Fixed-dose rate gemcitabine alone or alternating with FOLFIRI.3 (irinotecan,leucovorin and fluorouracil) in the first-line treatment of patients with metastatic pancreatic adenocarcinoma: An AGEO randomised phase II study (FIRGEM)

BackgroundFluorouracil and irinotecan-based, and gemcitabine-based regimens, are the standard of care in the first-line treatment of patients with metastatic pancreatic cancer. New approaches are needed to improve survival and quality of life. Whether a sequential approach alternating irinotecan, fluorouracil and gemcitabine may be effective and tolerable in patients with metastatic pancreatic cancer is unknown.MethodsIn this randomised, multicentre, open-label, phase 2 trial, patients with metastatic pancreatic adenocarcinoma, World Health Organisation (WHO) performance status 0–1, and bilirubin levels <1.5 upper limit of normal values (ULN) were randomised 1:1 to receive as first-line treatment either FOLFIRI.3 (irinotecan, leucovorin and fluorouracil) alternating with fixed-dose rate gemcitabine as 2-month periods (FIRGEM, arm A), or fixed-dose rate gemcitabine alone (arm B). Treatment was continued until disease progression or limiting toxicity. The primary end-point was the crude progression-free survival (PFS) rate at 6 months. The study is registered with EudraCT (N° 2006-005703-34).ResultsBetween October 2007 and March 2011, 98 patients were enroled. The observed 6-month PFS rate was 43.5% (95% confidence interval (CI), [28.6–58.4%]) in arm A reaching the Fleming decision rules criteria to reject H0 and 26.1% (95% CI [12.9–39.3%]) in arm B.Objective response rates were 37% (23–51%) in arm A and 10% (1–19%) in arm B. Median PFS (5.0 versus 3.4 months, hazard ratio (HR) = 0.59 [0.38–0.90]) and overall survival (11.0 versus 8.2 months, HR = 0.71 [0.46–1.10]) were higher in arm A compared to arm B. The most frequent grade 3–4 toxicities were neutropenia (49%/24%; febrile neutropenia, 4%/0% in arms A/B), diarrhoea (arm A, 12% and arm B, 0%), and nausea/vomiting (8%/4%). No toxic deaths occurred.ConclusionThe FIRGEM strategy appears to be effective and feasible in patients with metastatic pancreatic cancer.     

A prospective randomised phase-II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer: A study of the CESAR Central European Society for Anticancer Drug Research–EWIV

BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours and is still associated with a poor prognosis in advanced disease. To improve the standard therapy with gemcitabine, we initiated a prospective randomised phase-II trial with gemcitabine (GEM) versus gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. The rational of adding sunitinib was its putative antiangiogenic mechanism of action.MethodsA total of 106 eligible patients with locally advanced, unresectable or metastatic PDAC without previous system therapy were randomised to receive GEM at a dosage of 1.000 mg/m² d1, 8, 15 q28 versus a combination of SUNGEM at a dosage of GEM 1.000 mg/m² d1 + 8 and sunitinib 50 mg p.o. d1–14, q21d. The primary end-point was progression free survival (PFS), secondary end-points were overall survival (OS), toxicity and overall response rate (ORR).ResultsThe confirmatory analysis of PFS was based on the intend-to-treat (ITT) population (N = 106). The median PFS was 13.3 weeks (95% confidence interval (95%-CI): 10.4–18.1 weeks) for GEM and 11.6 weeks for SUNGEM (95%-CI: 7.0–18.0 weeks; p = 0.78 one-sided log-rank). The ORR was 6.1% (95%-CI: 0.7–20.2%) for GEM and for 7.1% (95%-CI: 0.9–23.5%) for SUNGEM (p = 0.87). The median time to progression (TTP) was 14.0 weeks (95%-CI: 12.4–22.3 weeks) for GEM and 18.0 weeks (95%-CI: 11.3–19.3 weeks) for SUNGEM (p = 0.60; two-sided log-rank). The median OS was 36.7 weeks (95%-CI: 20.6–49.0 weeks) for the GEM arm and 30.4 weeks (95%-CI: 18.1–37.6 weeks) for the SUNGEM (p = 0.78, one-sided log-rank). In regard to toxicities, suspected SAEs were reported in 53.7% in the GEM arm and 71.2% in the SUNGEM arm. Grade 3 and 4 neutropenia was statistically significantly higher in the SUNGEM arm with 48.1% versus 27.8% in the GEM arm (p = 0.045, two sided log-rank).ConclusionsThe combination SUNGEM was not sufficient superior in locally advanced or metastatic PDAC compared to GEM alone in regard to efficacy but was associated with more toxicity.     

