A Q-TWiST analysis comparing panitumumab plus best supportive care (BSC) with BSC alone in patients with wild-type KRAS metastatic colorectal cancer

Background:

Panitumumab+best supportive care (BSC) significantly improved progression-free survival (PFS) vs BSC alone in patients with chemo-refractory wild-type KRAS metastatic colorectal cancer (mCRC). We applied the quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) analysis to provide an integrated measure of clinical benefit, with the objective of comparing quality-adjusted survival between the two arms. As the trial design allowed patients on BSC alone to receive panitumumab after disease progression, which confounded overall survival (OS), the focus of this analysis was on PFS.

Methods:

For each treatment group, the time spent in the toxicity (grade 3 or 4 adverse events; TOX), time without symptoms of disease or toxicity (TWiST), and relapse (after disease progression; REL) states were estimated by the product-limit method, and adjusted using utility weights derived from patient-reported EuroQoL 5-dimensions measures. Sensitivity analyses were performed in which utility weights (varying from 0 to 1) were applied to time in the TOX and REL health states.

Results:

There was a significant difference between groups favouring panitumumab+BSC in quality-adjusted PFS (12.3 weeks vs 5.8 weeks, respectively, P<0.0001) and quality-adjusted OS (P=0.0303).

Conclusion:

In patients with chemo-refractory wild-type KRAS mCRC, panitumumab+BSC significantly improved quality-adjusted survival compared with BSC alone.     

Q-TWiST analysis to estimate overall benefit for patients with metastatic renal cell carcinoma treated in a phase III trial of sunitinib vs interferon-α

Background:

In a randomised phase III trial of treatment-naive patients with metastatic renal cell carcinoma, sunitinib showed significant improvement in progression-free survival (PFS) compared with interferon (IFN)-α. We assessed between-treatment differences in overall benefit using a quality-adjusted Time Without Symptoms of disease progression or Toxicity of treatment (TWiST; Gelber and Goldhirsch) analysis.

Methods:

In this analysis, in which only grade 3/4 treatment-related toxicities were included, overall survival was partitioned into three health states: toxicity (time with toxicity after randomisation and before progression), time without symptoms of disease progression or toxicity, and time from progression until death. Between-treatment differences in the mean duration of each state were calculated. A threshold utility analysis was used to assess quality-adjusted TWiST (Q-TWiST) outcomes.

Results:

Q-TWiST scores showed that quality-adjusted survival time was greater with sunitinib than with IFN-α, even though certain grade 3/4 toxicities occurred more frequently with sunitinib. For both treatments, the mean number of days with toxicity was small compared with PFS. This effect was more pronounced with sunitinib in which time spent without progression or toxicity was 151 days greater than with IFN-α.

Conclusion:

Patients randomised to sunitinib had longer clinical benefit, defined as Q-TWiST scores, than patients randomised to IFN-α.     

Q-TWiST analysis comparing ipilimumab/dacarbazine vs placebo/dacarbazine for patients with stage III/IV melanoma

Background:

Study CA184024 was a multinational, randomised, double-blind, phase 3 study comparing ipilimumab/dacarbazine (DTIC) vs placebo/DTIC in patients with untreated stage III/IV melanoma, which showed that ipilimumab significantly improves survival in patients with metastatic melanoma. The objective of this analysis was to compare the quality-adjusted survival experience among patients in this trial.

Methods:

Survival time was partitioned into health states: toxicity, time before progression without toxicity, and relapse until death or end of follow-up. Q-TWiST (quality-adjusted time without symptoms of disease or toxicity of treatment) was calculated as the utility-weighted sum of the mean health state durations. Analyses were repeated over extended follow-up periods.

Results:

Based on a combination of trial-based and external utility scores, the Q-TWiST difference in this trial was 0.50 months (P=0.0326) favoring ipilimumab after 1 year. The Q-TWiST difference was 1.5 months with 2 years of follow-up (P=0.0091), 2.36 months at 3 years (P=0.005) and 3.28 months at 4 years (P=0.0074).

