Phase II Trial of Fulvestrant With Metronomic Capecitabine for Postmenopausal Women With Hormone Receptor-Positive,HER2-Negative Metastatic Breast Cancer

BackgroundIn this phase II study, we explored efficacy and toxicity of combined endocrine and low-dose metronomic chemotherapy therapy consisting of fulvestrant and capecitabine in estrogen and/or progesterone receptor-positive, HER2-negative MBC.Patients and MethodsPatients with ≤ 1 previous hormonal treatment in the metastatic setting received an injection fulvestrant loading dose 500 mg on day 1, 250 mg on days 15 and 29 followed by 250 mg every 28 days along with continuous oral capecitabine in divided doses. The total fixed daily dose of capecitabine was either 1500 mg or 2000 mg, depending on the patient’s weight (< 80 kg vs. ≥ 80 kg). Primary end points were PFS and TTP. Toxicity was assessed by continuous evaluations of treatment-emergent adverse events (AEs) and changes from baseline in laboratory values.ResultsForty-one women, with a mean age of 64.5 years, were enrolled. Patients completed a median of 11 monthly treatment cycles. Median PFS was 14.98 months (95% confidence interval [CI], 7.26-upper limit [UL] not estimated) and median TTP was 26.94 months (95% CI, 7.26-UL not estimated). Median overall survival was 28.65 months (95% CI, 23.95-UL not estimated). Treatment was well tolerated with < 10% Grade 3 palmar-plantar erythrodysesthesia. Overall, the most frequent AEs were palmar-plantar erythrodysesthesia, fatigue, and nausea.ConclusionFulvestrant with metronomic capecitabine demonstrates substantial activity in hormone receptor-positive MBC and is well tolerated. Combined chemoendocrine approaches should be further explored considering the low toxicity of the combination with meaningful TTP.     

Sorafenib in patients with progressed and refractory bone tumors

Patients with metastatic, progressive, or recurrent bone tumors have a dismal outcome. Sorafenib has been proposed as an effective salvage regimen for some malignancies. Thus, we sought to evaluate this approach for young patients with relapsed or refractory bone tumors. Twelve patients with refractory bone tumors (two with Ewing sarcoma, two with chondrosarcoma, and eight with osteosarcoma) received salvage treatment with sorafenib. All patients had standard tumor imaging and laboratory evaluation. All toxicities were documented. At the time of the beginning of sorafenib treatment median age among 12 patients was 18 years (range 4.1–27.9 years), eight were male, and eight had osteosarcoma. All received sorafenib because of relapse. Seven patients were treated parallel to other standard chemotherapy. Overall response rate was 75%. Median time to sorafenib time to progression for patients with osteosarcoma was 4 months (range 1.8–7.9 months). Four patients (33%) are alive, in that two with no evidence of disease with a median follow-up of 41 months (range 26.5–60.9 months). The estimated 5 year overall survival (OS) for the whole group was 64.49%. There were no serious toxicities. Sorafenib is well-tolerated in young patients with bone tumors, and particularly could be an option for patients with metastatic disease and refractory osteosarcoma. Sorafenib only allows to extend OS and different procedures are needed to achieve permanent remission. This regimen deserves further investigation in the upfront management of patients with high-risk bone tumors.     

Combining carboplatin and etoposide in docetaxel-pretreated patients with castration-resistant prostate cancer: a prospective study evaluating also neuroendocrine features

BackgroundThere is currently no standard treatment for patients with castration-resistant prostate cancer (CRPC) whose disease progresses after docetaxel-based chemotherapy. The purpose of this study was to prospectively assess the anticancer activity and tolerance of the carboplatin–etoposide combination in this setting while evaluating neuroendocrine (NE) features.Patients and methodsPatients with CRPC and metastases who experienced failure after first-line docetaxel-based chemotherapy were treated with carboplatin (area under the curve 5, day 1) and etoposide (80 mg/m²/day from days 1 to 3), repeated every 3 weeks. The association between serum chromogranin A (CgA), neuron-specific enolase (NSE), prostate-specific antigen-doubling time (PSADT), and treatment efficacy was studied.ResultsForty patients with CRPC who had received docetaxel with (n = 20) or without (n = 20) estramustine received the carboplatin–etoposide combination as second-line chemotherapy. A prostate-specific antigen (PSA) response defined as a PSA decline ≥50% was achieved in nine patients (23%). Median progression-free survival (PFS) was 2.1 months (range 0.6–9.6) and median overall survival was 19 months (range 2.1–27.7). Pain response was achieved in 15 (53%) of 28 assessable patients. Toxicity, including mainly grades 3–4 anaemia (25%) and febrile neutropenia in only 2% of patients, was manageable. Baseline CgA, NSE, or PSADT were not significant predictors for response or PFS. The PSA response rates were 18% and 31% in patients with normal and elevated serum CgA, respectively. It was 25% and 20%, respectively, in patients with normal and elevated serum NSE.ConclusionsCombining carboplatin and etoposide as second-line chemotherapy in patients with CRPC is active and well tolerated in spite of a limited PFS. Activity was observed in CRPC with and without NE features.     

