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.     

Randomised phase III trial of trabectedin versus doxorubicin-based chemotherapy as first-line therapy in translocation-related sarcomas

AimThis randomised phase III trial evaluated first-line trabectedin versus doxorubicin-based chemotherapy (DXCT) in patients with advanced/metastatic translocation-related sarcomas (TRS).MethodsPatients were randomly assigned (1:1) to receive trabectedin 1.5 mg/m² 24-h intravenous (i.v.) infusion every 3 weeks (q3wk) (Arm A), or doxorubicin 75 mg/m² i.v. q3wk, or doxorubicin 60 mg/m² i.v. plus ifosfamide (range, 6–9 g/m²) i.v. q3wk (Arm B). Progression-free survival (PFS) by independent review was the primary efficacy end-point.ResultsOne hundred and twenty-one patients were randomised; 88 of them had TRS confirmed by central pathology review (efficacy population). Twenty-nine PFS events were assessed by independent review (16 with trabectedin; 13 with DXCT). PFS showed non-significant difference between arms (stratified log rank test, p = 0.9573; hazard ratio = 0.86, p = 0.6992). At the time of this analysis, 63.9% and 58.3% of patients were alive in trabectedin and DXCT arms, respectively. There was no statistically significant difference in survival curves. Response rate according to Response Evaluation Criteria in Solid Tumours (RECIST) v.1.0 was significantly higher in DXCT arm (27.0% versus 5.9%), but response according to Choi criteria showed fewer differences between treatment arms (45.9% versus 37.3%). Safety profile was as expected for both arms, with higher incidence of severe neutropenia, alopecia and mucositis in the DXCT arm.ConclusionNeither trabectedin nor doxorubicin-based chemotherapy showed significant superiority in the first-line treatment of patients with advanced translocation-related sarcoma.     

Efficacy and tolerability of trabectedin in elderly patients with sarcoma: subgroup analysis from a phase III,randomized controlled study of trabectedin or dacarbazine in patients with advanced liposarcoma or leiomyosarcoma

BackgroundTreatment options for soft tissue sarcoma (STS) patients aged ≥65 years (elderly) can be limited by concerns regarding the increased risk of toxicity associated with standard systemic therapies. Trabectedin has demonstrated improved disease control in a phase III trial (ET743-SAR-3007) of patients with advanced liposarcoma or leiomyosarcoma after failure of anthracycline-based chemotherapy. Since previous retrospective analyses have suggested that trabectedin has similar safety and efficacy outcomes regardless of patient age, we carried out a subgroup analysis of the safety and efficacy observed in elderly patients enrolled in this trial.Patients and methodsPatients were randomized 2 : 1 to trabectedin (n = 384) or dacarbazine (n = 193) administered intravenously every-3-weeks. The primary end point was overall survival (OS); secondary end points were progression-free survival (PFS), time-to-progression, objective response rate (ORR), duration of response, symptom severity, and safety. A post hoc analysis was conducted in the elderly patient subgroup.ResultsAmong 131 (trabectedin = 94; dacarbazine = 37) elderly patients, disease characteristics were well-balanced and consistent with those of the total study population. Treatment exposure was longer in patients treated with trabectedin versus dacarbazine (median four versus two cycles, respectively), with a significantly higher proportion receiving prolonged therapy (≥6 cycles) in the trabectedin arm (43% versus 23%, respectively; P = 0.04). Elderly patients treated with trabectedin showed significantly improved PFS [4.9 versus 1.5 months, respectively; hazard ratio (HR)=0.40; P = 0.0002] but no statistically significant improvement in OS (15.1 versus 8.0 months, respectively; HR = 0.72; P = 0.18) or ORR (9% versus 3%, respectively; P = 0.43). The safety profile for elderly trabectedin-treated patients was comparable to that of the overall trabectedin-treated study population.ConclusionsThis subgroup analysis of the elderly population of ET743-SAR-3007 suggests that elderly patients with STS and good performance status can expect clinical benefit from trabectedin similar to that observed in younger patients.Trial registrationwww.clinicaltrials.gov, NCT01343277.     

