To predict progression-free survival and overall survival in metastatic renal cancer treated with sorafenib: pilot study using dynamic contrast-enhanced Doppler ultrasound

IntroductionThe objective of this study was to evaluate dynamic contrast-enhanced Doppler ultrasound (DCE-US) with perfusion software (Vascular Recognition Imaging) and contrast agent injection as a predictor of tumour response, progression-free survival (PFS) and overall survival (OS).Patients and methodsThirty patients with a metastatic renal cell carcinoma (RCC) already enrolled in a double-blind randomised study were evaluated. Examinations were performed at baseline, and after 3 and 6 weeks on sorafenib or a placebo in patients with tumour targets that were accessible to DCE-US.ResultsA total of 85 examinations were performed, 30 at baseline, 28 at 3 weeks and 27 at 6 weeks. The combination of a decrease in contrast uptake exceeding 10% and stability or a decrease in tumour volume allowed us to discriminate seven good responders and 20 poor responders at 3 weeks. There was a statistically significant difference in PFS (p = 10⁻⁴) and OS (p = 10⁻⁴) between good and poor responders.ConclusionDCE-US is a new noninvasive imaging technique which might be an effective tool for evaluating antiangiogenic drugs in renal cancer.     

The association of pre-treatment neutrophil to lymphocyte ratio with response rate, progression free survival and overall survival of patients treated with sunitinib for metastatic renal cell carcinoma

BackgroundSunitinib is a standard treatment for metastatic renal cell carcinoma (mRCC). The neutrophil to lymphocyte ratio (NLR), an index of systemic inflammation, is associated with outcome in several cancer types.AimsTo study the association of pre-treatment neutrophil to lymphocyte ratio with response rate, progression free survival (PFS) and overall survival (OS) of patients treated with sunitinib for mRCC.MethodsWe retrospectively studied an unselected cohort of patients with mRCC, who were treated with sunitinib. Logistic regression model was used to analyse response rate. Cox regression models were fitted to identify risk factors associated with PFS and OS. We investigated how pre-treatment NLR is associated with these clinical outcomes after adjusting for confounding covariates. Regression tree for censored data method was used to find the best NLR cut-off value.ResultsBetween 2004 and 2011, 133 patients with mRCC were treated with sunitinib. One hundred and nine were included in the NLR analysis, from which were excluded patients without available data on pre-treatment NLR or with comorbidities/recent treatments known to be associated with a change of blood counts. Factors associated with PFS were low NLR ⩽ 3 (HR = 0.285, p < 0.001), past nephrectomy (HR = 0.38, p = 0.035), sunitinib dose reduction/treatment interruption (HR = 0.6, p = 0.014) and the use of antiotensin system inhibitors (HR = 0.537, p = 0.008). Low NLR ⩽ 3 was associated with OS (HR = 0.3, p = 0.043).ConclusionsIn patients with mRCC treated with sunitinib, pre-treatment NLR may be associated with PFS and OS. This should be investigated prospectively, and if validated applied in clinical practice and clinical trials.     

Sorafenib and sunitinib for elderly patients with renal cell carcinoma

BackgroundSunitinib and sorafenib are small-molecule tyrosine kinase inhibitors with known antitumor activity in advanced renal cell carcinoma.Materials and MethodsWe retrospectively assess the response and tolerance of elderly patients with renal cell carcinoma to these two agents. Data of patients aged ≥ 70 years receiving sorafenib or sunitinib at the Centre Léon Bérard were analyzed. Forty-eight patients received sorafenib or sunitinib as a first line treatment, 8 received sorafenib followed by sunitinib and 4 received the reverse sequence. Objective responses (ORs), stable disease (SD), toxicity, overall survival (OS) and progression-free survival (PFS) were reported.ResultsSorafenib and sunitinib achieved similar OR + SD rates (79% vs. 71% respectively). Median PFS was 6 months in first-line sorafenib treated patients and 5 months in the sunitinib group. Median OS was 16 months in first-line sorafenib-treated patients and 15 months in the sunitinib group. In patients receiving sorafenib followed by sunitinib, median PFS was 11.5 months, and median OS was 13.1 months. With the reverse sequence, median PFS was 8.1 months and median OS was 15 months. Treatment modifications were more frequent in sunitinib-treated patients, in first or second line (75% vs. 50%). Limitations are the retrospective design of the study and the small number of patients.ConclusionFirst-line sunitinib and sorafenib seem equally efficient in elderly patients treated for advanced renal carcinomas, but sunitinib is less well tolerated. Sequential treatment with sorafenib followed by sunitinib seems to be better tolerated. These results should be confirmed in a larger prospective study.     