Conclusion:

During the first year of study, there was little difference between groups in quality-adjusted survival. However, after 2, 3 and 4 years follow-up for patients with extended survival, the benefits of IPI+DTIC vs PLA+DTIC for advanced melanoma continue to accrue.     

Phase II study of first-line sagopilone plus prednisone in patients with castration-resistant prostate cancer: a phase II study of the Department of Defense Prostate Cancer Clinical Trials Consortium

Background:

Preclinical studies in prostate cancer (PC) models demonstrated the anti-tumour activity of the first fully synthetic epothilone, sagopilone. This is the first study to investigate the activity and safety of sagopilone in patients with metastatic castration-resistant PC (CRPC).

Methods:

Chemotherapy-naïve patients with metastatic CRPC received sagopilone (one cycle: 16 mg m⁻² intravenously over 3 h q3w) plus prednisone (5 mg twice daily). The primary efficacy evaluation was prostate-specific antigen (PSA) response rate (⩾50% PSA reduction confirmed ⩾28 days apart). According to the Simon two-stage design, ⩾3 PSA responders were necessary within the first 13 evaluable patients for recruitment to continue until 46 evaluable patients were available.

Results:

In all, 53 patients received ⩾2 study medication cycles, with high compliance. Mean individual dose was 15.1±1.4 mg m⁻² during initial six cycles, mean dose intensity 94±9%. The confirmed PSA response rate was 37%. Median overall progression-free survival was 6.4 months. The most commonly reported adverse events (>10% of patients) were peripheral neuropathy (94.3%), fatigue (54.7%) and pain in the extremities (47.2%). Sagopilone was associated with very little haematological toxicity.

Conclusion:

This study shows that first-line sagopilone has noteworthy anti-tumour activity and a clinically significant level of neuropathy for patients with metastatic chemotherapy-naïve CRPC.     

Inhibition of renin-angiotensin system affects prognosis of advanced pancreatic cancer receiving gemcitabine

Background:

The renin–angiotensin system (RAS) is thought to have a role in carcinogenesis, and RAS inhibition may prevent tumour growth.

Methods:

We retrospectively investigated the impact of angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) in 155 patients with pancreatic cancer receiving gemcitabine monotherapy. Patients were divided into three groups: the ACEI/ARB group (27 patients receiving an ACEI or ARB for hypertension (HT)), the non-ACEI/ARB with HT group (25 patients receiving antihypertensive drugs other than ACEIs or ARBs), and the non-HT group (103 patients receiving no antihypertensive drugs).

Results:

Patient characteristics were not different, except for age and HT medications. Progression-free survival (PFS) was 8.7 months in the ACEI/ARB group, 4.5 months in the non-ACEI/ARB with HT group, and 3.6 months in the non-HT group. Overall survival (OS) was 15.1 months in the ACEI/ARB group, 8.9 months in the non-ACEI/ARB with HT group, and 9.5 months in the non-HT group. The use of ACEIs/ARBs was a significant prognostic factor for both PFS (P=0.032) and OS (P=0.014) in the multivariate analysis.

Conclusions:

The ACEIs/ARBs in combination with gemcitabine might improve clinical outcomes in patients with advanced pancreatic cancer. Prospective trials are needed to test this hypothesis.     

Cost-effectiveness of alternative strategies for integrating MRI into breast cancer screening for women at high risk

Background:

Magnetic resonance imaging (MRI) is recommended for women at high risk for breast cancer. We evaluated the cost-effectiveness of alternative screening strategies involving MRI.

Methods:

Using a microsimulation model, we generated life histories under different risk profiles, and assessed the impact of screening on quality-adjusted life-years, and lifetime costs, both discounted at 3%. We compared 12 screening strategies combining annual or biennial MRI with mammography and clinical breast examination (CBE) in intervals of 0.5, 1, or 2 years vs without, and reported incremental cost-effectiveness ratios (ICERs).