Randomised,placebo-controlled,double-blind,parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer

BackgroundThis phase III study investigated the addition of aflibercept to gemcitabine, in patients with advanced pancreatic cancer.Patients and methodsPatients with metastatic pancreatic cancer were randomly assigned to receive either intravenous (i.v.) aflibercept, 4 mg/kg every 2 weeks, or matching placebo combined with gemcitabine, 1000 mg/m² i.v. weekly for 7 weeks out of 8, then weekly for 3 weeks out of 4 until progressive disease, unacceptable toxicity or withdrawal of consent. The primary objective was to demonstrate an improvement in overall survival (OS) between the treatment arms.ResultsThe study was stopped for futility following a planned interim analysis of OS in 427 randomised patients. With a median follow-up of 7.9 months, based on the 546 patients at study termination, median OS was 7.8 months in the gemcitabine plus placebo arm (n = 275) versus 6.5 months in the gemcitabine plus aflibercept arm (n = 271), which was not significant (hazard ratio 1.165, 95% confidence interval (CI) 0.921–1.473, p = 0.2034). Median progression-free survival was 3.7 months in both arms. Treatment discontinuations due to adverse events were more frequent in the aflibercept than in the placebo-containing arm (23% versus 12%).ConclusionAdding aflibercept to gemcitabine did not improve OS in patients with metastatic pancreatic cancer.     

A phase IIb multicentre study comparing the efficacy of trabectedin to doxorubicin in patients with advanced or metastatic untreated soft tissue sarcoma: The TRUSTS trial

PurposeTo evaluate whether trabectedin as first-line chemotherapy for advanced/metastatic soft tissue sarcoma prolongs progression-free survival (PFS), compared to doxorubicin and, in the phase IIb part here, to select the most appropriate trabectedin treatment schedule (3-hour or 24-hour infusion) in terms of safety, convenience and efficacy.Patients and methodsIn this randomised multicentre prospective dose-selection phase IIb superiority trial, 133 patients were randomised between doxorubicin (n = 43), trabectedin (3-hour infusion, T3h) (n = 47) and trabectedin (24-hour infusion, T24h) (n = 43). PFS was defined as time from random assignment until objective progression by response evaluation criteria in solid tumours (RECIST 1.1), a global deterioration of the health status requiring discontinuation of the treatment, or death from any cause.ResultsThe study was terminated due to lack of superiority in both trabectedin treatment arms as compared to the doxorubicin control arm. Median PFS was 2.8 months in the T3h arm, 3.1 months in the T24h arm and 5.5 months in the doxorubicin arm. No significant improvements in PFS were observed in the trabectedin arms as compared to the doxorubicin arm (T24h versus doxorubicin: hazard ratio (HR) 1.13, 95% confidence interval (CI) 0.67–1.90, P = .675; T3h versus doxorubicin: HR 1.50, 95% CI 0.91–2.48, P = .944). Only one toxic death occurred in the T3h arm, but treatment had to be stopped due to toxicity in 7 (15.2%) (T3h), 8 (19.5%) (T24h) and 1 (2.5%) doxorubicin patients.ConclusionDoxorubicin continues to be the standard treatment in eligible patients with advanced/metastatic soft-tissue sarcoma (STS). Trabectedin 1.5 mg/m²/24-hour infusion is the overall proven approach to delivering this agent in the second-line setting for patients with advanced or metastatic STS.     

An indirect comparison of the toxicity of sunitinib and pazopanib in metastatic clear cell renal cancer

BackgroundBoth sunitinib and pazopanib are widely used as first line therapy in metastatic renal cancer (mRCC). The efficacy of these agents appears similar but they may have distinct toxicity profiles. In this study we compare the severity of symptomatic and asymptomatic toxicity associated with sunitinib and pazopanib.MethodsTwo sequential prospective single arm phase II studies investigated either 12 weeks of sunitinib (n = 43) or pazopanib (n = 34) prior to nephrectomy in untreated mRCC. Toxicity was defined as either symptomatic (hand and foot syndrome, mucositis, nausea, fatigue, diarrhoea, oedema, headache, pain, anorexia and change in taste) or asymptomatic (liver toxicity or haematological toxicity). Pazopanib (800 mg once daily (OD)) and sunitinib (50 mg 4/2) were given. Regular Common Toxicity Criteria (CTC) toxicity assessment was performed during the first 12 weeks of therapy.ResultsThere was no significant difference in the overall number of toxic events (grade 1–4) for sunitinib and pazopanib (mean number of toxic events/patients: 1.97 versus 1.96: p > 0.05). Increased grade 2–4 symptomatic toxicity events occurred with sunitinib (hazard ratio (HR) 1.67 [95% confidence interval (CI): 1.11–2.56] p < 0.03). Sunitinib was associated with an increased grade 2–4 mucositis (16% versus 0% p = 0.02) and fatigue (42% versus 15% p = 0.01). Pazopanib was associated with more frequent grade 1 diarrhoea (39% versus 12%: p = 0.03). Dose reductions for symptomatic toxicity occurred more frequently with sunitinib (26% versus 6% p < 0.05). There was no difference in the occurrence of asymptomatic toxicity.ConclusionThis indirect analysis suggests sunitinib and pazopanib have distinct toxicity profiles which may help guide patient’s choice. Further comparative data from randomised trials are awaited.     