Metronomic Oral Cyclophosphamide Chemotherapy Possibly Contributes to Stabilization of Disease in Patients With Metastatic Castration-Resistant Prostate Cancer: A Prospective Analysis of Consecutive Cases

Introduction/BackgroundCastration-resistant prostate cancer remains a therapeutic challenge, even after establishing the survival benefits of docetaxel chemotherapy. Metronomic chemotherapy stabilizes various cancers through antiangiogenic and immunomodulatory effects. We evaluate the activity of metronomic oral cyclophosphamide chemotherapy in metastatic CRPC patients, and assess predictive factors for clinical outcomes.Patients and MethodsTwenty-four patients with metastatic CRPC received an oral cyclophosphamide and dexamethasone regimen. Of those, 11 patients (45.8%) had been exposed and resistant to previous docetaxel chemotherapy. Six patients had refused to receive docetaxel chemotherapy, and 7 patients could not receive the therapy because of deteriorated performance status. All patients had already shown resistance to continuous dexamethasone therapy. Demographic and clinical data were collected prospectively.ResultsA total of 16 patients (66.7%) experienced a reduction in PSA levels, and PSA decrease ≥ 50% was observed in 8 patients (33.3%). The median PSA progression-free and overall survival were 5.0 months and 19.0 months, respectively. The favorable PSA decrease had no associations with the progression-free and overall survival, but 7 patients (29.2%) in whom response had exceeded 8 months achieved long overall survival of 28 months in median. None of the patients discontinued therapy because of the presence of toxicities.ConclusionMetronomic cyclophosphamide is an active and well tolerated chemotherapy and can be an option for metastatic CRPC patients. The benefit of this regimen could not always be evaluated according to a favorable PSA decrease; thus, we must identify the predictive factors of response other than known clinical factors.     

Sorafenib and bevacizumab combination targeted therapy in advanced neuroendocrine tumour: A phase II study of Spanish Neuroendocrine Tumour Group (GETNE0801)

BackgroundSorafenib and bevacizumab as single agents have shown efficacy and acceptable toxicity in NETs phase II trials. Sorafenib and bevacizumab combination has shown manageable toxicity in phase I trials in solid tumours. The purpose of this study was to evaluate the safety and efficacy of the combination of sorafenib and bevacizumab in patients with advanced neuroendocrine tumours.MethodsOpen-label, uncontrolled, multicenter, phase II clinical trial. Eligibility criteria: age ? 18 years, histologically confirmed measurable advanced NETs; 1 prior chemotherapy allowed; ECOG-PS 0–2. Patients were treated during 6 months and followed up for an additional 6 months. Treatment: sorafenib 200 mg bid (days 1–5 of each week) and bevacizumab 5 mg/kg once every 2 weeks (day 1, week 1). Tumour response was performed according to RECIST (v1.0) every 2 months during the treatment period. Adverse events were graded according to CTCAE (v3.0).Findings44 Patients enrolled, 59.1% men, median age 60 years (range 32–76). 70.5% carcinoid tumours, 29.5% pancreatic tumour. Baseline target lesions mainly in the liver (86.4%). Global PFSR was 90.9% (91.7% carcinoid tumours and 88.9% pancreatic tumours). Median PFS was 12.4 months, median TTP was 14.5 months, ORR was 9.4% and DCR was 95.1%. Most common grade 3–4 toxicities: asthenia (11.4%) and hand–foot skin reaction (15.9%).InterpretationSorafenib and bevacizumab combination showed clinical benefit but unfavourable safety results compared with drugs in monotherapy. Further development of this combination is not warranted and a sequential approach is recommended instead.     