Trabectedin in patients with advanced soft tissue sarcoma: A retrospective national analysis of the French Sarcoma Group

AimThe French Sarcoma Group performed this retrospective analysis of the ‘RetrospectYon’ database with data of patients with recurrent advanced soft tissue sarcoma (STS) treated with trabectedin 1.5 mg/m² as a 24-h infusion every three weeks.MethodsPatients who achieved non-progressive disease after six initial cycles could receive long-term trabectedin treatment until disease progression.ResultsOverall, 885 patients from 25 French centres were included. Patients received a median of four trabectedin cycles (range: 1–28). The objective response rate was 17% (six complete/127 partial responses) and 50% (n = 403) of patients had stable disease for a disease control rate of 67%. After a median follow-up of 22.0 months, median progression-free survival (PFS) and overall survival (OS) were 4.4 and 12.2 months, respectively. After six cycles, 227/304 patients with non-progressive disease received trabectedin until disease progression and obtained a significantly superior median PFS (11.7 versus 7.6 months, P < 0.003) and OS (24.9 versus 16.9 months, P < 0.001) compared with those who stopped trabectedin treatment. Deaths and unscheduled hospitalisation attributed to drug-related events occurred in 0.5% and 9.4% of patients, respectively.ConclusionThe results of this real-life study demonstrate that treatment with trabectedin of patients with STS yielded comparable or improved efficacy outcomes versus those observed in clinical trials. A long-term treatment with trabectedin given until disease progression is associated with significantly improved PFS and OS.     

First-line anthracycline-based chemotherapy for angiosarcoma and other soft tissue sarcoma subtypes: Pooled analysis of eleven European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group trials

BackgroundAngiosarcoma is a rare subtype of soft tissue sarcoma (STS). Doxorubicin is the standard first-line chemotherapy for advanced STS. It is not known whether angiosarcoma response to anthracycline-based chemotherapy is different to other STS subtypes.MethodsPooled data were analysed from 11 prospective randomised and non-randomised European Organisation for Research and Treatment of Cancer (EORTC) clinical trials of first-line anthracycline-based chemotherapy for advanced STS. Baseline patient characteristics, chemotherapy response, progression free survival (PFS) and overall survival (OS) of angiosarcoma patients were compared with other STS patients. Analysis was performed to identify factors prognostic for angiosarcoma response to chemotherapy, PFS and OS.ResultsWith a median follow-up of 4.2 years, data from 108 locally advanced and metastatic angiosarcoma patients and 2557 patients with other STS histologies were analysed. 25% of angiosarcoma patients had a complete or partial response to chemotherapy compared to 21% for other STS histotypes. The median PFS was 4.9 months and OS 9.9 months, which were not significantly different from other STS histotypes. In univariate analysis, bone metastases were an adverse prognostic factor for OS (hazard ratio (HR) 1.66, 95% confidence interval (CI) 1.03–2.67; p = 0.036). Tumour grade was as an adverse prognostic factor for PFS (HR 1.72, 95% CI 1.01–2.92; p = 0.044) and OS (HR 2.03; 95% CI 1.16–3.56; p = 0.011). Compared to single agent anthracyclines, doxorubicin + ifosfamide was associated with improved PFS (HR 0.53, 95% CI 0.33–0.86; p = 0.010) and OS (HR 0.53, 95% CI 0.32–0.90; p = 0.018).ConclusionsAngiosarcoma response and survival following first-line anthracycline-based chemotherapy was similar to other STS histotypes. Our analysis provides a useful measure of angiosarcoma response to chemotherapy for comparison with future clinical trials.     

Comparison of Response Evaluation Criteria in Solid Tumours and Choi criteria for response evaluation in patients with advanced soft tissue sarcoma treated with trabectedin: A retrospective analysis

BackgroundTo assess the additional value of density measurement using contrast-enhancement sequences (Choi assessment) in a real-life cohort of adult soft tissue sarcoma patients treated with trabectedin.MethodsEligibility criteria included adults (age ⩾18) treated between 01/2007 and 12/2011, with at least two trabectedin cycles after failure or intolerance to doxorubicin/ifosfamide. Baseline and first computed tomography (CT)-scans were centrally reviewed by an experienced radiologist.ResultsThe retrospective cohort consists of 134 (73 female) patients treated with trabectedin 1.5 mg/m² given as a 24-h infusion every 3 weeks. Patients received a median of five trabectedin cycles (range: 2–33) and the main cause of discontinuation was progressive disease (PD) (n = 105, 78.4%). Response Evaluation Criteria in Solid Tumours (RECIST) assessment was feasible in 128 (95.5%) patients, with Choi assessment performed in 92 (68.7%) patients, generally due to inadequate sequences or exclusive lung metastases. Concordance between both methods was fair (Kappa = 0.290). We identified five patients with false PD (i.e. PD according to RECIST but stable disease/partial response as per Choi). Univariate analysis did not identify any predictive factors for false PD. Median overall survival (OS) of patients with PD as per RECIST but stable disease/partial response (SD/PR) according to Choi was better than for patients with PD according to both RECIST and Choi (14 months versus 8 months; p = 0.052).ConclusionsChoi assessment may identify patients with false PD who achieved improved efficacy outcomes, suggesting that trabectedin may delay tumour progression even in the case of non-dimensional response. Dual size and tumour density assessment may be more suitable to evaluate responses to trabectedin in sarcoma patients as well as to improve the decision-making strategies for the continuation of trabectedin therapy.     

