Dose selection trial of metronomic oral vinorelbine monotherapy in patients with metastatic cancer: a hellenic cooperative oncology group clinical translational study

BACKGROUND: Metronomic chemotherapy is considered an anti-angiogenic therapy that involves chronic administration of low-dose chemotherapy at regular short intervals. We investigated the optimal metronomic dose of oral vinorelbine when given as monotherapy in patients with metastatic cancer. METHODS: Patients with recurrent metastatic breast (BC), prostate (PC) or non-small cell lung cancer (NSCLC) and adequate organ functions were randomly assigned to 30, 40 or 50 mg vinorelbine, taken orally three times a week. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent or maximum 24 months. Primary endpoint was time-to-treatment failure (TTF) and secondary were progression-free survival (PFS), toxicity, changes in blood concentrations of angiogenesis-associated biomarkers and pharmacokinetics. RESULTS: Seventy-three patients were enrolled. Four-month TTF rate did not differ between the three arms: 25.9% (11.1%-46.2% 95% Confidence Interval), 33.3% (15.6%-55.3%) and 18.2% (5.2%-40.3%) for the 30 mg, 40 mg and 50 mg arms (p-value = 0.56). Objective response was seen in 2 patients with NSCLC (treated at 30 and 50 mg respectively), one with BC (at 40 m g) and one with PC (at 50 mg) and lasted from 4 to 100 weeks, with maximum response duration achieved at 50 mg. Adverse events were mild and negligible and did not differ between the three arms. Blood levels of vinorelbine reached steady state from the second week of treatment and mean values for the 30, 40 and 50 mg were respectively 1.8 ng/ml (SD 1.10), 2.2 ng/ml (SD 1.87) and 2.6 ng/ml (SD 0.69). Low pre-treatment blood concentrations of FGF2 and IL8 predicted favorable response to therapy (p values 0.02 and 0.006, respectively), while high levels of TEK gene transcript predicted treatment resistance. CONCLUSIONS: Considering the antitumor activity and response duration, the negligible toxicity of the highest dose investigated and the lack of drug accumulation over time, we suggest that 50 mg given three times a week is the optimal dose for metronomic oral vinorelbine. Further investigation of metronomic oral vinorelbine (MOVIN) at this dose is warranted in combination with conventional chemotherapy regimens and targeted therapies. TRIAL REGISTRATION: Clinicaltrials.gov NCT0027807

Duration of adjuvant chemotherapy for stage III colon cancer

BACKGROUND Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures. METHODS We performed a prospective, preplanned, pooled analysis of six randomized, phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) administered for 3 months, as compared with 6 months. The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12. RESULTS After 3263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P=0.01 for superiority). CONCLUSIONS Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup. (Funded by the National Cancer Institute and others.

Paraneoplastic pemphigus regression after thymoma resection

<p>Abstract</p> <p>Background</p> <p>Among human neoplasms thymomas are associated with highest frequency with paraneoplastic autoimmune diseases.</p> <p>Case presentation</p> <p>A case of a 42-year-old woman with paraneoplastic pemphigus as the first manifestation of thymoma is reported. Transsternal complete thymoma resection achieved pemphigus regression. The clinical correlations between pemphigus and thymoma are presented.</p> <p>Conclusion</p> <p>Our case report provides further evidence for the important role of autoantibodies in the pathogenesis of paraneoplastic skin diseases in thymoma patients. It also documents the improvement of the associated pemphigus after radical treatment of the thymoma.</p

Pooled Analysis of Elderly Patients with Non-small Cell Lung Cancer Treated with Front Line Docetaxel/Gemcitabine Regimen: The Hellenic Oncology Research Group Experience