Bisphosphonates combined with sunitinib may improve the response rate, progression free survival and overall survival of patients with bone metastases from renal cell carcinoma

BackgroundBisphosphonates are used to prevent skeletal events of bone metastases, and may exhibit antitumour effects. We aimed to evaluate whether bisphosphonates can bring a response rate (RR), progression free survival (PFS) and overall survival (OS) benefit to patients with bone metastasis from renal cell carcinoma (RCC) that is treated with sunitinib.MethodsWe performed a multicentre retrospective study of patients with bone metastases from RCC that was treated with sunitinib. The effect of bisphosphonates on RR, PFS and OS was tested with adjustment for known prognostic factors using a chi-square test from contingency table and partial likelihood test from Cox regression model.ResultsBetween 2004 and 2011, 209 patients with metastatic RCC were treated with sunitinib, 76 had bone metastases, 35 bisphosphonates users and 41 non-users. The groups of bisphosphonates users and non-users were balanced regarding known prognostic factors. Objective response was partial response/stable disease 86% (n = 30) versus 71% (n = 29), and progressive disease 14% (n = 5) versus 29% (n = 12) (p = 0.125, OR 2.48) in users versus non-users, respectively. Median PFS was 15 versus 5 months (HR = 0.55, p < 0.0001), and median OS was not reached (with a median follow-up time of 45 months) versus 14 months (HR = 0.4, p = 0.029), in favour of users. In multivariate analysis of the entire patient cohort (n = 76), factors associated with PFS were bisphosphonates use (HR = 0.58, p = 0.035), and pre-treatment neutrophil to lymphocyte ratio >3 (HR = 3.5, p = 0.009). Factors associated with OS were bisphosphonates use (HR = 0.5, p = 0.008), elevated pre-treatment alkaline phosphatase (HR = 2.9, p = 0.003) and sunitinib induced HTN (HR = 0.63, p < 0.0001).ConclusionsBisphosphonates may improve the RR, PFS and OS of sunitinib treatment in RCC with bone metastases.     

Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma

BackgroundIn Japan and South Korea, transarterial chemoembolisation (TACE) is an important locoregional treatment for patients with unresectable hepatocellular carcinoma (HCC). Sorafenib, a multikinase inhibitor, has been shown effective and safe in patients with advanced HCC. This phase III trial assessed the efficacy and safety of sorafenib in Japanese and Korean patients with unresectable HCC who responded to TACE.MethodsPatients (n = 458) with unresectable HCC, Child-Pugh class A cirrhosis and ?25% tumour necrosis/shrinkage 1–3 months after 1 or 2 TACE sessions were randomised 1:1 to sorafenib 400 mg bid or placebo and treated until progression/recurrence or unacceptable toxicity. Primary end-point was time to progression/recurrence (TTP). Secondary end-point was overall survival (OS).FindingsBaseline characteristics in the two groups were similar; >50% of patients started sorafenib >9 weeks after TACE. Median TTP in the sorafenib and placebo groups was 5.4 and 3.7 months, respectively (hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.70–1.09; P = 0.252). HR (sorafenib/placebo) for OS was 1.06 (95% CI, 0.69–1.64; P = 0.790). Median daily dose of sorafenib was 386 mg, with 73% of patients having dose reductions and 91% having dose interruptions. Median administration of sorafenib and placebo was 17.1 and 20.1 weeks, respectively. No unexpected adverse events were observed.InterpretationThis trial, conducted prior to the reporting of registrational phase III trials, found that sorafenib did not significantly prolong TTP in patients who responded to TACE. This may have been due to delays in starting sorafenib after TACE and/or low daily sorafenib doses.     