Phase II randomized study of trabectedin given as two different every 3 weeks dose schedules (1.5 mg/m2 24 h or 1.3 mg/m2 3 h) to patients with relapsed,platinum-sensitive,advanced ovarian cancer

BackgroundThis randomized, open-label, phase II clinical trial evaluated the optimal regimen of trabectedin administered every 3 weeks in patients with platinum-sensitive, relapsed, advanced ovarian cancer (AOC).Patients and methodsPatients previously treated with less than two or two previous chemotherapy lines were randomized to receive trabectedin 1.5 mg/m² 24 h (arm A, n = 54) or 1.3 mg/m² 3 h (arm B, n = 53). Objective response rate (ORR) per RECIST was the primary efficacy end point. Toxic effects were graded according to the National Cancer Institute—Common Toxicity Criteria v. 2.0.ResultsORR was 38.9% [95% confidence interval (CI) 25.9% to 53.1%; arm A] and 35.8% (95% CI 23.1% to 50.2%; arm B) (intention-to-treat primary analysis). Median time to progression was 6.2 months (95% CI 5.3–8.6 months; arm A) and 6.8 months (95% CI 4.6–7.4 months; arm B). Frequent severe adverse events were nausea/vomiting (24%, arm A; 15%, arm B) and fatigue (15%, arm A; 10%, arm B). Common severe laboratory abnormalities were transient, noncumulative neutropenia (55%, arm A; 37%, arm B) and transaminase increases (alanine aminotransferase, 55%, arm A; 59%, arm B).ConclusionsBoth every-3-weeks trabectedin regimes, 1.5 mg/m² 24 h and 1.3 mg/m² 3 h, were active and reasonably well tolerated in AOC platinum-sensitive patients. Trabectedin every-3-weeks has promising activity and deserves to be further evaluated in relapsed AOC.     

Effective local control of advanced soft tissue sarcoma with neoadjuvant chemoradiotherapy and surgery: A single institutional experience

PurposeThere is a sound theoretical basis but little clinical evidence substantiating the benefits of concurrent chemoradiotherapy with two-drug chemotherapy for locally advanced soft tissue sarcomas. Our five-year data on the feasibility and effectiveness of neoadjuvant chemoradiotherapy with systemically effective doses of adriamycin and ifosfamide combined is presented here.Patients and methodsBetween 2000 and 2011, 53 patients with UICC (2010) stage I (n = 1, 1.9%), II (n = 12, 22.7%) or III (n = 40, 75.5%) nonmetastatic soft tissue sarcoma received neoadjuvant chemoradiotherapy with ifosfamide (1.5 g/m²/day, d1–5, q28) and doxorubicin (50 mg/m²/day, d3, q28) plus concurrent radiotherapy with a target dose of 50–64 Gy (median 60 Gy). The treatment of 34 patients (64.2%) was combined with hyperthermia.ResultsAt five years, the local control rate was 89.9% (± 5.7%), distant metastasis-free survival 66.6% (± 7.6%), and survival 83.3% (± 6%). The R0 resection rate was 81.1%. Radiotherapy was completed as planned in all patients and chemotherapy in 42/53 (70.2%). Grades III (n = 21, 29.6%) and IV (n = 18, 34%) leukopenia was the main acute adverse event. All acute and chronic non-hematologic toxicities were moderate.ConclusionNeoadjuvant chemoradiotherapy for soft tissue sarcoma is associated with good feasibility, manageable acute and late toxicities, and high local efficacy.     

