on this topic enabling an updated detailed overview of the landscape of management of ALK-rearranged NSCLC.

Phase I trial of ZD1694, a new folate-based thymidylate synthase inhibitor, in patients with solid tumors.

PURPOSE: To perform a phase I clinical and pharmacologic study of ZD1694 (Tomudex, Alderley Park, United Kingdom), a new folate-based thymidylate synthase (TS) inhibitor, in patients with advanced malignancy. PATIENTS AND METHODS: From February 1991 to January 1993, 61 patients with a range of solid tumor received 161 courses of ZD1694 given as a single 15-minute intravenous infusion every 3 weeks, at escalating doses from 0.1 to 3.5 mg/m2. Pharmacokinetic (PK) analysis was performed with the first two courses of treatment. There were 33 men and 28 women with a median age of 53 years (range, 21 to 73). Fifty-five patients (90%) had previously received chemotherapy. RESULTS: Reversible liver toxicity and dose-related gastrointestinal (GI) and bone marrow toxicity occurred at > or = 1.6 mg/m2. Liver function usually returned to normal with repeated treatment, but GI and bone marrow toxicities generally became more severe. No renal toxicity was observed. The maximum-tolerated dose (MTD) was 3.5 mg/m2, at which, in addition to antiproliferative toxicities, four of six patients (67%) developed severe malaise that consisted of anorexia, nausea, and asthenia, with rapidly decreasing performance status that limited re-treatment. Abnormal liver function was also seen in four patients (67%). At 3.0 mg/m2, grades III and IV diarrhea were seen in six of 23 patients (26%) and grade IV myelosuppression in two others. Liver toxicity was self-limiting and not associated with severe malaise. Two patients had a partial response to treatment. PK analysis showed that plasma elimination was triexponential, with pronounced variability in the mean terminal half-life (t1/2gamma) for a given dose ranging from 8.2 to 105 hours. There was a linear relationship between dose and both the area under the concentration-time curve (AUC) and maximum concentration (Cmax), but no clear association between these parameters and response or toxicity. CONCLUSION: The dose of ZD1694 recommended for phase II trials is 3.0 mg/m2.

Leucovorin rescue from raltitrexed (tomudex)-induced antiproliferative effects: in vitro cell line and in vivo mouse studies.

Raltitrexed (RTX) is an antifolate thymidylate synthase (TS) inhibitor that is effective for the treatment of advanced colorectal cancer and other solid tumors. However, a small minority of patients receiving RTX monotherapy will experience grade III/IV gastrointestinal toxicity that can be life-threatening, particularly if copresenting with neutropenia. Lack of vigilance in recognition and treatment of symptoms of toxicity or violations of protocol have led to treatment-related deaths in some hospitals. The safety of RTX could be improved if an effective rescue agent was available. Leucovorin (LV) is a reduced folate cofactor that competes with RTX for transport and polyglutamation in both tumor and normal tissues and thus has potential as a rescue agent. In vitro cell studies are presented suggesting that the growth-inhibitory, and potentially cytotoxic, effects of RTX on populations of viable cells can be reversed by the delayed administration of LV. The mechanisms involved are inhibition of further drug uptake and polyglutamation and a redistribution and/or reduction in the concentration of preformed raltitrexed polyglutamates. A more clinically relevant in vivo mouse model was used to test the hypothesis further. BALB/c mice treated with 100 mg/kg/day x 4 days of RTX were used as a model for gastrointestinal and bone marrow toxicity. LV (200 mg/kg), which was given after the onset of severe weight loss and diarrhea (twice daily, days 5-7), prevented further weight loss and induced earlier recovery. This was accompanied by improvement in the histological appearance of the intestine (day 7) and the concentration of neutrophils and platelets in the blood (day 9). BALB/c mice could not tolerate 100 mg/kg daily x 5 days unless LV (200 mg/kg twice daily) was given on days 6-8. Measurement of RTX (polyglutamates) by RIA after 100 mg/kg RTX daily (days 1-4) showed less drug in plasma (3-4-fold), liver (8-11-fold), kidney (3-4-fold), and small intestinal epithelium (3-4-fold) on day 7 in LV-treated mice (100 or 200 mg/kg twice daily) compared with controls. A single injection of 100 mg/kg RTX (day 1) gave plasma levels of 3-4 pmol/ml on day 4 that are more clinically relevant. Administration of LV (100 or 200 mg/kg; twice daily on days 4-6) reduced the RTX concentration in the liver 2-4-fold on days 7, 9, and 11 compared with controls. A model is proposed where LV and/or its anabolic products can compete with RTX uptake into tissues and interfere with the homeostatic regulation of RTX polyglutamates. These data support the use of LV rescue in the small minority of patients treated with RTX who present with a severe pattern of antiproliferative toxicities. The use of LV is not recommended routinely because the antitumor activity of RTX may similarly be reversed.

Optimizing the erythromycin breath test for use in cancer patients.