Pilot trial of sunitinib therapy in patients with von Hippel-Lindau disease

BackgroundVon Hippel–Lindau (VHL) disease induces vascular neoplasms in multiple organs. We evaluated the safety and efficacy of sunitinib in VHL patients and examined the expression of candidate receptors in archived tissue.MethodsPatients with VHL were given four cycles of 50 mg sunitinib daily for 28 days, followed by 14 days off. Primary end point was toxicity. Modified RECIST were used for efficacy assessment. We evaluated 20 archival renal cell carcinomas (RCCs) and 20 hemangioblastomas (HBs) for biomarker expression levels using laser-scanning cytometry (LSC).ResultsFifteen patients were treated. Grade 3 toxicity included fatigue in five patients. Dose reductions were needed in 10 patients. Eighteen RCC and 21 HB lesions were evaluable. Six of the RCCs (33%) responded partially, versus none of the HBs (P = 0.014). LSC revealed that mean levels of phosphorylated vascular endothelial growth factor receptor-2 were lower in HB than in RCC endothelium (P = 0.003) and mean phosphorylated fibroblast growth factor receptor substrate-2 (pFRS2) levels were higher in HB (P = 0.003).ConclusionsSunitinib treatment in VHL patients showed acceptable toxicity. Significant response was observed in RCC but not in HB. Greater expression of pFRS2 in HB tissue than in RCC raises the hypothesis that treatment with fibroblast growth factor pathway-blocking agents may benefit patients with HB.     

Efficacy of sunitinib in patients with metastatic or unresectable renal cell carcinoma and renal insufficiency

AimThe aim of this retrospective, registry-based study was to analyse treatment outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib and renal insufficiency (RI).MethodsThe cohort included 790 patients treated with sunitinib between 2006 and 2013. At the start of sunitinib therapy 22, 234, and 534 patients had severe (glomerular filtration rate [GFR] <30 ml/min/1.73 m²), moderate (GFR 30–60 ml/min/1.73 m²) or mild RI/normal renal function (GFR >60 ml/min/1.73 m²), respectively.ResultsFor the three groups defined above, median progression-free survival (PFS) (95% confidence interval [CI]) was 5.3 months (0.1–18.5), 8.1 months (6.2–9.9) and 11.3 months (9.4–13.2) (p = 0.244), and median overall survival (OS) was 26.3 months (1.2–51.4), 21.2 months (13.2–29.1) and 26.3 months (22.6–29.9) (p = 0.443), respectively. The disease control rates were 45.5%, 56.4% and 59.2%, respectively (p = 0.374). No unexpected toxicity was reported in the patients with RI, but the treatment was more frequently discontinued because of adverse events and the duration of therapy was significantly shorter in these patients (p = 0.007).ConclusionsDuration of first-line targeted treatment for mRCC was significantly shorter for patients with RI, and may have translated into a trend to shorter PFS. These results highlight the need for optimal management of side-effects in patients with mRCC and RI.     

Heterogeneity of Metabolic Response to Systemic Therapy in Metastatic Breast Cancer Patients

AimThe aim of this retrospective study was to describe the intra-individual heterogeneity of the ¹⁸F-labelled fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) response among lesions in bone-dominant metastatic breast cancer patients treated with systemic therapies.Patients and methodsThe metabolic response was analysed by comparing PET/CT scans carried out before and during a new treatment phase (n = 46) in 25 bone-dominant metastatic breast cancer patients. Patients presented both bone and extra-bone metastases in 48% treatment phases. The metabolic response was analysed according to European Organization for Research and Treatment of Cancer (EORTC) criteria. A heterogeneous response was defined as the coexistence of responding and non-responding lesions within the same patient.ResultsThe lesion-based response analysis showed a heterogeneous metabolic response in 48% of treatment phases. In the subset with both bone and extra-bone metastases (n = 20), PET/CT showed discordant responses between bone and extra-bone metastases in 6/20 (30%) treatment phases. Considering all the cases included in the study, the time to progression (TTP) was longer in cases with a metabolic response compared with the cases with a metabolic non-response (P = 0.02). In cases with a PET/CT non-response, TTP seemed to be lower in those with a homogeneous non-response compared with those with a heterogeneous metabolic response (P = 0.07).ConclusionWhole-body FDG-PET allows frequent heterogeneous responses after systemic therapy to be identified in bone-dominant metastatic breast cancer patients.     

