Patient-reported outcome (PRO) results from the AGITG DOCTOR trial: a randomised phase 2 trial of tailored neoadjuvant therapy for resectable oesophageal adenocarcinoma.

BACKGROUND: AGITG DOCTOR was a randomised phase 2 trial of pre-operative cisplatin, 5 fluorouracil (CF) followed by docetaxel (D) with or without radiotherapy (RT) based on poor early response to CF, detected via PET, for resectable oesophageal adenocarcinoma. This study describes PROs over 2 years. METHODS: Participants (N = 116) completed the EORTC QLQ-C30 and oesophageal module (QLQ-OES18) before chemotherapy (baseline), before surgery, six and 12 weeks post-surgery and three-monthly until 2 years. We plotted PROs over time and calculated the percentage of participants per treatment group whose post-surgery score was within 10 points (threshold for clinically relevant change) of their baseline score, for each PRO scale. We examined the relationship between Grade 3+ adverse events (AEs) and PROs. This analysis included four groups: CF responders, non-responders randomised to DCF, non-responders randomised to DCF + RT, and "others" who were not randomised. RESULTS: Global QOL was clinically similar between groups from 6 weeks post-surgery. All groups had poorer functional and higher symptom scores during active treatment and shortly after surgery, particularly the DCF and DCF + RT groups. DCF + RT reported a clinically significant difference (-13points) in mean overall health/QOL between baseline and pre-surgery. Similar proportions of patients across groups scored +/- 10 points of baseline scores within 2 years for most PRO domains. Instance of grade 3+ AEs were not related to PROs at baseline or 2 years. CONCLUSIONS: By 2 years, similar proportions of patients scored within 10 points of baseline for most PRO domains, with the exception of pain and insomnia for the DCF + RT group. Non-responders randomised to DCF or DCF + RT experienced additional short-term burden compared to CF responders, reflecting the longer duration of neoadjuvant treatment and additional toxicity. This should be weighed against clinical benefits reported in AGITG DOCTOR. This data will inform communication of the trajectory of treatment options for early CF non-responders. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry (ANZCTR), ACTRN12609000665235 . Registered 31 July 2009.

Preoperative cisplatin, fluorouracil, and docetaxel with or without radiotherapy after poor early response to cisplatin and fluorouracil for resectable oesophageal adenocarcinoma (AGITG DOCTOR): results from a multicentre, randomised controlled phase II trial.

BACKGROUND: Patients with oesophageal/gastro-oesophageal junction adenocarcinoma (EAC) not showing early metabolic response (EMR) to chemotherapy have poorer survival and histological response rates <5%. We investigated whether tailoring neoadjuvant therapy can improve outcomes in these patients. PATIENTS AND METHODS: Patients with resectable EAC were enrolled and randomised into two single-arm, multicentre phase II trials. After induction cisplatin and 5-fluorouracil (CF), all were assessed by day 15 positron emission tomography (PET). Patients with an EMR [maximum standardised uptake values (SUVmax) ≥35% reduction from baseline to day 15 PET] received a second CF cycle then oesophagectomy. Non-responders were randomised 1 : 1 to two cycles of CF and docetaxel (DCF, n = 31) or DCF + 45 Gy radiotherapy (DCFRT, n = 35) then oesophagectomy. The primary end point was major histological response (<10% residual tumour) in the oesophagectomy specimen; secondary end points were overall survival (OS), progression-free survival (PFS), and locoregional recurrence (LR). RESULTS: Of 124 patients recruited, major histological response was achieved in 3/45 (7%) with EMR, 6/30 (20%) DCF, and 22/35 (63%) DCFRT patients. Grade 3/4 toxicities occurred in 12/45 (27%) EMR (CF), 13/31 (42%) DCF, and 25/35 (71%) DCFRT patients. No treatment-related deaths occurred. LR by 3 years was seen in 5/45 (11%) EMR, 10/31 (32%) DCF, and 4/35 (11%) DCFRT patients. PFS [95% confidence interval (CI)] at 36 months was 47% (31% to 61%) for EMR, 29% (15% to 45%) for DCF, and 46% (29% to 61%) for DCFRT patients. OS (95% CI) at 60 months was 53% (37% to 67%) for EMR, 31% (16% to 48%) for DCF, and 46% (29% to 61%) for DCFRT patients. CONCLUSIONS: EMR is associated with favourable OS, PFS, and low LR. For non-responders, the addition of docetaxel augmented histological response rates, but OS, PFS, and LR remained inferior compared with responders. DCFRT improved histological response and PFS/LR outcomes, matching the EMR group. Early PET/CT has the potential to tailor therapy for patients not showing an early response to chemotherapy. TRIAL REGISTRATION: ACTRN12609000665235.

