S100A2 is a predictive biomarker of adjuvant therapy benefit in pancreatic adenocarcinoma

BackgroundPrognosis of patients with pancreatic adenocarcinoma (PAC) remains poor. S100A2 has been recently suggested as a negative prognostic biomarker in PAC. We aimed to investigate its prognostic and/or predictive value in a large independent multicentric cohort of patients with resected PAC.MethodsSequential samples of 471 patients were retrospectively collected; 142 patients did not receive adjuvant treatment (30%) and 329 (70%) received an adjuvant treatment. We measured protein levels of S100A2 by semiquantitative immunohistochemistry with tissue microarrays and correlated with patients’ overall survival (OS) and disease-free survival (DFS).ResultsS100A2 protein status was obtained in 462 (98%) patients. Its expression was low, moderate or high in 59%, 12% and 2% of cases, respectively. It was not correlated with DFS or OS in the whole population, neither in the subgroup of patients who did not receive adjuvant treatment. However among patients who received an adjuvant therapy, moderate/high levels of S100A2 were significantly associated with longer OS and DFS in multivariate analysis (hazard ratios of 0.63, p = 0.022 and 0.67, p = 0.017, respectively), whereas low S100A2 was not. Interaction tests for adjuvant therapy were statistically significant both for the OS and the DFS (p = 0.001 and p = 0.023, respectively). On multivariate analysis, S100A2 retained independent predictive values (OS: p < 0.001, DFS: p = 0.003) with a significant benefit of adjuvant therapy for those patients with moderate/high S100A2.ConclusionsS100A2 expression predicts longer DFS and OS in patients treated with adjuvant therapy and should be evaluated as a predictive biomarker.     

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.     

The prognostic significance of minimal residual disease in adult Egyptian patients with precursor acute lymphoblastic leukemia

BackgroundMinimal residual disease (MRD) studies in adult acute lymphoblastic leukemia (ALL) give highly significant prognostic information superior to other standard criteria as age, gender and total leucocytic count (TLC) in distinguishing patients at high and low risk of relapse.ObjectivesWe aimed to determine the value of MRD monitoring by flowcytometry (FCM) in predicting outcome in adult Precursor ALL patients.Patients and methodsBone marrow (BM) samples were analyzed by 4-color FCM collected at diagnosis and after induction therapy (MRD1) to correlate MRD positivity with disease free survival (DFS) and overall survival (OS).ResultsStudy included 57 adult ALL patients (44 males and 13 females) with a median age of 22 years (18–49). DFS showed no significant difference with age, gender and initial TLC (p = 0.838, 0.888 and 0.743, respectively). Cumulative DFS at 2 years was 34% for B-lineage ALL (n: 35) and 57% for T-lineage ALL (n: 18) (p = 0.057). Cumulative DFS at 2 years was 7% for MRD1 positive (high risk, HR) versus 57% for MRD1 negative patients (Low risk, LR) (p < 0.001). Cumulative DFS at 2 years was 29% for HR patients (n: 26) versus 55% for LR (n: 27) according to GMALL classification (p = 0.064). Cumulative OS did not differ according to age, gender and TLC (p = 0.526, 0.594 and 0.513, respectively). Cumulative OS at 2 years was 36% for B ALL (n: 39) versus 77% for TALL (n: 18) (p = 0.016) and was 49% for Philadelphia chromosome (Ph) negative patients versus 0% for Ph-positive patients (p < 0.001). Regarding MRD1, OS at 2 years was 18% for MRD1 HR (n: 17) versus 65% for MRD1 LR (n: 38) (p < 0.001). OS was 35% for high-risk patients (n: 30) and 62% for low-risk patients (n: 27) classified according to GMALL risk stratification (p = 0.017).ConclusionMRD by FCM is a strong independent predictor of outcome in terms of DFS and OS and is a powerful informative parameter in guiding individual treatment in ALL patients.     

