Efficacy and safety of weekly paclitaxel in elderly patients with heavily pretreated platinum-resistant ovarian carcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17552-e17552
Author(s):  
Rodrigo Sanchez-Bayona ◽  
Pablo Tolosa ◽  
Ana Sanchez de Torre ◽  
Alicia Castelo ◽  
Elsa Bernal-Hertfelder ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Ovarian Carcinoma ◽  
Progression Free Survival ◽  
High Grade ◽  
Efficacy And Safety ◽  
Free Survival ◽  
Serous Ovarian Carcinoma ◽  
Platinum Resistant ◽  
Heavily Pretreated ◽  
Grade 3

e17552 Background: In platinum-resistant ovarian cancer treatment, single-agent paclitaxel can be used alone or in combination with bevacizumab. We aimed to assess the efficacy and safety profile of a weekly paclitaxel (WP) scheme in heavily pretreated platinum-resistant high-grade serous ovarian carcinoma. Methods: We retrospectively analyzed 30 adult patients with platinum-resistant high-grade serous ovarian carcinoma treated with WP at our institution between 2015 and 2020. Patients with platinum-resistant ovarian, fallopian tube or primary carcinoma of the peritoneum who had received at least 3 doses of WP (80 mg/m2) alone or in combination with bevacizumab until disease progression or unacceptable toxicity were included in the analysis. Progression-free survival was assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1. Information about toxicity was gathered from medical reports and lab tests. Kaplan-Meier curves and Log-rank test were performed for survival estimates. Results: In our sample, the median age was 68 years (IQR: 60-75) and the median number of previous lines of systemic treatment was 3 (range 1-5). 40% of patients received WP in combination with bevacizumab. The disease control rate was 60.7% (42.9% partial response and 17.8% stable disease). In the overall analysis, the median progression-free survival (mPFS) was 5.0 months (95% CI: 2.0-7.1 months). The presence of ascites significantly shortened the mPFS compared to patients without it (1.1 vs 5.1 months, p < 0.001). Even though the addition of bevacizumab to WP improved the mPFS, the difference was not statistically significant compared to WP alone (7.1 vs 4.06 months, p=0.30). Peripheral neuropathy was the most common adverse event (78% all grades, 18% grade 3). No grade 3 hematologic toxicity was registered. Treatment was discontinued in 6 patients (20%) – 4 due to peripheral neuropathy and two because of toxicoderma. Conclusions: In our sample, WP was an active and safe regimen in heavily pretreated platinum-resistant ovarian carcinoma. WP was well tolerated in elderly patients. The presence of ascites was associated to a shorter PFS in patients treated with WP compared to ascites-free patients.

Μελέτη δεικτών μεθυλίωσης στον καρκίνο των ωοθηκών

2019 ◽  
Author(s):  
Λυδία Γιαννοπούλου
Keyword(s):  
Overall Survival ◽  
Ovarian Carcinoma ◽  
Real Time ◽  
Tumor Cells ◽  
Progression Free Survival ◽  
Circulating Tumor Dna ◽  
High Grade ◽  
Free Survival ◽  
Serous Ovarian Carcinoma ◽  
Tumor Dna