Results:

Based on an ICER threshold of $100 000/QALY, the most cost-effective strategy for women at 25% lifetime risk was to stagger MRI and mammography plus CBE every year from age 30 to 74, yielding ICER $58 400 (compared to biennial MRI alone). At 50% lifetime risk and with 70% reduction in MRI cost, the recommended strategy was to stagger MRI and mammography plus CBE every 6 months (ICER=$84 400). At 75% lifetime risk, the recommended strategy is biennial MRI combined with mammography plus CBE every 6 months (ICER=$62 800).

Conclusions:

The high costs of MRI and its lower specificity are limiting factors for annual screening schedule of MRI, except for women at sufficiently high risk.     

Nab-paclitaxel plus gemcitabine for metastatic pancreatic adenocarcinoma after Folfirinox failure: an AGEO prospective multicentre cohort

Background:

There is currently no standard second-line treatment for metastatic pancreatic adenocarcinoma (MPA), and progression-free survival is consistently <4 months in this setting. The aim of this study was to evaluate the efficacy and tolerability of Nab-paclitaxel plus gemcitabine (A+G) after Folfirinox failure in MPA.

Methods:

From February 2013 to July 2014, all consecutive patients treated with A+G for histologically proven MPA after Folfirinox failure were prospectively enrolled in 12 French centres. A+G was delivered as described in the MPACT trial, until disease progression, patient refusal or unacceptable toxicity.

Results:

Fifty-seven patients were treated with Nab-paclitaxel plus gemcitabine, for a median of 4 cycles (range 1–12). The disease control rate was 58%, with a 17.5% objective response rate. Median overall survival (OS) was 8.8 months (95% CI: 6.2–9.7) and median progression-free survival was 5.1 months (95% CI: 3.2–6.2). Since the start of first-line chemotherapy, median OS was 18 months (95% CI: 16–21). No toxic deaths occurred. Grade 3–4 toxicities were reported in 40% of patients, consisting of neutropenia (12.5%), neurotoxicity (12.5%), asthenia (9%) and thrombocytopenia (6.5%).

Conclusions:

A+G seems to be effective, with a manageable toxicity profile, after Folfirinox failure in patients with MPA.     

The effect of DCIS grade on rate, type and time to recurrence after 15 years of follow-up of screen-detected DCIS

Background:

The incidence of ductal carcinoma in situ (DCIS) rose rapidly when the NHS Breast Screening Programme (NHSBSP) started in 1988. Some authorities consider that this represents both over-diagnosis and over-treatment. We report long-term follow-up of DCIS diagnosed in the first 10 years (April 1988 to March 1999) of the West Midlands NHSBSP.

Methods:

840 noninvasive breast cancers were recorded on the national breast screening computer system. Following exclusions, and thorough case note and pathology review, 700 DCIS cases were identified for follow-up.

Results:

After a median follow-up of 183 (range 133 to 259) months, 102 (14.6%) first local recurrences were identified, 49 (48%) were invasive. Median time to first noninvasive recurrence was 15 months, and 60 months for invasive recurrence. Median time to invasive recurrence was 76 months from initially high-grade DCIS, and 131 months from low/intermediate grade DCIS. For the seven women, presenting with metastasis as their first event, the median time was 82 (range 15 to 188) months. The cumulative proportion developing recurrence at 180 months was twice as high as at 60 months.

Interpretation:

Short-term follow-up of patients diagnosed with DCIS will miss significant numbers of events, especially invasive local recurrences.     

Cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric cancer: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)

Background:

Cetuximab enhances the efficacy of chemotherapy in several cancer types. This trial assessed the activity of cetuximab and chemotherapy in advanced gastric cancer.

Methods:

Patients with previously untreated, metastatic, gastric cancer received cetuximab 400 mg m⁻² at first infusion followed by weekly infusions of 250 mg m⁻² combined with FUFOX (oxaliplatin 50 mg m⁻², 5-FU 2000 mg m⁻², and DL-folinic acid 200 mg m⁻² d1, 8, 15 and 22 qd36). The primary endpoint was tumour response.