IntroductionThirty to 40% of patients with non-small cell lung cancer (NSCLC) are older than 70 years and rarely are enrolled in clinical trials. Moreover, in clinical practice, >75% of patients older than 65 years with metastatic NSCLC never receive any kind of chemotherapy.PurposeTo retrospectively evaluate the impact of age on efficacy and toxicity of chemotherapy regimens in patients with advanced NSCLC treated with the docetaxel-gemcitabine combination.Patients and MethodsPooled data from six clinical trials of the Hellenic Oncology Research Group were analyzed. According to their age, patients were divided into two groups: those with age <70 years and those with ≥70 years.ResultsA total of 858 patients were included in this analysis. Six hundred sixty-six (77.6%) patients were younger than 70 years, whereas 192 (22.4%) patients where ≥70-year-old. Overall response rate was 30.3% and 30.2% for patients <70 years and ≥70 years, respectively (p = 0.974). The median time to tumor progression was 4.1 and 4.5 months for patients <70 years and ≥70 years, respectively (p = 0.948). Median overall survival was 9.9 and 9.2 months for patients <70 and ≥70, respectively (p = 0.117). The multivariate analysis revealed performance status (PS) (p = 0.0001) and stage (p = 0.0001) as independent factors with significant impact on the hazard of death. Chemotherapy was well tolerated, but the incidence of grade III/IV mucositis was significantly higher in elderly patients (0.2% versus 1.5% for patients <70 versus ≥70 years, respectively; p = 0.011).ConclusionThe docetaxel/gemcitabine regimen has a comparable efficacy and tolerance in young (<70 years) and elderly (≥70 years) patients

Duration of adjuvant doublet chemotherapy (3 or 6 months) in patients with high-risk stage II colorectal cancer

PURPOSE: As oxaliplatin results in cumulative neurotoxicity, reducing treatment duration without loss of efficacy would benefit patients and healthcare providers. PATIENTS AND METHODS: Four of the six studies in the International Duration of Adjuvant Chemotherapy (IDEA) collaboration included patients with high-risk stage II colon and rectal cancers. Patients were treated (clinician and/or patient choice) with either fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) and randomly assigned to receive 3- or 6-month treatment. The primary end point is disease-free survival (DFS), and noninferiority of 3-month treatment was defined as a hazard ratio (HR) of &lt; 1.2- v 6-month arm. To detect this with 80% power at a one-sided type one error rate of 0.10, a total of 542 DFS events were required. RESULTS: 3,273 eligible patients were randomly assigned to either 3- or 6-month treatment with 62% receiving CAPOX and 38% FOLFOX. There were 553 DFS events. Five-year DFS was 80.7% and 83.9% for 3-month and 6-month treatment, respectively (HR, 1.17; 80% CI, 1.05 to 1.31; P [for noninferiority] .39). This crossed the noninferiority limit of 1.2. As in the IDEA stage III analysis, the duration effect appeared dependent on the chemotherapy regimen although a test of interaction was negative. HR for CAPOX was 1.02 (80% CI, 0.88 to 1.17), and HR for FOLFOX was 1.41 (80% CI, 1.18 to 1.68). CONCLUSION: Although noninferiority has not been demonstrated in the overall population, the convenience, reduced toxicity, and cost of 3-month adjuvant CAPOX suggest it as a potential option for high-risk stage II colon cancer if oxaliplatin-based chemotherapy is suitable. The relative contribution of the factors used to define high-risk stage II disease needs better understanding

Prognostic and predictive value of Immunoscore in stage III colorectal cancer: pooled analysis of 2,608 cases from the SCOT and IDEA-HORG studies