Is quantitative oestrogen receptor expression useful in the evaluation of the clinical prognosis? Analysis of a homogeneous series of 797 patients with prospective determination of the ER status using simultaneous EIA and IHC

ObjectiveOestrogen receptor (ER) determination in breast cancer (BC) is a major yardstick for the prognosis and for response to hormonal therapy (HT). As several techniques have been proposed for ER quantification, the purpose of our study was to assess whether the qualitative or quantitative analysis of ER expression might influence the prognosis and response to treatment.Materials and methodsWe analysed overall survival (OS) and disease-free survival (DFS) in 797 primary BC cases with ER determination by enzyme immunoassay (EIA) and immunohistochemistry (IHC). The clinical impact according to qualitative or quantitative analysis of ER expression was assessed. Response to HT was evaluated according to quantitative EIA-determined ER expression levels.ResultsAccording to the qualitative analysis of ER expression, patients with EIA-determined and IHC-determined ER-positive tumours had significantly longer OS and DFS (p < 0.001). The analysis stratified on quartiles of ER levels showed significantly different outcomes according to EIA- and IHC-determined subgroups. In the group of patients who received adjuvant treatment, 5-year OS was significantly different between the groups, with a clear benefit for the highest EIA-determined ER quartiles (p < 0.001). Comparatively, in terms of 5-year DFS, a clear separation was noted between groups for adjuvant treatment (p < 0.001). The group with moderate ER+ values was clearly distinct from the ER-negative population. Quantitative ER expression helped to better distinguish the beneficial or detrimental effect of HT within quartiles of ER-expressing tumours. Based on the STEPP analysis which showed a trend towards an ER effect on DFS as a function of HT assignment, we confirm the benefit of HT in patients with a very high EIA-determined ER level and a detrimental impact on negative and weakly positive groups.ConclusionQuantitative ER expression in BC helps to better discriminate heterogeneity in clinical outcome and response to HT.     

Prognostic relevance of disseminated tumour cells from the bone marrow of early stage breast cancer patients – Results from a large single-centre analysis

BackgroundThis is the largest single-centre study to determine the prognostic relevance of disseminated tumour cells (DTCs) from the bone marrow (BM) of stage I-III breast cancer patients. Additionally, we aimed to analyse the impact of DTC detection on adjuvant bisphosphonate (BP) treatment efficacy.MethodsBM aspirates were collected during primary surgery for early breast cancer (EBC; T1–4, N0–2, M0) at Tuebingen University, Germany, between January 2001 and January 2013. DTCs were identified by immunocytochemistry (pancytokeratin antibody A45/B-B3) and cytomorphology. We retrospectively estimated the influence of DTC detection and BP treatment on disease-free survival (DFS) and overall survival (OS) using univariate (log-rank test) and multivariate (cox regression) analysis.FindingsBM aspirates were available from 3141 patients. In 803 (26%) of these, DTCs were detectable. As compared to DTC-negative patients, DTC-positive patients more frequently had larger tumors (p < 0.001), lymph node involvement (p < 0.001), hormonal receptor positive tumours (p < 0.001) and HER2-positive tumours (p = 0.048). DTC-positive patients were at an increased risk of relapse (hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.34–2.25, p < 0.001) and death (HR 1.44 95% CI 1.13–1.86, p = 0.004). In the multivariate analysis DTCs were an independent predictor of DSF and OS. Additionally, BP treatment had no significant influence on DFS or OS in DTC-negative patients, while it was significantly associated with increased DFS (p < 0.001) and OS (p = 0.006) in DTC-positive patients.InterpretationThese data confirm the clinical validity of DTCs from the BM for prognostication of early breast cancer patients. Further studies are warranted to determine whether DTCs are predictive for adjuvant treatment efficacy using bisphosphonates.     

Single organ metastatic disease and local disease status,prognostic factors for overall survival in stage IV non-small cell lung cancer: Results from a population-based study

PurposeTo analyse the prognostic impact on overall survival (OS) of single versus multiple organ metastases, organ affected, and local disease status in a population based stage IV non-small cell lung cancer (NSCLC) cohort.MethodsIn this observational study, data were analysed of all histologically confirmed stage IV NSCLC patients diagnosed between 1 January 2006 and 31 December 2012 registered in the Netherlands Cancer Registry. Location of metastases before treatment was registered. Multivariable survival analyses [age, gender, histology, M-status, local disease status, number of involved organs, actual organ affected] were performed for all patients and for an ¹⁸fluorodeoxyglucose-positron emission tomography (¹⁸FDG-PET)-staged subgroup.Results11,094 patients were selected: 60% male, mean age 65 years, 73% adenocarcinoma. Median OS for 1 (N = 5676), 2 (N = 3280), and ⩾3 (N = 2138) metastatically affected organs was 6.7, 4.3, 2.8 months, respectively (p < 0.001). Hazard ratio (HR) for 2 versus 1 organ(s) was 1.33 (p < 0.001), for ⩾3 versus 1 organ(s) 1.91 (p < 0.001). Results were confirmed in the ¹⁸FDG-PET-staged cohort (N = 1517): patients with single organ versus 2 and ⩾3 organ metastases had higher OS (8.6, 5.7, 3.8 months, HR 1.40 and 2.17, respectively, p < 0.001). In single organ metastases, OS for low versus high TN-status was 8.5 versus 6.5 months [HR 1.40 (p < 0.001)]. ¹⁸FDG-PET-staged single organ metastases patients with low TN-status had a superior OS than those with high TN-status (11.6 versus 8.2 months, HR 1.62, p < 0.001).ConclusionPatients with single organ metastases stage IV NSCLC have a favourable prognosis, especially in combination with low TN status. They have to be regarded as a separate subgroup of stage IV disease.     