Oxaliplatin and 5-FU/folinic acid (modified FOLFOX6) with or without aflibercept in first-line treatment of patients with metastatic colorectal cancer: the AFFIRM study.

BACKGROUND: The combination of aflibercept with FOLFIRI has been shown to significantly prolong overall survival in patients with metastatic colorectal cancer (mCRC) after progression on oxaliplatin-based therapy. This trial evaluated the addition of aflibercept to oxaliplatin-based first-line treatment of patients with mCRC. PATIENTS AND METHODS: Patients with mCRC were randomized to receive first-line therapy with mFOLFOX6 plus aflibercept (4 mg/kg) or mFOLFOX6 alone. The primary end point of this phase II study was the progression-free survival (PFS) rate at 12 months in each arm. The analysis of efficacy between the arms was a pre-planned secondary analysis. RESULTS: Of 236 randomized patients, 227 and 235 patients were evaluable for the primary efficacy analysis and safety, respectively. The probabilities of being progression-free at 12 months were 25.8% [95% confidence interval (CI) 17.2-34.4] for the aflibercept/mFOLFOX6 arm and 21.2% (95% CI 12.2-30.3) for the mFOLFOX6 arm. The median PFS was 8.48 months (95% CI 7.89-9.92) for the aflibercept/mFOLFOX6 arm and 8.77 months (95% CI 7.62-9.27) for the mFOLFOX6 arm; the hazard ratio of aflibercept/mFOLFOX6 versus mFOLFOX6 was 1.00 (95% CI 0.74-1.36). The response rates were 49.1% (95% CI 39.7-58.6) and 45.9% (95% CI 36.4-55.7) for patients treated with and without aflibercept, respectively. The most frequent treatment-emergent grade 3/4 adverse events (AEs) excluding laboratory abnormalities reported for aflibercept/mFOLFOX6 versus mFOLFOX6 were neuropathy (16.8% versus 17.2%) and diarrhea (13.4% versus 5.2%). Neutropenia grade 3/4 occurred in 36.1% versus 29.3%. The most common vascular endothelial growth factor inhibition class-effect grade 3/4 AEs for aflibercept/mFOLFOX6 versus mFOLFOX6 were hypertension (35.3% versus 1.7%), proteinuria (9.2% versus 0%), deep vein thrombosis (5.9% versus 0.9%) and pulmonary embolism (5.9% versus 5.2%). CONCLUSION: No difference in PFS rate was observed between treatment groups. Adding aflibercept to first-line mFOLFOX6 did not increase efficacy but was associated with higher toxicity. CLINICAL TRIAL NUMBER: NCT00851084, www.clinicaltrials.gov, EudraCT 2008-004178-41.

INPP4B is an oncogenic regulator in human colon cancer.

Inositol polyphosphate 4-phosphatase type II (INPP4B) negatively regulates phosphatidylinositol 3-kinase signaling and is a tumor suppressor in some types of cancers. However, we have found that it is frequently upregulated in human colon cancer cells. Here we show that silencing of INPP4B blocks activation of Akt and serum- and glucocorticoid-regulated kinase 3 (SGK3), inhibits colon cancer cell proliferation and retards colon cancer xenograft growth. Conversely, overexpression of INPP4B increases proliferation and triggers anchorage-independent growth of normal colon epithelial cells. Moreover, we demonstrate that the effect of INPP4B on Akt and SGK3 is associated with inactivation of phosphate and tensin homolog through its protein phosphatase activity and that the increase in INPP4B is due to Ets-1-mediated transcriptional upregulation in colon cancer cells. Collectively, these results suggest that INPP4B may function as an oncogenic driver in colon cancer, with potential implications for targeting INPP4B as a novel approach to treat this disease.

Predicting 5-fluorouracil toxicity in colorectal cancer patients from peripheral blood cell telomere length: a multivariate analysis.

