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.     

High-sensitivity human papilloma virus genotyping reveals near universal positivity in anal squamous cell carcinoma: Different implications for vaccine prevention and prognosis

BackgroundCharacterisation of human papilloma virus (HPV) infection in anal squamous cell carcinoma (ASCC) may have dual importance: first, aetiological; second, prognostic, informing outcome after chemo-radiotherapy (CRT). We undertook HPV genotyping, and allelic characterisations, to evaluate the aetiological role of HPV while simultaneously evaluating the impact of HPV genotyping on relapse-free (RFS) and overall survival (OS).MethodDual-primer HPV genotyping (subtypes 6, 11, 16, 18, 31, 33, 45, 52, 58) and DNA sequencing of HPV 16 positive tumours were analysed in 151 consecutively referred ASCCs, previously characterised by immunohistochemistry for p16 expression. In 110 patients treated with CRT, factors influencing RFS and OS were evaluated using univariate and multivariate models.ResultsHPV positivity was observed in 95%. HPV 16 accounted for 89%; of these, 64% harboured the T350G E6 variant. HPV 16 positivity was significantly correlated with improved 5-year RFS (62% versus 40%; p = 0.027) and OS (59% versus 38%; p = 0.019). p16 expression was also significantly correlated with improved 5-year RFS (positive versus negative: 65% versus 16%; p < 0.0001) and OS (63% versus 13%; p < 0.0001). In multivariable models that included HPV 16 status, p16 status, sex, and age, p16 expression remained an independent prognostic factor for RFS (p < 0.0001) and OS (p = 0.002).ConclusionIn ASCC, near-universal HPV detection rates were demonstrated, higher than generally reported in the literature, and supporting the development of multivalent HPV vaccinations for prevention. By contrast, p16 negatively, but not HPV 16 genotype, is an independent adverse prognosticator after chemo-radiotherapy in patients with ASCC.     

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

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

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.     

Categories of response to first line vascular endothelial growth factor receptor targeted therapy and overall survival in patients with metastatic renal cell carcinoma

IntroductionSequential use of targeted therapy (TT) has improved overall survival (OS) of patients with metastatic renal cell carcinoma (mRCC). The value of objective response (OR) as compared to stable disease (SD) is unclear. We aimed to investigate OR of first-line TT and its impact on OS.Material and methodsRetrospective analysis of OS among 331 mRCC patients with a first-line assessment according to RECIST 1.0. Characteristics between objective responders (complete response [CR] or partial remission [PR]), patients with SD and non-responders (progressive disease [PD] and toxicity [Tox]) were compared with the Chi-square test and the Kruskal–Wallis test. Kaplan–Meier analysis of OS and progression-free survival (PFS). Cox model analysis of Predictors of OS .ResultsBest response was CR, PR, SD, PD and Tox in 9 (2.7%), 61 (18.4%), 167 (50.5%), 80 (24.2%) and 14 (4.2%) patients respectively resulting in an OR rate of 21%. Median OS in months: CR 63.2; PR 37.6; SD 35.9; PD 14.6; TOX 22.5 (p < 0.0001). Median PFS for responders was 14.8, 11.5 for patients with SD and 2.5 for non-responders (p < 0.0001). Similarly median OS was 38.7, 35.9 and 15.5 (p < 0.00001). Primary resistance and a first-line PFS <6 months were the strongest independent predictors of OS. The achievement of OR as compared to SD did not impact OS.ConclusionsIn our cohort of unselected patients OR was not associated with superior OS as compared to SD.     

Survival comparision of three-dimensional radiotherapy alone with concurrent chemoradiotherapy for non-surgical esophageal carcinoma