A phase III adjuvant randomised trial of 6 cycles of 5-fluorouracil–epirubicine–cyclophosphamide (FEC100) versus 4 FEC 100 followed by 4 Taxol (FEC-T) in node positive breast cancer patients (Trial B2000)

BackgroundStandard adjuvant chemotherapy regimens for patients with node positive (N+) breast cancer consisted of anthracycline followed by taxane. The European Association for Research in Oncology embarked in 2000 on a phase III trial comparing 6 cycles of FEC₁₀₀ versus 4 FEC₁₀₀ followed by 4 Taxol. Primary end-point was disease free survival. Secondary end-points were overall survival, local recurrence free interval, metastases free interval and safety.Patients and methodsBetween March 2000 and December 2002, 837 patients were randomised between 6FEC₁₀₀ for 6 cycles (417 patients) or FEC₁₀₀ for 4 cycles then Taxol 175 mg/m²/3 weeks for 4 cycles (4FEC₁₀₀-4T) (420 patients). One thousand patients had been planned initially but the trial was closed earlier due to slow accrual.ResultsHazard ratios (HRs) were 0.99 for disease-free survival (DFS) (95%CI: 0.77–1.26; p = 0.91), and 0.85 for overall survival (OS) (95%CI: 0.62–1.15; p = 0.29). Nine-year DFS were 62.9% versus 62.5% for 6FEC₁₀₀ and 4FEC₁₀₀-4T, respectively. Nine-year OS were 73.9% versus 77% for 6FEC₁₀₀ and 4FEC₁₀₀-4T, respectively. Toxicity analyses based on 803 evaluable patients showed that overall grade 3–4 toxicities were similar in both arms (63% versus 58% for 6FEC₁₀₀ arm and 4FEC₁₀₀-4T arm, respectively; p = 0.16).ConclusionIn this trial replacing the last 2 FEC₁₀₀ cycles of 6FEC₁₀₀ regimen by 4 Taxol does not lead to a discernable DFS or OS advantage. The lack of a significant difference between the randomised treatment arms may however be due to a lack of power of this trial to detect small, yet clinically worthwhile, treatment benefits.     

A nomogram associated with high probability of malignant nodes in the surgical specimen after trimodality therapy of patients with oesophageal cancer

BackgroundThe presence of malignant lymph nodes (+ypNodes) in the surgical specimen after preoperative chemoradiation (trimodality) in patients with oesophageal cancer (EC) portends a poor prognosis for overall survival (OS) and disease-free survival (DFS). Currently, none of the clinical variables highly correlates with +ypNodes. We hypothesised that a combination of clinical variables could generate a model that associates with high likelihood of +ypNodes after trimodality in EC patients.MethodsWe report on 293 consecutive EC patients who received trimodality therapy. A multivariate logistic regression analysis that included pretreatment and post-chemoradiation variables identified independent variables that were used to construct a nomogram for +ypNodes after trimodality in EC patients.ResultsOf 293 patients, 91 (31.1%) had +ypNodes. OS (p = 0.0002) and DFS (p < 0.0001) were shorter in patients with +ypNodes compared to those with –ypNodes. In multivariable analysis, the significant variables for +ypNodes were: baseline T-stage (odds ratio [OR], 7.145; 95% confidence interval [CI], 1.381–36.969; p = 0.019), baseline N-stage (OR, 2.246; 95% CI, 1.024–4.926; p = 0.044), tumour length (OR, 1.178; 95% CI, 1.024–1.357; p = 0.022), induction chemotherapy (OR, 0.471; 95% CI, 0.242–0.915; p = 0.026), nodal uptake on post-chemoradiation positron emission tomography (OR, 2.923; 95% CI, 1.007–8.485; p = 0.049) and enlarged node(s) on post-chemoradiation computerised tomography (OR, 3.465; 95% CI, 1.549–7.753; p = 0.002). The nomogram after internal validation using the bootstrap method (200 runs) yielded a high concordance index of 0.756.ConclusionOur nomogram highly correlates with the presence of +ypNodes after chemoradiation, however, considerably more refinement is needed before it can be implemented in the clinic.     