Human equilibrative nucleoside transporter 1 is not predictive for gemcitabine efficacy in advanced pancreatic cancer: Translational results from the AIO-PK0104 phase III study with the clone SP120 rabbit antibody

BackgroundThe role of human equilibrative nucleoside transporter 1 (hENT1) as a predictive biomarker for gemcitabine efficacy in advanced pancreatic cancer remains unclear to date.Patients and methodsAIO-PK0104 was a German multicenter phase III trial comparing gemcitabine/erlotinib followed by capecitabine (GEC) with capecitabine/erlotinib followed by gemcitabine (CEG) in advanced pancreatic cancer. Archival tumour tissue from 169 of the 274 eligible study patients was available for a central and standardised immunohistochemistry staining for hENT1 expression using the SP120 rabbit monoclonal anti-hENT1 antibody. Within a retrospective translational subgroup analysis, biomarker data were correlated with efficacy end-points.ResultsThirty-nine out of 130 fresh-cut slides were scored as hENT1^high (30%), whereas 91 samples were classified as hENT1^low (70%). For the 62 patients randomised to CEG median overall survival was estimated with 6.4 months in the hENT1^low compared to 6.9 months in the hENT1^high subgroup (Hazard Ratio (HR) 0.88, 95% confidence interval (CI) 0.48–1.61, p = 0.67). For the 68 patients randomised to GEC survival was 5.7 months in the hENT1^low compared to 4.4 months in the hENT1^high subgroup (HR 1.16, 95% CI 0.69–1.96, p = 0.57). In 101 patients receiving gemcitabine at any time during study treatment (either within the 1st- or 2nd-line setting) hENT1^low cases had a median overall survival of 7.5 months and hENT1^high patients an overall survival of 4.4 months (HR 1.30, 95% CI 0.84–2.03, p = 0.24), respectively.ConclusionWithin this subgroup analysis from Arbeitsgemeinschaft Internistische Onkologie-pancreatic cancer (AIO-PK0104), no evidence supporting the use of hENT1 as a predictive biomarker for gemcitabine efficacy in patients with advanced pancreatic cancer was found.     

Reaching women who do not participate in the regular cervical cancer screening programme by offering self-sampling kits: A systematic review and meta-analysis of randomised trials

IntroductionPopulation coverage for cervical cancer screening is an important determinant explaining differences in the incidence of cervical cancer between countries. Offering devices for self-sampling has the potential to increase participation of hard-to-reach women.MethodsA systematic review and meta-analysis were performed to evaluate the participation after an invitation including a self-sampling device (self-sampling arm) versus an invitation to have a sample taken by a health professional (control arm), sent to under-screened women.ResultsSixteen randomised studies were found eligible. In an intention-to-treat analysis, the pooled participation in the self-sampling arm was 23.6% (95% confidence interval (CI) = 20.2–27.3%), when self-sampling kits were sent by mail to all women, versus 10.3% (95% CI = 6.2–15.2%) in the control arm (participation difference: 12.6% [95% CI = 9.3–15.9]). When women had to opt-in to receive the self-sampling device, as used in three studies, the pooled participation was not higher in the self-sampling compared to the control arm (participation difference: 0.2% [95% CI = −4.5–4.9%]).ConclusionAn increased participation was observed in the self-sampling arm compared to the control arm, if self-sampling kits were sent directly to women at their home address. However, the size of the effect varied substantially among studies. Since participation was similar in both arms when women had to opt-in, future studies are warranted to discern opt-in scenarios that are most acceptable to women.     

Randomised phase II trial of photodynamic therapy plus oral fluoropyrimidine,S-1, versus photodynamic therapy alone for unresectable hilar cholangiocarcinoma