PurposeRadiotherapy is the main treatment method for patients with locally advanced, unresectable esophageal cancer. The aim of this study is to compare overall survival (OS) using 3D radiotherapy (3DRT) alone with concurrent chemoradiotherapy (CCRT) in 296 non-surgical esophageal carcinoma patients.Patents and methodsOver 10 years, of the 480 patients with esophageal carcinoma treated with 3DRT with or without chemotherapy, 148 patients each comprised 3DRT and CCRT groups after propensity score matching.ResultsThe 5- and 10-year OS (P = 0.337) and PFS (P = 0.715) rates for 3DRT alone were 22.0%, 14.4% and 26.1%, 23.2%, respectively, compared with 28.8%, 18.6% and 34.7%, 29.1% for CCRT, respectively. CCRT did not improve 5-year and 10-year OS or PFS in 60–70 Gy group (OS: 27.5% and 25.2%; 17.9% and 17.0%, P = 0.938; PFS: 38.3% and 31.8%; 31.9% and 27.8%, P = 0.890) nor reduce 10-year hematogenous metastasis (31.7% and 28.3%, P = 0.698). CCRT improved 5-year OS and PFS of 50.0–59.9 Gy group (OS: 33.3% and 12.0%, P = 0.029; PFS: 33.1% and 10.6%, P = 0.081). For 3DRT, the 5-year OS and PFS rates were significantly better in the 60–70 Gy group (P = 0.017) compared with 50.0–59.9 Gy group (P = 0.002). For CCRT group, 5-year OS and PFS favored the 50.0–59.9 Gy group, but the difference was insignificant. Major toxicities were greater with CCRT compared with 3DRT.ConclusionFor non-surgical esophageal carcinoma patients, 3DRT combined with CCRT was effective in prolonging both OS and PFS.     

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 and predictive role of neutrophil/lymphocytes ratio in metastatic colorectal cancer: a retrospective analysis of the TRIBE study by GONO

BackgroundNeutrophil/lymphocyte ratio (NLR), defined as absolute neutrophils count divided by absolute lymphocytes count, has been reported as poor prognostic factor in several neoplastic diseases but only a few data are available about unresectable metastatic colorectal cancer (mCRC) patients (pts). The aim of our study was to evaluate the prognostic and predictive role of NLR in the TRIBE trial.Patients and methodsPts enrolled in TRIBE trial were included. TRIBE is a multicentre phase III trial randomizing unresectable and previously untreated mCRC pts to receive FOLFOXIRI or FOLFIRI plus bevacizumab. A cut-off value of 3 was adopted to discriminate pts with low (NLR < 3) versus high (NLR ≥ 3) NLR, as primary analysis. As secondary analysis, NLR was treated as an ordinal variable with three levels based on terciles distribution.ResultsNLR at baseline was available for 413 patients. After multiple imputation at univariate analysis, patients with high NLR had significantly shorter progression-free survival (PFS) [hazard ratio (HR) 1.27 (95% CI 1.05–1.55), P = 0.017] and overall survival (OS) [HR 1.56 (95% CI 1.25–1.95), P < 0.001] than patients with low NLR. In the multivariable model, NLR retained a significant association with OS [HR 1.44 (95% CI 1.14–1.82), P = 0.014] but not with PFS [HR 1.18 (95% CI 0.95–1.46), P = 0.375]. No interaction effect between treatment arm and NLR was evident in terms of PFS (P for interaction = 0.536) or OS (P for interaction = 0.831). Patients with low [HR 0.84 (95% CI 0.64–1.08)] and high [HR 0.73 (95% CI 0.54–0.97)] NLR achieved similar PFS benefit from the triplet and consistent results were obtained in terms of OS [HR 0.83 (95% CI 0.62–1.12) for low NLR; HR 0.82 (95% CI 0.59–1.12) for high NLR].ConclusionThis study confirmed the prognostic role of NLR in mCRC pts treated with bevacizumab plus chemotherapy in the first line, showing the worse prognosis of pts with high NLR. The advantage of the triplet is independent of NLR at baseline.     

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.     

Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17

BackgroundRight- and left-sided colon cancers (RC, LC) differ with respect to biology, pathology and epidemiology. Previous data suggest a mortality difference between RC and LC. We examined if primary tumour side also predicts for outcome in chemotherapy refractory, metastatic colon cancer (MCC). We also compared RC versus LC as a predictor of efficacy of epidermal growth factor receptor (EGFR) inhibition with cetuximab.MethodsReanalyzing NCIC CO.17 trial (cetuximab versus best supportive care [BSC]), we coded the primary tumour side as RC (caecum to transverse colon) or LC (splenic flexure to rectosigmoid). The association between tumour side and baseline characteristics was assessed. Cox regression models determined factors affecting overall survival (OS) and progression free survival (PFS).ResultsPatients with RC (150/399) had more poorly differentiated, mutant KRAS, mutated PIK3CA and wild-type BRAF tumours, fewer liver and lung metastases, and shorter interval between diagnosis and study entry. Among BSC patients, tumour side was not prognostic for PFS (hazard ratios (HR) 1.07 [0.79–1.44], p = 0.67) or OS (HR 0.96 [0.70–1.31], p = 0.78). Among wild-type KRAS patients, those with LC had significantly improved PFS when treated with cetuximab compared to BSC (median 5.4 versus 1.8 months, HR 0.28 [0.18–0.45], p < 0.0001), whereas those with RC did not (median 1.9 versus 1.9 months, HR 0.73 [0.42–1.27], p = 0.26), [interaction p = 0.002].ConclusionIn refractory MCC, tumour location within the colon is not prognostic, but is strongly predictive of PFS benefit from cetuximab therapy. Additional research is needed to understand the molecular differences between RC and LC and their interaction with EGFR inhibition.     