KRAS mutations are associated with inferior clinical outcome in patients with metastatic colorectal cancer,but are not predictive for benefit with cediranib

PurposeThe prognostic potential of KRAS mutations in advanced colorectal cancer (CRC) patients and the impact of KRAS mutation status on the effectiveness of chemotherapy or vascular endothelial growth factor (VEGF) signalling inhibitor therapy remain unclear. KRAS mutation status was evaluated retrospectively as a potential prognostic/predictive marker of clinical outcomes using tumour samples from patients with metastatic CRC receiving cediranib or placebo plus FOLFOX/XELOX in a Phase III trial (HORIZON II; NCT00399035).MethodsKRAS codon 12 and 13 mutation analyses were performed using a commercially available, allele-specific, amplification refractory mutation system (ARMS)-based polymerase chain reaction (PCR) assay. Retrospective analyses of progression-free survival (PFS) and overall survival (OS) according to KRAS mutation status were performed for patients randomised to cediranib 20 mg or placebo.ResultsKRAS status was determined in 599/1076 patients (cediranib 20 mg, n = 285/502; cediranib 30 mg, n = 110/216; placebo, n = 204/358). Baseline characteristics were similar across KRAS mutant (n = 258; 24.0%), wild-type (n = 341; 31.7%) and status unknown (n = 477; 44.3%) groups. There was a trend towards improved PFS and OS in the wild-type versus mutant subgroups independent of treatment (cediranib 20 mg and placebo: PFS hazard ratio (HR) = 0.85 [median PFS: wild-type = 8.5 months; mutant = 8.3 months]; OS HR = 0.71 [median OS: wild-type = 20.9 months; mutant = 16.9 months]). Treatment effects were similar between KRAS subgroups for cediranib 20 mg versus placebo (PFS: wild-type HR = 0.78, mutant HR = 0.82; OS: wild-type HR = 0.92, mutant HR = 1.01).ConclusionData from this large randomised Phase III study show that KRAS codon 12/13 mutations have negative prognostic value in metastatic CRC patients receiving treatment with FOLFOX/XELOX, but KRAS mutation status is not predictive of treatment benefit with cediranib, using PFS or OS.     

Gastric carcinoma at Tanta Cancer Center: A comparative retrospective clinico-pathological study of the elderly versus the non-elderly

Background and aimsTo study the clinico-pathological features, treatments and outcomes of gastric carcinoma (GC) in the elderly (⩾65 years) and the non-elderly Egyptian patients.MethodsThis retrospective cohort study included 168 patients with histologically confirmed GC treated at Tanta Cancer Center between 2003 and 2007.ResultsCompared to the non-elderly, elderly patients had significantly higher proportion of tumors involving the cardia (p = 0.034) and of adenocarcinoma NOS histology (p = 0.032). Treatments were largely comparable in the two groups. Response to palliative chemotherapy was achieved in 44.4% of the elderly and 25.5% of the non-elderly patients (p = 0.417). The median overall survival (OS), disease-free survival (DFS) and progression-free survival (PFS) were 6, 17 and 3 months, respectively. The median OS was 4 months in the elderly compared to 9 months in the non-elderly (p = 0.005). The median DFS was 4 months in the elderly compared to 20 months in the non-elderly (p = 0.004). The median PFS was 2 months in the elderly compared to 3 months in the non-elderly (p = 0.685). In multivariate analysis, poor performance status was an independent predictor of poor OS, DFS and PFS. Non-curative or no surgery and lack of chemotherapy use were independent predictors of poor OS. Age was an independent predictor of poor DFS.ConclusionsCompared to the non-elderly, GC in the elderly has similar clinico-pathological characteristics and exhibits comparable outcomes with the same treatment options. Treatments should be tailored to each patient.     

Prognostic factors in adolescents and young adults (AYA) with high risk soft tissue sarcoma (STS) treated by adjuvant chemotherapy: A study based on pooled European Organisation for Research and Treatment of Cancer (EORTC) clinical trials 62771 and 62931