Phase I trial to investigate the safety, pharmacokinetics and efficacy of sorafenib combined with docetaxel in patients with advanced refractory solid tumours

AimThe safety, pharmacokinetics and efficacy of sorafenib plus docetaxel in patients with advanced refractory cancer were investigated in a Phase I, dose-escalation trial.MethodsTwenty-seven patients in four Cohorts received docetaxel on Day 1 (Cohorts 1 and 4: 75 mg/m²; Cohorts 2 and 3: 100 mg/m²) plus sorafenib on Days 2–19 (Cohorts 1 and 2: 200 mg twice-daily (bid); Cohorts 3 and 4: 400 mg bid) in 21-day cycles.ResultsMost common adverse events (AEs) (Grade 3–5) included neutropenia (89%), leucopaenia (81%), hand–foot skin reaction (30%) and fatigue (30%). The most common drug-related AEs leading to dose reduction/interruption or permanent discontinuation were dermatologic (41%), gastrointestinal (26%) and constitutional (22%). Coadministration of sorafenib altered the pharmacokinetics of docetaxel. On average, docetaxel area under the concentration–time curve (AUC)_0–24 increased by 5% (Cohort 1), 54% (Cohort 2), 36% (Cohort 3) and 80% (Cohort 4) with docetaxel plus sorafenib, while C_max increased by 16–32%, independent of sorafenib/docetaxel doses. Three of 25 evaluable patients (11%) had partial responses; 14 (52%) had stable disease.ConclusionDose-limiting dermatologic AEs were more common than expected for either therapy alone. A starting dose of docetaxel 75 mg/m² plus sorafenib 400 mg bid (with dose reductions for dermatological toxicities) is proposed for Phase II.     

Low body mass index and sarcopenia associated with dose-limiting toxicity of sorafenib in patients with renal cell carcinoma

BackgroundPatients with severe depletion of skeletal muscle (sarcopenia) are prone to dose-limiting toxicity (DLT) during fluoropyrimidine therapy. We hypothesized that sarcopenia may also predict toxicity of targeted therapy drugs.Materials and methodsMetastatic renal cell cancer (RCC) patients (n = 55) received sorafenib 400 mg b.i.d. Weight, height and skeletal muscle cross-sectional area at the third lumbar vertebra were measured by computed tomography (CT). Toxicity was assessed.ResultsDLT occurred in 22% of patients overall, of which three-quarters were dose reductions to 400 mg and the remainder entailed termination of treatment. DLT was most common (41%) in sarcopenic patients whose body mass index (BMI) was <25 kg/m² and least common (13%) in patients who were not sarcopenic and/or overweight or obese (P = 0.03). Toxicity was especially prevalent in sarcopenic male patients with BMI < 25, with 71% of men with these characteristics being unable to continue treatment at 800 mg/day. By contrast, only 5% of male patients whose muscle index was above the cut-off for sarcopenia and only 11% of male patients whose BMI was >25 experienced a DLT.ConclusionBMI < 25 kg/m² with diminished muscle mass is a significant predictor of toxicity in metastatic RCC patients treated with sorafenib.     

What are the Gastrointestinal Endoscopic Requirements of a Cancer Centre?

