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

Prognostic stratification of patients with advanced renal cell carcinoma treated with sunitinib: comparison with the Memorial Sloan-Kettering prognostic factors model

<p>Abstract</p> <p>Background</p> <p>The treatment paradigm in advanced renal cell carcinoma (RCC) has changed in the recent years. Sunitinib has been established as a new standard for first-line therapy. We studied the prognostic significance of baseline characteristics and we compared the risk stratification with the established Memorial Sloan Kettering Cancer Center (MSKCC) model.</p> <p>Methods</p> <p>This is a retrospective analysis of patients treated in six Greek Oncology Units of HECOG. Inclusion criteria were: advanced renal cell carcinoma not amenable to surgery and treatment with Sunitinib. Previous cytokine therapy but no targeted agents were allowed. Overall survival (OS) was the major end point. Significance of prognostic factors was evaluated with multivariate cox regression analysis. A model was developed to stratify patients according to risk.</p> <p>Results</p> <p>One hundred and nine patients were included. Median follow up has been 15.8 months and median OS 17.1 months (95% CI: 13.7-20.6). Time from diagnosis to the start of Sunitinib (<= 12 months vs. >12 months, p = 0.001), number of metastatic sites (1 vs. >1, p = 0.003) and performance status (PS) (<= 1 vs >1, p = 0.001) were independently associated with OS. Stratification in two risk groups ("low" risk: 0 or 1 risk factors; "high" risk: 2 or 3 risk factors) resulted in distinctly different OS (median not reached [NR] vs. 10.8 [95% confidence interval (CI): 8.3-13.3], p < 0.001). The application of the MSKCC risk criteria resulted in stratification into 3 groups (low and intermediate and poor risk) with distinctly different prognosis underlying its validity. Nevertheless, MSKCC model did not show an improved prognostic performance over the model developed by this analysis.</p> <p>Conclusions</p> <p>Studies on risk stratification of patients with advanced RCC treated with targeted therapies are warranted. Our results suggest that a simpler than the MSKCC model can be developed. Such models should be further validated.</p

Potential value of PTEN in predicting cetuximab response in colorectal cancer: An exploratory study

<p>Abstract</p> <p>Background</p> <p>The epidermal growth factor receptor (EGFR) is over-expressed in 70–75% of colorectal adenocarcinomas (CRC). The anti-EGFR monoclonal antibody cetuximab has been approved for the treatment of metastatic CRC, however tumor response to cetuximab has not been found to be associated with EGFR over-expression by immunohistochemistry (IHC). The aim of this study was to explore EGFR and the downstream effector phosphatase and tensin homologue deleted on chromosome 10 (PTEN) as potential predictors of response to cetuximab.</p> <p>Methods</p> <p>CRC patients treated with cetuximab by the Hellenic Cooperative Oncology group, whose formalin-fixed paraffin-embedded tumor tissue was available, were included. Tissue was tested for EGFR and PTEN by IHC and fluorescence in situ hybridization (FISH).</p> <p>Results</p> <p>Eighty-eight patients were identified and 72 were included based on the availability of tissue blocks with adequate material for analysis on them. All patients, except one, received cetuximab in combination with chemotherapy. Median follow-up was 53 months from diagnosis and 17 months from cetuximab initiation. At the time of the analysis 53% of the patients had died. Best response was complete response in one and partial response in 23 patients. In 16 patients disease stabilized. Lack of PTEN gene amplification was associated with more responses to cetuximab and longer time to progression (p = 0.042).</p> <p>Conclusion</p> <p>PTEN could be one of the molecular determinants of cetuximab response. Due to the heterogeneity of the population and the retrospective nature of the study, our results are hypothesis generating and should be approached with caution. Further prospective studies are needed to validate this finding.</p

Αξιολόγηση της προγνωστικής ακρίβειας της κλίμακας εκτίμησης κινδύνου SAPS II για την πρόβλεψη της θνησιμότητας ασθενών μονάδων εντατικής θεραπείας: Συστηματική ανασκόπηση και μετα-ανάλυση