Results:

Overall, 52 patients were enrolled. The most common grade 3/4 toxicities were diarrhoea (33%), and skin toxicity (24%). Efficacy was evaluable in 46 patients who showed a response rate of 65% (CI 95%: 50–79%) including four complete responses. Time to progression (TTP) was 7.6 months (CI 95%: 5.0–10.1 months) and overall survival (OS) was 9.5 months (CI 95%: 7.9–11.1 months). Epidermal growth factor receptor (EGFR) was detectable in 60% of tumours but showed no correlation with treatment outcome. A KRAS mutation was found in only 1 of 32 (3%) tumour samples analysed.

Conclusion:

Cetuximab plus FUFOX showed an interesting high response rate in metastatic gastric cancer. Cetuximab plus platinum–fluoropyrimidine chemotherapy is at present being investigated in a phase III randomised controlled trial.     

Cellular senescence predicts treatment outcome in metastasised colorectal cancer

Background:

Cellular senescence is a terminal cell-cycle arrest that occurs in response to activated oncogenes and DNA-damaging chemotherapy. Whether cancer cell senescence at diagnosis might be predictive for treatment outcome is unknown.

Methods:

A senescence index (SI) was developed and used to retrospectively correlate the treatment outcome of 30 UICC stage IV colorectal cancer (CRC) patients with their SI at diagnosis.

Results:

5-Fluorouracil/leucovorin-treated CRC patients achieved a significantly longer progression-free survival when presenting with SI-positive tumours before therapy (median 12.0 vs 6.0 months; P=0.044).

Conclusion:

Cancer cell senescence predicts treatment outcome in metastasised CRC. Prospective analyses of larger patient cohorts are needed.     

Evaluation of prognostic factors in liver-limited metastatic colorectal cancer: a preplanned analysis of the FIRE-1 trial

Background:

Liver-limited disease (LLD) denotes a specific subgroup of metastatic colorectal cancer (mCRC) patients.

Patients and Methods:

A total of 479 patients with unresectable mCRC from an irinotecan-based randomised phase III trial were evaluated. Patients with LLD and non-LLD and hepatic resection were differentiated. Based on baseline patient characteristic, prognostic factors for hepatic resection were evaluated. Furthermore, prognostic factors for median overall survival (OS) were estimated via Cox regression in LLD patients.

Results:

Secondary liver resection was performed in 38 out of 479 patients (resection rate: 7.9%). Prognostic factors for hepatic resection were LLD, lactate dehydrogenase (LDH), node-negative primary, alkaline phosphatase (AP) and Karnofsky performance status (PS). Median OS was significantly increased after hepatic resection (48 months), whereas OS in LLD (17 months) and non-LLD (19 months) was comparable in non-resected patients. With the inapplicability of Koehne''s risk classification in LLD patients, a new score based on only the independent prognostic factors LDH and white blood cell (WBC) provided markedly improved information on the outcome.

Conclusion:

Patients undergoing hepatic resection showed favourable long-term survival, whereas non-resected LLD patients and non-LLD patients did not differ with regard to progression-free survival and OS. The LDH levels and WBC count were confirmed as prognostic factors and provide a useful and simple score for OS-related risk stratification also in LLD.     

Cost-effectiveness analysis of XELOX for metastatic colorectal cancer based on the NO16966 and NO16967 trials

Background:

The purpose of the study was to evaluate the cost-effectiveness of capecitabine plus oxaliplatin (XELOX) compared with 5-fluorouracil/folinic acid and oxaliplatin (FOLFOX4) as first-line or second-line chemotherapy in patients with metastatic colorectal cancer.

Methods:

On the basis of NO16966 and NO16967 trials, mean costs and effectiveness were calculated from patient-level data. Until the disease progressed, the mean costs were calculated from the perspective of health-care payers in Japan. We estimated mean quality-adjusted progression-free survival days (QAPFSD), considering adverse events and patient preference for chemotherapy regimens. Utility scores were obtained by a web-based survey from general people, randomly sampled from a large panel adjusted for sex and age.