AimsTo describe the elective endoscopy requirements of a cancer centre.Materials and methodsA prospective register of all patients referred from a cancer centre to our unit over a period of 1 year was maintained. Emergency procedures out of hours were not included.ResultsThe Endoscopic Unit at the Chelsea and Westminster Hospital provides a service to the local population of southwest London and the Fulham Road branch of the Royal Marsden Hospital. Between 1 January and 31 December 2003, 3720 new National Health Service patients with cancer were seen at the Royal Marsden Hospital; 1423 of these patients were seen at the Fulham Road branch. In the same period, the Endoscopy Unit at the Chelsea and Westminster Hospital investigated 5270 patients. Of these, 426 patients (8.1%) were referred from the Royal Marsden Hospital. In total, these patients underwent 491 procedures. Two hundred and fifty-three patients were men, with a median age of 65 years (range 22–100), and 173 were women, with a median age of 58 years (range 18–100). The diagnostic procedures carried out included colonoscopy (n = 125), upper gastrointestinal endoscopy (n = 136), flexible sigmoidoscopy (n = 90), endoscopic ultrasound (n = 24), anorectal physiology measurement (n = 5) and endoscopic retrograde cholangio-pancreatography (ERCP) (n = 1). Therapeutic procedures included ERCP (biliary stents/sphincterotomy/stone extraction) (n = 38), placement of percutaneous endoscopic gastrostomy (n = 29), balloon dilatation of oesophageal strictures (n = 25), oesophageal, gastric, duodenal or colonic stent insertion or laser therapy (n = 16), naso-jejunal tube insertion (n = 1) and banding of oesophageal varices (n = 1). All patients were treated as day cases. Four patients were admitted for observation after their investigation. All others were discharged home or back to the Royal Marsden Hospital.ConclusionsCancer centres increasingly require diagnostic, palliative and therapeutic endoscopic support as part of the acute and follow-up management of patients. Many procedures are urgent. This study suggests that a significant number of patients being managed in a cancer centre will require endoscopic intervention and the range of procedures, equipment and skills required is wide.     

Sorafenib as third- or fourth-line treatment of advanced gastrointestinal stromal tumour and pretreatment including both imatinib and sunitinib,and nilotinib: A retrospective analysis

BackgroundTyrosine kinase inhibitors (TKI) improve the outcome of patients with advanced gastrointestinal stromal tumour (GIST), but treatment failure is frequent, and prognosis then bleak. Smaller trials in this setting suggested activity for sorafenib, a multikinase inhibitor of receptor tyrosine kinases and RAF serine/threonine kinases.Patients and methodsWe retrospectively evaluated the efficacy of sorafenib, starting dose 400 mg twice daily, in a large community-based cohort of 124 patients treated in 12 European and one United States (U.S.) cancer centre. All but one patient had a WHO performance score 0–2. All had failed both imatinib and sunitinib, 68 patients nilotinib and 26 had failed investigational therapy, too.ResultsTwelve (10%) patients responded to sorafenib and 70 (57%) patients achieved disease stabilisation. Sorafenib was moderately tolerated, and toxicity reported in 56% of the patients. Rash, hand-foot-syndrome and diarrhea occurred frequently. Sorafenib dosage was reduced in a third of patients, but this did not have an impact on progression-free survival (PFS) (p = 0.15). Median PFS was 6.4 months (95% confidence interval [CI], 4.6–8.0 months) and median overall survival (OS) 13.5 months (95% CI, 10.0–21.0 months). Patients with a good performance status and those who responded to sorafenib had a significant better PFS.ConclusionWe conclude that sorafenib is active in GIST resistant to imatinib, sunitinib and nilotinib. These results warrant further investigation of sorafenib or similar molecules in GIST.     

Renal protection with magnesium subcarbonate and magnesium sulphate in patients with epithelial ovarian cancer after cisplatin and paclitaxel chemotherapy: a randomised phase II study

BackgroundThe aim of this study was to examine the effect of magnesium supplementation on nephrotoxicity accompanying standard cisplatin-based chemotherapy in patients with epithelial ovarian cancer (EOC).Patients and methodsA double-blind, placebo-controlled, randomised study was conducted in which study arm magnesium sulphate (5 g) was administered before each course of standard chemotherapy with paclitaxel (135 mg/m²/24 h) plus cisplatin (75 mg/m²) every 3 weeks in patients with EOC. Magnesium subcarbonate (500 mg), three times per day orally, was administered during the treatment intervals. The control arm was administered a placebo instead of both magnesium salts. Magnesium serum levels (sMg) and GFR markers: serum levels of creatinine (sCr), Cockroft–Gault (ClCG) and Modification Diet of Renal Disease (MDRD) formulae were recorded before each cycle, and 3 weeks after the sixth course.Results41 EOC patients were randomised and 40 were eligible. sMg varied significantly between the supplemented and placebo groups (p<0.0001). The control group showed a significantly greater decrease of GFR assessed by: sCr (p = 0.0069), ClCG (p = 0.0077) and MDRD (p = 0.032) formulae compared with the magnesium supplemented group.ConclusionsThese results demonstrate the nephroprotective effect of magnesium supplementation during chemotherapy with cisplatin.     

Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer: A double-blind placebo-controlled multicentre phase II AIO study with biomarker and serum programme

BackgroundSince sorafenib has shown activity in different tumour types and gemcitabine regimens improved the outcome for biliary tract cancer (BTC) patients, we evaluated first-line gemcitabine plus sorafenib in a double-blind phase II study.Patients and methods102 unresectable or metastatic BTC patients with histologically proven adenocarcinoma of gallbladder or intrahepatic bile ducts, Eastern Cooperative Oncology Group (ECOG) 0–2 were randomised to gemcitabine (1000 mg/m² once weekly, first 7-weeks + 1-week rest followed by once 3-weeks + 1-week rest) plus sorafenib (400 mg twice daily) or placebo. Treatment continued until progression or unacceptable toxicity. Tumour samples were prospectively stained for sorafenib targets and potential biomarkers. Serum samples (first two cycles) were measured for vascular endothelial growth factors (VEGFs), vascular endothelial growth factor receptor 2 (VEGFR-2) and stromal cell-derived factor 1 (SDF1)α by enzyme-linked immunosorbent assay (ELISA).ResultsGemcitabine plus sorafenib was generally well tolerated. Four and three patients achieved partial responses in the sorafenib and placebo groups, respectively. There was no difference in the primary end-point, median progression-free survival (PFS) for gemcitabine plus sorafenib versus gemcitabine plus placebo (3.0 versus 4.9 months, P = 0.859), and no difference for median overall survival (OS) (8.4 versus 11.2 months, P = 0.775). Patients with liver metastasis after resection of primary BTC survived longer with sorafenib (P = 0.019) compared to placebo. Patients who developed hand-foot syndrome (HFS) showed longer PFS and OS than patients without HFS. Two sorafenib targets, VEGFR-2 and c-kit, were not expressed in BTC samples. VEGFR-3 and Hif1α were associated with lymph node metastases and T stage. Absence of PDGFRβ expression correlated with longer PFS.ConclusionThe addition of sorafenib to gemcitabine did not demonstrate improved efficacy in advanced BTC patients. Biomarker subgroup analysis suggested that some patients might benefit from combined treatment.     

Mitomycin C with continuous fluorouracil or with cisplatin in combination with radiotherapy for locally advanced anal cancer (European Organisation for Research and Treatment of Cancer phase II study 22011-40014)

PurposeTo assess the feasibility and activity of radio-chemotherapy with mitomycin C (MMC) and cisplatin (CDDP) in locally advanced squamous cell anal carcinoma with reference to radiotherapy (RT) combined with MMC and fluorouracil (5-FU).Patients and methodsPatients with measurable disease >4 cm N0 or N+ received RT (36 Gy + 2 week gap + 23.4 Gy) with either MMC/CDDP or MMC/5-FU (MMC 10 mg/m² d1 of each sequence; 5-FU 200 mg/m²/day c.i.v. daily; CDDP 25 mg/m² weekly). Forty patients/arm were needed to exclude a RECIST objective response rate (ORR), 8 weeks after treatment, of <75% (Fleming 1, α = 10%, β = 10%).ResultsThe ORR was 79.5% (31/39) (lower bound confidence interval [CI]: 68.8%) with MMC/5-FU versus 91.9% (34/ 37) (lower bound CI: 82.8%) with MMC/CDDP. In the MMC/5-FU group, two patients (5.1%) discontinued treatment due to toxicity versus 11 (29.7%) in the MMC/CDDP group. Nine grade 3 haematological events occurred with MMC/CDDP versus none with 5-FU/MMC. The rate of other toxicities did not differ. There was no toxic death. Thirty-one patients in the MMC/5-FU arm (79.5%) and 18 in the MMC/CDDP arm (48.6%) were fully compliant with the protocol treatment (p = 0.005).ConclusionsRadio-chemotherapy with MMC/CDDP seems promising as only MMC/CDDP demonstrated enough activity (RECIST ORR >75%) to be tested further in phase III trials; MMC/5-FU did not. MMC/CDDP also had an overall acceptable toxicity profile.     

