Impact of age and medical comorbidity on adjuvant treatment outcomes for stage III colon cancer: a pooled analysis of individual patient data from four randomized,controlled trials

XELOX or FOLFOX should be considered as standard treatment options for the adjuvant management of stage III colon cancer in all age groups and in patients with comorbidities.BackgroundAdjuvant oxaliplatin plus capecitabine or leucovorin/5-fluorouracil (LV/5-FU) (XELOX/FOLFOX) is the standard of care for stage III colon cancer (CC); however, there is disagreement regarding oxaliplatin benefit in patients aged >70. In most analyses, the impact of medical comorbidity (MC) has not been assessed. Efficacy and safety of adjuvant XELOX/FOLFOX versus LV/5-FU were compared with respect to age and MC using pooled data from four randomized, controlled trials, selected for access to patient-level MC data and including commonly endorsed and utilized regimens.Patients and methodsIndividual data from patients with stage III CC in NSABP C-08, XELOXA, X-ACT, and AVANT were pooled, excluding bevacizumab-treated patients. Patients were grouped by treatment, MC (low versus high), or age (<70 versus ≥70), and compared for disease-free survival (DFS), overall survival (OS), and adverse events (AEs). Multivariable Cox proportional hazards regression controlled for gender, T stage, and N stage.ResultsDFS benefits were shown for XELOX/FOLFOX versus LV/5-FU regardless of age or MC, although benefits were modestly attenuated for patients aged ≥70. Hazard ratios were 0.68 (P < 0.0001) and 0.77 (P < 0.014) for <70 and ≥70 age groups; 0.69 (P < 0.0001) and 0.59 (P < 0.0001) for Charlson Comorbidity Index ≤1 and >1 groups; and 0.70 (P < 0.0001) and 0.58 (P < 0.0001) for National Cancer Institute Combined Index ≤1 and >1 groups. OS was also significantly improved in all groups. Grade 3/4 serious AE rates were comparable across cohorts and MC scores and higher in patients aged ≥70. Oxaliplatin-relevant grade 3/4 AEs, including neuropathy, were comparable across ages and MC scores.ConclusionsResults further support consideration of XELOX or FOLFOX as standard treatment options for the adjuvant management of stage III CC in all age groups and in patients with comorbidities, consistent with those who were eligible for these clinical trials.     

Identifying the target NSCLC patient for maintenance therapy: an analysis from a placebo-controlled,phase III trial of maintenance pemetrexed (H3E-MC-JMEN)

BackgroundThis was a post hoc analysis of patients with non-squamous histology from a phase III maintenance pemetrexed study in advanced non-small cell lung cancer (NSCLC).Patients and methodsThe six symptom items' [average symptom burden index (ASBI)] mean at baseline was calculated using the lung cancer symptom scale (LCSS). Low and high symptom burden (LSB, ASBI < 25; HSB, ASBI ≥ 25) and performance status (PS: 0, 1) subgroups were analyzed for treatment effect on progression-free survival (PFS) and overall survival (OS) using the Cox proportional hazard models adjusted for demographic/clinical factors.ResultsSignificantly longer PFS and OS for pemetrexed versus placebo occurred in LSB patients [PFS: median 5.1 versus 2.4 months, hazard ratio (HR) 0.49, P < 0.0001; OS: median 17.5 versus 11.0 months, HR 0.63, P = 0.0012] and PS 0 patients (PFS: median 5.5 versus 1.7 months, HR 0.36, P < 0.0001; OS: median 17.7 versus 10.3 months, HR 0.54, P = 0.0019). Significantly longer PFS, but not OS, occurred in HSB patients (median 3.7 versus 2.8 months, HR 0.50, P = 0.0033) and PS 1 patients (median 4.4 versus 2.8 months, HR 0.60, P = 0.0002).ConclusionsASBI and PS are associated with survival for non-squamous NSCLC patients, suggesting that maintenance pemetrexed is useful for LSB or PS 0 patients following induction.     