The erythromycin breath test (EBT) is a putative in vivo probe for drug metabolism by cytochrome P450 3A4 (CYP3A4). Because many anticancer drugs are metabolized by this system, we sought to further develop the EBT as a tool for predicting the clearance, in cancer patients, of drugs metabolized by CYP3A4. Sixteen adult patients with incurable cancer were studied. The EBT was performed on day 1 and breath sampled after the i.v. injection of 4 microCi of 14C-erythromycin. The breath 14CO2 flux (CERt) was estimated at 11 time points over 2 h. On day 2, the EBT was repeated midway through a 10-min infusion of 100 mg of erythromycin lactobionate, and the plasma pharmacokinetics of erythromycin were determined. The infusion of 100 mg of erythromycin did not modify the EBT results significantly. The values of the conventional EBT parameter CER20 min obtained on day 1 were comparable for most subjects (0.03-0.06% dose/min), with the exception of an individual receiving the known CYP3A4 inducers dexamethasone and phenytoin who returned a value of 0.14% dose/min. There was no significant correlation between any of the conventional EBT parameters and erythromycin clearance. However, two parameters reflecting early emergence of breath radioactivity (1/TMAX and CER3 min/CERMAX) correlated significantly with erythromycin clearance (P = 0.005 and 0.006, respectively). Novel parameters derived from the EBT are significantly correlated with the clearance of erythromycin even in the presence of confounding factors, such as metastatic liver disease, altered protein binding, and comedication. These parameters may enable dose optimization of cytotoxics metabolized by CYP3A4.

Balb/c mice as a preclinical model for raltitrexed-induced gastrointestinal toxicity.

Raltitrexed (RTX) is an antifolate thymidylate synthase (TS) inhibitor used for the treatment of advanced colorectal cancer. RTX induces proliferating tissue toxicities that are largely confined to the intestine, with diarrhea being a severe side effect in a small but significant minority of patients. Similarly, weight loss and diarrhea were observed in BALB/c mice, and a maximum tolerated dose (MTD) was determined as approximately 5-10 mg/kg/day x 5 days. At an equivalent dose of 10 mg/kg/day x 5 days (dl-5), DBA2 mice lost considerably less weight, leading to a higher MTD (>500 mg/kg/day x 5 days), and there was no evidence of diarrhea. Histopathological consequences of damage, such as changes in small intestinal crypt architecture and villus atrophy induced by the 10-mg/kg/day dose, were greater and of longer duration in BALB/c mice. A higher dose of RTX (100 mg/kg/day x 5) induced weight loss and histopathological damage similar to that seen in BALB/c mice (10 mg/kg/ day x 5) but was of later onset, nadir, and recovery. Small changes to the colon were only observed in BALB/c mice. Pretreatment levels of plasma thymidine, deoxyuridine (approximately 1 microM), and folate (approximately40 ng/ml) were similar in both mouse strains. A single injection of radiolabeled RTX (5 mg/kg/ day) did not lead to any marked difference 24 h later in the total drug concentration and distribution of polyglutamates (comprising 70-80% of drug extracted) in the liver, kidney, and intestinal epithelium (large and small intestine) between the two mouse strains. Further studies used a RIA to measure RTX polyglutamate formation in tissues at various times and drug doses. This led to the conclusion that, although there was a higher accumulation of RTX in BALB/c small intestinal epithelium (days 4-6), it may be an effect secondary to another undetermined cause of increased drug sensitivity. This model represents a vehicle by which the etiology and treatment of severe clinical toxicity induced by RTX may be evaluated.

Long-term follow-up of a randomised trial of combined chemoradiotherapy induction treatment, with and without maintenance chemotherapy in patients with small cell carcinoma of the lung.

The toxicity and efficacy of concomitant chemotherapy and radiotherapy as induction therapy was evaluated in patients with previously untreated small cell carcinoma of the lung (SCLC), and in responding patients the value of maintenance chemotherapy was examined. 202 patients received induction chemotherapy with cisplatin and etoposide (EP), in combination with cranial and local radiotherapy. 85 patients (42%) developed grades III and IV myelosuppression, the main toxicity of induction treatment. Of the 154 responding patients, 129 were randomised to maintenance chemotherapy with vincristine, doxorubicin and cyclophosphamide (VAC) or no further treatment. The response rate for the limited disease patients (LD) was 87%, 62% achieving a complete response (CR) and the response rate for extensive disease patients (ED) was 68%, with 26% achieving a CR. 17 patients (11%) completed 10 courses of maintenance chemotherapy. 32 patients (57%) developed grade III and IV neutropenia. Median survival for all patients was 53 weeks (LD, 70 weeks; ED, 42.5 weeks). There was no significant difference in overall survival (OS) or disease-free survival (DFS) in the two randomisation arms. This study shows that EP combined with radiotherapy is an effective induction regimen in SCLC. Maintenance chemotherapy with VAC is not associated with increased survival but has significant toxicity after such induction treatment.