BackgroundWe conducted a retrospective study, pooling data from two clinical trials in high risk soft tissue sarcoma (STS) patients, with the objective of comparing two different age groups: 15–29 years (adolescents and young adults (AYA) population) and ?30 years. The aim was to determine prognostic factors for the AYA population.MethodsPatients selected for analysis were treated in two randomised trials of adjuvant chemotherapy in STS (European Organisation for Research and Treatment of Cancer (EORTC) 62771 and 62931). A total of 793 patients were included with a median follow-up (FU) of 8.74 years (AYA population: n = 161, median FU 9.46 years; patients ?30 years: n = 632, median FU 8.62 years). Study endpoints were overall survival (OS) and relapse-free survival (RFS). The variables of the multivariate analysis were gender, subtype and grade, tumour size and localisation (limb versus other), absence or presence of local recurrence and treatment (control arm versus adjuvant chemotherapy).ResultsPatients’ characteristics were globally similar with two exceptions, histological subtype (p = 0.0043) and tumour size (p < .0001). The commonest sarcoma subtype in the AYA population was synovial sarcoma (29%), whereas leiomyosarcoma (18%), malignant fibrous histiocytoma (MFH, presently being termed undifferentiated pleomorphic sarcoma (UPS), 16%) and liposarcoma (15%) were more frequent in patients ?30 years. For OS, independent favourable prognostic factors were low grade and small tumour size for both groups; radical resection and MFH or liposarcoma subtype were favourable factors for patients ?30 years only. For RFS, favourable prognostic factors were small tumour size and low grade for both groups; tumour location in the extremities was a favourable factor for the AYA population only, whereas radical resection and adjuvant chemotherapy treatment were favourable factors for patients ?30 years only.ConclusionsSignificant differences could be found concerning prognostic factors between the AYA population and older patients. Interestingly, adjuvant chemotherapy was associated with improved RFS only in patients ?30 years. The results may have further implications for the treatment of STS patients in different age groups, as well as the design of future clinical trials.     

Correlation of progression-free and post-progression survival with overall survival in advanced colorectal cancer

BackgroundPolychemotherapy and biological drugs have increased therapeutic options and outcomes of advanced colorectal cancer (CRC). We examined the relation between progression-free survival (PFS), post-progression survival (PPS) and overall survival (OS) in trials of modern (oxaliplatin- and irinotecan-based) chemotherapy alone or with targeted therapies for advanced CRC. We also evaluated surrogacy of PFS and OS.Patients and methodsA PubMed search identified 34 randomized trials. We split the OS, PFS and PPS and evaluated the correlation between OS and either PFS or PPS.ResultsThe median PPS and PFS were 10.75 and 8.4 months, respectively. For all trials, PPS was strongly associated with OS [regression coefficient (R²) = 0.8; Spearman's rank correlation coefficient (r) = 0.88], whereas PFS was moderately associated with OS (R² = 0.43; r = 0.64). In trials with targeted therapies, the correlation of PPS with OS was 0.88. However, across all trials, correlation between differences in median PFS (ΔPFS) and median OS (ΔOS) is 0.59 (P = 0.0007), confirming PFS/OS surrogacy.ConclusionOur findings indicate that in recent first-line, phase III, trials, OS becomes more associated with PPS than PFS. However, improvements in PFS are strongly associated with improvements in OS. In this setting so, PFS may be an appropriate surrogate for OS.     

Impact of primary tumour resection on survival of patients with colorectal cancer and synchronous metastases treated by chemotherapy: Results from the multicenter,randomised trial Fédération Francophone de Cancérologie Digestive 9601

ObjectiveTo assess the impact of primary tumour resection on overall survival (OS) of patients diagnosed with stage IV colorectal cancer (CRC).DesignAmong the 294 patients with non-resectable colorectal metastases enrolled in the Fédération Francophone de Cancérologie Digestive (FFCD) 9601 phase III trial, which compared different first-line single-agent chemotherapy regimens, 216 patients (73%) presented with synchronous metastases at study entry and constituted the present study population. Potential baseline prognostic variables including prior primary tumour resection were assessed by univariate and multivariate Cox analyses. Progression-free survival (PFS) and OS curves were compared with the logrank test.ResultsAmong the 216 patients with stage IV CRC (median follow-up, 33 months), 156 patients (72%) had undergone resection of their primary tumour prior to study entry. The resection and non-resection groups did not differ for baseline characteristics except for primary tumour location (rectum, 14% versus 35%; p = 0.0006). In multivariate analysis, resection of the primary was the strongest independent prognostic factor for PFS (hazard ratio (HR), 0.5; 95% confidence interval [CI], 0.4–0.8; p = 0.0002) and OS (HR, 0.4; CI, 0.3–0.6; p < 0.0001). Both median PFS (5.1 [4.6–5.6] versus 2.9 [2.2–4.1] months; p = 0.001) and OS (16.3 [13.7–19.2] versus 9.6 [7.4–12.5]; p < 0.0001) were significantly higher in the resection group. These differences in patient survival were maintained after exclusion of patients with rectal primary (n = 43).ConclusionResection of the primary tumour may be associated with longer PFS and OS in patients with stage IV CRC starting first-line, single-agent chemotherapy.     