Quality of life (QoL) analyses from OPTIMAL (CTONG-0802), a phase III,randomised, open-label study of first-line erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC)

BackgroundThe OPTIMAL study found that erlotinib improved progression-free survival (PFS) versus standard chemotherapy in Chinese patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC). This report describes the quality of life (QoL) and updated PFS analyses from this study.Patients and methodsChinese patients ≥18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR (exon 19 deletion or exon 21 L858R point mutation) received erlotinib (150 mg/day; n = 82) or gemcitabine–carboplatin (n = 72). The primary efficacy end point was PFS; QoL was assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire, Trial Outcome Index (TOI) and Lung Cancer Subscale (LCS).ResultsPatients receiving erlotinib experienced clinically relevant improvements in QoL compared with the chemotherapy group in total FACT-L, TOI and LCS (P < 0.0001 for all scales). Erlotinib scored better than chemotherapy for all FACT-L subscales from baseline to cycles 2 and 4 (non-significant). In the updated analysis, PFS was significantly longer for erlotinib than chemotherapy (median PFS 13.7 versus 4.6 months; HR = 0.164, 95% CI = 0.105–0.256; P < 0.0001), which was similar to the previously reported primary analysis.ConclusionErlotinib improves QoL compared with standard chemotherapy in the first-line treatment of patients with EGFR mutation-positive advanced NSCLC.     

Clinicopathologic Characteristics,Treatment Outcomes,and Acquired Resistance Patterns of Atypical EGFR Mutations and HER2 Alterations in Stage IV Non–Small-Cell Lung Cancer

BackgroundThe clinicopathologic characteristics, acquired resistance patterns, and outcomes among patients with atypical EGFR mutations and HER2 alterations remain underexplored.Patients and MethodsA single-center retrospective review was conducted. Oncogenes assessed include typical EGFR (t-EGFR; exon 19 del and L858R), atypical EGFR (a-EGFR; G719X, exon 20, L861Q), HER2 (exon 19, exon 20, amplifications), gene fusions (ALK, ROS1, RET), RAS (KRAS, NRAS), and RAF (BRAF V600E). Progression-free survival (PFS), overall survival (OS), disease control rate, and objective response rate (Response Evaluation Criteria in Solid Tumors 1.1) were collected.ResultsAmong 570 patients, we found 55 a-EGFR mutations (13 G719X, 38 exon 20, 4 L861Q) and 31 HER2 alterations (2 exon 19 mutations, 27 exon 20 insertions, 2 amplifications). Patients with EGFR and HER2 alterations had increased lung and bone metastases relative to patients with gene fusions, RAS/RAF mutations, and no identified driver oncogenes (P < .001). Patients with EGFR exon 20 insertions had a median PFS to EGFR tyrosine kinase inhibitors (TKIs) of 5 months and an OS of 16 months—significantly worse than exon 19 del and L858R (Bonferroni correction; P < .001), but not G719X or L861Q. Relative to t-EGFR mutations, T790M and MET amplification occurred less frequently as acquired resistance mechanisms among a-EGFR samples (P < .001). Ten patients with a-EGFR mutations and HER2 alterations received single-agent immune checkpoint inhibitors (ICIs) with no radiographic responses and a median PFS of 2 months.ConclusionEGFR and HER2-mutated NSCLC have a high rate of synchronous lung and bone metastases. Patients with a-EGFR mutations have inferior responses to EGFR-directed therapies with lower rates of acquired T790M and MET amplification. Responses to ICIs are uniformly poor. Novel therapeutic approaches are needed.     

COMPliance and Arthralgia in Clinical Therapy: the COMPACT trial,assessing the incidence of arthralgia,and compliance within the first year of adjuvant anastrozole therapy

BackgroundThis prospective study evaluated the relationship between arthralgia and compliance during the first year of adjuvant anastrozole therapy in postmenopausal women with hormone receptor-positive early breast cancer.Patients and methodsCOMPliance and Arthralgia in Clinical Therapy (COMPACT) was an open-label, multicenter, noninterventional study conducted in Germany. Patients had started adjuvant anastrozole 3–6 months before the study start. The primary end points were arthralgia, compliance, and the relationship between compliance and arthralgia, assessed at specific time points.ResultsOverall, 1916 patients received upfront anastrozole. Mean arthralgia scores were increased from baseline at each visit up to 9 months. Compliance with anastrozole therapy gradually decreased over time from baseline to 9 months (P < 0.001). At 9 months, investigators estimated that >95% of patients were compliant versus patient reports of <70%. There was a significant association between arthralgia mean scores and noncompliance at 6 months (P < 0.0001), 9 months (P < 0.0001), and overall (P < 0.0001). Over time, new events or impairment of existing arthralgias were reported in 14% (3 months), 11% (6 months), and 9% (9 months) of patients.ConclusionArthralgia is important in the clinical management of women with early breast cancer and may contribute to noncompliance and clinical outcomes.ClinicalTrials.gov identifierNCT00857012.     