Εισαγωγή: Η σωστή διαχείριση των κρίσιμων νοσημάτων περιλαμβάνει τη γρήγορη και ακριβή ταυτοποίηση των βαρέως πασχόντων ασθενών. Ένα χρήσιμο εργαλείο που μπορεί να το επιτύχει αυτό είναι το ευρέως διαδομένο μοντέλο πρόβλεψης ενδονοσοκομειακής θνησιμότητας, SAPS II. Σκοπός της εργασίας αυτής είναι να συγκεντρώσει μελέτες εξωτερικής επικύρωσης του SAPS II μοντέλου από τη διεθνή βιβλιογραφία και να μετα-αναλύσει τα μέτρα προγνωστικής ακρίβειάς του. Μέθοδοι: Πραγματοποιήθηκε βιβλιογραφική αναζήτηση στο PUBMED την περίοδο από 16 Οκτωβρίου 2022 μέχρι 20 Νοέμβρη 2022. Eπιλέχθηκαν οι μελέτες που είχαν δημοσιευθεί από το 2003 έως το 2022 και αξιολογούσαν το SAPS II για την πρόβλεψη της θνησιμότητας σε ασθενείς ΜΕΘ. Οι πληροφορίες που εξήχθησαν ήταν τα χαρακτηριστικά των μελετών, τα χαρακτηριστικά των ασθενών, τα μέτρα προγνωστικής ακρίβειας και αξιολογήθηκε ο κίνδυνος συστηματικού σφάλματος για την κάθε μελέτη. Για τη μετα-ανάλυση χρησιμοποιήθηκε το εμβαδό της καμπύλής ROC (AUROC) που είναι μέτρο διακριτικής ικανότητας. Πραγματοποιήθηκε σύνθεση των αποτελεσμάτων, με την εφαρμογή μοντέλου τυχαίων επιδράσεων και διερεύνηση των πηγών ετερογένειας με αναλύσεις σε υπο-ομάδες. Αποτελέσματα: Έγινε διαλογή 728 άρθρων, εκ των οποίων στα 306(42%) εκτιμήθηκε το πλήρες κείμενο. Κρίθηκαν σχετικά με τη μελέτη τα 200, αλλά συμπεριλήφθηκαν μόνο όσα είχαν δημοσιευθεί το 2022 (25). Από τις 25 μελέτες, 23(69,7%) μελετούσαν την ενδονοσοκομειακή θνησιμότητα, 2(6%) τη θνησιμότητα εντός της ΜΕΘ και 8(23,3%) τη θνησιμότητα εντός 1 μήνα, ενώ 11 (44%) κρίθηκαν με χαμηλό κίνδυνο συστηματικού σφάλματος, 11(44%) με ασαφή κίνδυνο και 3 (12%) με υψηλό κίνδυνο. Η συνθετική εκτίμηση του AUROC ήταν 0,75 (95% CI: 0,72-0,78). Παρατηρήθηκε σημαντικός βαθμός ετερογένειας (Ι2= 98%) ιδιαίτερα σε επίπεδο μεταξύ των μελετών, με το 95% διαστημα πρόβλεψης του AUROC να διαμορφώνεται μεταξύ 0,58 και 0,87. Οι αναλύσεις σε υπο-ομάδες ανάλογα την έκβαση και τον κίνδυνο συστηματικού σφάλματος έδειξαν ότι δεν υπάρχει στατιστικά σημαντική διαφορά μεταξύ των υπο-ομάδων. Συμπεράσματα: Το μοντέλο SAPS II ως εργαλείο πρόβλεψης θνησιμότητας σε ασθενείς ΜΕΘ επιτυγχάνει ικανοποιητική διακριτική ικανότητα. Η απουσία όμως των μέτρων βαθμονόμησης και η περιορισμένη ανάλυση καμπύλης απόφασης καθιστούν αδύνατη την πλήρη και συνεπή αξιολόγηση του μοντέλου και την εδραίωση του ως ένα χρήσιμο εργαλείο για την καθημερινή κλινική πράξη.Introduction: The ideal management of severe diseases includes the fast and precise identification of critical care patients. A useful tool that can achieve that is the widely used prognostic model of in-hospital mortality, SAPS II. The objective of this study is to gather external validation studies of SAPS II from the international literature and to meta-analyze its predictive performace measurements. Methods: A systematic search was conducted between October 16 and November 20, 2022. Studies were chosen if they were published between 2003 and 2022, and reviewed SAPS II on predicting ICU patients’ mortality. Data that were extracted included study and patients’ characteristics, predictive performance measurements and the risk of bias was assessed for each study. The discrimination measure that was used for the meta-analysis was the Area Under the ROC curve (AUROC). We synthesized the results with the use of a random effects model and researched the source of heterogeneity by subgroup analysis. Results: A total of 728 articles were screened, 306(42%) of which had their full text assessed. Of those 200 were judged as suitable, but only those that were published in 2022 (25) were included in the study. Of the 25 studies, 23 (69,7%) researched in-hospital mortality, 2 (6%) ICU mortality, 8 (23,3%) 1-month mortality, while 11 (44%) were found to have low risk of bias, 11 (44%) unclear risk of bias and 3 (12%) high risk of bias. The pooled estimate of AUROC was 0,75 (95% CI: 0,72-0,78). A high degree of between study heterogeneity was noted (I2 = 98%), with a 95% prediction interval of AUROC between 0,58 and 0,87. Subgroup analysis depending on type of event and overall risk of bias showed no statistical difference between the groups. Conclusions: The SAPS II model can achieve a decent discrimination as a tool of predicting ICU mortality. However, the absence of calibration measurements and the limited use of decision curve analysis deter the absolute and consistent review of the model and its establishment as a useful tool for daily clinical practice

Evaluation of the prognostic and predictive role of HER2 and topoisomerase II alpha gene status in breast cancer patients