Ο καρκίνος των ωοθηκών αποτελεί τον τέταρτο συχνότερα εμφανιζόμενο γυναικολογικό καρκίνο και την πέμπτη αιτία θανάτου σχετιζόμενη με καρκίνο στις γυναίκες. Χαρακτηρίζεται από αξιοσημείωτη ιστολογική και μοριακή ετερογένεια, με κυριότερο υπότυπο τον ορώδη καρκίνο ωοθηκών υψηλού βαθμού κακοήθειας (high grade serous ovarian carcinoma, HGSC), που μελετήθηκε στη διατριβή. Η παρούσα διατριβή έχει σκοπό τη μελέτη της μεθυλίωσης επιλεγμένων γονιδίων στον ορώδη καρκίνο ωοθηκών υψηλού βαθμού κακοήθειας. Τα κλινικά δείγματα που χρησιμοποιήθηκαν είναι δείγματα πρωτοπαθών όγκων, αντίστοιχα δείγματα παρακείμενων ιστών, καθώς και αντίστοιχα δείγματα κυκλοφορούντος καρκινικού DNA (circulating tumor DNA, ctDNA) από τις ίδιες ασθενείς. Οι μεθοδολογίες που εφαρμόστηκαν συνιστούν την real-time MSP για την ανίχνευση της μεθυλίωσης σε δείγματα πρωτοπαθών όγκων, παρακείμενων ιστών και πλάσματος, καθώς και την MS-HRMA για τον ημιποσοτικό προσδιορισμό της μεθυλίωσης σε δείγματα πρωτοπαθών όγκων και παρακείμενων ιστών. Αρχικά εξετάστηκε η μεθυλίωση του ογκοκατασταλτικού γονιδίου RASSF1A, όπου πραγματοποιήθηκε μία συγκριτική μελέτη σε δείγματα πρωτοπαθών όγκων, παρακείμενων ιστών και ctDNA ασθενών με HGSC. Η μεθυλίωση του γονιδίου στα δείγματα πρωτοπαθών όγκων και παρακείμενων ιστών συσχετίστηκε με σημαντικά μειωμένη ολική επιβίωση (overall survival, OS) των ασθενών. Τα συνολικά αποτελέσματα της μελέτης υπέδειξαν για πρώτη φορά την προγνωστική σημασία της μεθυλίωσης του γονιδίου στον HGSC. Στη συνέχεια, ακολούθησε μελέτη μεθυλίωσης του γονιδίου ESR1, όπου πραγματοποιήθηκε μελέτη σε δείγματα πρωτοπαθών όγκων και ctDNA ασθενών με HGSC. Η μεθυλίωση του γονιδίου στα δείγματα πρωτοπαθών όγκων συσχετίστηκε με σημαντικά αυξημένα OS και διάστημα επιβίωσης χωρίς εξέλιξη της νόσου (progression free survival, PFS) των ασθενών. H παρούσα μελέτη αποτέλεσε μία προσπάθεια αποσαφήνισης του ρόλου της μεθυλίωσης του γονιδίου στον HGSC. Ακολούθησαν οι μελέτες μεθυλίωσης γονιδίων που εμπλέκονται σε μοριακά μονοπάτια που διαταράσσονται στον HGSC, όπως τα γονίδια BRCA1 και MGMT που συμμετέχουν σε διαφορετικές πορείες επιδιόρθωσης του DNA, το γονίδιο NR2F1 που συμμετέχει ενεργά στην κυτταρική αδράνεια, τα γονίδιο RASSF10 που εμπλέκεται στην ανάπτυξη χημειοαντίστασης, καθώς και το γονίδιο RKIP που συμμετέχει στην ΕΜΤ διαδικασία. Ύστερα από τη συνολική επεξεργασία των αποτελεσμάτων, παρατηρήθηκε στατιστικά σημαντική συσχέτιση της μεθυλίωσης του γονιδίου NR2F1 στα δείγματα πρωτοπαθών όγκων, με μειωμένο PFS. Επιπλέον, η μεθυλίωση του γονιδίου BRCA1 στο ctDNA συσχετίστηκε με σημαντικά αυξημένο PFS. Τέλος, πραγματοποιήθηκε μελέτη της έκφρασης του γονιδίου PD-L1 σε δείγματα κυκλοφορούντων καρκινικών κυττάρων (circulating tumor cells, CTCs) ασθενών με HGSC, με την εφαρμογή RT-qPCR. Με βάση τα αποτελέσματα της μελέτης, παρατηρήθηκε στατιστικά σημαντική συσχέτιση της έκφρασης του γονιδίου με μειωμένη OS των ασθενών, υποδεικνύοντας μία πιθανή προγνωστική σημασία στον HGSC.

Effect of weekly administration of bevacizumab, eribulin, and oxalilplatin in patients with heavily pretreated serous ovarian carcinoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e16506-e16506 ◽  
Author(s):  
Yuji Ikeda ◽  
Masashi Takano ◽  
Naoki Sasaki ◽  
Tsunekazu Kita ◽  
Yoshihiro Kikuchi ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Gynecologic Cancer ◽  
Evaluation Criteria ◽  
Progression Free Survival ◽  
Complete Response ◽  
Significant Activity ◽  
Weekly Administration ◽  
Serous Ovarian Carcinoma ◽  
Heavily Pretreated ◽  
Grade 3