Randomised phase II/III study of docetaxel with or without risedronate in patients with metastatic Castration Resistant Prostate Cancer (CRPC), the Netherlands Prostate Study (NePro)

BackgroundThis multicentre, randomised, open label, phase II/III study aimed to investigate the potential benefit of adding risedronate (R) to docetaxel (D) in patients with metastatic Castration Resistant Prostate Cancer (CRPC).Patients and methodsCRPC patients with bone metastasis were randomly assigned to receive D 75 mg/m² every 3 weeks and prednisone as first line chemotherapy, with or without R 30 mg oral once daily. The primary end-point was time to progression (TTP). A composite end-point of objective progression by RECIST criteria, PSA progression, or pain progression, whichever occurred first, was applied. The study had 80% power to detect an improvement of 30% in median TTP in the DR group (two-sided α = 0.05).ResultsFive hundred and ninety-two men (301 D versus 291 DR) were randomised. TTP was 7.4 [D] versus 6.5 [DR] months (p = 0.75). PSA and pain response rates were similar, 66.3% [D] versus 65.9% [DR] and 27.9% [D] versus 31.2% [DR], respectively. Median overall survival (OS) was 18.4 [D] versus 19.2 [DR] months (p = 0.33). There were no differences in toxicity.ConclusionThe addition of the third generation bisphosphonate, risedronate, in the setting of effective first line docetaxel based chemotherapy did not increase efficacy, as indicated by the lack of improvement in TTP, OS, PSA- and pain response.     

Urinary N-telopeptide (uNTx) is an independent prognostic factor for overall survival in patients with bone metastases from castration-resistant prostate cancer

BackgroundIn patients with bone metastases from castration-resistant prostate cancer (CRPC) not pretreated with a bisphosphonate elevated N-telopeptide of type I collagen (uNTx), a marker of bone resorption, predicts skeletal-related events (SRE). The aim of this study was to assess the prognostic value of uNTx for overall survival (OS) and the incidence of SRE in patients with bone metastases from CRPC receiving zoledronic acid.MethodsFrom 2004 to 2007, 94 patients with bone metastases from CRPC receiving zoledronic acid for at least 2 months were screened for uNTx.ResultsMedian age was 66 years (range 46–88). Median serum prostate-specific antigen (PSA) was 66 ng/ml (0–3984) and median uNTx was 19 nmol/mM creatinine (3–489). During follow-up, 38 patients (40%) experienced an SRE. Median OS was 20 months [95% (CI) confidence interval 15–24). In the multivariate analysis, elevated uNTx [hazard ratio (HR) 2.2 (95% CI 1.2–4.0)], serum PSA [HR 2.8 (95% CI 1.6–5.1)], and ECOG performance status were the only independent prognostic factors for OS. Median OS was 12 months (10–16) and 25 months (21–34) in patients with uNTx ≥20 nmol/mM creatinine and in those with uNTx <20 nmol/mM creatinine, respectively.ConclusionAn elevated uNTx level is an independent prognostic factor for OS in patients with bone metastases from CRPC receiving a bisphosphonate.     

Efficacy of Oxaliplatin Plus Pemetrexed in Chemotherapy Pretreated Metastatic Castration-Resistant Prostate Cancer

BackgroundAlthough new androgen-targeted therapies offer prolonged survival in metastatic castration-resistant prostate cancer (CRPC), most men still face progressive disease and require additional therapy. Oxaliplatin and pemetrexed have each shown modest activity in the treatment of CRPC. Given their favorable nonoverlapping toxicity profiles, we studied them in combination.Patients and MethodsMen with CRPC whose disease had progressed on 1 or 2 previous chemotherapy regimens, including a taxane, were eligible. All participants received oxaliplatin 120 mg/m² and pemetrexed 500 mg/m² intravenously every 21 days. The primary end point was response rate; objective responses were determined using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0, criteria and the Prostate Cancer Working Group (1999) criteria. Secondary end points included progression-free survival and OS.ResultsForty-seven men received a median of 6 cycles (range, 1-21). The overall response rate was 30% (95% confidence interval [CI], 18%-45%), including 10 men with RECIST responses of the 40 who had measurable disease (25%). Overall, 64% had a prostate-specific antigen (PSA) decline and 74% of men had clinical disease control (partial response or stable disease as their best response). Median progression-free survival was 5.8 months (95% CI, 3.8-7.6), with a median OS of 11.9 months. Six of 15 evaluable patients (40%) experienced a pain response. Nineteen patients (40%) experienced a grade 3 or 4 hematologic toxicity, and 16 (34%) experienced a grade 3 nonhematologic toxicity. One patient died while participating in the study.ConclusionCombination oxaliplatin and pemetrexed (PemOx) is an effective and tolerable second- or third-line treatment for men with CRPC.     