A phase I study of sunitinib in combination with FOLFIRI in patients with untreated metastatic colorectal cancer

BackgroundThis study evaluated the maximum tolerated dose (MTD) of sunitinib, a multitargeted tyrosine kinase inhibitor, combined with FOLFIRI (irinotecan 180 mg/m² given over 90 min i.v. and l-leucovorin 200 mg/m² given over 120 min on day 1, followed by 5-FU 400 mg/m² bolus and then 2400 mg/m² infused over 46 h) in untreated metastatic colorectal cancer (mCRC).Patients and methodsIn this multicentre, phase I, open-label, dose-finding trial, FOLFIRI was administered every 2 weeks. Two sunitinib regimens were explored: Schedule 4/2 (4 weeks on, 2 weeks off; 37.5 and 50 mg/day) and continuous daily dosing (CDD; 37.5 and 25 mg/day). Dose-limiting toxic toxicities (DLTs) were evaluated during weeks 1–6. Efficacy was a secondary objective.ResultsThirty-seven patients were enrolled. The 37.5 mg/day Schedule 4/2 cohort had zero of six DLTs, was expanded by 15 patients and declared the MTD. The MTD was exceeded at all other sunitinib doses and schedules; DLTs included febrile neutropenia (n = 1), grade 4 neutropenia (n = 4) and grade 3 deep vein thrombosis with grade 4 neutropenia (n = 1). At the MTD, non-haematologic grade 3/4 adverse events with a frequency of >10% were diarrhoea, vomiting and lethargy, and the objective response rate was 57.9% (95% confidence interval 33.5–79.7).ConclusionsThe MTD of sunitinib combined with FOLFIRI in chemotherapy-naive mCRC was 37.5 mg/day on Schedule 4/2. CDD of sunitinib at 37.5 or 25 mg/day plus FOLFIRI was not feasible.     

Efficacy and toxicity of sunitinib in patients with metastatic renal cell carcinoma with renal insufficiency

BackgroundPatients with metastatic renal cell carcinoma (mRCC) with renal insufficiency are generally excluded from clinical trials, despite their increasing numbers. Thus, we evaluated the efficacy and toxicity of sunitinib in such patients.Patients and methodsKorean patients with mRCC with renal insufficiency who had received sunitinib as first-line treatment between January 2008 and May 2012 were included. Patient characteristics, clinical outcomes and toxicities were evaluated. Overall survival (OS) and progression-free survival (PFS) were determined according to the degree of renal impairment.ResultsThe median age of the 34 patients evaluated was 66 years, 90% had an Eastern Cooperative Oncology Group performance status of 0 or 1 and the median glomerular filtration rate was 46.5 mL min⁻¹·1.73 m⁻² (range, 21.1–59.5). The starting sunitinib dose was 37.5 and 50 mg for 12 and 22 patients, respectively. A 4-weeks-on–2-weeks-off regimen was followed for 31 patients; a 2-weeks-on–2-weeks-off regimen, for one patient; and a daily regimen, for two patients. The best response was partial response in eight patients and stable disease in 12. Median OS and PFS times were 26.3 months (95% confidence interval [CI]: 17.1–35.3) and 12.2 months (95% CI: 10.2–13.2), respectively. Common non-haematologic adverse events (AEs) were stomatitis, rash, general oedema and fatigue. The most common AEs of ⩾grade 3 severity were fatigue, neutropenia and thrombocytopenia.ConclusionsIn patients with mRCC with renal insufficiency, sunitinib was efficacious and did not cause increased toxicity. Thus, clinicians should not hesitate to treat patients with mRCC with renal insufficiency with sunitinib.     