Overall survival with cisplatin–gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL)

BackgroundBevacizumab, the anti-vascular endothelial growth factor agent, provides clinical benefit when combined with platinum-based chemotherapy in first-line advanced non-small-cell lung cancer. We report the final overall survival (OS) analysis from the phase III AVAiL trial.Patients and methodsPatients (n = 1043) received cisplatin 80 mg/m² and gemcitabine 1250 mg/m² for up to six cycles plus bevacizumab 7.5 mg/kg (n = 345), bevacizumab 15 mg/kg (n = 351) or placebo (n = 347) every 3 weeks until progression. Primary end point was progression-free survival (PFS); OS was a secondary end point.ResultsSignificant PFS prolongation with bevacizumab compared with placebo was maintained with longer follow-up {hazard ratio (HR) [95% confidence interval (CI)] 0.75 (0.64–0.87), P = 0.0003 and 0.85 (0.73–1.00), P = 0.0456} for the 7.5 and 15 mg/kg groups, respectively. Median OS was >13 months in all treatment groups; nevertheless, OS was not significantly increased with bevacizumab [HR (95% CI) 0.93 (0.78–1.11), P = 0.420 and 1.03 (0.86–1.23), P = 0.761] for the 7.5 and 15 mg/kg groups, respectively, versus placebo. Most patients (∼62%) received multiple lines of poststudy treatment. Updated safety results are consistent with those previously reported.ConclusionsFinal analysis of AVAiL confirms the efficacy of bevacizumab when combined with cisplatin–gemcitabine. The PFS benefit did not translate into a significant OS benefit, possibly due to high use of efficacious second-line therapies.     

Primary cardiac sarcomas: A retrospective study of the French Sarcoma Group

IntroductionPrimary cardiac sarcomas (PCS) are rare tumours of dismal prognosis.MethodsData of 124 patients with PCS referred to institutions of the French Sarcoma Group (FSG) from 1977 and 2010 were reviewed.ResultsMedian age was 48.8 years. PCS were poorly-differentiated sarcomas (N = 45, 36.3%), angiosarcomas (N = 40, 32.3%), leiomyosarcomas (N = 16, 12.9%) and others (N = 23, 18.6%). At diagnosis, 100 patients (80.6%) were localised and 24 (19.4%) metastatic. Tumours were located in the right (N = 47, 38.8%), left atrial cavities (N = 45, 37.2%) or encompassed several locations in nine cases (7.4%). Surgery was performed in 81 cases (65.3%). Heart transplant was performed in five patients. Radiotherapy adjuvant (N = 18, 14.5%) or alone (N = 6, 4.8%) was performed in non-metastatic patients only (N = 24, 19.4%). With a median follow-up of 51.2 months, median overall survival (OS) was 17.2 months for the entire cohort, 38.8 months after complete resection versus 18.2 after incomplete resection and 11.2 months in non-resected patients. Radiotherapy was associated with improved progression-free survival (PFS) on multivariate analysis. Chemotherapy was significantly associated with better OS only in non-operated patients but not in operated patients. In non-metastatic patients, surgery (hazard ratio [HR] = 0.42, p < 0.001), male gender (HR = 0.56, p = .032) was associated with better OS and surgery (HR = 0.61; p = .076), radiotherapy (HR = 0.43; p = .004) and chemotherapy (HR = 0.30, p = .003) improved PFS.ConclusionOnly surgical resection is associated with a perspective of prolonged survival. Chemotherapy is associated with a better outcome in non-resected patients.     