Abiraterone acetate in metastatic castration-resistant prostate cancer: A retrospective review of the Princess Margaret experience of (I) low dose abiraterone and (II) prior ketoconazole

IntroductionAbiraterone (AA) is a CYP17 inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC). Data suggest similar pharmacokinetics of 250–500 mg of AA with high-fat meals (‘low-dose’) and 1000 mg in the fasting state (‘full-dose’). Ketoconazole (KT) is a less potent CYP17 inhibitor previously widely used in mCRPC.ObjectiveTo study outcomes of men with mCRPC treated with low-dose AA and/or with prior exposure to KT.Patients and methodsRetrospective chart review of all men treated with AA at the Princess Margaret Cancer Centre between November 2009 and March 2013. Outcome measures were prostate-specific antigen response rate (PSA-RR), biochemical progression-free survival (bPFS), treatment duration and overall survival (OS). Associations between AA dose or prior KT and outcomes were assessed using chi-square test for PSA-RR and log-rank test for bPFS, treatment duration and OS.ResultsIn total, 111 men who received AA were evaluable, of which 21 received low-dose AA and 23 received prior KT. There was a non-significant difference in PSA-RR (43% versus 32%, p = 0.37), but no significant differences in median bPFS, median treatment duration and median OS (18.7 versus 16.6 months, p = 0.25) in the full and low-dose cohorts respectively, and for those who received prior KT or not (PSA-RR 48% versus 38%, p = 0.4; median OS 24.2 versus 16.5 months, p = 0.066, respectively).ConclusionsLow-dose AA or prior KT treatment were not associated with poorer outcome in men with mCRPC treated with AA. These observations may have implications for drug sequencing and dose in resource-limited settings.     

Mesenchymal chondrosarcoma: Prognostic factors and outcome in 113 patients. A European Musculoskeletal Oncology Society study

BackgroundMesenchymal chondrosarcoma (MCS) is a distinct, very rare sarcoma with little evidence supporting treatment recommendations.Patients and methodsSpecialist centres collaborated to report prognostic factors and outcome for 113 patients.ResultsMedian age was 30 years (range: 11–80), male/female ratio 1.1. Primary sites were extremities (40%), trunk (47%) and head and neck (13%), 41 arising primarily in soft tissue. Seventeen patients had metastases at diagnosis. Mean follow-up was 14.9 years (range: 1–34), median overall survival (OS) 17 years (95% confidence interval (CI): 10.3–28.6). Ninety-five of 96 patients with localised disease underwent surgery, 54 additionally received combination chemotherapy. Sixty-five of 95 patients are alive and 45 progression-free (5 local recurrence, 34 distant metastases, 11 combined). Median progression-free survival (PFS) and OS were 7 (95% CI: 3.03–10.96) and 20 (95% CI: 12.63–27.36) years respectively. Chemotherapy administration in patients with localised disease was associated with reduced risk of recurrence (P = 0.046; hazard ratio (HR) = 0.482 95% CI: 0.213–0.996) and death (P = 0.004; HR = 0.445 95% CI: 0.256–0.774). Clear resection margins predicted less frequent local recurrence (2% versus 27%; P = 0.002). Primary site and origin did not influence survival. The absence of metastases at diagnosis was associated with a significantly better outcome (P < 0.0001). Data on radiotherapy indications, dose and fractionation were insufficiently complete, to allow comment of its impact on outcomes. Median OS for patients with metastases at presentation was 3 years (95% CI: 0–4.25).ConclusionsPrognosis in MCS varies considerably. Metastatic disease at diagnosis has the strongest impact on survival. Complete resection and adjuvant chemotherapy should be considered as standard of care for localised disease.     