Purpose Immunoscore (IS) is prognostic in stage III colorectal cancer (CRC) and may predict benefit of duration (6 v 3 months) of adjuvant infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. We sought to determine IS prognostic and predictive value in stage-III CRC treated with adjuvant FOLFOX or oral capecitabine and infusional oxaliplatin (CAPOX) in the SCOT and IDEA-HORG trials. Methods Three thousand sixty-one cases had tumor samples, of which 2,643 (1,792 CAPOX) were eligible for IS testing. Predefined cutoffs (IS-Low and IS-High) were used to classify cases into two groups for analysis of disease-free survival (3-year DFS) and multivariable-adjusted hazard ratios (mvHRs) by Cox regression. Results IS was determined in 2,608 (99.5%) eligible cases, with 877 (33.7%) samples classified as IS-Low. IS-Low tumors were more commonly high-risk (T4 and/or N2; 52.9% IS-Low v 42.2% IS-High; P &lt; .001) and in younger patients (P = .024). Patients with IS-Low tumors had significantly shorter DFS in the CAPOX, FOLFOX, and combined cohorts (mvHR, 1.52 [95% CI, 1.28 to 1.82]; mvHR, 1.58 [95% CI, 1.22 to 2.04]; and mvHR, 1.55 [95% CI, 1.34 to 1.79], respectively; P &lt; .001 all comparisons), regardless of sex, BMI, clinical risk group, tumor location, treatment duration, or chemotherapy regimen. IS prognostic value was greater in younger (≤65 years) than older (&gt;65 years) patients in the CAPOX cohort (mvHR, 1.92 [95% CI, 1.50 to 2.46] v 1.28 [95% CI, 1.01 to 1.63], PINTERACTION = .026), and in DNA mismatch repair proficient than deficient mismatch repair disease (mvHR, 1.68 [95% CI, 1.41 to 2.00] v 0.67 [95% CI, 0.30 to 1.49], PINTERACTION = .03), although these exploratory analyses were uncorrected for multiple testing. Adding IS to a model containing all clinical variables significantly improved prediction of DFS (likelihood ratio test, P &lt; .001) regardless of MMR status. Conclusion IS is prognostic in stage III CRC treated with FOLFOX or CAPOX, including within clinically relevant tumor subgroups. Possible variation in IS prognostic value by age and MMR status, and prediction of benefit from extended adjuvant therapy merit validation

Screening of the DNA mismatch repair genes MLH1, MSH2 and MSH6 in a Greek cohort of Lynch syndrome suspected families

<p>Abstract</p> <p>Background</p> <p>Germline mutations in the DNA mismatch repair genes predispose to Lynch syndrome, thus conferring a high relative risk of colorectal and endometrial cancer. The <it>MLH1, MSH2 </it>and <it>MSH6 </it>mutational spectrum reported so far involves minor alterations scattered throughout their coding regions as well as large genomic rearrangements. Therefore, a combination of complete sequencing and a specialized technique for the detection of genomic rearrangements should be conducted during a proper DNA-testing procedure. Our main goal was to successfully identify Lynch syndrome families and determine the spectrum of <it>MLH1</it>, <it>MSH2 </it>and <it>MSH6 </it>mutations in Greek Lynch families in order to develop an efficient screening protocol for the Greek colorectal cancer patients' cohort.</p> <p>Methods</p> <p>Forty-two samples from twenty-four families, out of which twenty two of Greek, one of Cypriot and one of Serbian origin, were screened for the presence of germline mutations in the major mismatch repair genes through direct sequencing and MLPA. Families were selected upon Amsterdam criteria or revised Bethesda guidelines.</p> <p>Results</p> <p>Ten deleterious alterations were detected in twelve out of the twenty-four families subjected to genetic testing, thus our detection rate is 50%. Four of the pathogenic point mutations, namely two nonsense, one missense and one splice site change, are novel, whereas the detected genomic deletion encompassing exon 6 of the <it>MLH1 </it>gene has been described repeatedly in the LOVD database. The average age of onset for the development of both colorectal and endometrial cancer among mutation positive families is 43.2 years.</p> <p>Conclusion</p> <p>The mutational spectrum of the MMR genes investigated as it has been shaped by our analysis is quite heterogeneous without any strong indication for the presence of a founder effect.</p

Tumor BRCA1, RRM1 and RRM2 mRNA Expression Levels and Clinical Response to First-Line Gemcitabine plus Docetaxel in Non-Small-Cell Lung Cancer Patients

Overexpression of RRM1 and RRM2 has been associated with gemcitabine resistance. BRCA1 overexpression increases sensitivity to paclitaxel and docetaxel. We have retrospectively examined the effect of RRM1, RRM2 and BRCA1 expression on outcome to gemcitabine plus docetaxel in advanced non-small-cell lung cancer (NSCLC) patients. = 0.001). Low BRCA1 expression was the only factor significantly associated with longer time to progression in 31 patients receiving cisplatin-based second-line therapy.The mRNA expression of BRCA1, RRM1 and RRM2 is potentially a useful tool for selecting NSCLC patients for individualized chemotherapy and warrants further investigation in prospective studies