Results:

Incremental effectiveness of XELOX as first-line and second-line chemotherapy for colorectal cancer patients was significantly greater. By use of XELOX, patients gained 10.5 QAPFSD from first-line treatment or 11.3 QAPFSD from second-line treatment. Capecitabine plus oxaliplatin (XELOX) was also proven to significantly reduce treatment costs by €3000 (JPY 360 000) and €2300 (JPY 270 000) for first-line and second-line treatment, respectively. In health-care settings in the United Kingdom, XELOX decreased medical costs for National Health Service by £7600 and £3900 for patients who received first-line and second-line treatment, respectively.

Conclusion:

Capecitabine plus oxaliplatin (XELOX) as first-line and second-line chemotherapy was ‘dominant''. In terms of effectiveness and cost, XELOX was superior to FOLFOX4.     

Allogeneic stem cell transplantation for patients with advanced rhabdomyosarcoma: a retrospective assessment

Background:

Allogeneic haematopoietic stem cell transplantation (allo-SCT) may provide donor cytotoxic T cell-/NK cell-mediated disease control in patients with rhabdomyosarcoma (RMS). However, little is known about the prevalence of graft-vs-RMS effects and only a few case experiences have been reported.

Methods:

We evaluated allo-SCT outcomes of 30 European Group for Blood and Marrow Transplantation (EBMT)-registered patients with advanced RMS regarding toxicity, progression-free survival (PFS) and overall survival (OS) after allo-SCT. Twenty patients were conditioned with reduced intensity and ten with high-dose chemotherapy. Twenty-three patients were transplanted with HLA-matched and seven with HLA-mismatched grafts. Three patients additionally received donor lymphocyte infusions (DLIs). Median follow-up was 9 months.

Results:

Three-year OS was 20% (s.e.±8%) with a median survival time of 12 months. Cumulative risk of progression was 67% (s.e.±10%) and 11% (s.e.±6%) for death of complications. Thirteen patients developed acute graft-vs-host disease (GvHD) and five developed chronic GvHD. Eighteen patients died of disease and four of complications. Eight patients survived in complete remission (CR) (median: 44 months). No patients with residual disease before allo-SCT were converted to CR.

Conclusion:

The use of allo-SCT in patients with advanced RMS is currently experimental. In a subset of patients, it may constitute a valuable approach for consolidating CR, but this needs to be validated in prospective trials.     

Quality of Life in the Trastuzumab for Gastric Cancer Trial

Background.

The Trastuzumab for Gastric Cancer phase III trial demonstrated that combining trastuzumab with chemotherapy significantly improved overall survival compared with chemotherapy alone in HER2-positive advanced gastric or gastroesophageal junction cancer. We report health-related quality of life (HRQoL) and quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) results from this trial.

Patients and Methods.

Patients were randomized to receive six cycles of chemotherapy given every 3 weeks (capecitabine or fluorouracil, plus cisplatin) either alone or combined with administration of trastuzumab every 3 weeks until disease progression. At each clinical visit, HRQoL was assessed using two European Organization for Research and Treatment of Cancer quality of life questionnaires, QLQ-C30 and QLQ-STO22. Q-TWiST methodology was applied retrospectively using the clinical data and utility coefficients.

Results.

Trastuzumab plus chemotherapy prolonged time to 10% definitive deterioration in all QLQ-C30 and QLQ-STO22 scores, including QLQ-C30 global health status versus chemotherapy alone, from 6.4 months to 10.2 months. In addition, trastuzumab plus chemotherapy extended Q-TWiST by 2.42 months compared with chemotherapy alone.

Conclusion.

Compared with chemotherapy alone, trastuzumab plus chemotherapy prolongs time to deterioration of HRQoL and increases quality-adjusted survival in patients with HER2-positive gastric or gastroesophageal junction cancer.     

A dose-escalating phase I of imatinib mesylate with fixed dose of metronomic cyclophosphamide in targeted olid tumours

Background:

Preclinical findings suggest that imatinib mesylate (IM) and metronomic cyclophosphamide (MC) combination provides synergistic antiangiogenic activity on both pericytes and endothelial cells.