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.     

Efficacy and Safety of Carboplatin Plus Paclitaxel as the First-, Second-, and Third-line Chemotherapy in Men With Castration-resistant Prostate Cancer

IntroductionCarboplatin and paclitaxel (CP) had shown moderate efficacy in treating castration-resistant prostate cancer (CRPC) before standard first-line docetaxel chemotherapy became available. Currently, for patients with homology-directed repair gene defects as well as for unselected patients, platinum chemotherapy is administered after all standard treatments have been ineffective. Here, we retrospectively studied the efficacy and safety of CP administered as the first-, second-, and third-line chemotherapy in patients with CRPC.Patients and MethodsA retrospective chart review was performed for 58 patients with CRPC who received CP between 2001 and 2018 in a single institution. Twenty-seven patients received CP as the first-line chemotherapy, 21 as the second-line after docetaxel, and 10 as the third-line after docetaxel and cabazitaxel. Prostate-specific antigen (PSA) responses (> 50% decline of PSA from baseline), progression-free survival, overall survival, and adverse events were examined.ResultsPSA responses at any time were 55.6%, 19.0%, and 10.0%; PSA responses at 12 weeks were 48.1%, 14.3%, and 10.0%; the median progression-free survival was 3, 1, and 1 month; and the median overall survival was 19, 11, and 6 months, respectively, for the first-, second-, and third-line settings. The only patient who achieved exceptional and durable PSA response in the third-line setting had a deleterious germline BRCA2 mutation (5645C>A). The adverse event profile was favorable.ConclusionCP shows moderate efficacy against CRPC in the first-line setting, but shows little effect in the third-line setting. CP after docetaxel and cabazitaxel may be recommended in selected patients with CRPC with homology-directed repair gene defects.     

Multicenter phase II study of trabectedin in patients with metastatic castration-resistant prostate cancer

BackgroundThis multicenter phase II trial evaluated the efficacy and safety of trabectedin in metastatic castration-resistant prostate cancer (CRPC).Patients and methodsTwo schedules were evaluated in three cohorts: weekly as 3-h i.v. infusion at 0.58 mg/m² for 3 out of 4 weeks (Cohort A, n = 33), and every 3 weeks (q3wk) as 24-h infusion at 1.5 mg/m² (Cohort B1, n = 5) and 1.2 mg/m² (Cohort B2, n = 20). The primary end point was prostate-specific antigen (PSA) response; secondary end points included safety, tolerability and time to progression (TTP).ResultsTrabectedin resulted in PSA declines ≥50% in 12.5% (Cohort A) and 10.5% (Cohort B2) of patients. Among men pretreated with taxane-based chemotherapy, PSA response was 13.6% (Cohort A) and 15.4% (Cohort B2). PSA responses lasted 4.1–8.6 months, and median TTP was 1.5 months (Cohort A) and 1.9 months (Cohort B2). The dose of 1.5 mg/m² (approved for soft tissue sarcoma) given as 24-h infusion q3wk was not tolerable in these patients. At 1.2 mg/m² q3wk and 0.58 mg/m² weekly, the most common adverse events were nausea, fatigue and transient neutropenia and transaminase increase.ConclusionsTwo different trabectedin schedules showed modest activity in metastatic CRPC. Further studies may require identification of predictive factors of response in prostate cancer.     

A phase II study of sorafenib in patients with chemo-naive castration-resistant prostate cancer.