BACKGROUND: Identifying various pretreatment factors that predict chemotherapy-induced toxicity in colorectal cancer (CRC) patients undergoing treatment for their disease is crucial to optimising patient care. METHODS: Seventy-three patients received adjuvant 5-fluorouracil (5FU)/leucovorin using either the Mayo Clinic (n=42) or a weekly schedule (n=31) and evaluated for clinical toxicity. Pretreatment blood analysis included measures of plasma uracil and dihydrouracil, peripheral blood mononuclear cell (PBMNC) telomere length (TL), standard biochemistry and cell differential analysis. On the first day of treatment 5FU-pharmacokinetic variables of area under the curve, half life and clearance were also measured. These variables together with age and gender were used in univariate and multivariate analysis as predictors of clinical toxicity. RESULTS: For the Mayo schedule the primary toxicities were neutropenia (69%), mucositis (58%) and leukopenia (46%), with 70% of patients presenting with haematological toxicity ≥grade 1 (neutropenia and/or leukopenia). Multivariate analysis showed that haematological toxicity was predicted by short TL, high platelet lymphocyte ratio (PLR) and low neutrophil count (R(2)=0.38, P<0.0006), whereas mucositis was predicted by age, TL and PLR (R(2)=0.34, P<0.001). For the weekly schedule diarrhoea predominated (16%), with female gender as the only predictive factor. Although measures of uracil metabolism correlated well with 5FU metabolism (r=0.45-0.49), they did not indicate abnormal pyrimidine metabolism in this cohort and not surprisingly failed to predict for 5FU toxicity. CONCLUSION: Short TL of PBMNC and an increased PLR were strong predictors of mucositis and haematological toxicity in CRC patients undergoing 5FU treatment in the adjuvant setting.

Bevacizumab is equally effective and no more toxic in elderly patients with advanced colorectal cancer: a subgroup analysis from the AGITG MAX trial: an international randomised controlled trial of Capecitabine, Bevacizumab and Mitomycin C.

BACKGROUND: In an ageing population, a greater proportion of geriatric patients will be considered for systemic chemotherapy. Colorectal cancer (CRC) is a common malignancy and will be a major health issue in geriatrics. We used the MAX population to investigate whether age affected the improved outcome found in CRC when bevacizumab is added to capecitabine chemotherapy. PATIENTS AND METHODS: MAX, a three arm study of Capecitabine (C) versus CBevacizumab (CB) versus CBMitomycin C (CBM), found an improvement in progression-free survival (PFS), with addition of B [+/- mitomycin C (MMC)] to C. This analysis assesses the effect of adding B (+/- MMC) to C on PFS, overall survival (OS), response rate (RR), toxicity and dose intensity in geriatric patients (age ≥ 75 years). RESULTS: Ninety-nine patients (21%) were aged 75-86 years. Baseline characteristics were well balanced. Eighty-eight per cent commenced C at the lower optional dose of 2000 mg/m(2)/day; days 1-14, q21 (61% for <75 years) and 88% were Eastern Cooperative Oncology Group 0-1. Co-morbidities were as expected in this population. The addition of B significantly improved PFS in geriatric patients(C 5.8 months versus CB 8.8 months, Hazard ratio (HR) 0.65 and C versus CBM 10.4 months HR 0.38). The interaction test for OS, RR and PFS revealed no impact of age. Dose intensity was maintained >90% in all patients. There were no major differences in toxicity patterns between age cohorts. CONCLUSIONS: Addition of B to C significantly improved PFS in this geriatric population, with similar benefits to those aged <75 years. Treatment was well tolerated with no signal of increased toxicity (including thromboembolism) when compared with those aged <75 years.

The GOFURTGO Study: AGITG phase II study of fixed dose rate gemcitabine-oxaliplatin integrated with concomitant 5FU and 3-D conformal radiotherapy for the treatment of localised pancreatic cancer.