The prognostic impact of functional imaging with (123)I-mIBG in patients with stage 4 neuroblastoma >1 year of age on a high-risk treatment protocol: results of the German Neuroblastoma Trial NB97

Aim/Purpose¹²³I-meta-iodobenzylguanidine (¹²³I-mIBG) scintigraphy is well established for staging and evaluation of response in children with high-risk neuroblastoma but its prognostic value in highly intensive first-line treatment protocols is uncertain. The presence of any ¹²³I-mIBG positive tumour tissue was correlated with event-free survival (EFS) and overall survival (OS).Patients and methodsThe prognostic impact of residual ¹²³I-mIBG uptake into the primary tumour and metastases for predicting outcome in 113 stage 4 neuroblastoma patients >1 year of the German Neuroblastoma Trial NB97 was assessed using a univariate log-rank test and multivariate Cox regression analysis.ResultsAll patients had ¹²³I-mIBG positive disease at initial staging. After four courses of induction chemotherapy, 71% of patients were still ¹²³I-mIBG positive for the primary tumour and 61% for metastases. After six courses, 39% of patients had ¹²³I-mIBG uptake by the primary tumour and 45% residual ¹²³I-mIBG positive metastatic disease. The ¹²³I-mIBG status of the primary tumour site had no bearing on outcome. Residual ¹²³I-mIBG positive metastatic disease after four (3-y-EFS 25.7 ± 5.3% versus 55.9 ± 7.6%, p = 0.009; 3-y-OS 49.8 ± 6.1% versus 65.0 ± 7.3%; p = 0.021) and after six chemotherapy cycles (3-y-EFS 27.5 ± 6.2% versus 47.4 ± 6.4%, p = 0.011; 3-y-OS 50.5 ± 7.1% vs 60.0 ± 6.4%, p = 0.031) was associated with poor outcome.ConclusionFunctional imaging with ¹²³I-mIBG scintigraphy can identify poor responders with any persistent metastatic ¹²³I-mIBG uptake who are at a high risk of disease relapse. ¹²³I-mIBG response of the primary tumour site had no bearing on outcome.     

A double-blind,randomised, placebo-controlled,phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer

BackgroundWe conducted a phase 2b, randomised, double-blind, placebo-controlled screening trial to evaluate the addition of the multikinase inhibitor sorafenib (antiproliferative/antiangiogenic) to first-line paclitaxel for human epidermal growth factor receptor 2 (HER2)-negative locally recurrent/metastatic breast cancer.MethodsPatients were randomised to paclitaxel (90 mg/m², weekly, intravenously, 3 weeks on/1 week off) plus sorafenib (400 mg, orally, twice daily) or placebo. The primary endpoint was progression-free survival (PFS). A sample size of 220 patients was planned with relative risk ?0.82 (1-sided α = 0.14) after 120 events supporting a treatment effect.FindingsPatients were randomised in India (n = 170), the United States (n = 52) and Brazil (n = 15). Median PFS was 6.9 months for sorafenib versus 5.6 months for placebo (hazard ratio (HR) = 0.788; 95% confidence interval (CI), 0.558–1.112; P = 0.1715 [1-sided P = 0.0857]). The addition of sorafenib increased time to progression (median, 8.1 versus 5.6 months; HR = 0.674; 95% CI 0.465–0.975; P = 0.0343) and improved overall response (67% versus 54%; P = 0.0468). Overall survival did not statistically differ (median, 16.8 versus 17.4 months; HR = 1.022; 95% CI 0.715–1.461; P = 0.904). Grade 3/4 toxicities (sorafenib versus placebo) included hand-foot skin reaction (31% versus 3%), neutropenia (13% versus 7%) and anaemia (11% versus 6%). Two treatment-related deaths occurred (malaria and liver dysfunction) in the sorafenib arm.InterpretationThe addition of sorafenib to paclitaxel improved disease control but did not significantly improve PFS to support a phase 3 trial of similar design. Toxicity of the combination was manageable with dose reductions.FundingNorthwestern University, Onyx Pharmaceuticals, Bayer Healthcare Pharmaceuticals.