BackgroundHilar cholangiocarcinoma is an uncommon cancer and its overall incidence is increasing. Photodynamic therapy (PDT) has been proposed as palliative management for unresectable hilar cholangiocarcinoma (UHC). To date, little is known about the role of the addition of systemic chemotherapy to PDT for UHC. We performed a prospective, randomised, phase II trial to compare PDT plus S-1 and PDT alone for UHC.MethodsPatients with UHC were randomly assigned (in a 1:1 ratio) to PDT plus S-1 or PDT alone. The primary end-point was overall survival. The secondary end-points were progression-free survival, complications, re-intervention rate and quality of life. This trial is registered with clinicalTrials.gov, number NCT00869635.FindingsBetween February 2009 and May 2012, we randomly assigned 21 patients to receive PDT plus S-1 and 22 to receive PDT alone. The UHC patients treated with PDT plus S-1 showed higher 1-year survival rate compared with the patients treated with PDT alone (76.2% versus 32%, P = 0.003) and prolonged overall survival (median 17 months, 95% confidence interval [CI]: 12.6–21.4, versus 8 months, 95% CI: 6–10, P = 0.005, hazard ratio [HR], 0.36; 95% CI: 0.17–0.75). Regarding the secondary end-points, PDT plus S-1 was associated with prolonged progression-free survival compared with PDT alone (median 10 months [95% CI: 4.1–16] versus 2 months [95% CI: 0.4–3.5], P = 0.009 (HR for progression 0.39, 95% CI: 0.19–0.83). There were no differences in the number of PDT sessions, the frequency of cholangitis, overall adverse events or the quality of life in either group.InterpretationsPDT plus S-1 was well tolerated and was associated with a significant improvement of overall survival and progression-free survival compared with PDT alone in patients with UHC. These findings warrant further clinical investigation of PDT plus S-1 in patients with UHC.     

Role of cardioprotective therapy for prevention of cardiotoxicity with chemotherapy: A systematic review and meta-analysis

BackgroundCardiotoxicity is a well-recognised complication of chemotherapy with anthracycline and/or trastuzumab, and its prevention remains an important challenge in cancer survivorship. Several successful preventative strategies have been identified in animal trials. We sought to assemble the clinical evidence that prophylactic pharmacological interventions could prevent left ventricular (LV) dysfunction and heart failure in patients undergoing chemotherapy.MethodsWe undertook a systemic review of the evidence from randomised trials and observational studies where a prophylactic intervention was compared with a control arm in patients with a normal ejection fraction and no past history of heart failure. The primary outcome was development of heart failure (HF), a drop in ejection fraction (EF) or both. A random-effects model was used to combine relative risks (RR) and 95% confidence intervals (CIs), and a meta-regression was undertaken to assess the impact of potential covariates.FindingsData were collated from 14 published articles (n = 2015 paediatric and adult patients) comprising 12 randomised controlled trials and two observational studies. The most studied chemotherapeutic agents were anthracyclines, and prophylactic agents included dexrazoxane, statins, beta-blocker and angiotensin antagonists. There were 304 cardiac events in the control arm compared to 83 in the prophylaxis arm (RR = 0.31 [95% CI: 0.25–0.39], p < 0.00001). Cardiac events were reduced with dexrazoxane (RR = 0.35 [95% CI 0.27–0.45], p < 0.00001), beta-blockade (RR = 0.31 [95% CI 0.16–0.63], p = 0.001), statin (RR = 0.31 [95% CI 0.13–0.77], p = 0.01) and angiotensin antagonists (RR = 0.11 [95% CI 0.04–0.29], p < 0.0001).InterpretationProphylactic treatment with dexrazoxane, beta-blocker, statin or angiotensin antagonists appear to have similar efficacy for reducing cardiotoxicity.     

Cardiovascular toxicity following sunitinib therapy in metastatic renal cell carcinoma: a multicenter analysis

BackgroundRecent data have shown that cardiotoxicity represents a potentially important side-effect in patients treated with sunitinib. We reviewed cardiac adverse events in patients with metastatic renal cell carcinoma (RCC) who underwent treatment with this agent.Patients and methodsThe medical records of 175 patients with metastatic RCC treated with sunitinib at eight Italian institutions were retrospectively reviewed. Alterations in left ventricular ejection fraction (LVEF) and blood pressure were evaluated. Patients with preexisting cardiac risk factors were specifically scrutinized for increased expression of cardiac changes.ResultsGrade 3 hypertension was seen in 17 patients (9.7%); in 12 of these 17, hypertension developed after receiving the third sunitinib cycle. Among these 17 patients, 12 (70.6%) also experienced left ventricular systolic (LVEF) dysfunction; in all, 33 of the 175 patients (18.9%) developed some degree of cardiac abnormality, of which 12 were classified as grade 3 LVEF dysfunction and/or congestive heart failure (CHF) (6.9%). Significant univariate associations for predictors of CHF were history of hypertension (P = 0.008), history of coronary heart disease (P = 0.0005) and prior treatment with an angiotensin-converting enzyme inhibitor (P = 0.04). Multivariate analysis suggested that a history of coronary artery disease [odds ratio (OR) 18, 95% confidence interval (CI) 4–160, P = 0.005] and hypertension (OR 3, 95% CI 1.5–80, P = 0.04) was the only significant independent predictors of CHF.ConclusionsPatients undergoing sunitinib, especially those with a previous history of hypertension and coronary heart disease, are at increased risk for cardiovascular events and should be monitored for exacerbations of their hypertension and for evidence of LVEF dysfunction during treatment.     