Co-expression network analysis of long noncoding RNAs (IncRNAs) and cancer genes revealsSFTA1P and CASC2abnormalities in lung squamous cell carcinoma

Lung squamous cell carcinoma(LSCC) is the most common and aggressive lung tumor with poor clinical outcome. Previously studies showed that deregulation of long noncoding RNAs (lncRNAs) were involved in LSCC. We intended to figure out the role of lncRNAs in the regulation process of cancer-related genes and pathways they are involved. Data of 552 samples, including 501 cancer samples and 51 normal ones, were extracted from The Cancer Genome Atlas (TCGA). Differentially expressed lncRNAs (DEIs) were screened out (FDR<0.05, |logFC|>1) and then followed by GO ontology and KEGG annotation analysis. Oncogenes from COSMIC data set and Tumor suppressor genes (TSGs) from TSGene data set were collected and analyzed by gene Set Enrichment Analysis (GSEA) . The differentially expressed oncogenes and tumor supressor gene (TSGs) were obtained and co-expression analysis was conducted to generate co-expression lncRNA-gene pairs, which can be helpful in figuring out the role of lncRNA in the regulation of oncogenes and tumor suppressor genes. A total of 31 lncRNAs with low expression levels and 37 lncRNAs with high expression levels were screened out and most of them were enriched in pathways such as meiosis, male gamete generation, defensins. Of note, SFTA1P and CASC2 were found to be related with most of the oncogenes and TSGs by co-expression analysis. We suggested SFTA1P and CASC2 played important role in the regulation of both oncogene and TSGs during the carcinogenesis of LSCC and have the potential to be applied in future diagnosis, prognostic process and target therapy of LSCC.     

The Prognostic Significance of the Biomarker p16 in Oropharyngeal Squamous Cell Carcinoma

AimsThere is an increasing incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell cancers (OPSCC) mostly associated with favourable outcomes. p16 immunohistochemistry is a surrogate marker for HPV positivity in OPSCC. The prognostic strength of p16 over traditional prognostic factors is not fully characterised. In this study, we evaluated the clinical and demographic differences between p16-positive and -negative OPSCC and characterised its prognostic strength versus traditional prognostic factors.Materials and methodsFormalin-fixed, paraffin-embedded blocks and clinical information from 217 OPSCC patients, treated with radiotherapy (alone or in combination with other therapies) between 2000 and 2010 were collected retrospectively. Immunohistochemistry for p16 protein was carried out; cancer-specific survival (CSS), recurrence-free survival (RFS) and locoregional control (LRC) were calculated for both univariate and multivariate analyses.ResultsNinety-two per cent of the OPSCC originated from tonsil and tongue base sites, 61% were p16 positive. Patients with p16-positive OPSCC were younger (P < 0.0001), with lower alcohol (P = 0.0002) and tobacco (P = 0.0001) exposure. The tumours were less differentiated (P = 0.0069), had a lower T stage (P = 0.0027), higher nodal status (P = 0.014) and higher American Joint Committee on Cancer (AJCC) prognostic group (P = 0.0036). AJCC prognostic group was significant for RFS (P = 0.0096) and CSS (P = 0.018) in patients with p16-negative OPSCC, but not those with p16-positive tumours (P = 0.30 and 0.54). Other significant factors for CSS and RFS in univariate analysis were: pretreatment haemoglobin (P < 0.0001 and <0.0001), chemoradiotherapy (P = 0.005 and 0.03) and P16 status (P < 0.0001 and 0.0001). In multivariate analysis, p16 positivity was the strongest independent prognostic variable for both CSS, RFS and LRC (P < 0.0001, hazard ratio 4.15; 95% confidence interval 2.43–7.08), (P < 0.0001, hazard ratio 6.15; 95% confidence interval 3.57–10.61) and (P = 0.001, hazard ratio 3.74; confidence interval 1.76–7.95).ConclusionThis study shows that p16 is the single most important prognostic variable in OPSCC, surpassing traditional prognostic factors for both CSS and RFS. Furthermore, disease stage has no prognostic significance in p16-positive patients, highlighting the need for routine p16 assessment in OPSCC.     