Time to initiation of adjuvant chemotherapy in patients with rapidly proliferating early breast cancer

AimTo evaluate the optimal time interval from definitive surgery to commencing chemotherapy in early breast cancer (EBC).Patients and methodsThe relationship between time to initiation of adjuvant chemotherapy (TTC), calculated in weeks, and disease-free (DFS) or overall survival (OS), was assessed in 921 EBC patients with rapidly proliferating tumours (thymidine labelling index >3% or G3 or Ki67 >20%), randomised in a phase III clinical trial (NCT01031030) to receive chemotherapy with or without anthracyclines (epirubicin → cyclophosphamide, methotrexate and fluorouracil (CMF) versus CMF → epirubicin versus CMF). DFS, OS and 95% confidence intervals (95% confidence interval (CI)) were calculated by the Kaplan–Meier method. Multivariate Cox analysis was performed in relation with nodal involvement, oestrogen receptor and human epidermal growth factor receptor 2 (HER2) status, Ki67 value, type of adjuvant chemotherapy, menopausal status and tumour size.ResultsAt a median follow-up of 105 months (range 2–188), a prolonged TTC resulted in a significant increase in the risk of relapse: hazard ratio (HR) 1.15 (95% CI 1.02–1.30, p = 0.019). Using a backward elimination procedure, TTC, tumour size and nodal involvement remained significantly associated with DFS. A time-dependent receiver-operating characteristic (ROC) curve analysis was subsequently utilised to evaluate the best cut-off for TTC, identifying 7 weeks as the best threshold for longer OS (p = 0.043): 8-year OS 88% (95% CI 85–90) for patients with a TTC <7 weeks and 78% (95% CI 68–87) for the other group.ConclusionsOur results confirm that a shorter TTC may reduce relapses and possibly also improve clinical outcome in patients with highly proliferating EBC.     

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.     

The elevated C-reactive protein level is associated with poor prognosis in prostate cancer patients treated with radiotherapy

BackgroundC-reactive protein (CRP) is a sensitive marker of inflammation that has been linked with prognosis in various solid tumours. In the present study, we analysed the prognostic relevance of elevated plasma CRP levels in prostate cancer patients treated with radiotherapy.MethodsA total of 261 prostate cancer patients treated with 3D-conformal radiotherapy were evaluated retrospectively. Cancer specific survival (CSS), overall survival (OS) and clinical disease-free survival (DFS) were assessed using Kaplan–Meier analysis. To evaluate the independent prognostic significance of CRP plasma levels, multivariate Cox regression models were applied.ResultsThe median follow-time was 80 months. Applying receiver operating characteristics (ROC) analysis, the optimal cut-off level for the plasma CRP was 8.6 mg l⁻¹. An elevated CRP level was associated with decreased CSS in univariate (hazard ratio (HR) 3.36, 95% confidence interval (CI) 1.42–7.91; p = 0.006) and multivariate analysis (HR 4.31, 95% CI 1.22–15.1; p = 0.023). Furthermore, a significant association with OS was detected in univariate (HR 2.69, 95% CI 1.57–4.59; p < 0.001) and multivariate analyses (HR 3.24, 95% CI 1.84–5.71, p < 0.001). Multivariate analysis also showed a significant association between plasma CRP and clinical DFS (HR 2.07, 95% CI 1.02–4.17; p = 0.043).ConclusionsIn the present study, an elevated plasma CRP (⩾8.6 mg l⁻¹) has been identified as a prognostic factor for poor CSS, OS and DFS in prostate cancer patients undergoing radiotherapy. The association between elevated CRP levels and poor prognosis was independent of other measures of prognosis such as tumour stage, Gleason grading and prostate specific antigen (PSA) level at diagnosis. If confirmed by additional studies, our findings may contribute to future individual risk assessment in prostate cancer patients.     

Low- and high-grade esthesioneuroblastomas display a distinct natural history and outcome