e16506 Background: Eribulin, inhibiting a protein component of tubulin, extend the lifespan of patients with late-stage breast cancer who are not benefiting paclitaxel. Bevacizumab (B) is known to enhance chemotherapeutic efficacy of platinum agents. We evaluated the effect of weekly administration of B with eribulin and oxaliplatin (EriOX) in recurrent or refractory serous ovarian carcinoma patients (ROC) pretreated with paclitaxel and carboplatin. Methods: Thirteen patients with ROC had treated with weekly-B and EriOX consisting of B (2mg/kg), eribulin (1mg/m2) and oxaliplatin (30mg/m2). The response and adverse effects (AE) were evaluated using the response evaluation criteria in solid tumors (RECIST), CA125 Gynecologic Cancer Intergroup (GCIG) criteria, and common terminology criteria for adverse events (CTCAE) version 4.0. Results: One patient is still under treatment of two cycles. We evaluated 12 patients at least two or more cycles of weekly B and EriOX. Ten patients (83%) were primarily stage 3 or 4. Ten patients (83%) had received three or more regimens of chemotherapy. All patients were pretreated with paclitaxel and carboplatin and 9 patients (75%) had been pretreated with platinum containing regimen within 6 months. According to the RECIST evaluation, 2 patients (17%) had a complete response (CR), 1 patient (8%) had a partial remission (PR) and 3 patients (25%) had a stable disease (SD). The response rate (CR+PR) and clinical benefit rate (CR+PR+SD) were 25% and 50%, respectively. Median progression-free survival was 3 months (range: 1-5 months). Hematological AEs with grade 3/4 were observed in 2 patients (17%). Hypo albuminemia and edema with grade 3 were in 1 patient (8%), respectively. However, all AE were manageable and torelable. Conclusions: Weekly B and EriOX administration had significant activity with mild AE in patients with paclitaxel and platinum resistant ROC. These results warrant further prospective study.

Subgroup analysis of rucaparib versus chemotherapy as treatment for BRCA-mutated, advanced, relapsed ovarian carcinoma: Effect of platinum sensitivity in the randomized, phase 3 study ARIEL4.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5517-5517
Author(s):  
Amit M. Oza ◽  
Alla Sergeevna Lisyanskaya ◽  
Alexander A. Fedenko ◽  
Mikhail Dvorkin ◽  
Andreia Cristina de Melo ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Subgroup Analysis ◽  
Brca Mutation ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Platinum Sensitivity ◽  
Platinum Sensitive ◽  
Platinum Resistant ◽  
Heavily Pretreated

5517 Background: In ARIEL4 (NCT02855944), rucaparib significantly improved the primary endpoint of progression-free survival (PFS) vs chemotherapy (CT) in patients with advanced, relapsed ovarian carcinoma (OC) harboring a deleterious BRCA1/2 (BRCA) mutation (median PFS 7.4 [95% CI 7.3–9.1] vs 5.7 [5.5–7.3] months; hazard ratio (HR) 0.64 [95% CI 0.49–0.84]; P=0.001). This prespecified exploratory analysis investigated the effect of platinum sensitivity on the efficacy of rucaparib vs CT in ARIEL4. Methods: Patients were randomized 2:1 to oral rucaparib 600 mg twice daily or CT and stratified based on progression-free interval (≥1 to <6 months = platinum resistant; ≥6 to <12 months = partially platinum sensitive; ≥12 months = fully platinum sensitive). In the CT group, patients with platinum-resistant or partially platinum-sensitive disease received weekly paclitaxel 60–80 mg/m2; patients with fully platinum-sensitive disease received investigator’s choice of platinum-based CT (single-agent carboplatin or cisplatin, or platinum doublet). Patients could crossover from CT to rucaparib following radiologic disease progression. Efficacy endpoints were explored in patients with a confirmed BRCA mutation (patients with a reversion mutation were excluded), based on the randomization strata of platinum sensitivity. Results: The visit cutoff date was September 30, 2020. PFS and objective response rates (ORR) per RECIST v1.1 for rucaparib vs CT across subgroups are presented in the Table. The most common treatment-emergent adverse events in the rucaparib group were anemia/decreased hemoglobin (platinum-resistant patients: rucaparib 47% vs CT 40%; partially platinum-sensitive patients: 63% vs 27%; fully platinum-sensitive patients: 58% vs 20%) and nausea (52% vs 21%; 51% vs 23%; 60% vs 68%). In the intent-to-treat population, 74/116 (64%) patients in the CT group crossed over to receive rucaparib: 39/59 (66%) with platinum-resistant, 25/31 (81%) with partially platinum-sensitive, and 10/26 (38%) with fully platinum-sensitive disease. Conclusions: Results from this exploratory subgroup analysis suggest that rucaparib is a reasonable treatment option for heavily pretreated patients across all platinum sensitivity subgroups. Safety was consistent with prior rucaparib studies. Clinical trial information: NCT02855944. [Table: see text]

scholarly journals Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma

2020 ◽  
pp. JCO.20.02259
Author(s):  
Paul G. Richardson ◽  
Albert Oriol ◽  
Alessandra Larocca ◽  
Joan Bladé ◽  
Michele Cavo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Free Survival ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Grade 3

