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Tesi etd-03182018-123845


Thesis type
Tesi di dottorato di ricerca
Author
SALVATORE, LISA
URN
etd-03182018-123845
Title
PHASE II RANDOMIZED STUDY OF MAINTENANCE TREATMENT WITH BEVACIZUMAB OR BEVACIZUMAB PLUS METRONOMIC CHEMOTHERAPY AFTER FIRST-LINE INDUCTION FOLFOXIRI PLUS BEVACIZUMAB FOR METASTATIC COLORECTAL CANCER PATIENTS. THE MOMA STUDY
Settore scientifico disciplinare
MED/06
Corso di studi
FISIOPATOLOGIA CLINICA
Commissione
tutor Prof. Falcone, Alfredo
Parole chiave
  • metastatic colorectal cancer
  • maintenance
  • metronomic
  • bevacizumab
  • folfoxiri
Data inizio appello
30/03/2018;
Consultabilità
parziale
Data di rilascio
30/03/2021
Riassunto analitico
Background<br>Tumoral growth, metastatic spread and disease progression are complex processes to which the formation of new blood vessels significantly contributes. Neoangiogenesis is a crucial therapeutic target for metastatic colorectal cancer as demonstrated by the effectiveness of biological drugs with exclusive or partial antiangiogenic activity such as bevacizumab, aflibercept and regorafenib. <br>The addition of bevacizumab to FOLFOXIRI as induction followed by its continuation with 5-fluorouracil until disease progression as maintenance, is an efficacious first­line treatment for metastatic colorectal cancer. Although alternating induction and maintenance phases is a common strategy in metastatic colorectal cancer, the optimal duration of induction and the optimal maintenance are open issues. <br>Metronomic chemotherapy may represent an alternative and better tolerated strategy for targeting tumor angiogenesis and preclinical evidences show that it may synergize with bevacizumab in order to maximize the antiangiogenic effect. The continuous administration of low- dose chemotherapy induces microvessel density decrease, hypoxia, endothelial cell alteration and apoptosis, and circulating progenitor cell decrease.<br>On the basis of such premises we have conducted the MOMA study to explore maintenance therapy with bevacizumab alone or bevacizumab plus metronomic chemotherapy following a 4-months induction phase with FOLFOXIRI plus bevacizumab.<br>Methods<br>MOMA (NCT02271464) is an Italian, no-profit, multicentric, phase II randomized study. <br>Patients with unresectable metastatic colorectal cancer, untreated for the metastatic disease, were randomized to receive 8 cycles of induction FOLFOXIRI plus bevacizumab, followed by bevacizumab (7.5 mg/Kg every 3 weeks) until the evidence of disease progression (arm A), or the same induction regimen followed by bevacizumab in combination with metronomic capecitabine and oral cyclophosphamide (Capecitabine: 500 mg/tid, cyclophosphamide: 50 mg/die) continuously, until progression (arm B). The primary end-point was first-line progression-free survival. FOLFOXIRI plus bevacizumab was reintroduced in patients undergoing disease progression during maintenance. Secondary end-points were response rate, resection rate, duration of response, time to strategy failure, time to 2nd progression, overall survival, safety profile and the evaluation of potential surrogate markers of bevacizumab and metronomic chemotherapy efficacy. <br>According to the comparative Rubinstein and Korn’s design, estimating a first-line progression-free survival of 11 months, to detect a HR of 0.75 favoring arm B, with 1 sided-alpha and beta errors of 15% and 80%, 173 events were required.<br>Results<br>From May 2012 to March 2015, 232 patients (117 in arm A and 115 in arm B) were randomized in 16 Italian centers. <br>Patients&#39; characteristics were (arm A/B): median age 61/62 years, ECOG PS 0 85%/85%, synchronous metastases 81%/83%, liver-only disease 27%/35%, right-sided primary 32%/42%, RAS mutant 66%/63%, BRAF mutant 7%/10%, RAS/BRAF wt 18%/14%, RAS or BRAF not evaluable 9%/13%. <br>At a median follow up of 25.7 months, 188 patients progressed. No significant difference in progression-free survival was reported between arms: median progression-free survival was 9.5 and 10.6 months in arm A and B, respectively (HR: 0.99; 70%CI 0.85-1.15, p=0.926). In the overall population response rate with FOLFOXIRI plus bevacizumab was 63% (arm A/B: 68%/58%) and disease control rate was 91% (arm A/B: 94%/88%). In the liver-limited subgroup (N=72), the secondary resection rate was 49% (arm A/B: 53%/45%). During induction, main grade 3/4 adverse events were neutropenia (all: 51.9%; arm A/B: 55%/47.8%), febrile neutropenia (all: 11.2%; arm A/B: 13.7%/8.7%), and diarrhea (all: 13.4%; arm A/B: 11.2%/15.7%). During maintenance, main grade 3/4 adverse events were hand&amp;foot syndrome (arm A/B: 0%/8%), hypertension (arm A/B: 4.6%/2.6%), and venous thrombosis (arm A/B: 2%/3%).<br>Conclusions<br>Activity of FOLFOXIRI plus bevacizumab is confirmed in a population with high prevalence of RAS and BRAF mutant metastatic colorectal cancer patients and with a shorter (4 months) treatment duration. <br>The addition of metronomic chemotherapy to maintenance with bevacizumab does not significantly improve progression-free survival and a fluoropyrimidine at standard dose plus bevacizumab remains the preferred maintenance after chemotherapy plus bevacizumab.<br>
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