BACKGROUND: Locally advanced inoperable pancreatic cancer (LAPC) has a poor prognosis. By increasing intensity of systemic therapy combined with an established safe chemoradiation technique, our intention was to enhance the outcomes of LAPC. In preparation for phase III evaluation, the feasibility and efficacy of our candidate regimen gemcitabine-oxaliplatin chemotherapy with sandwich 5-fluorouracil (5FU) and three-dimensional conformal radiotherapy (3DCRT) needs to be established. METHODS: A total of 48 patients with inoperable LAPC without metastases were given gemcitabine (1000 mg m(-2) d1 + d15 q28) and oxaliplatin (100 mg m(-2) d2 + d16 q28) in induction (one cycle) and consolidation (three cycles), and 5FU 200 mg m(-2) per day over 6 weeks during 3DCRT 54 Gy. RESULTS: Median duration of sustained local control (LC) was 15.8 months, progression-free survival (PFS) was 11.0 months, and overall survival was 15.7 months. Survival rates for 1, 2, and 3 years were 70.2%, 21.3%, and 12.8%, respectively. Global quality of life did not significantly decline from baseline during treatment, which was associated with modest treatment-related toxicity. CONCLUSION: Fixed-dose gemcitabine and oxaliplatin, combined with an effective and safe regimen of 5FU and 3DCRT radiotherapy, was feasible and reasonably tolerated. The observed improved duration of LC and PFS with more intensive therapy over previous trials may be due to patient selection, but suggest that further evaluation in phase III trials is warranted.

A nomogram to predict survival time in women starting first-line chemotherapy for advanced breast cancer.

Women starting first-line chemotherapy for advanced breast cancer have differing baseline characteristics and survival times. We sought to develop and validate a pragmatic prognostic nomogram to predict overall survival (OS) by using available clinical and laboratory data. The prognostic model was developed in a training cohort (n=693) from two first-line chemotherapy trials (ANZ8101 and ANZ8614) and validated in two other trials (ANZ0001 and ANZ9311) with 324 and 233 patients, respectively. The proportional-hazards model was constructed from pretreatment demographic and disease characteristics. Patients were classified into good (score <88), medium (88-157), and poor (>157) prognostic groups. A nomogram was constructed (n=1250) from the combined datasets of all four trials, based on the predictors identified in the training cohort. The nomogram predicted OS with a concordance index of 0.65 (95%CI, 0.62-0.67). Factors in the nomogram were age, performance status, estrogen receptor status, number of involved organs (lung, liver and brain), hemoglobin concentration, neutrophil count, and serum alkaline phosphatase. The median survival for good, medium, and poor prognosis was 15.4 months (95%CI, 12.7-19.1), 10.2 months (95%CI, 9.0-11.6), and 6.1 months (95%CI, 4.4-6.7), respectively. The actual and model-predicted probabilities of 18-month survival agreed well, after recalibration for the new baseline survival functions for each validation cohort. A nomogram combining seven readily available baseline characteristics enabled stratification of advanced breast cancer patients into three groups with significantly different survival times. This nomogram could be useful for individualising treatment and for stratifying patients in future randomized trials.

Association of thymidylate synthase enhancer region polymorphisms with thymidylate synthase activity in vivo.

Two known polymorphisms in the 5' enhancer region (ER) of the thymidylate synthase (TS) gene, a variable number of tandem repeats of a 28 bp sequence (2R/3R) and a further G>C single nucleotide substitution within the repeats, result in genotypes with 0-5 functional upstream stimulatory factor (USF) E-box consensus elements. However, the relationship between these polymorphisms, regulation of TS expression and patient response to fluoropyrimidine treatment has been inconsistent. In this study, seven possible TSER allele configurations showed similar patterns of luciferase gene expression regardless of cell type or USF-1 content, with no significant difference in promoter activity between the wild-type 2RGC and 3RGGC (1.40±0.37 vs 1.43±0.32, P=0.90), whereas the minor alleles, 2RCC and 3RGCC, were significantly reduced (0.84±0.17, P=0.01) and increased (3.19±0.72, P=0.001) respectively. Patient plasma levels of 2'-deoxyuridine, a surrogate marker of TS activity, were significantly different between genotypes (P<0.001) and inversely related to luciferase activity (P=0.02) but not to the absolute number of functional repeated elements (P=0.16), suggesting that the position, rather than the number of functional USF E-box repeats in the TSER, is responsible for determining gene expression in vitro and TS activity in vivo.

Can a familial gastrointestinal tumour syndrome be allelic with Waardenburg syndrome?