PurposeEsthesioneuroblastomas, also called olfactory neuroblastomas (ENB) represent a rare sinonasal neurectodermal tumour which prognostic factors are unsteadily described.Patients and methodsClinical and pathological characteristics were analysed in patients treated at Gustave Roussy Institute between 1979 and 2009.ResultsOut of 63 patients, 19 patients were reclassified and 44 patients were eligible for the analysis. Multivariate analysis revealed that T staging of the modified Dulguerov TNM staging and Hyams grade > III (that we termed high-grade ENB) were the only independent prognostic factors for overall survival (OS). As compared to patients with low-grade ENB (Hyams grade ? III), patients with high-grade ENB have higher T4 staging (p = 0.02), have frequent lymph node involvement (p = 0.009) and are more often unresectable (p = 0.005). Resected patients with high-grade ENB frequently displayed mainly leptomeningeal metastasis (n = 4/6) in contrast to patients with low-grade ENB who typically experience late loco-regional recurrence (n = 10/25). With a median follow-up of 9.6 years, median DFS and OS for resected low-grade ENB were 5.4 and 20.5 years, respectively. Conversely, median DFS and OS for high-grade ENB were 1.5 and 2.5 years, respectively.ConclusionLow and high-grade ENB display distinct patterns at presentation and relapse, leading to different prognosis. Therefore, they may be regarded as distinct entities.     

Microsatellite instability as a marker of prognosis and response to therapy: A meta-analysis of colorectal cancer survival data

Background and methodsWe have reviewed and pooled data from published studies to evaluate the relationship between microsatellite instability (MSI) and colorectal cancer (CRC) prognosis. Thirty-one eligible studies reporting survival in 12782 patients characterised for MSI were pooled using a fixed- or random-effects model.ResultsThe summary odds ratio (OR) estimate for overall survival (OS) associated with MSI was 0.6 (95%CI 0.53–0.69, p < 0.0001), with no evidence of heterogeneity. The effect was similar for disease-free survival (DFS) (OR = 0.58, 95%CI 0.47–0.72, p < 0.0001). In a subset of patients treated with 5-fluorouracil (5-FU)-based chemotherapy a significant improved prognosis was found for microsatellite stable (MSS) tumours (OR = 0.52, 95%CI 0.4–0.6, p < 0.0001) with no heterogeneity (p = 0.53; I² = 0%). By contrast a large heterogeneity characterised the data relative to 396 patients with MSI tumours (OR = 0.69, 95%CI 0.3–1.5, p = 0.1; heterogeneity: p = 0.03; I² = 58%).ConclusionsThis study confirmed the association between MSI and favourable prognosis as determined by both OS and DFS of CRC patients. A significant beneficial effect of 5-FU therapy was found for MSS tumours whilst no clear conclusion was reached for MSI tumours due to the high inter-study heterogeneity. We propose that this inconclusive result is due to the use of a single marker, such as MSI, that cannot account alone for the complexity of the mechanisms underlying 5-FU cytotoxicity. Future studies to predict response to 5-FU chemotherapy should include additional genome stability markers.     

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.     

Whole brain radiotherapy plus stereotactic radiosurgery (WBRT + SRS) versus surgery plus whole brain radiotherapy (OP + WBRT) for 1–3 brain metastases: Results of a matched pair analysis

This study is the first one to compare WBRT + SRS to OP + WBRT for 1–3 brain metastases. Survival (OS), intracerebral control (IC) and local control (LC) of the treated metastases were retrospectively evaluated in 52 patients undergoing WBRT + SRS and in 52 patients undergoing OP + WBRT. Both groups were matched for WBRT schedule, age, gender, performance status, tumour, number of brain metastases, extracerebral metastases, RPA class and interval from tumour diagnosis to WBRT. One-year OS was 56% after WBRT + SRS and 47% after OP + WBRT (p = 0.034). One-year IC was 66% and 50% (p = 0.003). One-year LC was 82% and 66% (p = 0.006). On multivariate analyses, it was found that improved OS was associated with younger age (p = 0.044), no extracerebral metastases (p < 0.001), RPA class 1 (p < 0.001) and longer interval from tumour diagnosis to WBRT (p = 0.001). IC was associated with younger age (p = 0.002) and longer interval (p = 0.004); WBRT + SRS achieved borderline significance (p = 0.052). Improved LC was associated with longer interval (p = 0.017); WBRT + SRS showed a trend (p = 0.09). WBRT + SRS appears at least as effective as OP + WBRT.     