Viscum album [L.] extract therapy in patients with locally advanced or metastatic pancreatic cancer: A randomised clinical trial on overall survival

BackgroundThe unfavourable side-effects of late-stage pancreatic cancer treatments call for non-toxic and effective therapeutic approaches. We compared the overall survival (OS) of patients receiving an extract of Viscum album [L.] (VaL) or no antineoplastic therapy.MethodsThis is a prospective, parallel, open label, monocentre, group-sequential, randomised phase III study. Patients with locally advanced or metastatic cancer of the pancreas were stratified according to a binary prognosis index, composed of tumour stage, age and performance status; and were evenly randomised to subcutaneous injections of VaL extracts or no antineoplastic therapy (control). VaL was applied in a dose-escalating manner from 0.01 mg up to 10 mg three times per week. Patients in both groups received best supportive care. The primary end-point was 12-month OS, assessed in a group-sequential analysis.FindingsWe present the first interim analysis, including data from 220 patients. Baseline characteristics were well balanced between the study arms. Median OS was 4.8 for VaL and 2.7 months for control patients (prognosis-adjusted hazard ratio, HR = 0.49; p < 0.0001). Within the ‘good’ prognosis subgroup, median OS was 6.6 versus 3.2 months (HR = 0.43; p < 0.0001), within the ‘poor’ prognosis subgroup, it was 3.4 versus 2.0 months respectively (HR = 0.55; p = 0.0031). No VaL-related adverse events were observed.ConclusionVaL therapy showed a significant and clinically relevant prolongation of OS. The study findings suggest VaL to be a non-toxic and effective second-line therapy that offers a prolongation of OS as well as less disease-related symptoms for patients with locally advanced or metastatic pancreatic cancer.     

Cigarette smoking and pancreatic cancer risk: More to the story than just pack-years

PurposeCigarette smoking is an established risk factor for pancreatic adenocarcinoma. However, few studies have thoroughly investigated the effects of independent smoking dimensions (duration, intensity, cumulative dose and time since quitting) on risk estimates. We analysed data from the Queensland Pancreatic Cancer Study (QPCS), an Australian population-based case-control study, with the aim of determining which smoking component is primarily important to pancreatic cancer risk.MethodsOur study included 705 pancreatic cancer patients and 711 controls. Logistic regression and generalised additive logistic regression (for non-linear dose effects) were used to determine odds ratios (ORs) and 95% confidence intervals (CIs).ResultsCompared to never-smokers, current smokers had an increased risk of pancreatic cancer (OR = 3.4; 95% CI 2.4–5.0) after adjustment for age, sex, education, alcohol intake and birth country. Of the various smoking dimensions, smoking duration and time since quitting had a greater effect on OR estimates (OR 1.3; 95% CI 1.1–1.4 and OR 0.8; 95% CI 0.7–0.8) than smoking intensity (OR 1.1; 95% CI 0.9–1.2), once ever-smoking was accounted for.ConclusionsThis study confirms the association between cigarette smoking and pancreatic adenocarcinoma, and provides evidence to suggest that smoking pattern, in addition to dose effect, may affect disease risk.     

Effects of erlotinib first-line maintenance therapy versus placebo on the health-related quality of life of patients with metastatic non-small-cell lung cancer

IntroductionMaintenance therapy can delay progression and prolong survival in metastatic non-small-cell lung cancer (mNSCLC). As treatment for mNSCLC is non-curative, its impact on patient health-related quality of life (HRQoL) is an important consideration. SATURN (Sequential Tarceva in Unresectable NSCLC) was a randomised, double-blind, placebo-controlled, multicentre study investigating the impact of erlotinib maintenance therapy on HRQoL in patients with locally advanced or recurrent NSCLC.Patients and MethodsEligible patients who had previously completed four cycles of platinum-based chemotherapy were randomised 1:1 to receive erlotinib 150 mg/day or placebo until disease progression, unacceptable toxicity or death. Patient HRQoL was assessed using the Functional Assessment of Cancer Therapy-Lung questionnaire, in terms of time to symptom progression (TSP), time to deterioration (TTD) in Trial Outcome Index (TOI) and TTD. Exploratory analysis was based on time to analgesia and appearance of key symptoms (pain, cough and dyspnoea).ResultsCompared with placebo, erlotinib maintenance therapy prolonged progression-free and overall survival by 41% and 23%, respectively. At baseline, HRQoL measures were comparable between the two treatment groups. Maintenance therapy with erlotinib did not impact on deterioration in HRQoL: TSP (hazard ratio [HR] = 0.91 [95% confidence interval (CI) 0.74–1.12]; n = 785), TTD in TOI (HR = 1.06 [95% CI 0.87–1.31]; n = 781) and TTD in HRQoL (HR = 0.96 [95% CI 0.79–1.16]; n = 776). Time to pain and time to analgesic use were significantly delayed in patients receiving erlotinib compared with placebo (HR = 0.61 [95% CI 0.42–0.88]; p = 0.0080 and HR = 0.66 [95% CI 0.46–0.94]; p = 0.0199, respectively). A non-significant trend towards delayed time to cough and time to dyspnoea (HR = 0.77 [95% CI 0.49–1.21] and HR = 0.75 [95% CI 0.48–1.17], respectively) was also observed.ConclusionsErlotinib maintenance therapy significantly extends progression-free survival without compromising patient HRQoL in comparison with placebo, with some improvement in symptoms.     