Maintenance pazopanib versus placebo in Non-Small Cell Lung Cancer patients non-progressive after first line chemotherapy: A double blind randomised phase III study of the lung cancer group,EORTC 08092 (EudraCT: 2010-018566-23, NCT01208064)

BackgroundSwitch maintenance is an effective strategy in the treatment of advanced Non-Small Cell Lung Cancer (NSCLC). Pazopanib is an oral, multi-targeted tyrosine kinase inhibitor (TKI). EORTC 08092 evaluated pazopanib given as maintenance treatment following standard first line platinum-based chemotherapy in patients with advanced NSCLC.MethodsPatients with non-progressive disease after 4–6 cycles of chemotherapy were randomised to receive either pazopanib 800 mg/day or matched placebo until progression or unacceptable toxicity. The primary end-point was overall survival and secondary end-points were progression-free survival (PFS) and safety.ResultsA total of 600 patients were planned to be randomised. The trial was prematurely stopped following an early interim analysis, after 102 patients were randomised to pazopanib (n = 50) or placebo (n = 52). Median age was 64 years in both arms. Median overall survival was 17.4 months for pazopanib and 12.3 months for placebo (adjusted hazard ratio (HR) 0.72 [95% confidence interval (CI) 0.40–1.28]; p = 0.257). Median PFS was 4.3 months versus 3.2 months (HR 0.67, [95% CI 0.43–1.03], p = 0.068). PFS rates at 4 months were 56% and 45% respectively. The majority of treatment-related adverse events (AEs) were grade 1–2. Grade 3–4 AEs (pazopanib versus placebo) were hypertension (38% versus 8%), neutropenia (8% versus 0%), and elevated SGPT (6% versus 0%). Of the patients randomised to pazopanib, 22% withdrew due to a treatment-related AE.ConclusionsSwitch maintenance with pazopanib following platinum-based chemotherapy in advanced NSCLC patients had limited side-effects. This study was stopped due to lack of efficacy by stringent criteria for PFS at a futility interim analysis.     

Treatment of adult nonmetastatic medulloblastoma patients according to the paediatric HIT 2000 protocol: A prospective observational multicentre study

BackgroundMedulloblastoma in adulthood is rare. Knowledge is limited, and the efficacy and toxicity of chemotherapy – especially in nonmetastatic disease – is still elusive.MethodsSeventy adults aged ?21 years (median age: 28.5 years) with nonmetastatic medulloblastoma were followed as observational patients within the prospective paediatric multicentre trial HIT 2000. Treatment consisted of radiotherapy (35.2 Gy to the craniospinal axis and a boost to 55.2 Gy to the posterior fossa) followed in most patients by maintenance chemotherapy (lomustine (CCNU), vincristine and cisplatin, n = 49).ResultsThe implementation of maintenance chemotherapy was feasible. Peripheral neuropathy (74%) and haematotoxicity (55%) during maintenance chemotherapy appear to be more common in adults than in children. At a median follow-up of 3.7 years, the 4-year event-free survival (EFS) and overall survival (OS) rates ± standard error (SE) were 68% ± 7% and 89% ± 5%. Patients with desmoplastic medulloblastoma and lateral tumour location (n = 19) had a lower EFS compared to patients with centrally located desmoplastic tumours (n = 10) (p = 0.011). Absence of residual postoperative tumour (n = 40) was associated to a lower rate of progression/relapse compared to present (n = 11) or unknown (n = 12) residual tumour status (p = 0.006). Lateral tumour location and unknown residual tumour status were independent negative prognostic factors.ConclusionsMaintenance chemotherapy is applicable in adults with nonmetastatic medulloblastoma. Histological subtype and tumour location were newly identified risk factors in this age-group, and should be further analysed in prospective trials.     