Familial gastrointestinal stromal tumours (GISTs) are rare but otherwise well-characterized tumour syndromes, most commonly occurring on a background of germline-activating mutations in the tyrosine kinase receptor c-KIT. The associated clinical spectrum reflects the constitutive activation of this gene product across a number of cell lines, generating gain-of-function phenotypes in interstitial cells of Cajal (GIST and dysphagia), mast cells (mastocytosis) and melanocytes (hyperpigmentation). We report a three-generation kindred harbouring a c-KIT germline-activating mutation resulting in multifocal GISTs, dysphagia and a complex melanocyte hyperpigmentation and hypopigmentation disorder, the latter with features typical of those observed in Waardenburg type 2 syndrome (WS2F). Sequencing of genes known to be causative for WS [microphthalmia transcription factor (MITF), Pax3, Sox10, SNAI2 ] failed to show any candidate mutations to explain this complex cutaneous depigmentation phenotype. Our case report conclusively expands the clinical spectrum of familial GISTs and shows a hitherto unrecognized link to WS. Possible mechanisms responsible for this novel cause of WS2F will be discussed.

Mechanism of trifluorothymidine potentiation of oxaliplatin-induced cytotoxicity to colorectal cancer cells.

Oxaliplatin (OHP) is an anticancer agent that acts by formation of Platinum-DNA (Pt-DNA) adducts resulting in DNA-strand breaks and is used for the treatment of colorectal cancer. The pyrimidine analog trifluorothymidine (TFT) forms together with a thymidine phosphorylase inhibitor (TPI) the anticancer drug formulation TAS-102, in which TPI enhances the bioavailability of TFT in vivo. In this in vitro study the combined cytotoxic effects of OHP with TFT were investigated in human colorectal cancer cells as a model for TAS-102 combinations. In a panel of five colon cancer cell lines (WiDr, H630, Colo320, SNU-C4 and SW1116) we evaluated the OHP-TFT drug combinations using the multiple drug-effect analysis with CalcuSyn software, in which the combination index (CI) indicates synergism (CI<0.9), additivity (CI=0.9-1.1) or antagonism (CI>1.1). Drug target analysis was used for WiDr, H630 and SW1116 to investigate whether there was an increase in Pt-DNA adduct formation, DNA damage induction, cell cycle delay and apoptosis. Trifluorothymidine combined with OHP resulted in synergism for all cell lines (all CI<0.9). This was irrespective of schedule in which either one of the drugs was kept at a constant concentration (using variable drug ratio) or when the two drugs were added in a 1 : 1 IC(50)-based molar ratio. Synergism could be increased for WiDr using sequential drug treatment schedules. Trifluorothymidine increased Pt-DNA adduct formation significantly in H630 and SW1116 (14.4 and 99.1%, respectively; P<0.05). Platinum-DNA adducts were retained best in SW1116 in the presence of TFT. More DNA-strand breaks were induced in SW1116 and the combination increased DNA damage induction (>20%) compared with OHP alone. Exposure to the drugs induced a clear cell-cycle S-phase arrest, but was dose schedule and cell line dependent. Trifluorothymidine (TFT) and OHP both induced apoptosis, which increased significantly for WiDr and SW1116 after TFT-OHP exposure (18.8 and 20.6% respectively; P<0.05). The basal protein levels of ERCC1 DNA repair enzyme were not related to the DNA damage that was induced in the cell lines. In conclusion, the combination of TFT with the DNA synthesis inhibitor OHP induces synergism in colorectal cancer cells, but is dependent on the dose and treatment schedule used.

Phase II study of vinflunine in patients with metastatic renal cell carcinoma.

PURPOSE: An open-label, multicentre, non-comparative phase II trial to determine the response rate of intravenous vinflunine as first line chemotherapy in patients with metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: Patients with metastatic RCC were treated with vinflunine 350 mg/m2 (n = 11) or 320 mg/m2 (n = 22) administered intravenously every 21 days. RESULTS: Out of 33 patients included in this study, one partial response was observed in the group treated at 350 mg/m2 and none in the group receiving 320 mg/m2 resulting in a response rate in this population of 9.1% (95% CI: 0.2-41.3). Median progression free survival was 5.6 months (95% CI: 2.8-14.4) for patients treated at 350 mg/m2, and 3.3 months (95% CI: 1.6-6.4) for those treated at 320 mg/m2.The median survival time was 10.4 months (95% CI: 6.8-12.4) for the whole study population. The principal toxicities were grade 3/4 neutropaenia -90.9% at 350 mg/m2 and 68.1% at 320 mg/m2, febrile neutropaenia was recorded in 3 patients (27.3%) at 350 mg/m2 and in 5 patients (22.7%) at 320 mg/m2. One episode of thromboembolic event was reported in 1 patient at each dose level. CONCLUSION: Vinflunine given intravenously once every 3 weeks has not shown any clinically relevant activity in the management of patients with metastatic renal cell carcinoma; tolerance of the treatment was better at a dose of 320 mg/m2 than at 350 mg/m2.