The HER2 gene has been established as a valid biological marker for the treatment of breast cancer patients with trastuzumab and probably other agents, such as paclitaxel or anthracyclines. The TOP2A gene has been associated with response to anthracyclines. The relationship of HER2/TOP2A gene status in the presence of centromere 17 (CEN17) gain with patient outcome following adjuvant treatment with anthracyclines, with or without paclitaxel, has not been established. Formalin-fixed paraffin-embedded tumor tissue samples from 1031 patients with high-risk operable breast cancer, enrolled in two consecutive phase III trials, were assessed in a central laboratory by fluorescence in situ hybridization for HER2/TOP2A gene amplification and CEN17 gain (CEP17 probe). HER2 and TOP2A amplification was defined as a gene/CEP17 ratio of ≥2.2 and ≥2.0, respectively, or gene copy number of higher than 6. Additionally, HER2, TopoIIa, ER/PgR and Ki67 expression was assessed by immunohistochemistry (IHC) and patients were classified according to their IHC phenotype. Treatment consisted of epirubicin-based adjuvant chemotherapy followed by hormonal therapy and radiation, as indicated. HER2 amplification was found in 23.7% of the patients and TOP2A amplification in 10.1%. In total, 41.8% of HER2-amplified tumors demonstrated TOP2A co-amplification. The median (range) of HER2, TOP2A and CEN17 gain was 2.55 (0.70-45.15), 2.20 (0.70-26.15) and 2.00 (0.70-26.55), respectively. Forty percent of the tumors were found to have CEN17 gene gain (51% of those with HER2 amplification). Adjusting for treatment groups in the Cox model, HER2 amplification, TOP2A amplification, CEN17 gain and HER2/TOP2A co-amplification were not associated with either relapse or death. HER2 amplification, TOP2A amplification, CEN17 gain and HER2/TOP2A co-amplification were not associated with outcome.Το γονίδιο HER2 έχει καθιερωθεί ως ένας σημαντικός βιολογικός δείκτης για τη θεραπεία με trastuzumab, και πιθανώς με άλλους παράγοντες, όπως η paclitaxel και οι anthracyclines, σε ασθενείς με καρκίνο μαστού. Η συσχέτιση της κατάστασης των γονιδίων HER2/TOP2A και της παρουσίας επαύξησης του κεντρομεριδίου 17 (CEN17), με την έκβαση των ασθενών, μετά από συμπληρωματική θεραπεία με ανθρακυκλίνες, με ή χωρίς paclitaxel, δεν έχει διευκρινιστεί. Κύβοι παραφίνης από 1031 ασθενείς με υψηλού κινδύνου χειρουργήσιμο καρκίνο μαστού, που έλαβαν μέρος σε δύο διαδοχικές μελέτες φάσης ΙΙΙ, ελέγχθηκαν σε κεντρικό εργαστήριο με FISH για την ενίσχυση των γονιδίων HER2/TOP2A και την επαύξηση CEN17 (CEP17 ιχνηθέτες). Η ενίσχυση του HER2 και TOP2A ορίστηκε ως ο λόγος γονιδίου/ CEN17≥2.2 και ≥2.0 αντίστοιχα ή ως αριθμός γονιδιακών αντιγράφων >6. Στο 23% των ασθενών διαπιστώθηκε ενίσχυση του HER2, ενώ ενίσχυση του TOP2A διαπιστώθηκε στο 10.1%. Συνολικά 41.8% των ασθενών με ενίσχυση του HER2 εμφάνισαν ταυτόχρονα ενίσχυση του TOP2A. Η διάμεσος (εύρος) επαύξηση του HER2, TOP2A και CEN17 βρέθηκαν 2.55 (0.70-45.15), 2.20 (0.70-26.15) και 2.00 (0.70-26.55) αντίστοιχα. Σαράντα της εκατό των όγκων είχαν επαύξηση του γονιδίου CEN17 (51% αυτών με HER2 ενίσχυση). Προσαρμόζοντας το πρότυπο COX στις ομάδες θεραπείας, η ενίσχυση του HER2, η ενίσχυση του TOP2A, η επαύξηση του CEN17 και η ταυτόχρονη ενίσχυση του λόγου HER2/TOP2A δε βρέθηκε να σχετίζονται ούτε με την υποτροπή, ούτε με το θάνατο. Συμπληρωματικά, HER2, TopoIIa, ER/PgR και η έκφραση του μιτωτικού Ki67 εκτιμήθηκαν με ανοσοϊστοχημεία (IHC) και οι ασθενείς κατατάχθηκαν ανάλογα με τον ανοστοϊτοχημικό τους φαινότυπο. Η θεραπεία περιελάμβανε χημιοθεραπέια βασισμένη στην epirubicin, ακολουθούμενη από ορμονοθεραπεία και ακτινοθεραπεία όπου είχε ένδειξη. Η ενίσχυση του HER2, η ενίσχυση του TOP2A, η επαύξηση του CEN17 και η ταυτόχρονη ενίσχυση του λόγου HER2/TOP2A δε σχετίστηκαν με την έκβαση των ασθενών