Postprogression survival for first-line chemotherapy in patients with advanced gastric cancer

BackgroundWith the increasing availability of active agents, the importance of postprogression survival (PPS) has been recognised for several malignancies. However, little is known of PPS in advanced gastric cancer.Patients and methodsA literature search identified 43 randomised trials in chemotherapy-naive patients with advanced gastric cancer. We partitioned overall survival (OS) into progression-free survival (PFS) and PPS, and then examined the correlation between median OS and either median PFS or median PPS. The correlation between differences in OS (ΔOS) and those in PFS (ΔPFS) between trial arms was also investigated.ResultsThe average median OS was significantly longer in recent (2006 and later) trials than in older (2005 and earlier) trials (10.60 versus 8.64 months, P < 0.001), as was the average median PPS (5.34 versus 3.74 months, P = 0.001). Median PPS was correlated with median OS for all trials (r = 0.732), and this correlation was more pronounced in recent trials (r = 0.850). By contrast, the correlation between median PFS and median OS was less pronounced in recent trials (r = 0.282), as was that between ΔPFS and ΔOS (r = 0.365).ConclusionAn increase in median PPS was found in accordance with an increase in median OS in recent trials compared with older trials for patients with advanced gastric cancer.     

An open-label,phase 2 study evaluating the efficacy and safety of the anti-IGF-1R antibody cixutumumab in patients with previously treated advanced or metastatic soft-tissue sarcoma or Ewing family of tumours

BackgroundCixutumumab (IMC-A12), a fully human immunoglobulin G1 (IgG1) monoclonal antibody, exerts preclinical activity in several sarcoma models and may be effective for the treatment of these tumours.MethodsIn this open-label, multicentre, phase 2 study, patients with previously treated advanced or metastatic rhabdomyosarcoma, leiomyosarcoma, adipocytic sarcoma, synovial sarcoma or Ewing family of tumours received intravenous cixutumumab (10 mg/kg) for 1 h every other week until disease progression or discontinuation. The primary end-point was the progression-free survival rate (PFR), defined as stable disease or better at 12 weeks. In each tier of disease histology, Simon’s optimum 2-stage design was applied (PFR at 12 weeks P0 = 20%, P1 = 40%, α = 0.10, β = 0.10). Stage 1 enrolled 17 patients in each disease group/tier, with at least four patients with stable disease or better required at 12 weeks to proceed to stage 2.ResultsA total of 113 patients were enrolled; all tiers except adipocytic sarcoma were closed after stage 1 due to futility. The 12-week PFR was 12% for rhabdomyosarcoma (n = 17), 14% for leiomyosarcoma (n = 22), 32% for adipocytic sarcoma (n = 37), 18% for synovial sarcoma (n = 17) and 11% for Ewing family of tumours (n = 18). Median progression-free survival (weeks) was 6.1 for rhabdomyosarcoma, 6.0 for leiomyosarcoma, 12.1 for adipocytic sarcoma, 6.4 for synovial sarcoma and 6.4 for Ewing family of tumours. Among all patients, the most frequent treatment-emergent adverse events (AEs) were nausea (26%), fatigue (23%), diarrhoea (23%) and hyperglycaemia (20%).ConclusionsPatients with adipocytic sarcoma may benefit from treatment with cixutumumab. Cixutumumab treatment was well tolerated, with limited gastrointestinal AEs, fatigue and hyperglycaemia.     

A randomized phase II study evaluating the combination of carboplatin-based chemotherapy with pertuzumab versus carboplatin-based therapy alone in patients with relapsed,platinum-sensitive ovarian cancer

BackgroundPertuzumab, a humanized monoclonal antibody targeting human epidermal growth factor receptor (HER)-mediated signalling, has shown activity in ovarian cancer in preclinical models and in the clinic. This randomized phase II study evaluated efficacy and safety of pertuzumab in combination with carboplatin-based chemotherapy in patients with platinum-sensitive, recurrent advanced ovarian cancer.Patients and methodsPatients were randomized to receive six cycles of chemotherapy (carboplatin and either paclitaxel (Taxol) or gemcitabine) with or without pertuzumab. The primary end point was progression-free survival (PFS) as determined by Response Evaluation Criteria in Solid Tumors and/or by CA 125 measurements. Secondary end points evaluated the response rate, safety profile, duration of response, time to progression and overall survival for both treatment arms.ResultsA total of 149 patients received either chemotherapy with pertuzumab (arm A, n = 74) or chemotherapy alone (arm B, n = 75). There was no significant difference either in median PFS or in the secondary end points between the two arms. No differences were seen in an exploratory biomarker analysis of HER3 mRNA expression between the two arms. Pertuzumab was well tolerated, with no increase in cardiac adverse events compared with chemotherapy alone.ConclusionsThe addition of pertuzumab to carboplatin-based chemotherapy did not substantially prolong PFS in unselected patients with platinum-sensitive ovarian cancer.     