Nutrition support improves patient outcomes, treatment tolerance and admission characteristics in oesophageal cancer.

AIMS: Patients with oesophageal cancer undergoing chemoradiation with curative intent are at high risk of malnutrition and its complications, including increased side effects of treatment. We have developed a nutrition pathway (NP), involving the early then periodic nutrition assessment of all patients presenting to the multidisciplinary oesophageal clinic who were planned to receive definitive chemoradiation. MATERIALS AND METHODS: Patients were assessed as at 'low', 'moderate' or 'severe' nutrition risk, and were provided with appropriate nutrition intervention ranging from preventative advice (low risk), oral nutrition support (moderate risk) to enteral feeding (severe risk). Outcomes for 24 patients treated before implementation of the NP were compared with those of 24 patients treated using the NP. RESULTS: Patients managed using the NP experienced less weight loss (mean weight change -4.2 kg +/-6.4 cf. -8.9 kg +/- 5.9, P = 0.03), greater radiotherapy completion rates (92% cf. 50%, P = 0.001), fewer patients had an unplanned hospital admission (46% cf. 75%, P = 0.04), and those that did had a shorter length of stay (3.2 days +/- 5.4 cf. 13.5 days +/- 14.1, P = 0.002). CONCLUSION: Early and regular nutrition assessment/intervention and a multidisciplinary approach to nutrition care results in improved treatment tolerance for patients with oesophageal cancer receiving chemoradiation.

A meta-analysis of two randomised trials of early chemotherapy in asymptomatic metastatic colorectal cancer.

This report constitutes a prospectively planned meta-analysis combining two almost identical trials undertaken in Australasia and Canada to study the effect of starting chemotherapy immediately in asymptomatic patients with metastatic colorectal cancer. Patients (n=168) were randomised to receive either immediate or delayed treatment (at onset of predefined symptoms). Australasian patients received either weekly 5-fluorouracil and leucovorin (500 and 20 mg m(-2), respectively) (n=59) or the daily x 5 Mayo Clinic schedule (425 and 20 mg m(-2), respectively) (n=42). Canadian patients were treated with the Mayo schedule (n=67). Otherwise, the two studies were almost identical in design and each used the European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 instrument for measuring quality of life (QoL). Treatment was continued until 6 months had elapsed or disease progression occurred. Low accrual led to trial suspension before the predetermined sample size for either study was reached. Median survival was not significantly better with immediate treatment (median 13.0 vs 11.0 months; hazard ratio, 1.15; 95% confidence interval (CI) 0.79-1.72; P=0.49). There was no statistically significant difference in progression-free survival (time from randomisation until first evidence of progression after chemotherapy, 10.2 vs 10.8 months; hazard ratio, 1.08; 95% CI 0.71-1.64; P=0.73). There was no difference in overall QoL or its individual domains between the two treatment strategies at baseline or at any subsequent time point. Early treatment of asymptomatic patients with metastatic colorectal cancer did not provide a survival benefit or improved QoL compared to withholding treatment until symptoms occurred.

Telomere length predicts neutrophil recovery in the absence of G-CSF after autologous peripheral blood stem cell transplantation.