Methods:

We have designed a 3+3 dose-escalating phase I trial with a fixed dose of MC (50 mg two times daily) plus IM (400 mg per day; 300 and 400 mg two times daily). Enrolled patients had IM- and sutininib-refractory advanced gastrointestinal stromal tumours (GIST) (n=17), chordoma (n=7) and mucosal melanoma (n=2). Dose-limiting toxicities were monitored for the first 6 weeks. Progression-free survival (PFS) and response assessment are based on RECIST 1.0 guidelines. Pharmacokinetics of IM were measured before and after exposure to MC.

Results:

No dose-limiting toxicity was observed. Fourteen patients of the expanded cohort received 400 mg two times daily of IM with MC. Apart from a case of possibly related acute leukaemia occurring after 4 years of treatment, we did not see unexpected toxicity. No drug–drug pharmacokinetic interaction was observed. There was no objective response. We have observed long-lasting stable disease in chordoma patients (median PFS=10.2 months; range, 4.2–18+) and short-term stable disease in heavily GIST pretreated patients (median PFS=2.3 months; range, 2.1–6.6).

Conclusion:

This combination is feasible and may warrant further exploration in refractory GIST or chordoma patients.     

Treatment of advanced hepatocellular carcinoma with very low levels of amplitude-modulated electromagnetic fields

Background:

Therapeutic options for patients with advanced hepatocellular carcinoma (HCC) are limited. There is emerging evidence that the growth of cancer cells may be altered by very low levels of electromagnetic fields modulated at specific frequencies.

Methods:

A single-group, open-label, phase I/II study was performed to assess the safety and effectiveness of the intrabuccal administration of very low levels of electromagnetic fields amplitude modulated at HCC-specific frequencies in 41 patients with advanced HCC and limited therapeutic options. Three-daily 60-min outpatient treatments were administered until disease progression or death. Imaging studies were performed every 8 weeks. The primary efficacy end point was progression-free survival ⩾6 months. Secondary efficacy end points were progression-free survival and overall survival.

Results:

Treatment was well tolerated and there were no NCI grade 2, 3 or 4 toxicities. In all, 14 patients (34.1%) had stable disease for more than 6 months. Median progression-free survival was 4.4 months (95% CI 2.1–5.3) and median overall survival was 6.7 months (95% CI 3.0–10.2). There were three partial and one near complete responses.

Conclusion:

Treatment with intrabuccally administered amplitude-modulated electromagnetic fields is safe, well tolerated, and shows evidence of antitumour effects in patients with advanced HCC.     

Everolimus in metastatic renal cell carcinoma patients intolerant to previous VEGFr-TKI therapy: a RECORD-1 subgroup analysis

Background:

A relevant percentage of patients with metastatic renal cell carcinoma develop intolerance to vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFr-TKIs) and require careful selection of subsequent treatment. This retrospective analysis evaluated the safety and efficacy of everolimus in patients enrolled in the phase-III RECORD-1 trial who discontinued previous VEGFr-TKI therapy because of toxicity.

Methods:

Patients with an adverse event (AE) as their primary reason for discontinuation of previous VEGFr-TKI therapy were included. Median progression-free survival (PFS) for VEGFr-TKI-intolerant patients in each arm was estimated using the Kaplan–Meier method, and effect on PFS (hazard ratio (HR)) was calculated using the Cox proportional hazard model.

Results:

In VEGFr-TKI-intolerant patients (n=58, 14%), median PFS was 5.4 months with everolimus and 1.9 months with placebo (HR: 0.32; P=0.004). In sunitinib-intolerant patients (n=26), median PFS was 5.1 months with everolimus and 2.8 months with placebo (HR: 0.28; P=0.033). Grade 3/4 AEs reported with everolimus in VEGFr-TKI-intolerant patients included infections (16%), fatigue (7%) and stomatitis (4%). The toxicity profile of everolimus was similar in the VEGFr-TKI-intolerant and overall study populations.