Elevated LDH predicts poor outcome of recurrent germ cell tumours treated with dose dense chemotherapy

Aims of the studyPrognostic factors for recurrent germ cell tumours (GCTs) treated with dose dense salvage chemotherapy have not been identified. This study determines whether lactate dehydrogenase (LDH) or established prognostic models can predict the outcome of recurrent GCTs treated with dose dense cisplatin-based chemotherapy.Patients and methodsRetrospective analysis of 117 consecutive male patients with a first recurrence of a GCT treated with dose dense chemotherapy at a single cancer centre. Characteristics associated with progression-free survival (PFS) and overall survival (OS) were identified by univariate and multivariate analyses. Prognostic criteria published by the Medical Research Council (MRC) and the Memorial Sloan Kettering Cancer Centre (MSK) were also applied in an attempt to validate them and to compare their performance to that of LDH.ResultsRaised LDH was significantly associated with poor PFS (hazard ratio (HR) = 3.7; p < 0.001) and OS (HR = 3.4; p = 0.001). Further factors associated with poor PFS and OS, respectively, were failure to achieve a complete response or marker negative partial response for at least 6 months (HR = 2.1; p = 0.033) and seminoma histology (HR = 3.4; p = 0.003). The MRC prognostic model, but not the MSK model, identified groups of patients with statistically significant differences in PFS and OS but raised LDH predicted OS and PFS with a higher HR.ConclusionsRaised LDH is associated with a poor prognosis in recurrent GCTs and outperforms established prognostic models in this setting. LDH as a prognostic factor should be validated prospectively and should also be assessed in patients receiving conventional dose chemotherapy regimens.     

Influence of low absolute lymphocyte count of patients with nongerminal center type diffuse large B-cell lymphoma with R-CHOP therapy

BackgroundRituximab has dramatic impact on outcome of patients with diffuse large B-cell lymphoma (DLBCL), especially nongerminal center (non-GC) type. A low absolute lymphocyte count (ALC) before rituximab, cyclophosphamide, vincristine, adriamycin, and prednisone (R-CHOP) therapy as a surrogate marker of immune status is associated with poor clinical outcome in DLBCL. Therefore, we hypothesized that low ALC before R-CHOP would have effect on the survival in non-GC type.Patients and methodsOne hundred and thirty-six DLBCL patients who were treated with R-CHOP from 2003 to 2007 were analyzed in the present study.ResultsALC ≥1.0 × 10⁹/l predicted a longer 3-year progression-free survival (PFS) and 3-year overall survival (OS) versus ALC <1.0 × 10⁹/l (82.6% versus 60.0%, P = 0.005 and 87.2% versus 62.0%, P < 0.001, respectively). Non-GC type had similar PFS and OS to germinal center type (68.2% versus 80.0%, P = 0.074 and 72.7% versus 82.9%, P = 0.111, respectively). However, considering clinical influence of the ALC according to immunophenotype, low ALC in non-GC type DLBCL was associated with lower PFS and OS compared with others (PFS, P = 0.002; OS, P < 0.001). Multivariate analysis revealed that low ALC in non-GC type had lower PFS [hazard ratio (HR) = 3.324, P = 0.001] and OS (HR = 4.318, P < 0.001), independent of international prognostic index.ConclusionA low ALC in non-GC type DLBCL counteracted the beneficial effect of rituximab on survival.     

Mechanism of drug resistance in relation to site of metastasis: Meta-analyses of randomized controlled trials in advanced breast cancer according to anticancer strategy

BackgroundBreast cancer is heterogeneous at different levels: biologic subtypes, intratumoral areas, and sites of metastases. Randomized controlled trials (RCTs) classify metastatic sites as visceral or non-visceral, but this has little influence in treatment decisions, particularly in the absence of clinical urgency. Indeed, it is unclear if response to treatments differs among sites of metastases.Patients and methodsRCTs investigating 3 different anticancer strategies in metastatic breast cancer were identified: (1) new hormonal therapy, (2) new targeted therapies in hormone receptor positive tumours (everolimus or palbociclib), and (3) new anti-HER2 therapies. RCTs reporting hazard ratios (HR) for Progression Free Survival (PFS) and Overall Survival (OS) for sub-groups based on sites of metastases were weighted using generic inverse variance approach, and pooled in meta-analyses using Revman 5.3. Subgroup difference was tested with Chi² statistics.ResultsEleven RCTs (6701 pts.) qualified. There was a significant difference in PFS between women with visceral versus non-visceral metastases when two endocrine strategies were compared, with benefits limited to women with visceral metastases [Pooled HR 0.85; 95% CI, 0.77–0.95 versus 1.02 (0.88–1.18) for non-visceral; p(difference) = 0.05]. However, combination of an endocrine therapy and a targeted therapy was associated with better PFS compared to endocrine therapy alone for both groups [HR 0.51 (0.43–0.60) versus 0.45 (0.36–0.56) for non-visceral; p(difference) = 0. 36]. Novel HER-2 targeted therapies were associated with significantly better PFS and OS only in visceral metastases [HR 0.59 (0.52–0.66) versus 0.71(0.44–1.13) for non-visceral, p(difference) = 0.45, for PFS; and 0.64 (0.56–0.73) versus 0.82 (0.57 = 1.19) for non-visceral, p(difference) = 0.20, for OS].ConclusionCombination of targeted agents and endocrine therapy results in concordant, superior PFS suggesting targetable endocrine resistance across metastatic sites. Discordant responses with endocrine strategy alone support use of targeted therapy, rather than change in endocrine agent at disease progression. HER2 targeted therapies may be less effective in areas of poor vascularization.     