nab-Paclitaxel plus carboplatin or gemcitabine versus gemcitabine plus carboplatin as first-line treatment of patients with triple-negative metastatic breast cancer: results from the tnAcity trial

BackgroundMetastatic triple-negative breast cancer (mTNBC) has a poor prognosis and aggressive clinical course. tnAcity evaluated the efficacy and safety of first-line nab-paclitaxel plus carboplatin (nab-P/C), nab-paclitaxel plus gemcitabine (nab-P/G), and gemcitabine plus carboplatin (G/C) in patients with mTNBC.Patients and methodsPatients with pathologically confirmed mTNBC and no prior chemotherapy for metastatic BC received (1 : 1 : 1) nab-P 125 mg/m² plus C AUC 2, nab-P 125 mg/m² plus G 1000 mg/m², or G 1000 mg/m² plus C AUC 2, all on days 1, 8 q3w. Phase II primary end point: investigator-assessed progression-free survival (PFS); secondary end points included overall response rate (ORR), overall survival (OS), percentage of patients initiating cycle 6 with doublet therapy, and safety.ResultsIn total, 191 patients were enrolled (nab-P/C, n = 64; nab-P/G, n = 61; G/C, n = 66). PFS was significantly longer with nab-P/C versus nab-P/G [median, 8.3 versus 5.5 months; hazard ratio (HR), 0.59 [95% CI, 0.38–0.92]; P = 0.02] or G/C (median, 8.3 versus 6.0 months; HR, 0.58 [95% CI, 0.37–0.90]; P = 0.02). OS was numerically longer with nab-P/C versus nab-P/G (median, 16.8 versus 12.1 months; HR, 0.73 [95% CI, 0.47–1.13]; P = 0.16) or G/C (median, 16.8 versus 12.6 months; HR, 0.80 [95% CI, 0.52–1.22]; P = 0.29). ORR was 73%, 39%, and 44%, respectively. In the nab-P/C, nab-P/G, and G/C groups, 64%, 56%, and 50% of patients initiated cycle 6 with a doublet. Grade ≥3 adverse events were mainly hematologic.ConclusionsFirst-line nab-P/C was active in mTNBC and resulted in a significantly longer PFS and improved risk/benefit profile versus nab-P/G or G/C.     

Transarterial chemoembolization followed by moderately hypofractionated radiotherapy in hepatocellular carcinoma: Long-term results of RTF3 regimen

PurposeIn early-stage hepatocellular carcinoma (HCC) patients merely fit for surgery, transarterial chemoembolization (TACE) achieve low long-term disease control. We evaluated the efficacy and safety of its combination with moderately hypofractionated radiotherapy (hRT) using RTF3 regimen.Material and methodsBetween 2006 and 2016, 61 consecutive patients treated in our single expert center for a Barcelona Clinic Liver Cancer (BCLC) A HCC by TACE followed by hRT 3 Gy/fraction were retrospectively included.ResultsSixty of the 61 included presented Child-Pugh A cirrhosis (A5, n = 41, 67.2%; A6: n = 19, 31.1%). Fourteen patients (22.9%) were already treated for a HCC, mainly by radiofrequency (n = 12). All patient received a TACE followed by 3 Gy per fraction hRT. Mean radiation dose was 54 Gy (range: 48–60). After a median follow-up of 118 months, median time-to-progression, progression-free survival (PFS) and overall survival (OS) was 21.3, 18.1, and 31.5 months, respectively. In univariate analysis, PFS was related to dose > 54 Gy (HR: 2, P = 0.036), and OS was correlated to Child-Pugh A6 or B7 (HR: 1.93, P = 0.03) and overall hRT time (HR: 1.06, P = 0.015). At progression, orthotopic liver transplantation was performed in 8 patients (13.1%). Severe symptomatic adverse events occurred in 12 patients (19.7%), mainly ascites (n = 7).ConclusionIn BCLC-A Child-Pugh A HCC patients ineligible to surgery or thermoablation, TACE-hRT is a safe and effective treatment. Prospective studies are needed to compare this association with radioembolization, TACE-stereotactic radiotherapy, and systemic treatments combinations.