Pharmacogenomics in lung adenocarcinomas: Study of RRM1, RRM2, BRCA1 as predictive factors of response to 1st line treatment of docetaxel-gemcitabine combination: Clinical assessment of efficacy in elderly patients

Aim 1: A phase II study was conducted in order to evaluate the efficacy of docetaxel/gemcitabine (DG) combination in elderly patients with lung adenocarcinomas. Seventy seven patients were enrolled. One (1.3%) complete and 23 (29.9%) partial responses were achieved (intention to treat analysis OR 31.2% 95% CI 20.82-41.51%) whereas tumor growth control was achieved in 53.3% of patients. The median TTP was 4.1 months, the median overall survival 9.4 months and the 1 and 2 year survival rate 37.9% and 10.7%. The DG regimen is an active and well tolerated front line chemotherapy for elderly patients with lung adenocarcinomas. Aim 2a: The mRNA expression of RRM1 and RRM2 in tumours from lung adenocarcinoma patients treated with docetaxel/gemcitabine was assessed and the results correlated with clinical outcome. RMM1 and RMM2 mRNA levels were determined by quantitative real time. PCR Amplification was successful in 42 (79%) of 53 enrolled patients. Low levels of RRM2 mRNA were associated with response to treatment (P=0.001). Patients with the lowest expression levels of RRM1 had a significantly longer time to progression (P=0.044) and overall survival (P=0.02) than patients with the highest levels. Patients with low levels of both RRM1 and RRM2 had a significantly higher response rate (60 vs 14.2% P=0.049) time to progression (9.9 vs 2.3 months P=0.003) and overall survival (15.4 vs 3.6 P=0.031) than patients with high levels of both RRM1 and RRM2 RRM1 and RRM2 mRNA expression in lung adenocarcinoma tumours is associated with clinical outcome to docetaxel/gemcitabine. Aim 2b: We have retrospectively examined the effect of RRM1, RRM2 and BRCA1 expression on outcome to gemcitabine plus docetaxel in advanced non-small cell lung cancer (NSCLC) patients. Tumor samples were collected from 102 chemotherapy naive advanced NSCLC patients. RRM1, RRM2 and BRCA1 mRNA levels were assessed by quantitative PCR and correlated with response time to progression and survival. As BRCA1 levels increased the probability of response increased (OR 1.09, p=0.01) and the risk of progression decreased (HR 0.99, p=0.36). As RRM1 and RRM2 levels increased the probability of response decreased (RRM1 OR 0.97, p=0.82, RRM2 OR 0.94 p=0.0001) and the risk of progression increased (RRM1, HR 1.02 p=0.001, RRM2 HR 1.005 p=0.01). An interaction observed between BRCA1 and RRM1 allowed patients to be classified in three risk groups according to combinations of gene expression levels with times to progression of 10.13, 4.17 and 2.30 months (p=0.001). Low BRCA1 expression was the only factor significantly associated with longer time to progression in 31 patients receiving cisplatin based second line therapy. The mRNA expression of BRCA1, RRM1 and RRM2 is potentially a useful tool for selecting NSCLC patients for individualized chemotherapy.