PURPOSE Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class–refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease.

scholarly journals Combining Correlated Outcomes and Surrogate Endpoints in a Network Meta-Analysis of Colorectal Cancer Treatments

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2663
Author(s):  
Tung Hoang ◽  
Jeongseon Kim
Keyword(s):  
Colorectal Cancer ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Efficacy And Safety ◽  
Cancer Treatments ◽  
Free Survival ◽  
Hazard Ratios ◽  
Credible Intervals ◽  
Grade 3 ◽  
Selection Of

This study aimed to investigate the efficacy and safety of systemic therapies in the treatment of unresectable advanced or metastatic colorectal cancer. Predicted hazard ratios (HRs) and their 95% credible intervals (CrIs) for overall survival (OS) were calculated from the odds ratio (OR) for the overall response rate and/or HR for progression-free survival using multivariate random effects (MVRE) models. We performed a network meta-analysis (NMA) of 49 articles to compare the efficacy and safety of FOLFOX/FOLFIRI±bevacizumab (Bmab)/cetuximab (Cmab)/panitumumab (Pmab), and FOLFOXIRI/CAPEOX±Bmab. The NMA showed significant OS improvement with FOLFOX, FOLFOX+Cmab, and FOLFIRI+Cmab compared with that of FOLFIRI (HR = 0.84, 95% CrI = 0.73–0.98; HR = 0.76, 95% CrI = 0.62–0.94; HR = 0.80, 95% CrI = 0.66–0.96, respectively), as well as with FOLFOX+Cmab and FOLFIRI+Cmab compared with that of FOLFOXIRI (HR = 0.69, 95% CrI = 0.51–0.94 and HR = 0.73, 95% CrI = 0.54–0.97, respectively). The odds of adverse events grade ≥3 were significantly higher for FOLFOX+Cmab vs. FOLFIRI+Bmab (OR = 2.34, 95% CrI = 1.01–4.66). Higher odds of events were observed for FOLFIRI+Pmab in comparison with FOLFIRI (OR = 2.16, 95% CrI = 1.09–3.84) and FOLFIRI+Bmab (OR = 3.14, 95% CrI = 1.51–5.89). FOLFOX+Cmab and FOLFIRI+Bmab showed high probabilities of being first- and second-line treatments in terms of the efficacy and safety, respectively. The findings of the efficacy and safety comparisons may support the selection of appropriate treatments in clinical practice. PROSPERO registration: CRD42020153640.

scholarly journals Expression of the cancer stem cell marker SSEA1 is associated with poor survival in metastatic high-grade serous carcinoma

2020 ◽  
Vol 477 (5) ◽  
pp. 677-685
Author(s):  
Ben Davidson ◽  
Arild Holth ◽  
Hiep Phuc Dong
Keyword(s):  
Stem Cell ◽  
Survival Analysis ◽  
Cancer Stem Cell ◽  
Ovarian Carcinoma ◽  
Progression Free Survival ◽  
Stem Cell Marker ◽  
Serous Carcinoma ◽  
High Grade ◽  
Poor Survival ◽  
Free Survival

Abstract The objective of the present study was to perform a quantitative analysis of cancer stem cell (CSC) marker expression in ovarian carcinoma effusions. The clinical role of SSEA1 in metastatic high-grade serous carcinoma (HGSC) was additionally analyzed. CD133, Nanog, SOX2, Oct3/4, SSEA1, and SSEA4 protein expressions were quantitatively analyzed using flow cytometry (FCM) in 24 effusions. SSEA1 expression by immunohistochemistry was analyzed in 384 HGSC effusions. Highly variable expression of CSC markers by FCM was observed, ranging from 0 to 78% of Ber-EP4-positive cells in the case of CD133, with the largest number of negative specimens seen for SSEA4. SSEA1 expression by immunohistochemistry was found in HGSC cells in 336/384 (89%) effusions, most commonly focally (< 5% of cells). SSEA1 was overexpressed in post-chemotherapy disease recurrence specimens compared with chemo-naïve HGSC effusions tapped at diagnosis (p = 0.029). In univariate survival analysis, higher SSEA1 expression was significantly associated with poor overall survival (p = 0.047) and progression-free survival (p = 0.018), though it failed to retain its prognostic role in Cox multivariate survival analysis in which it was analyzed with clinical parameters (p = 0.059 and p = 0.111 for overall and progression-free survival, respectively). In conclusion, CSC markers are variably expressed in ovarian carcinoma effusions. SSEA1 expression is associated with disease progression and poor survival in metastatic HGSC. Silencing this molecule may have therapeutic relevance in this cancer.