Survival in epithelial ovarian cancer: a multivariate analysis incorporating BRCA mutation status and platinum sensitivity

BackgroundPatients with BRCA-associated ovarian cancer (OC) have a survival advantage over those with sporadic OC. To further explore this, we examined the impact of prognostic factors on disease-free survival (DFS) and overall survival (OS) in patients with known BRCA mutation status.Patients and methodsWe reviewed stage III–IV OC patients treated at our institution between 1 December 1996 and 30 September 2006 and also tested on protocol for BRCA mutations. Impact on DFS and OS was determined by Kaplan–Meier analysis and a Cox proportional hazards model.ResultsOf the 110 patients, 36 had deleterious BRCA mutations [BRCA (+)] and 74 were BRCA wild type [BRCA(-)]. Thirty-one of 36 (86%) BRCA (+) and 60 of 74 (81%) BRCA (-) patients were platinum sensitive (P = 0.60). Median OS was longer for BRCA (+) patients (not reached versus 67.8 months; P = 0.02), but DFS was similar (26.9 versus 24.0, P = 0.3). On multivariate analysis, OS correlated with primary platinum sensitivity [HR = 0.15; 95% CI (confidence interval) 0.06–0.34] and BRCA (+) mutation status (HR = 0.33; 95% CI 0.12–0.86).ConclusionsBRCA mutation status predicted OS independent of primary platinum sensitivity, suggesting that underlying tumor biology contributes to disease outcome and may be worthy of consideration in future clinical trial design.     

Comparison of gefitinib and erlotinib efficacies as third-line therapy for advanced non-small-cell lung cancer

PurposeThe epidermal growth factor receptor inhibitors, gefitinib and erlotinib, are used as standard salvage therapy for advanced non-small-cell lung cancer (NSCLC). The aim of the present study was to compare their efficacies in this population.Patients and methodsThe Taiwan Cancer Registry and the National Health Insurance claim databases were searched for newly diagnosed patients with NSCLC from 2004 to 2007 who received gefitinib or erlotinib as third-line therapy. Overall survival (OS) and time to treatment failure (TTF) were determined from registered parameters. Treatment efficacies were compared by the log-rank test in total population and subsets with different clinical characteristics. The Cox’s proportion hazard model was used to estimate the adjusted hazard ratios in multivariate analyses.ResultsA total of 984 patients who received gefitinib (67%) or erlotinib (33%) were included. Patients receiving gefitinib or erlotinib had similar OS (median, 10.2 versus 9.9 months, p = 0.524) and TTF (median, 5.5 versus 3.4 months, p = 0.103). In multivariate analyses, both treatment groups had similar risk of overall mortality (adjusted hazard ratio [HR] = 1.04, p = 0.629) and treatment failure (adjusted HR = 0.94, p = 0.417). Comparing the treatments in subgroups based on age, tumour histology and gender also revealed no differences in OS and TTF. For patients who received gefitinib or erlotinib for more than 3 or 6 months, there was no difference in TTF but patients who received erlotinib had longer OS.ConclusionsGefitinib and erlotinib had similar efficacies as salvage therapy for advanced NSCLC in Taiwan.     

Expression of nuclear FIH independently predicts overall survival of clear cell renal cell carcinoma patients

AimThe hypoxia inducible factor (HIF) pathway plays an important role in sporadic clear cell renal cell carcinoma (ccRCC) by stimulating processes of angiogenesis, cell proliferation, cell survival and metastases formation. Herein, we evaluate the significance of upstream proteins directly regulating the HIF pathway; the prolyl hydroxylases domain proteins (PHD)1, 2 and 3 and factor-inhibiting HIF (FIH), as prognostic markers for ccRCC.MethodsImmunohistochemical marker expression was examined on a tissue microarray containing tumour tissue derived from 100 patients who underwent nephrectomy for ccRCC. Expression levels of HIF, FIH and PHD1, 2 and 3 were correlated with overall survival (OS) and clinicopathological prognostic factors.ResultsHIF-1α was positively correlated with HIF-2α (p < 0.0001), PHD1 (p = 0.024), PHD2 (p < 0.0001), PHD3 (p = 0.004), FIH (p < 0.0001) and VHL (p = 0.031). HIF-2α levels were significantly associated with FIH (p < 0.0001) and PHD2 (p = 0.0155). Mutations in the VHL gene, expression variations of HIF-1α, HIF-2α and PHD1, 2, 3 did not show a correlation to OS or clinicopathological prognostic factors. Tumour stage, grade, diameter, metastastic disease and intensity of nuclear FIH were significantly correlated to OS in univariable analysis (p = 0.023). Low nuclear FIH levels remained a strong independent prognostic factor in multivariable analysis (p = 0.009).ConclusionThese results show that low nuclear expression of FIH is a strong independent prognostic factor for a poor overall survival in ccRCC.