Στόχος 1: Πολυκεντρική μελέτη φάσης II και αξιολόγηση της αποτελεσματικότητας του συνδυασμού docetaxel και gemcitabine ως πρώτης γραμμής Χ/Θ σε ηλικιωμένους ασθενείς με αδενοκαρκίνωμα πνεύμονα. 77 ασθενείς >70 ετών εντάχθηκαν στη μελέτη. 1 ασθενής εμφάνισε πλήρη ανταπόκριση (1.3%) και 23 ασθενείς (29.9%) εμφάνισαν μερική ανταπόκριση [OR 0.31 (95%CI 0.21 0.42)] ενώ έλεγχος της νόσου επιτεύχθηκε στο 53.3%. Το διάμεσο διάστημα ελεύθερο προόδου νόσου ήταν 4.1 μήνες η διάμεση επιβίωση 9.4 μήνες και η μονοετής και διετής επιβίωση 37.9% και 10.7% αντίστοιχα. Η προοπτική αυτή μελέτη έδειξε ότι η χημειοθεραπεία 1ης γραμμής με docetaxel/gemcitabine είναι αποτελεσματική στους ηλικιωμένους ασθενείς με μεταστατικό ή τοπικά προχωρημένο αδενοκαρκίνωμα του πνεύμονα. Στόχος 2α: Να αξιολογηθούν τα επίπεδα έκφρασης mRNA των υποομάδων RRM1 και RRM2 και να συσχετιστούν με τα κλινικά αποτελέσματα σε ασθενείς με αδενοκαρκίνωμα πνεύμονα που θεραπεύονται με το συνδυασμό docetaxel και gemcitabine ως Χ/Θ 1ης γραμμής. Για να μελετήσουμε την έκφραση των γονίδιων RRM1 και RRM2 απομονώθηκε RNA από το υλικό του όγκου μετά από μικροτεμαχισμό με laser. Η ποσοτικοποίηση του εξαγόμενου RNA έγινε με RT-PCR. Στη μελέτη εντάχθηκαν 53 ασθενείς. Όταν οι ασθενείς ταξινομήθηκαν ανάλογα με την έκφραση RRM1 και RRM2 οι 10 ασθενείς με χαμηλά επίπεδα των mRNA RRM1 και RRM2 είχαν υψηλότερες απαντήσεις, ΤΤΡ και συνολική επιβίωση συγκριτικά με τους 7 ασθενείς με υψηλά επίπεδα και των δυο γονίδιων (απαντήσεις 60% vs 14.2%, p=0.049; time to progression: 9.9 vs 2.3 μήνες, p=0.003; συνολική επιβίωση: 15.4 vs 3.6 μήνες, p=0.031). Η πολυπαραγοντική ανάλυση έδειξε ότι τα υψηλά επίπεδα έκφρασης mRNA RRM2 σχετίζονταν σημαντικά με πτωχή απάντηση. Η μελέτη αυτή έδειξε για πρώτη φορά μια θετική σχέση μεταξύ της έκφρασης mRNA της RRM2 και της απάντησης σε συνδυασμό βασισμένο στη gemcitabine σε ασθενείς με αδενοκαρκίνωμα του πνεύμονα. Στόχος 2β: Να αξιολογηθούν τα επίπεδα έκφρασης mRNA των BRCA1, RRM1 και RRM2 και να συσχετιστούν με τη κλινική απάντηση σε Χ/Θ 1ης γραμμής με docetaxel και gemcitabine σε ασθενείς με μη-μικροκυτταρικό καρκίνο πνεύμονα. Η μεθοδολογία κατεργασίας των δειγμάτων είναι όμοια με την περιγραφείσα ανωτέρω. Κλινικά δεδομένα και εξαγωγή RNA για τα γονίδια BRCA1, RRM1 και RRM2 επιτεύχθηκε σε 96 δείγματα. Οι ασθενείς ταξινομήθηκαν σε 3 ομάδες ανάλογα με τον κίνδυνο προόδου νόσου βασισμένοι στην αλληλεπίδραση των επίπεδων mRNA BRCA1 και mRNA RRM1. 24 ασθενείς ήταν στη χαμηλού κινδύνου ομάδα, 42 ασθενείς στην ενδιάμεσου κίνδυνου ομάδα και 30 ασθενείς στην υψηλού κίνδυνου ομάδα. Το διάμεσο ΤΤΡ ήταν 10.13 μήνες για τους ασθενείς χαμηλού κίνδυνου 4.17 μήνες για τους ασθενείς ενδιάμεσου κίνδυνου και 2.3 μήνες για τους ασθενείς υψηλού κίνδυνου (p=0.001). Η έκφραση των RRM1, RRM2, BRCA1 αποτελεί ένα χρήσιμο εργαλείο για την εξατομικευμένη θεραπεία ασθενών με ΜΜΚΠ