A Golgi-specific protein PAQR3 is closely associated with the progression,metastasis and prognosis of human gastric cancers

BackgroundThe aim of this study is to determine whether PAQR3, a protein specifically localized in the Golgi apparatus, is associated with tumor progression, metastasis and survival of human patients with gastric cancer.Patients and methodsPAQR3 expression status was investigated in a large panel of gastric cancer (n = 300) and their corresponding para-cancerous histological normal tissues (PCHNT) at both mRNA and protein levels. The correlation of PAQR3 expression levels with clinical features such as metastasis and prognosis was analyzed. The effect of PAQR3 on the growth and migration of gastric cancer cells was also determined.ResultsPAQR3 was frequently down-regulated in gastric cancer samples compared with PCHNT at both mRNA and protein levels (both P < 0.0001). The expression level of PAQR3 was negatively correlated with Helicobacter pylori infection (P < 0.0001), tumor size (P < 0.0001), tumor stage (P < 0.0001), venous and lymphatic invasion (P < 0.0001), distant and nodal metastasis (P < 0.0001), and patient survival (P < 0.0001). Down-regulation of PAQR3 was highly correlated with increased epithelial–mesenchymal transition (EMT) in gastric cancer samples. In addition, PAQR3 overexpression was able to negatively modulate cell proliferation, migration and EMT of gastric cancer cells.ConclusionPAQR3 is markedly down-regulated in human gastric cancers. PAQR3 expression level is closely associated with the progression and metastasis of gastric cancers. PAQR3 is also a new genetic signature that can predict the prognosis of the patients with gastric cancer.     

Development and Validation of a Novel TP53 Mutation Signature That Predicts Risk of Metastasis in Primary Prostate Cancer

IntroductionProstate tumors with TP53 gene mutations are molecularly heterogenous, and the presence of TP53 gene mutations has been linked to inferior outcomes. We developed an RNA-based gene signature that detects underlying TP53 gene mutations and identifies wild-type prostate tumors that are analogous to TP53-mutant tumors.Materials and MethodsUsing genomic expression profiles from The Cancer Genome Atlas, we developed a mutation signature score to predict prostatic tumors with a molecular fingerprint similar to tumors with TP53 mutations. Area under the receiver operating characteristic curve assessed model accuracy in predicting TP53 mutations, and Cox regression models measured association between the signature and progression-free survival and metastasis-free survival (MFS).ResultsThe TP53 signature score achieved an area under the receiver operating characteristic curve of 0.84 in the training and 0.82 in the validation cohorts for predicting an underlying mutation. In three retrospective cohorts, a high score was prognostic for poor 5-year MFS: 46% versus 81% (hazard ratio [HR], 3.05; P < .0001; Johns Hopkins University cohort), 64% versus 83% (HR, 2.77; P < .0001; Mayo Clinic cohort), and 71% versus 97% (HR, 6.8; P = .0001; Brigham and Women’s Hospital cohort). The signature also identified TP53 wild-type tumors molecularly analogous to TP53 mutant tumors, wherein high signature score correlated with worse 5-year MFS (50% vs. 82%; HR, 3.05; P < .0001).ConclusionsThis novel mutational signature predicted tumors with TP53 mutations, identified TP53 wild-type tumors analogous to mutant tumors, and was independently associated with poor MFS. This signature can therefore be used to strengthen existing clinical risk-stratification tools.     

Prognostic value of neutrophil-to-lymphocyte ratio in older patients with head and neck cancer

IntroductionNeutrophil-to-lymphocyte ratio (NLR), may predict treatment response and outcomes in some human malignancies. However, NLR has rarely been examined in older patients with head and neck squamous cell carcinoma (HNSCC). This study evaluated factors, including pre-treatment evaluation tests, predictive of mortality in older patients with HNSCC.MethodsThis study prospectively enrolled 233 consecutive HNSCC patients aged 65 years or older. Pre-treatment evaluations included patient demographics, comorbidity, body weight loss, voice handicap index, dysphagia, Beck's depression inventory, comprehensive geriatric assessment, and circulating biomarkers. Cumulative incidence and cause-specific hazard functions were used to analyse the risk factors for overall mortality (OM), cancer mortality (CM), and non-cancer mortality (NCM).ResultsMultivariate analyses showed that age, performance scale, NLR, and nodal stage were independent predictors of OM and CM (all P < .05). Age, body weight loss, frailty, and NLR were independent predictors of NCM (all P < .05). Older age ≥ 75 years and NLR showed strong association with all OM, CM, and NCM (all P < .05). NLR >2.5 was related to a higher risk of OM (hazard ratio [HR] = 1.77, 95% confidence interval [CI]: 1.05–2.97, P = .031), CM (HR = 1.89, 95% CI: 1.09–3.29, P = .023), and NCM (HR = 6.29, 95% CI: 2.16–18.37, P = .001).ConclusionCancer and non-cancer mortalities among older patients with HNSCC may be predicted by several clinical and haematological data. NLR might be used as a circulating prognostic marker for mortality in older patients with HNSCC.     