scholarly journals A multicenter phase II study of Q3 week or weekly paclitaxel in combination with bevacizumab for the treatment of metastatic or unresectable angiosarcoma

Rare Tumors ◽  
2018 ◽  
Vol 10 ◽  
pp. 203636131877177 ◽  
Author(s):  
Nam Bui ◽  
Nikhil Kamat ◽  
Vinod Ravi ◽  
Sant Chawla ◽  
Marti Lohman ◽  
...  
Keyword(s):  
Median Overall Survival ◽  
Progression Free Survival ◽  
Weekly Paclitaxel ◽  
Comparable Efficacy ◽  
Progression Rate ◽  
Efficacy And Safety ◽  
Free Survival ◽  
Multicenter Phase ◽  
Grade 3 ◽  
To Receive

Paclitaxel (P) and bevacizumab (B) are agents that provide clinical benefit in advanced angiosarcoma (AS). The objective of this study was to assess the efficacy and safety of P-B in two different scheduled regimens. Patients were to receive P 200mg/m2 IV with B 15mg/kg IV every 21 days (Regimen A) or P 90mg/m2 IV weekly D1, 8, 15 with B 15mg/kg IV D1 of a 28 day cycle (Regimen B) x6 cycles. Maintenance B followed at a dose of 15 mg/kg intravenously once every 21 days. The primary end point was 4 month non-progression rate (NPR). A total of 16 patients were enrolled. 4 month NPR was 62.5% with median overall survival 16 months and median progression free survival 5.06 months. 11 patients made it to cycle 3 and were evaluable for response with 1 CR (9%), 4 PR (36%), 2 SD (18%), and 6 PD (36%). There were ten grade 3 toxicities and four grade 4 toxicities. The breakdown between the two regimens revealed comparable efficacy and safety. Paclitaxel and Bevacizumab is an active regimen in angiosarcoma. Q3 week and weekly paclitaxel appear similar in efficacy and safety.

scholarly journals Subcutaneous Administration of Bortezomib in Combination with Thalidomide and Dexamethasone for Treatment of Newly Diagnosed Multiple Myeloma Patients

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Shenghao Wu ◽  
Cuiping Zheng ◽  
Songyan Chen ◽  
Xiaoping Cai ◽  
Yuejian Shi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Adverse Events ◽  
Subcutaneous Administration ◽  
Progression Free Survival ◽  
The Other ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Free Survival ◽  
Grade 3

Objective. To investigate the efficacy and safety of the treatment of the newly diagnosed multiple myeloma (MM) patients with the therapy of subcutaneous (subQ) administration of bortezomib and dexamethasone plus thalidomide (VTD) regimen.Methods. A total of 60 newly diagnosed MM patients were analyzed. 30 patients received improved VTD regimen (improved VTD group) with the subQ injection of bortezomib and the other 30 patients received conventional VTD regimen (VTD group).The efficacy and safety of two groups were analyzed retrospectively.Results. The overall remission (OR) after eight cycles of treatment was 73.3% in the VTD group and 76.7% in the improved VTD group (P>0.05). No significant differences in time to 1-year estimate of overall survival (72% versus 75%,P=0.848) and progression-free survival (median 22 months versus 25 months;P=0.725) between two groups. The main toxicities related to therapy were leukopenia, neutropenia, thrombocytopenia, asthenia, fatigue, and renal and urinary disorders. Grade 3 and higher adverse events were significantly less common in the improved VTD group (50%) than VTD group (80%,P=0.015).Conclusions. The improved VTD regimen by changing bortezomib from intravenous administration to subcutaneous injection has noninferior efficacy to standard VTD regimen, with an improved safety profile and reduced adverse events.