Conclusion:

Everolimus is well tolerated and efficacious with no increased toxicity in patients intolerant to VEGFr-TKI therapy.     

Fenretinide-dependent upregulation of death receptors through ASK1 and p38�� enhances death receptor ligand-induced cell death in Ewing's sarcoma family of tumours

Background:

Sustained p38^MAPK phosphorylation upregulates p75 neurotrophin (p75^NTR) and induces apoptosis in Ewing''s sarcoma family of tumours (ESFT). As fenretinide induces ESFT death through sustained p38^MAPK phosphorylation, we hypothesised that this may be effected through upregulation of death receptors (DRs) and that treatment of fenretinide plus DR ligands may enhance apoptosis.

Methods:

DR expression was determined by flow cytometry. Trypan blue exclusion assays, caspase-8 flow cytometry and immunoblotting for Bid were used to measure cell death.

Results:

Fenretinide upregulated cell surface expression of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors, FAS and p75^NTR, in an ASK1- and p38α-dependent manner. Cotreatment with fenretinide and DR ligands resulted in synergistic death compared with either agent alone; caspase-8 and Bid were cleaved in a time-dependent manner. Fenretinide did not increase DR expression in non-malignant cells. Furthermore, fenretinide, TRAIL or a combination of both agents was non-cytotoxic to non-malignant cells. Etoposide and actinomycin D increased expression of all DRs examined, whereas vincristine increased FAS alone. Only actinomycin D and TRAIL, and etoposide with TRAIL or FasL, enhanced death compared with either agent alone.

Conclusion:

The synergistic death observed with fenretinide and DR ligands suggests that this combination may be an attractive strategy for the treatment of ESFT.     

The relationship between vitamin D and chemotherapy-induced toxicity - a pilot study

Background:

There are anecdotal data that lower levels of vitamin D may be associated with increased levels of toxicity in individuals receiving chemotherapy; we therefore wished to investigate this further.

Methods:

From a cohort of over 11 000 individuals, we included those who had vitamin D levels (serum 1,25(OH)₂D3) measured before and during chemotherapy. They were analysed for side effects correlating Chemotherapy Toxicity Criteria with vitamin D levels, normalising data for general markers of patient health including C-reactive protein and albumin.

Results:

A total of 241 (2% of the total cohort) individuals entered the toxicity analysis. We found no overall difference in toxicity effects experienced by patients depending on whether they were vitamin D depleted or had sufficient levels (P=0.78).

Conclusion:

This pilot study suggests routine vitamin D measurement during treatment does not appear to be necessary in the management of chemotherapy-induced toxicity.     

Explorative study to identify novel candidate genes related to oxaliplatin efficacy and toxicity using a DNA repair array

Purpose:

To identify new polymorphisms (single nucleotide polymorphisms, SNPs) in DNA repair pathways that are associated with efficacy and toxicity in patients receiving oxaliplatin and capecitabine for advanced colorectal cancer (ACC).

Methods:

We studied progression-free survival (PFS) in 91 ACC patients, of whom germ-line DNA was isolated and genotyped using an Asper Biotech array. Overall survival (OS) and toxicity were studied as secondary end points. A step-wise selection of SNPs was performed, involving univariate and multivariate log-rank tests and Cox regression analysis, with age and performance status as covariates.

Results:

A total of 81 SNPs in 46 genes on the array were selected for further analysis, based on genotyping success rates and minor allele frequencies. After step-wise selection, we found that homozygosity for the ataxia telangiectasia mutated gene (ATM) rs1801516 or excision repair cross-complementing gene (ERCC5) rs1047768 SNPs was associated with shorter PFS; however there were no significant associations (P>0.01) with OS or toxicity.

Discussion:

This is the first study describing the pathway gene approach for the selection of new candidate genes involved in oxaliplatin efficacy and toxicity. The results suggest that the ATM and ERCC5 genes may be associated with oxaliplatin efficacy in ACC.