Early magnesium modifications as a surrogate marker of efficacy of cetuximab-based anticancer treatment in KRAS wild-type advanced colorectal cancer patients

BackgroundKRAS wild-type mutational status is necessary but not sufficient to get benefit from epidermal growth factor receptor inhibition. Predictive markers are currently being evaluated. In this study, we investigated early hypomagnesemia as a predictor of efficacy and outcome in terms of time to progression (TtP) and overall survival (OS) in a cohort of patients affected by advanced colorectal adenocarcinoma KRAS wild-type cetuximab-treated.Patients and methodsOne hundred and forty-three patients affected by stage IV colorectal adenocarcinoma KRAS wild type receiving cetuximab + irinotecan (CTX+IRI) as third-line anticancer treatment and resistant to oxaliplatin- and irinotecan-based chemotherapy were retrospectively included. Magnesium plasma levels were measured before the first day and 7, 14, 21 and 28 days after CTX+IRI infusion.ResultsThe median magnesium basal value showed a statistically significant decrease after the start of CTX+IRI treatment (at 28 days, P < 0.0001). Patients with an early decrease of magnesium levels >50% compared with the basal level had a higher tumor response rate (55.8% versus 16.7%, P < 0.0001), a longer TtP (6.3 versus 3.6, P < 0.0001) and a longer median OS (11.0 versus 8.1, P = 0.002).ConclusionsWe have shown that early hypomagnesemia could be a predictor of efficacy and outcome in those patients. Magnesium circulating level is an easy and inexpensive biomarker to routinely be detected in patients treated with cetuximab.     

Generalisability of Common Oncology Clinical Trial Eligibility Criteria in the Real World

AimsStrict oncology clinical trial eligibility criteria can contribute to low accrual and result in poorly generalisable study findings. Using common eligibility criteria, we sought to (i) determine how many patients would be eligible versus ineligible and (ii) describe real-world patterns of treatments and outcomes between those considered trial eligible and ineligible.Materials and methodsThe Alberta Cancer Registry was used to assemble a population-based cohort of patients diagnosed with 11 common malignancies between 2004 and 2015. We considered age >75 years, anaemia, comorbid conditions (heart disease, uncontrolled diabetes, kidney disease, liver disease) and history of a prior malignancy or immunosuppression to be exclusion criteria. Logistic regression was used to characterise the likelihood of receiving treatment. Cox regression models were constructed to determine cancer-specific and overall survival.ResultsWe identified 125 316 cancer patients, of whom 53% were men; the median age was 66 (interquartile range 48–84) years. Approximately 38% of patients were considered trial ineligible. The most common reasons for ineligibility were advanced age (24%) and heart disease (16%). In this ineligible group, 12, 47 and 19% still underwent chemotherapy, surgery and radiotherapy, respectively. Compared with ineligible patients, eligible patients were more likely to undergo chemotherapy (odds ratio 1.98, 95% confidence interval 1.89–2.07, P < 0.0001), surgery (odds ratio 1.39, 95% confidence interval 1.32–1.46, P < 0.0001) and radiotherapy (odds ratio 1.46, 95% confidence interval 1.4–1.52, P < 0.0001). Compared with ineligible patients who did not receive treatment, those considered ineligible but who still received treatment experienced improved cancer-specific survival (hazard ratio 0.75, 95% confidence interval 0.74–0.77, P < 0.0001) and overall survival (hazard ratio 0.89, 95% confidence interval 0.87–0.90, P < 0.0001).ConclusionsA significant proportion of real-world patients are unable to participate in clinical trials due to stringent exclusion criteria, but many still receive treatment in routine practice. The eligibility criteria of oncology clinical trials should be broadened.     