Prior long response to androgen deprivation predicts response to next-generation androgen receptor axis targeted drugs in castration resistant prostate cancer

BackgroundThere is an urgent need for qualified predictive biomarkers of sensitivity for the treatments used in patients with castration-resistant prostate cancer (CRPC). We attempted to identify ready-to-use clinical predictors of improved outcome in metastatic CRPC (mCRPC) patients treated with next generation androgen receptor (AR) axis targeted drugs.Patients and methodsWe reviewed a cohort of patients who received AR axis targeted drugs for CRPC at two major French cancer centres. The predictive role of several clinical, biological and radiological parameters on progression-free survival (PFS) was studied.ResultsThe study cohort consisted of 173 patients. Median duration of response to initial androgen deprivation therapy (ADT) (time to castration resistance, TTCRPC) was 17.8 months. The 50% prostate-specific antigen (PSA) response rate to AR axis targeted drugs was 16% (95% confidence interval (CI): 6–27) and 41% (95% CI: 30–47) in patients with TTCRPC of under and over 12 months respectively (p = 0.005). Median PFS was 2.8 months (95% CI: 2.1–3.9) and 5.8 (95% CI: 4.6–7.8; HR: 0.58, p = 0.002). In patients treated with post-docetaxel enzalutamide (n = 57), median PFS was 2.8 months and 8.6 months, (Hazard ratio (HR) = 3.1; 95% CI: 1.6–5.8, p = 0.0016) according to TTCRPC, whereas no difference was observed in placebo-treated patients (n = 27). The 50% PSA response rate to enzalutamide was 8% (95% CI: 0–38) and 58% (95% CI: 42–73) in patients with a TTCRPC of under and over 12 months respectively (p < 0.001).ConclusionThe previous duration of response to ADT is a predictor of sensitivity to next generation AR axis targeted drugs in patients with mCRPC.     

90Y-clivatuzumab tetraxetan with or without low-dose gemcitabine: A phase Ib study in patients with metastatic pancreatic cancer after two or more prior therapies

BackgroundFor patients with metastatic pancreatic adenocarcinoma, there are no approved or established treatments beyond the 2nd line. A Phase Ib study of fractionated radioimmunotherapy was undertaken in this setting, administering ⁹⁰Y-clivatuzumab tetraxetan (yttrium-90-radiolabelled humanised antibody targeting pancreatic adenocarcinoma mucin) with or without low radiosensitising doses of gemcitabine.MethodsFifty-eight patients with three (2–7) median prior treatments were treated on Arm A (N = 29, ⁹⁰Y-clivatuzumab tetraxetan, weekly 6.5 mCi/m² doses × 3, plus gemcitabine, weekly 200 mg/m² doses × 4 starting 1 week earlier) or Arm B (N = 29, ⁹⁰Y-clivatuzumab tetraxetan alone, weekly 6.5 mCi/m² doses × 3), repeating cycles after 4-week delays. Safety was the primary endpoint; efficacy was also evaluated.ResultsCytopaenias (predominantly transient thrombocytopenia) were the only significant toxicities. Fifty-three patients (27 Arm A, 26 Arm B, 91% overall) completed ⩾1 full treatment cycles, with 23 (12 Arm A, 11 Arm B; 40%) receiving multiple cycles, including seven (6 Arm A, 1 Arm B; 12%) given 3–9 cycles. Two patients in Arm A had partial responses by RECIST criteria. Kaplan–Meier overall survival (OS) appeared improved in Arm A versus B (hazard ratio [HR] 0.55, 95% CI: 0.29–0.86; P = 0.017, log-rank) and the median OS for Arm A versus Arm B increased to 7.9 versus 3.4 months with multiple cycles (HR 0.32, P = 0.004), including three patients in Arm A surviving >1 year.ConclusionsClinical studies of ⁹⁰Y-clivatuzumab tetraxetan combined with low-dose gemcitabine appear feasible in metastatic pancreatic cancer patients beyond 2nd line and a Phase III trial of this combination is now underway in this setting.     