SUMMARY: Haemopoietic regeneration after autologous peripheral blood progenitor cell (PBPC) transplantation can be delayed in some patients despite adequate infusion of CD34(+) cells. This suggests variability in the proliferation potential of the implanted cells, a capacity that may be predicted by their telomere length. To test this theory, telomere length was measured on stored apheresis samples from 36 patients aged 46.6+/-11.1 years, who had undergone successful autologous PBPC transplantation with a median of 5.6 x 10(6)/kg (1.3 x 10(6)-36.1 x 10(6)/kg) CD34(+) cells. The mean PBPC telomere length for the cohort was 9.4+/-2.3 kbp. For patients who did not receive G-CSF post transplantation (n=7), days to absolute neutrophil recovery (ANC), >/=0.1, 0.5 and 1.0 x 10(9) cells/l, were significantly inversely correlated with telomere length of the infused PBPC (r=-0.88, -0.81, -0.77, respectively; P<0.05,). However, no correlation was found for patients who received G-CSF from day 1 post transplantation (n=20). These data suggest that for transplantation with sufficient CD34(+) cells, neutrophil recovery is less efficient in patients receiving infusions of cells with short telomeres, but this deficiency can be corrected with adequate post transplantation administration of G-CSF. Bone Marrow Transplantation (2004) 34, 439-445. doi:10.1038/sj.bmt.1704607 Published online 19 July 2004

Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer.

BACKGROUND: This study was designed to demonstrate that efficacy [progression-free survival (PFS)] of CAELYX [pegylated liposomal doxorubicin HCl (PLD)] is non-inferior to doxorubicin with significantly less cardiotoxicity in first-line treatment of women with metastatic breast cancer (MBC). PATIENTS AND METHODS: Women (n=509) with MBC and normal cardiac function were randomized to receive either PLD 50 mg/m2 (every 4 weeks) or doxorubicin 60 mg/m2 (every 3 weeks). Cardiac event rates were based on reductions in left ventricular ejection fraction as a function of cumulative anthracycline dose. RESULTS: PLD and doxorubicin were comparable with respect to PFS [6.9 versus 7.8 months, respectively; hazard ratio (HR)=1.00; 95% confidence interval (CI) 0.82-1.22]. Subgroup results were consistent. Overall risk of cardiotoxicity was significantly higher with doxorubicin than PLD (HR=3.16; 95%CI 1.58-6.31; P<0.001). Overall survival was similar (21 and 22 months for PLD and doxorubicin, respectively; HR=0.94; 95%CI 0.74-1.19). Alopecia (overall, 66% versus 20%; pronounced, 54% versus 7%), nausea (53% versus 37%), vomiting (31% versus 19%) and neutropenia (10% versus 4%) were more often associated with doxorubicin than PLD. Palmar-plantar erythrodysesthesia (48% versus 2%), stomatitis (22% versus 15%) and mucositis (23% versus 13%) were more often associated with PLD than doxorubicin. CONCLUSIONS: In first-line therapy for MBC, PLD provides comparable efficacy to doxorubicin, with significantly reduced cardiotoxicity, myelosuppression, vomiting and alopecia.

Relapse patterns after chemo-radiation for carcinoma of the oesophagus.

AIM: The detailed review of patterns of failure in this report was undertaken to identify the continuing obstacles to the successful management of oesophageal cancer, and to establish whether there is a case to compare definitive chemo-radiation (Def-CR) and surgery for patients with squamous cancer in a randomized controlled trial. MATERIALS AND METHODS: First and subsequent sites of failure were reviewed in 274 patients treated with Def-CR using two cycles of cisplatin, infusional fluorouracil and 60 Gy; and 92 patients with limited chemo-radiation (CR), using one cycle and 35 Gy, followed by surgery (CR-Surg). All were treated on prospective non-randomized trials run by the Trans-Tasman Radiation Oncology Group between 1985 and 1999. Failure patterns were analysed using competing risks methodology, and pre-treatment variables predicting survival were identified by proportional hazards modelling. RESULTS: Site, stage, performance status and gender were independently predictive of survival following Def-CR. Local failure was evident in 42.3% of patients, but distant failure in isolation occurred in an additional 18.1%. Lowest rates of local and distant failure at 5 years (29.9% and 26%) occurred in patients with squamous cancer (SCC) located in the upper-third, whose 5-year survival was also the most favourable (49.2%). Survival was least favourable in patients with adenocarcinoma (AC) in the lower two-thirds (18.1%) due to higher rates of local (51.5%) and distant (36.1%) failure. Local failure occurred in 31.5% of patients undergoing CR-Surg but distant failure in isolation was observed in a further 34.7%. Outcomes were least favourable in patients with AC of the lower-third in whom 57.7% failed distantly and 5-year survival was 3.8%. Response to pre-operative chemo-radiation was also strongly predictive of outcome. Patients with no residual cancer in the resection specimen had the lowest rates of local (0%) and distant (16.7%) failure and the best survival (64.9%). Survival in patients with residual cancer in nodes, however, was extremely poor (3.5%) with distant failure occurring in 66.7%. CONCLUSION: The concurrent administration of chemotherapy with radiotherapy seems to have improved loco-regional control and has exposed distant failure as an obstacle to further improvements in outcome. Site, histological subtype, gender and response to chemo-radiation may predict biological differences in oesophageal cancer (OC) that influence outcome. A good case for a randomized comparison between Def-CR and CR-Surg in patients with SCC in the lower two-thirds exists.