Clinical pharmacokinetics of docetaxel.

Docetaxel (Taxotere), a semi-synthetic analog of paclitaxel (Taxol), is a promoter of microtubule polymerization leading to cell cycle arrest at G2/M, apoptosis and cytotoxicity. Docetaxel has significant activity in breast, non-small-cell lung, ovarian and head and neck cancers. Docetaxel has undergone phase I study in a number of schedules, including different infusion durations and various treatment cycles. Doses studied in adults have ranged from 5 to 145 mg/m2 and those in children from 55 to 235 mg/m2. The most frequently used regimen in adults is 100 mg/m2 every 3 weeks. A 1-hour infusion every 3 weeks has been favoured in phase II and III studies, and the disposition of docetaxel after such treatment is best described by a 3 compartment model with alpha, beta and gamma half-lives of 4.5 minutes, 38.3 minutes and 12.2 hours, respectively. The disposition of docetaxel appears to be linear, the area under the plasma concentration-time curve (AUC) increasing proportionately with dose. Docetaxel is widely distributed in tissues with a mean volume of distribution of 74 L/m2 after 100 mg/m2, every 3 weeks. The mean total body clearance after this schedule is approximately 22 L/h/m2, principally because of hepatic metabolism by the cytochrome P450 (CYP)3A4 system and biliary excretion into the faeces. Renal excretion is minimal (< 5%). Docetaxel is > 90% bound in plasma. Population pharmacokinetic studies of docetaxel have demonstrated that clearance is significantly decreased with age, decreased body surface area, increased concentrations of alpha 1-acid glycoproteinand albumin. Importantly, patients with elevated plasma levels of bilirubin and/or transaminases have a 12 to 27% decrease in docetaxel clearance and should receive reduced doses. Although docetaxel is metabolised by CYP3A4, phase I combination studies have not shown major evidence of significant interaction between docetaxel and other drugs metabolised by the same pathway. Nevertheless, care should be taken with the use of known CYP3A4 inhibitors such as erythromycin, ketoconazole and cyclosporin. Conversely, increased doses may be required for patients receiving therapy known to induce this cytochrome (e.g. anticonvulsants). Perliminary data suggest the erythromycin breath test, an indicator of CYP3A4 function, is a predictor of toxicity after treatment with docetaxel. Such methodologies may eventually enable clinicians to individualise doses of docetaxel for patients with cancer.

Clinical and preclinical pharmacokinetics of raltitrexed.

Raltitrexed is a specific, folate-based inhibitor of thymidylate synthase with activity in advanced colorectal cancer comparable with that of fluorouracil (5-fluorouracil) plus folinic acid. Its activity is enhanced by rapid cellular entry and polyglutamation, with the polyglutamated derivatives having approximately 100-fold greater inhibitory potency than the parent compound. A number of phase I/pharmacokinetic studies have been performed, including schedules involving a 15-minute infusion every 3 weeks, weekly x 6 every 8 weeks, and every 2 weeks. The maximum tolerated dose (MTD) for the 3-weekly schedule was 3.5 to 4.5 mg/m2 in adults and 6 mg/m2 in a paediatric population. The MTDs for the other schedules have not yet been reported. The disposition of raltitrexed in patients is best described by a 3-compartment model with a terminal half-life (t1/2gamma) of 260 hours, the latter being subject to significant interpatient variability. A similar protracted t1/2gamma has been detected in all of the animal species studied. Together with evidence from the mass-balance studies performed, this delayed elimination suggests considerable sequestration of raltitrexed in tissues, predominantly as polyglutamate forms. Nevertheless, there has been no pharmacokinetic evidence of drug accumulation in plasma following repeated administration. On the basis of animal experiments, the oral bioavailability and penetration of raltitrexed into cerebrospinal fluid are both likely to be limited in the clinical setting. Raltitrexed is over 90% bound to plasma protein over the concentration range of 20 to 100 micromol/L. Apart from poly-glutamation, raltitrexed does not appear to be metabolised to a significant extent, and most of the excreted drug (approximately 20% of the administered dose) is recovered unchanged in the urine within the first 24 hours post-administration. The average clearance of raltitrexed is 2.4 L/h (40 ml/min), and this value is significantly reduced in patients with compromised renal function (glomerular filtration rate of 25 to 65 ml/min). These patients are more likely to experience severe antiproliferative toxicity with raltitrexed. A careful evaluation of renal function, particularly in the elderly, is warranted. It has not been possible to establish strong correlations between the plasma pharmacokinetics of raltitrexed and toxicity, and the cellular pharmacokinetics of raltitrexed may be more predictive. Studies in mice have demonstrated that delayed administration of folinic acid can assist in the recovery of animals from antiproliferative toxicity, possibly by promoting the release of polyglutamated drug from tissues. This approach should be evaluated as a rescue regimen in patients with severe proliferative toxicity.