A randomised phase II study of pemetrexed versus pemetrexed + erlotinib as second-line treatment for locally advanced or metastatic non-squamous non-small cell lung cancer

IntroductionPemetrexed and erlotinib have been approved as second-line monotherapy for locally advanced or metastatic non-small cell lung cancer (NSCLC). This multicentre, randomised, open-label, parallel phase II study assessed efficacy and safety of pemetrexed versus pemetrexed + erlotinib in patients with advanced non-squamous NSCLC.MethodsNSCLC stage III–IV patients who failed one prior platinum-based chemotherapy regimen, ≥1 measurable lesion by Response Evaluation Criteria in Solid Tumors, and Eastern Cooperative Oncology Group performance status ≤2 were eligible. Patients received pemetrexed 500 mg/m² with vitamin B₁₂ and folic acid q3w alone or combined with erlotinib 150 mg daily. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival (OS), time-to-treatment failure (TTTF), response and toxicity.ResultsOf 165 randomised non-squamous patients, 159 were treated (pemetrexed: 83; pemetrexed + erlotinib: 76). The median PFS (months; 95% CI) was 2.89 (1.94, 3.38) for pemetrexed versus 3.19 (2.86, 4.70) for pemetrexed + erlotinib (hazard ratio [HR] 0.63; 95% CI: (0.44, 0.90); P = 0.0047). The median OS (months; 95% CI) was 7.75 (5.29, 10.41) for pemetrexed versus 11.83 (8.18, 16.66) for pemetrexed + erlotinib (HR: 0.68; 95% CI: 0.46, 0.98; P = 0.019). The median TTTF (months: 95% CI) was 2.4 (1.74, 2.99) for pemetrexed versus 3.0 (2.23, 4.07) for pemetrexed + erlotinib (HR 0.64; 95% CI: 0.46, 0.89; P = 0.0034). One patient died in pemetrexed + erlotinib arm due to febrile neutropenia. Grades 3/4 drug-related toxicities (in ≥5% of patients) in pemetrexed/pemetrexed + erlotinib were febrile neutropenia (2.4%/10.5%), diarrhoea (1.2%/5.3%), rash (1.2%/9.2%); anaemia (6%/11.8%), leukopenia (9.6%/23.7%), neutropenia (9.6%/25.0%), and thrombocytopenia (4.8%/14.5%).ConclusionsPemetrexed + erlotinib treatment significantly improved PFS, OS and TTTF in 2nd line non-squamous NSCLC and was associated with an increase in grade 3/4 toxicities compared with pemetrexed alone.     

Statins and survival outcomes in patients with metastatic renal cell carcinoma

BackgroundA growing body of evidence has demonstrated the anti-neoplastic activity of statins. The objective of this study was to investigate the effect of statin use on survival in patients with metastatic renal cell carcinoma (mRCC) treated in the modern therapy era.Patients and methodsWe conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Statistical analyses were performed using Cox regression and the Kaplan–Meier method.ResultsWe identified 4736 patients treated with sunitinib (n = 1059), sorafenib (n = 772), axitinib (n = 896), temsirolimus (n = 457), temsirolimus + interferon (IFN)-α (n = 208), bevacizumab + temsirolimus (n = 393), bevacizumab + IFN-α (n = 391) or IFN-α (n = 560), of whom 511 were statin users. Overall, statin users demonstrated an improved overall survival (OS) compared to non-users (25.6 versus 18.9 months, adjusted hazard ratio [aHR] 0.801, 95% confidence interval [CI] 0.659–0.972, p = 0.025). When stratified by therapy type, a benefit in OS was demonstrated in statin users compared to non-users in individuals receiving therapy targeting vascular endothelial growth factor (28.4 versus 22.2 months, aHR 0.749, 95% CI 0.584–0.961, p = 0.023) or mammalian target of rapamycin (18.6 versus 14.0 months, aHR 0.657, 95% CI 0.445–0.972, p = 0.035) but not in those receiving IFN-α (15.6 versus 14.8 months, aHR 1.292, 95% CI 0.703–2.275, p = 0.410). Adverse events were similar between users and non-users.ConclusionsWe demonstrate that statin use may be associated with improved survival in patients with mRCC treated in the targeted therapy era. Statins could represent an adjunct therapy for patients with mRCC; however, this is hypothesis generating and requires prospective evaluation.     

Accelerated partial breast irradiation using intensity-modulated radiotherapy versus whole breast irradiation: 5-year survival analysis of a phase 3 randomised controlled trial