Phase I and pharmacokinetic study of docetaxel in combination with epirubicin and cyclophosphamide in advanced cancer: dose escalation possible with granulocyte colony-stimulating factor, but not with prophylactic antibiotics.

BACKGROUND: The objective of this phase I trial was to determine the maximally tolerated doses of the combination of docetaxel, epirubicin and cyclophosphamide. PATIENTS AND METHODS: Patients with advanced cancer, World Health Organization (WHO) performance status 0 to 2, who had received up to one prior chemotherapy regimen were treated with docetaxel, epirubicin and cyclophosphamide repeated every 21 days. The cyclophosphamide dose was fixed at 600 mg/m(2) and the dose levels studied were: docetaxel/epirubicin; 60/60, 75/60, 75/75, 75/90, 85/90 and 85/105 mg/m(2). There was provision for the addition of prophylactic ciprofloxacin and granulocyte colony-stimulating factor (G-CSF) in separate steps if dose-limiting toxicity (DLT) was neutropenia related. RESULTS: Forty-three patients were entered and all were assessable for toxicity. Dose-limiting toxicity, predominantly febrile neutropenia, was surprisingly seen at the first dose level. The addition of prophylactic ciprofloxacin did not permit dose escalation, but dose escalation was possible with the addition of G-CSF. The highest administered dose level with G-CSF was docetaxel 85 mg/m(2) and epirubicin 105 mg/m(2) with DLTs in five of six patients. Treatment was well tolerated in 10 patients treated at the recommended dose level (85/90) with only one patient experiencing DLT. Responses were seen in a range of malignancies including breast and anaplastic thyroid cancers. No significant pharmacokinetic interaction was observed, but a transient increase in epirubicinol plasma concentration occurred during and after docetaxel infusion. CONCLUSIONS: The recommended dose level of docetaxel 85 mg/m(2), epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2) with G-CSF support has a favorable toxicity profile and is suitable for further investigation in phase II and III trials.

Phase I study of docetaxel plus ifosfamide in patients with advanced cancer.

The aim of this study was to determine the maximum tolerated dose of a fixed dose of docetaxel when combined with continuous infusion ifosfamide, with and without G-CSF support, in the treatment of advanced cancer, and to evaluate anti-tumour activity of this combination. Thirty-one patients with advanced malignancies were treated with docetaxel 75 mg/m(2) intravenously on days 1, and ifosfamide at increasing dose levels from 1500 mg/m(2)/day to 2750 mg/m(2)/day as a continuous infusion from day 1-3, every 3 weeks. A total of 107 cycles of treatment were administered. Without G-CSF support dose-limiting toxicity of grade 4 neutropenia greater than 5 days duration occurred at dose level 1. With the addition of G-CSF the maximum tolerated dose was docetaxel 75 mg/m(2) on day 1 and ifosfamide 2750 mg/m(2)/day on days 1-3. Dose limiting toxicity (DLT) included ifosfamide-induced encephalopathy, febrile neutropenia and grade three mucositis. Three complete responses and 3 partial responses were seen. This combination of docetaxel and infusional ifosfamide is feasible and effective. The recommended dose for future phase II studies is docetaxel 75 mg/m(2) on day 1 and ifosfamide 2500 mg/m(2)/day continuous infusion on days 1-3.

Phase II trial of pemetrexed disodium (ALIMTA, LY231514) in chemotherapy-naïve patients with advanced non-small-cell lung cancer.

BACKGROUND: To evaluate the efficacy and safety of pemetrexed therapy for chemotherapy-naïve patients with surgically incurable non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.