Increasing Rates of No Treatment in Advanced-Stage Non–Small Cell Lung Cancer Patients: A Propensity-Matched Analysis

IntroductionVariation in treatment and survival outcomes for NSCLC is high among patients with stage III or IV disease, but patients with untreated NSCLC have not been critically analyzed to evaluate for improvable outcomes. We evaluated treatment trends and their association with oncologic outcomes for NSCLC, hypothesizing that there are a substantial number of untreated patients who are similar to patients who undergo treatment.MethodsLinear regression was used to calculate trends in utilization of treatment. Kaplan-Meier and Cox regression modeling were used to determine predictors of receiving treatment. Propensity matching was used to compare survival among subsets of treated versus untreated patients.ResultsPatients with primary NSCLC were identified from the National Cancer Data base from 1998 to 2012, and 21% of patients (190,539) received no treatment. For stage IIIA and IV, the proportion of untreated patients increased over the study period by 0.21% and 0.4%, respectively (p = 0.003 and p < 0.0001). Regardless of stage, untreated patients had significantly shorter overall survival (OS) (p < 0.0001). Propensity-matched analyses of 6144 stage IIIA patient pairs treated with chemoradiation versus no treatment confirmed shorter OS for untreated patients (median 16.5 versus 6.1 months, p < 0.0001). For 19,046 stage IV patient pairs treated with chemotherapy versus no treatment, similar results were obtained (median OS 9.3 versus 2.0 months, p < 0.0001).ConclusionsThe proportion of untreated patients with stage IIIA and IV disease is increasing. Survival outcomes among patients with advanced-stage disease are superior with treatment, independent of selection bias. The benefits and risks of treatment should be carefully assessed before choosing to forego treatment.     

Outcomes of patients with metastatic renal cell carcinoma that do not meet eligibility criteria for clinical trials

BackgroundTargeted therapies in metastatic renal cell carcinoma (mRCC) have been approved based on registration clinical trials that have strict eligibility criteria. The clinical outcomes of patients treated with targeted agents but are ineligible for trials are unknown.Patients and MethodsmRCC patients treated with vascular endothelial growth factor-targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky performance status (KPS) <70%, nonclear-cell histology, brain metastases, hemoglobin ≤9 g/dl, creatinine >2× the upper limit of normal, corrected calcium ≥12 mg/dl, platelet count of <100 × 10³/uL, or neutrophil count <1500/mm³.ResultsOverall, 768 of 2210 (35%) patients in the International Metastatic RCC Database Consortium (IMDC) were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression-free survival (PFS) and median overall survival of first-line targeted therapy were 22% versus 29% (P = 0.0005), 5.2 versus 8.6 months, and 12.5 versus 28.4 months (both P < 0.0001), respectively. Second-line PFS (if applicable) was 2.8 months in the trial ineligible versus 4.3 months in the trial eligible patients (P = 0.0039). When adjusted by the IMDC prognostic categories, the HR for death between trial ineligible and trial eligible patients was 1.55 (95% confidence interval 1.378–1.751, P < 0.0001).ConclusionsThe number of patients that are ineligible for clinical trials is substantial and their outcomes are inferior. Specific trials addressing the unmet needs of protocol ineligible patients are warranted.     

Quality of life and disease-related symptoms in previously treated Japanese patients with non-small-cell lung cancer: results of a randomized phase III study (V-15-32) of gefitinib versus docetaxel

BackgroundThis report describes quality of life (QoL) findings of a randomized study comparing gefitinib with docetaxel in patients with advanced/metastatic pretreated non-small-cell lung cancer.Patients and methodsThis open-label, phase III study randomized 490 Japanese patients to gefitinib (250 mg/day) or docetaxel (60 mg/m²/3 weeks), with survival as the primary outcome. Preplanned QoL analyses included Functional Assessment of Cancer Therapy-Lung (FACT-L), Trial Outcome Index (TOI) and Lung Cancer Subscale (LCS) improvement rates, and mean change from baseline.ResultsGefitinib showed statistically significant benefits over docetaxel in QoL improvement rates (FACT-L 23% versus 14%, P = 0.023; TOI 21% versus 9%, P = 0.002) and mean change from baseline score [mean treatment difference: FACT-L 3.72 points, 95% confidence interval (CI) 0.55–6.89, P = 0.022; TOI 4.31 points, 95% CI 2.13–6.49, P < 0.001], although differences did not meet the clinically relevant six-point change. There were no significant differences between treatments in LCS improvement rates (23% versus 20%, P = 0.562) or mean change from baseline score (0.63 points, 95% CI -0.07 to 1.34, P = 0.077).ConclusionsGefitinib improved aspects of QoL over docetaxel, with superior objective response rate and a more favorable tolerability profile and no statistically significant difference in overall survival (although noninferiority was not statistically proven).     