BACKGROUND: The purpose of this trial was to evaluate the antitumor activity of sorafenib, a multikinase inhibitor of cell proliferation and angiogenesis, in patients with castration-resistant prostate cancer. PATIENTS AND METHODS: This was a multicenter, two-stage, phase II study. Sorafenib 400 mg was administered orally twice daily continuously. Primary end point was prostate-specific antigen (PSA) 'response' defined as a > or =50% decrease for > or =4 weeks. RESULTS: In all, 28 patients were enrolled. Eastern Cooperative Oncology Group performance status was zero or one in 19 and 9 patients. Two patients had no metastases, and 26 had bone and/or lymph node disease. A median of two cycles (range 1-8) was delivered. Adverse events were typical for sorafenib. The PSA response rate was 3.6% [95% confidence interval (CI) 0.1% to 18.3%] with response occurring in one patient (baseline = 10 000 and nadir = 1643 microg/l). No measurable disease responses occurred in eight patients. Time to PSA progression was 2.3 months (95% CI 1.8-6.4). Of 16 patients who discontinued sorafenib and then did not receive any immediate therapy, 10 had postdiscontinuation PSA declines of 7%-52%. CONCLUSIONS: Sorafenib has limited activity using current PSA criteria. The declines in PSA observed on treatment discontinuation indicate an effect on PSA production/secretion. Further study may be warranted but needs to consider the limitations of PSA as an indicator of progression and response.     

Sequential treatment with sorafenib and sunitinib in metastatic renal cell carcinoma: clinical outcomes from a retrospective clinical study

Sorafenib and sunitinib are inhibitors of receptor protein tyrosine kinases (TKIs) and are approved for the treatment of metastatic renal cell carcinoma (mRCC). Although the mTOR inhibitor everolimus is effective for the treatment of patients who have failed TKI therapy, it is important to consider all available treatment options before switching therapy mode of action. Herein, we report outcomes in patients with mRCC switched to sorafenib following disease progression on sunitinib treatment. The medical records of 35 patients treated between November 2006 and November 2009 at two large referral centers in Greece were retrospectively analyzed for time-to-progression (TTP), overall survival (OS), and tolerability of sorafenib after sunitinib. Median TTP and OS on sorafenib were 4.9 and 11.5 months, respectively. Among 33 patients evaluable for tumor response, three had a partial response and 17 achieved disease stabilization (objective response rate 8.5%; total clinical benefit rate 57%). Sorafenib was well tolerated, with mostly grade 1/2 adverse events and no treatment-related deaths. Sorafenib was effective and well tolerated in this group of patients. The TTP with sorafenib following sunitinib was comparable to outcomes reported previously, providing further support that TKIs should be used in sequence before switching to an mTOR inhibitor.     

Phase II randomised discontinuation trial of cabozantinib in patients with advanced solid tumours

BackgroundCabozantinib is an inhibitor of tyrosine kinases, including MET, vascular endothelial growth factor receptor, AXL and RET. This multi-cohort phase II randomised discontinuation trial explored anticancer activity of cabozantinib in nine tumour types.Patients and methodsCabozantinib was administered (100 mg, once daily) to patients with advanced, recurrent or metastatic cancers. Those with stable disease at week 12 were randomised 1:1 to cabozantinib or placebo. Primary end-points were objective response rate (ORR) at week 12 and progression-free survival (PFS) in the randomised phase.ResultsA total of 526 patients were enrolled. The highest ORR was observed in ovarian cancer (OC) (21.7%); the largest PFS benefit was observed in castration-resistant prostate cancer (CRPC) (median 5.5 versus 1.4 months for placebo; hazard ratio 0.14, 95% confidence interval: 0.04, 0.52). Disease control rates were >40% for CRPC, OC, melanoma, metastatic breast cancer (MBC), hepatocellular carcinoma (HCC) and non–small cell lung cancer. Median duration of response ranged from 3.3 (MBC) to 11.2 months (OC). Encouraging efficacy results and symptomatic improvements prompted early suspension of the randomised stage and conversion to open-label non-randomised expansion cohorts. Dose reductions to manage adverse events (AEs) occurred in 48.7% of patients. The most frequent grade III–IV AEs were fatigue (12.4%), diarrhoea (10.5%), hypertension (10.5%) and palmar-plantar erythrodysesthesia syndrome (8.7%).ConclusionsClinical antitumour activity of cabozantinib was observed in a subset of tumour types: CRPC and OC were evaluated further in expansion cohorts. Phase III programs were initiated in CRPC and HCC. Interpretation of efficacy outcomes was limited by early termination of the randomised portion of the trial.Trial registration numberNCT00940225.     