Genetic polymorphisms of SLC28A3, SLC29A1 and RRM1 predict clinical outcome in patients with metastatic breast cancer receiving gemcitabine plus paclitaxel chemotherapy

BackgroundPaclitaxel and gemcitabine (PG) combination chemotherapy is effective as a maintenance chemotherapeutic regimen in metastatic breast cancer (MBC) patients because it increases progression-free survival (PFS), which increases overall survival (OS). The primary purpose of our study was to investigate the association between genetic polymorphisms in the genes involved in PG pathways and clinical outcomes in MBC patients treated with PG chemotherapy.MethodsA total of 324 MBC patients were enrolled in this prospective multicenter trial of PG as the first-line chemotherapy. Eighty-five of the 324 patients from two institutes were available for analysis of single nucleotide polymorphisms (SNPs). Germline DNA was extracted from peripheral blood mononuclear cells. Thirty-eight SNPs in 15 candidate genes selected from pathways that may influence the metabolism and transport of, or sensitivity, to PG were analysed.ResultsThe median PFS and OS of all 324 patients were 8.7 months (95% confidence interval [CI]: 7.5–9.6 months) and 26.9 months (95% CI: 23.6–30.1 months), respectively. An SNP in SLC28A3 (rs7867504, C/T) was associated with OS (CC or CT versus TT: 37 versus 21 months, p = 0.027, hazard ratio [HR] 2.6, 95% CI: 1.1–6.3). SLC29A1 GA haplotype had a significantly shorter OS (p = 0.030, HR 3.391, 95% CI: 1.13–10.19). RRM1 (ribonucleotide reductase large subunit M1) SNP (rs9937), and haplotypes ATAA and ATGA were significantly associated with neurotoxicity.ConclusionGenetic polymorphisms in SLC28A3, SLC29A1 and RRM1 can influence the clinical outcome of MBC patients treated with PG chemotherapy. Further studies on the functional mechanisms relating to these germline polymorphisms in these genes are warranted.     

Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer

BackgroundWe analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC).Patients and methodsALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders.ResultsAmong 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4–5.6) versus 10.3 months (95% CI: 8.6–12.0), P < 0.001; OS 15.0 months (95% CI: 5.0–24.9) versus 50.0 months (95% CI: 22.9–77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3–4.1) versus 6.2 months (95% CI: 1.8–10.5), P = 0.021; OS 2.0 months (95% CI: 0.0–4.6) versus 9.0 months (95% CI: 6.1–11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9–7.2) versus 14.0 months (95% CI: 8.0–20.1), P < 0.001; OS 17.0 months (95% CI: 6.7–27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1–10.7) versus 9.9 months (95% CI: 6.4–13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001).ConclusionsIn ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.     

Prognostic importance of cell-free DNA in chemotherapy resistant ovarian cancer treated with bevacizumab

AimTreatment of multiresistant epithelial ovarian cancer (EOC) is palliative and patients who have become resistant after multiple lines of chemotherapy often have an unmet need for further and less toxic treatment. Anti-angiogenic therapy has attracted considerable attention in the treatment of EOC in combination with chemotherapy. However, only a minor subgroup will benefit from the treatment and there is an obvious need for new markers to select such patients.The purpose of this study was to investigate the effect of single-agent bevacizumab in multiresistant EOC and the importance of circulating cell-free DNA (cfDNA) in predicting treatment response.MethodsOne hundred and forty-four patients with multi-resistant EOC were treated with single-agent bevacizumab 10 mg/kg every three weeks. Baseline plasma samples were analysed for levels of cfDNA by real-time polymerase chain reaction (PCR).ResultsEighteen percent responded to treatment according to CA125 and 5.6% had partial response by Response Evaluation Criteria in Solid Tumours (RECIST). Stable disease was seen in 53.5% and 48.6% of the patients by CA125 and RECIST, respectively. Median progression free survival (PFS) and overall survival (OS) were 4.2 and 6.7 months, respectively. Cell-free DNA was highly correlated to PFS (p = 0.0004) and OS (p = 0.005) in both univariate and multivariate analyses (PFS, hazard ratio (HR) = 1.98, p = 0.002; OS, HR = 1.66, p = 0.02), as patients with high cfDNA had a poor outcome.ConclusionsSingle-agent bevacizumab treatment in multiresistant EOC appears to be a valuable treatment option with acceptable side-effects. Cell-free DNA showed independent prognostic importance in patients treated with bevacizumab and could be applied as an adjunct for treatment selection.     