A Prospective, Randomized, Phase III Study of Bortezomib, Melphalan, Prednisone and Thalidomide (VMPT) Versus Bortezomib, Melphalan and Prednisone (VMP) in Elderly Newly Diagnosed Myeloma Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 652-652 ◽  
Author(s):  
Antonio Palumbo ◽  
Sara Bringhen ◽  
Davide Rossi ◽  
Valeria Magarotto ◽  
Francesco Di Raimondo ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Chromosomal Abnormalities ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Gastrointestinal Complications ◽  
Free Survival ◽  
Weekly Infusion ◽  
Grade 3

Abstract Background: In newly diagnosed myeloma patients the combination of bortezomib with melphalan-prednisone (VMP) was superior to MP. In relapsed-refractory patients the 4 drug combination of bortezomib-melphalan-prednisone-thalidomide (VMPT) induced a high proportion of complete responses (CR). Methods: Newly diagnosed myeloma patients (N=393) older than 65 years, from 58 centers in Italy, were randomly assigned to receive VMPT (N=193) or VMP (N=200). Initially, patients were treated with nine 6-week cycles of VMPT (bortezomib 1.3 mg/m2 days 1,4,8,11,22,25,29,32 in cycles 1–4 and days 1,8,22,29 in cycles 5–9; melphalan 9 mg/m2 days 1–4; prednisone 60 mg/m2 days 1–4 and thalidomide 50 mg days 1–42, followed by bortezomib 1.3 mg/m2 every 15 days and thalidomide 50 mg/day as maintenance) or VMP (bortezomib, melphalan and prednisone at the same doses and schedules previously described without maintenance). In March 2007, the protocol was amended: both VMPT and VMP schedules were changed to nine 5-week cycles and bortezomib schedule was modified to weekly administration (bortezomib 1.3 mg/m2 days 1,8,15,22 in cycles 1–9). Primary end-point was progression-free survival (PFS). Results: Patient characteristics were similar in both groups: median age was 71 years, 23% of patients were aged > 75 years. Patients who received at least 1 cycle were evaluated: 152 patients for VMPT (62 received bortezomib bi-weekly infusion and 90 weekly infusion) and 152 patients for VMP (62 received bortezomib bi-weekly infusion and 90 weekly infusion). Data were analyzed in intention-to-treat. The very good partial response (VGPR) rate was higher in the VMPT group (55% versus 42%, p=0.02), including a CR rate of 31% in the VMPT group and 16% in the VMP group (p=0.003). In the subgroup treated with weekly infusion of bortezomib, VGPR was 59% for VMPT and 37% for VMP (p=0.004), including 28% CR for VMPT and 10% for VMP (p=0.004). Subgroup analyses did not show any statistical difference between responses and either age, B2-microglobulin or chromosomal abnormalities, such as del13, t(4;14), t(14;16) and del17. After a median follow-up of 13.6 months, the 2-year PFS was 83.9% in the VMPT group and 75.7% in the VMP group (HR=0.73, 95% CI 0.38–1.42, p=0.35). In patients who received weekly infusion of bortezomib, the 2-year PFS was 86.8% in the VMPT group and 78.1% in the VMP group (HR=0.65, 95% CI 0.24–1.8, p=0.41). In patients who achieved CR after induction, the 2-year PFS was 100% for VMPT and 79% for VMP (p=0.02). The 3-year overall survival (OS) was 89.5% in the VMPT group and 88.7% in the VMP group (HR=1.02, 95% CI 0.43–2.46, p=0.96). The incidence of grade 3–4 adverse events (AEs) was similar in both groups. In the VMPT patients and in the VMP patients, the more frequent AEs were neutropenia (36% vs 31%), thrombocytopenia (20% vs 19%), peripheral neuropathy (18% vs 12%), infections (14% vs 10%), and gastrointestinal complications (7% vs 8%), respectively. The weekly infusion of bortezomib significantly decreased the incidence of grade 3–4 peripheral neuropathy (9% for VMPT and 3% for VMP). Conclusion: VMPT is superior to VMP in terms of response rates. Longer follow-up is needed to assess their effects on PFS and OS. The weekly infusion of bortezomib significantly reduced the incidence of grade 3–4 peripheral neuropathy without influencing outcome. Table. Complete responses, progression-free survival and peripheral neuropathy in all patients and in those who received weekly infusion of bortezomib VMPT group (n=152) VMP group (n=152) All patients (n=152) Subgroup with bortezomib weekly infusion (n=90) All patients (n=152) Subgroup with bortezomib weekly infusion (n=90) CR rate (%) 31 28 16 10 2-year PFS (%) 84 87 76 78 Grade 3–4 peripheral neuropathy (%) 18 9 12 3

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