Lenalidomide Monotherapy in Chemotherapy-Naive,Castration-Resistant Prostate Cancer Patients: Final Results of a Phase II Study

BackgroundWe investigated the activity of lenalidomide, which has antiangiogenic, antineoplastic, and immunomodulatory properties, in chemotherapy-naive, castration-resistant prostate cancer (CRPC) patients.PatientsPatients received 25 mg/d lenalidomide for 21 days in 28-day cycles, until disease progression or unacceptable toxicity developed. Endpoints included overall response rate and clinical benefit (overall response + stable disease), toxicity, time to radiographic progression, and time to prostate-specific antigen (PSA) progression, overall survival, and quality of life.ResultsThirty-two patients were enrolled in the study; of these, 77% (n = 25) had Gleason scores ≥ 7. The median age was 74 years (58-89 y), the median PSA level was 66 ng/mL (2-919 ng/mL), and 5 of 32 patients (17%) had liver or lung involvement. The median number of lenalidomide cycles was 3 (1-16 cycles). Stable disease was seen in 20 patients, for a clinical benefit rate of 63%. The median time to radiographic progression was 4 months (2-16 mo); the median overall survival was 20 months. Of 27 PSA-evaluable patients, 13 (48%) had a decline in PSA level; 3 (11%) had > 50% PSA decrease; the median time to PSA progression was 3 months (2-9 mo). Grade 3/4 hematologic toxicities were the most common adverse events without adverse impact on quality of life. Serious adverse events occurred in 14 patients (44%), including 1 patient (3%) with a rash definitely related to lenalidomide.ConclusionLenalidomide monotherapy demonstrates modest activity in chemotherapy-naive CRPC.     

Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: subset analyses of the phase III Sorafenib Asia-Pacific trial

BackgroundThe phase III Sorafenib Asia–Pacific (AP) trial—conducted in China, Taiwan and South Korea – confirmed that sorafenib improves overall survival (OS) and is safe for patients with advanced hepatocellular carcinoma (HCC). We performed a series of exploratory subset analyses to determine whether baseline status affected response to sorafenib.MethodsIn the Sorafenib AP trial, 226 patients with well-preserved liver function (>95% Child-Pugh A) were randomised 2:1 to sorafenib 400 mg bid or matching placebo. Subanalyses were based on aetiology (hepatitis B virus present/absent); tumour burden (macroscopic vascular invasion and/or extrahepatic spread present/absent); presence or absence of either lung or lymph node metastasis at baseline, Eastern Cooperative Oncology Group performance status (0, 1–2); serum concentrations of alanine aminotransferase/aspartate aminotransferase (normal, mildly elevated, moderately elevated), alpha-fetoprotein (normal/elevated) and total bilirubin (normal/elevated); and whether or not there was a history of hepatectomy or transarterial chemoembolisation/embolisation. Subgroup assessments included OS, time to progression (TTP), disease control rate and safety.FindingsSorafenib consistently improved both median OS and median TTP, compared with placebo (range of hazard ratios (HR), 0.32–0.87 and 0.31–0.75, respectively). The most common grade 3/4 adverse events were hand-foot skin reaction, diarrhoea and fatigue, the incidence of which was similar between subgroups.InterpretationThe efficacy and safety profiles of sorafenib in the subpopulations described were comparable with those in the overall study population. These exploratory analyses suggest that sorafenib is effective for patients from the AP region with advanced HCC, irrespective of baseline status.     