High subcutaneous adipose tissue predicts the prognosis in metastatic castration-resistant prostate cancer patients in post chemotherapy setting

BackgroundCancer studies have shown that body mass index (BMI), skeletal muscle mass (SMM) and adipose tissue indexes are linked to overall survival (OS) and progression-free survival (PFS). New treatments (abiraterone acetate, enzalutamide cabazitaxel, radium-223, sipuleucel-T) have improved patient outcomes in metastatic castration-resistant prostate cancer (mCRPC). Our objective was to analyse whether body composition parameters exert a prognostic role in mCRPC patients treated with next generation of androgen receptor (AR) axis inhibitors (abiraterone and enzalutamide).MethodsAll mCRPC patients from our institution who were enrolled in two prospective trials, assessing the efficacy of abiraterone acetate and the efficacy of enzalutamide, were selected. SMM, visceral and subcutaneous adipose tissue (SAT) indexes were assessed with computed tomography imaging by measuring cross-sectional areas of the tissues.ResultsIn the 120 patients with available data, median OS and PFS were respectively: 16 months (95% confidence interval [CI] = 12–19) and 4 months (95% [CI] = 3–6). OS was associated with the SAT index: median survival was 15 months (95% [CI] 9–18) for patients with a SAT index < median value and 18 months (95% [CI] 13–30) for patients with a SAT index above (P = 0.008). In multivariate analyses, only the occurrence of visceral metastasis (P = 0.004), pain (P = 0.015) and SAT index (P = 0.036) were statistically significant predictors of OS. From baseline to 3 months, the SMM index loss was 2.49 ± 0.44 cm²/m² (P < 0.001) corresponding to nearly 3.4 kg of muscle loss.ConclusionsHigh volume of SAT is independently associated with overall survival in mCRPC patients treated with next generation AR axis inhibitors.     

Worldwide human papillomavirus genotype attribution in over 2000 cases of intraepithelial and invasive lesions of the vulva

BackgroundHuman papillomavirus (HPV) contribution in vulvar intraepithelial lesions (VIN) and invasive vulvar cancer (IVC) is not clearly established. This study provides novel data on HPV markers in a large series of VIN and IVC lesions.MethodsHistologically confirmed VIN and IVC from 39 countries were assembled at the Catalan Institute of Oncology (ICO). HPV-DNA detection was done by polymerase chain reaction using SPF-10 broad-spectrum primers and genotyping by reverse hybridisation line probe assay (LiPA₂₅) (version 1). IVC cases were tested for p16^INK4a by immunohistochemistry (CINtec histology kit, ROCHE).An IVC was considered HPV driven if both HPV-DNA and p16^INK4a overexpression were observed simultaneously. Data analyses included algorithms allocating multiple infections to calculate type-specific contribution and logistic regression models to estimate adjusted prevalence (AP) and its 95% confidence intervals (CI).ResultsOf 2296 cases, 587 were VIN and 1709 IVC. HPV-DNA was detected in 86.7% and 28.6% of the cases respectively. Amongst IVC cases, 25.1% were both HPV-DNA and p16^INK4a positive. IVC cases were largely keratinising squamous cell carcinoma (KSCC) (N = 1234). Overall prevalence of HPV related IVC cases was highest in younger women for any histological subtype. SCC with warty or basaloid features (SCC_WB) (N = 326) were more likely to be HPV and p16^INK4a positive (AP = 69.5%, CI = 63.6–74.8) versus KSCC (AP = 11.5%, CI = 9.7–13.5). HPV 16 was the commonest type (72.5%) followed by HPV 33 (6.5%) and HPV 18 (4.6%). Enrichment from VIN to IVC was significantly high for HPV 45 (8.5-fold).ConclusionCombined data from HPV-DNA and p16^INK4a testing are likely to represent a closer estimate of the real fraction of IVC induced by HPV. Our results indicate that HPV contribution in invasive vulvar cancer has probably been overestimated. HPV 16 remains the major player worldwide.