BackgroundAccelerated partial breast irradiation (APBI) has been introduced as an alternative treatment method for selected patients with early stage breast cancer (BC). Intensity-modulated radiotherapy (IMRT) has the theoretical advantage of a further increase in dose conformity compared with three-dimensional techniques, with more normal tissue sparing. The aim of this randomised trial is to compare the local recurrence and survival of APBI using the IMRT technique after breast-conserving surgery to conventional whole-breast irradiation (WBI) in early stage BC.MethodsThis study was performed at the University of Florence (Florence, Italy). Women aged more than 40 years affected by early BC, with a maximum pathological tumour size of 25 mm, were randomly assigned in a 1:1 ratio to receive either WBI or APBI using IMRT. Patients in the APBI arm received a total dose of 30 Gy to the tumour bed in five daily fractions. The WBI arm received 50 Gy in 25 fractions, followed by a boost on the tumour bed of 10 Gy in five fractions. The primary end-point was occurrence of ipsilateral breast tumour recurrences (IBTRs); the main analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT02104895.FindingsA total of 520 patients were randomised (260 to external WBI and 260 to APBI with IMRT) between March 2005 and June 2013. At a median follow-up of 5.0 years (Interquartile Range (IQR) 3.4–7.0), the IBTR rate was 1.5% (three cases) in the APBI group (95% confidence interval (CI) 0.1–3.0) and in the WBI group (three cases; 95% CI 0.0–2.8). No significant difference emerged between the two groups (log rank test p = 0.86). We identified seven deaths in the WBI group and only one in the APBI group (p = 0.057). The 5-year overall survival was 96.6% for the WBI group and 99.4% for the APBI group. The APBI group presented significantly better results considering acute (p = 0.0001), late (p = 0.004), and cosmetic outcome (p = 0.045).InterpretationTo our knowledge, this is the first randomised study using the IMRT technique for APBI delivery. No significant difference in terms of IBTR and overall survival was observed between the two arms. APBI displayed a significantly better toxicity profile.     

Non-linear dose–response relationship between cigarette smoking and pancreatic cancer risk: Evidence from a meta-analysis of 42 observational studies

BackgroundQuestion remains about the shape of the dose–response relationship between cigarette smoking and pancreatic cancer risk.MethodsRelevant studies were identified by searching PubMed, ISI Web of Science and China National Knowledge Infrastructure (CNKI) databases and by reviewing the reference lists of retrieved articles. Random-effects models were applied to estimate summary relative risks (RRs).ResultsForty-two publications were finally included. The overall meta-analysis showed evidence of non-linear association between smoking intensity and pancreatic cancer risk (P for non-linearity = 0.000). Compared with non-smokers, the summary RRs were 1.5 (95% confidence interval (CI): 1.4, 1.6) for 10 cigarettes/day, 1.9 (95% CI: 1.8, 2.0) for 20 cigarettes/day, 2.0 (95% CI: 1.9, 2.1) for 30 cigarettes/day and 2.1 (95% CI: 1.9, 2.3) for 40 cigarettes/day with marginal between-study heterogeneity (I² = 29%). Similar results were also found for smoking duration and cumulative amount of cigarettes smoked. Besides, the summary RR for former smokers reduced with increasing time since quitting smoking compared with current smokers without heterogeneity (P for non-linearity = 0.008, I² = 0%). The results of stratified analysis by study design were comparable to those of overall meta-analysis. When stratified by sex, non-linear dose–response associations were detected for all metrics of cigarette smoking in women, while linear relationships were observed for smoking duration and cumulative amount of cigarettes smoked in men except for smoking intensity.ConclusionThis meta-analysis reveals a non-linear dose–response association between cigarette smoking and pancreatic cancer risk, but it might differ between sexes.     

Randomised,double-blind trial of carboplatin and paclitaxel with daily oral cediranib or placebo in patients with advanced non-small cell lung cancer: NCIC Clinical Trials Group study BR29

IntroductionThis randomised double-blind placebo-controlled study evaluated the addition of cediranib, an inhibitor of vascular endothelial growth factor receptors 1–3, to standard carboplatin/paclitaxel chemotherapy in advanced non-small cell lung cancer.MethodsEligible patients received paclitaxel (200 mg/m²) and carboplatin (area under the concentration time curve 6) intravenously every 3 weeks. Daily oral cediranib/placebo 20 mg was commenced day 1 of cycle 1 and continued as monotherapy after completion of 4–6 cycles of chemotherapy. The primary end-point of the study was overall survival (OS). The trial would continue to full accrual if an interim analysis (IA) for progression-free survival (PFS), performed after 170 events of progression or death in the first 260 randomised patients, revealed a hazard ratio (HR) for PFS of ⩽0.70.ResultsThe trial was halted for futility at the IA (HR for PFS 0.89, 95% confidence interval [CI] 0.66–1.20, p = 0.45). A final analysis was performed on all 306 enrolled patients. The addition of cediranib increased response rate ([RR] 52% versus 34%, p = 0.001) but did not significantly improve PFS (HR 0.91, 95% CI 0.71–1.18, p = 0.49) or OS (HR 0.94, 95% CI 0.69–1.30, p = 0.72). Cediranib patients had more grade 3 hypertension, diarrhoea and anorexia.ConclusionsThe addition of cediranib 20 mg daily to carboplatin/paclitaxel chemotherapy increased RR and toxicity, but not survival.