Phase II study of pegylated liposomal doxorubicin plus vinorelbine in breast cancer with previous anthracycline exposure

Thirty-five patients with metastatic breast cancer (MBC) entered a phase II study of pegylated liposomal doxorubicin 35 mg/m2 intravenously (i.v.) on day 1 plus vinorelbine 30 mg/m2 i.v. on day 1 every 4 weeks. Patients were required to have measurable disease, previous chemotherapy with an anthracycline-containing regimen, and a normal left ventricular ejection fraction (LVEF). Thirty-four patients were assessable for response and toxicity. The overall response rate (on an intent-to-treat basis) was 35% (12 of 34; 95% CI, 20%-54%). One complete response and 11 partial responses were noted. In addition, 14 patients (41%) had stable disease of > 4 months duration, and 7 patients (20.5%) had disease progression. The response rates to the combination when it was used as first- and second-line chemotherapy were 31% (4 of 13) and 38% (8 of 21), respectively. Median time to disease progression was 7 months (range, 1-35 months) and median overall survival was 13 months (range, 2 to > 62 months). Neutropenia was the most frequent toxicity (grade 4 in 44% of patients and 19% of cycles), but neutropenic fever was seen in only 3 cases. No septic deaths occurred. Nonhematologic grade 3 side effects included skin toxicity (palmar-plantar erythrodysesthesia syndrome, 6%) and mucositis (15%). Late alopecia was seen in 53% of patients (grade 1 in 41%, and grade 2 in 12%). The median LVEFs were 64% (range, 50%-81%) at baseline and 62% (range, 37%-70%) after treatment. Three patients presented an LVEF decrease to < 50%; however, no clinical heart failure was noted, and 2 of these patients recovered normal values after cessation of therapy. The combination of pegylated liposomal doxorubicin and vinorelbine can be safely administered to patients with anthracycline-pretreated MBC and is active in this population.     

Phase II Clinical Trial With Pegylated Liposomal Doxorubicin (CAELYX(R)/Doxil(R)) and Quality of Life Evaluation (EORTC QLQ-C30) in Adult Patients With Advanced Soft Tissue Sarcomas: A study of the Spanish Group for Research in Sarcomas (GEIS)

Background: Pegylated liposomal doxorubicin (PLD), a formulation with pharmacokinetic differences with respect to doxorubicin (DXR), might benefit patients with advanced soft tissue sarcoma (STS) pretreated with DXR.Patients and methods: Patients with measurable and progressive STS received PLD at 35 mg/(2) every 3 weeks. Quality of life before and during treatment was assessed with EORTC QLQ-C30.Results: Twenty-eight patients, 22 DXR-pretreated, were given 140 cycles (median 3, range 1-18). Activity in 27 patients (5 GIST): one complete and one partial remission (both non-GIST and without prior DXR), 12 stabilizations and 13 progressions (response rate 7.4%, 95% CI: 0-17%). Grade 3 toxicity: palmar-plantar erythrodysesthesia (19% of patients), stomatitis (4%) or cutaneous (4%). Neutropenia grade>/=3 was detected in 16% of patients. Median relative dose intensity was 95%. Progression-free rate at 3 and 6 months was, respectively, 48 and 22%, median progression-free survival 5.8 months and median overall survival 8.7 months. QLQ-C30 at baseline and at weeks 6-11 in 23 and 13 patients, respectively, showed good reliability and validity. Quality of life did not seem to worsen during therapy.Conclusions: PLD did not induce objective remissions in 22 STS patients pretreated with DXR, but progression-free rate figures support the use of this agent in patients who have not progressed under a DXR-containing regimen. The toxicity observed was comparable to that of other PLD schedules.     

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.     

Pooled safety analysis of BAY 43-9006 (sorafenib) monotherapy in patients with advanced solid tumours: Is rash associated with treatment outcome?

In this analysis of the safety and efficacy of BAY 43-9006 (sorafenib) -- a novel, oral multi-kinase inhibitor with effects on tumour and its vasculature -- pooled data were obtained from four phase I dose-escalation trials. Time to progression (TTP) was compared in patients with/without grade 2 skin toxicity/diarrhoea. Grade 3 hand-foot skin reactions (HFS; 8%) and diarrhoea (6%) were common. At the recommended 400mg bid dose for phase II/III trials (RDP), 15% of patients experienced grade 2/3 HFS, and 24% experienced grade 2/3 diarrhoea. Sorafenib induced stable disease for 6 months in 12% of patients (6% stabilized for 1 year). Patients receiving sorafenib doses at or close to the RDP, who experienced skin toxicity/diarrhoea, had a significantly increased TTP compared with patients without such toxicity (P < 0.05). Sorafenib was well tolerated at the RDP, and induced sustained disease stabilization, particularly in patients with skin toxicity/diarrhoea.