Hypertension and angiotensin system inhibitors: impact on outcome in sunitinib-treated patients for metastatic renal cell carcinoma

BackgroundTo examine the association between hypertension (HTN), angiotensin system inhibitors (ASI) use and survival outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib (SU).MethodsWe retrospectively reviewed all patients with mRCC who received SU as first-line treatment in Gustave Roussy from April 2004 to November 2013. The HTN (either pre-existing or secondary to SU), use of ASI (either before or during SU) were analysed. Overall survival (OS) and progression-free survival (PFS) of different exposures were compared with log-rank test. The associations between exposures and survival outcomes were estimated with hazard ratios (HRs) and 95% confidence interval (CI) through a multivariable Cox model adjusted for age, gender, International mRCC Database Consortium risk group and histology.ResultsAmong 213 patients with a 3.6-year median follow-up, 134 were hypertensive and 105 were ASI users with a significant association between the two exposures (P < 0.0001). Hypertensive patients have longer OS (median: 41.6 versus 16.4 months, P < 0.0001) and longer PFS (median: 12.9 versus 5.6 months, P < 0.0001) than non-hypertensive patients (n = 79). ASI users (n = 105) had more HTN_PRE compared with those (n = 108) who did not (65% versus 19%, P < 0.001). Multivariable analysis showed that hypertensive patients were significantly associated with OS (P = 0.05) and marginally with PFS (P = 0.06) while ASI intake was significantly associated with better OS [HR = 0.40; 95% CI (0.24–0.66), P < 0.001] and PFS [HR = 0.55 (0.35–0.86), P = 0.009]. The latter remain statistically significantly associated after controlling for the number of metastases. There is no difference on outcome between patients who receive ASI before starting SU and those who received ASI during SU treatment.ConclusionConcomitant use of ASI may significantly improve OS and PFS in mRCC patients receiving SU. HTN is marginally associated with the outcome in these patients.     

Does Gleason score at initial diagnosis predict efficacy of abiraterone acetate therapy in patients with metastatic castration-resistant prostate cancer? An analysis of abiraterone acetate phase III trials

BackgroundThe usefulness of Gleason score (<8 or ≥8) at initial diagnosis as a predictive marker of response to abiraterone acetate (AA) plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) was explored retrospectively.Patients and methodsInitial diagnosis Gleason score was obtained in 1048 of 1195 (COU-AA-301, post-docetaxel) and 996 of 1088 (COU-AA-302, chemotherapy-naïve) patients treated with AA 1 g plus prednisone 5 mg twice daily by mouth or placebo plus prednisone. Efficacy end points included radiographic progression-free survival (rPFS) and overall survival (OS). Distributions and medians were estimated by Kaplan–Meier method and hazard ratio (HR) and 95% confidence interval (CI) by Cox model.ResultsBaseline characteristics were similar across studies and treatment groups. Regardless of Gleason score, AA treatment significantly improved rPFS in post-docetaxel [Gleason score <8: median, 6.4 versus 5.5 months (HR = 0.70; 95% CI 0.56–0.86), P = 0.0009 and Gleason score ≥8: median, 5.6 versus 2.9 months (HR = 0.58; 95% CI 0.48–0.72), P < 0.0001] and chemotherapy-naïve patients [Gleason score <8: median, 16.5 versus 8.2 months (HR = 0.50; 95% CI 0.40–0.62), P < 0.0001 and Gleason score ≥8: median, 13.8 versus 8.2 months (HR = 0.61; 95% CI 0.49–0.76), P < 0.0001]. Clinical benefit of AA treatment was also observed for OS, prostate-specific antigen (PSA) response, objective response and time to PSA progression across studies and Gleason score subgroups.ConclusionOS and rPFS trends demonstrate AA treatment benefit in patients with pre- or post-chemotherapy mCRPC regardless of Gleason score at initial diagnosis. The initial diagnostic Gleason score in patients with mCRPC should not be considered in the decision to treat with AA, as tumour metastases may no longer reflect the histology at the time of diagnosis.Clinical trials numberCOU-AA-301 (NCT00638690); COU-AA-302 (NCT00887198).