title: Increased mean corpuscular volume of red blood cells predicts response to metronomic capecitabine and cyclophosphamide in combination with bevacizumab.
abstract: BACKGROUND
  There is an urgent need for the identification of commonly assessable predictive factors in the treatment of patients with metastatic breast cancer.
  
  
  METHODS
  During the course of a treatment including low dose metronomic oral cyclophosphamide and capecitabine plus i.v. bevacizumab (plus erlotinib in one third of the patients) for metastatic breast cancer, we observed that a relevant number of patients developed repeatedly elevated levels of mean corpuscular volume (MCV) of red blood cells without a significant fall in hemoglobin levels. We conducted a retrospective analysis on these 69 patients to evaluate if the increase in MCV could be associated to tumor response.
  
  
  RESULTS
  During the course of treatment 42 out of 69 patients (61%) developed macrocytosis. Using Cox proportional hazards modeling that incorporated macrocytosis (MCV ≥ 100 fl) as a time-dependent covariate, macrocytosis resulted in a halved risk of disease progression (HR 0.45; 95% CI, 0.22-0.92, p-value 0.028). In a landmark analysis limited to patients with no sign of progression after 24 weeks of treatment, median time to progression was 72 weeks (48 weeks after landmark) in patients who had developed macrocytosis, and 43 weeks (19 weeks after landmark) in patients who had not (p=0.023).
  
  
  CONCLUSIONS
  Macrocytosis inversely related to risk of disease progression in patients treated with metronomic capecitabine plus cyclophosphamide and bevacizumab for metastatic breast cancer. This finding may be explained through thymidylate synthase inhibition by capecitabine. Whether bevacizumab has a role in determining macrocytosis, similarly to what happens with sunitinib, has to be further investigated. If other studies will confirm our findings, macrocytosis might be used as an early marker of response during metronomic treatment with capecitabine and cyclophosphamide with or without bevacizumab.
authors.affiliation: Medical Senology Research Unit, Department of Medicine, European Institute of Oncology, Milan, Italy. silvia.dellapasqua@ieo.it
authors.forename: Silvia
authors.initials: S
authors.lastname: Dellapasqua
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bagnardi
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertolini
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Sandri
authors.forename: Davide
authors.initials: D
authors.lastname: Pastrello
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cancello
authors.forename: Emilia
authors.initials: E
authors.lastname: Montagna
authors.forename: Alessandra
authors.initials: A
authors.lastname: Balduzzi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Mancuso
authors.forename: Alberto
authors.initials: A
authors.lastname: Luini
authors.forename: Aron
authors.initials: A
authors.lastname: Goldhirsch
authors.forename: Marco
authors.initials: M
authors.lastname: Colleoni
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology; D000069287:Capecitabine; D003520:Cyclophosphamide / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018450:Disease Progression; D018572:Disease-Free Survival; D004911:Erythrocyte Volume / Q000187:drug effects*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D012189:Retrospective Studies; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000068258:Bevacizumab; D000069287:Capecitabine; D003520:Cyclophosphamide; D013940:Thymidylate Synthase; D005472:Fluorouracil