TY - JOUR
T1 - Phase 1/2 study of valproic acid and short-course radiotherapy plus capecitabine as preoperative treatment in low-moderate risk rectal cancer-V-shoRT-R3 (Valproic acid - short RadioTherapy - rectum 3rd trial)
AU - Avallone, Antonio
AU - Piccirillo, Maria Carmela
AU - Delrio, Paolo
AU - Pecori, Biagio
AU - Di Gennaro, Elena
AU - Aloj, Luigi
AU - Tatangelo, Fabiana
AU - D'Angelo, Valentina
AU - Granata, Cinzia
AU - Cavalcanti, Ernesta
AU - Maurea, Nicola
AU - Maiolino, Piera
AU - Bianco, Franco
AU - Montano, Massimo
AU - Silvestro, Lucrezia
AU - Terranova Barberio, Manuela
AU - Roca, Maria Serena
AU - Di Maio, Massimo
AU - Marone, Pietro
AU - Botti, Gerardo
AU - Petrillo, Antonella
AU - Daniele, Gennaro
AU - Lastoria, Secondo
AU - Iaffaioli, Vincenzo R.
AU - Romano, Giovanni
AU - Caracò, Corradina
AU - Muto, Paolo
AU - Gallo, Ciro
AU - Perrone, Francesco
AU - Budillon, Alfredo
PY - 2014/11/24
Y1 - 2014/11/24
N2 - Background: Locally advanced rectal cancer (LARC) is a heterogeneous group of tumors where a risk-adapted therapeutic strategy is needed. Short-course radiotherapy (SCRT) is a more convenient option for LARC patients than preoperative long-course RT plus capecitabine. Histone-deacetylase inhibitors (HDACi) have shown activity in combination with RT and chemotherapy in the treatment of solid tumors. Valproic acid (VPA) is an anti-epileptic drug with HDACi and anticancer activity. In preclinical studies, our group showed that the addition of HDACi, including VPA, to capecitabine produces synergistic antitumour effects by up-regulating thymidine phosphorylase (TP), the key enzyme converting capecitabine to 5-FU, and by downregulating thymidylate synthase (TS), the 5-FU target. Methods/Design: Two parallel phase-1 studies will assess the safety of preoperative SCRT (5 fractions each of 5 Gy, on days 1 to 5) combined with (a) capecitabine alone (increasing dose levels: 500-825 mg/m2/bid), on days 1-21, or (b) capecitabine as above plus VPA (oral daily day -14 to 21, with an intra-patient titration for a target serum level of 50-100 microg/ml) followed by surgery 8 weeks after the end of SCRT, in low-moderate risk RC patients. Also, a randomized phase-2 study will be performed to explore whether the addition of VPA and/or capecitabine to preoperative SCRT might increase pathologic complete tumor regression (TRG1) rate. A sample size of 86 patients (21-22/arm) was calculated under the hypothesis that the addition of capecitabine or VPA to SCRT can improve the TRG1 rate from 5% to 20%, with one-sided alpha = 0.10 and 80% power. Discussion: This project aims to improve the efficacy of preoperative treatment of LARC and to decrease the inconvenience and the cost of standard long-course RT. Correlative studies could identify both prognostic and predictive biomarkers and could add new insight in the mechanism of interaction between VPA, capecitabine and RT.
AB - Background: Locally advanced rectal cancer (LARC) is a heterogeneous group of tumors where a risk-adapted therapeutic strategy is needed. Short-course radiotherapy (SCRT) is a more convenient option for LARC patients than preoperative long-course RT plus capecitabine. Histone-deacetylase inhibitors (HDACi) have shown activity in combination with RT and chemotherapy in the treatment of solid tumors. Valproic acid (VPA) is an anti-epileptic drug with HDACi and anticancer activity. In preclinical studies, our group showed that the addition of HDACi, including VPA, to capecitabine produces synergistic antitumour effects by up-regulating thymidine phosphorylase (TP), the key enzyme converting capecitabine to 5-FU, and by downregulating thymidylate synthase (TS), the 5-FU target. Methods/Design: Two parallel phase-1 studies will assess the safety of preoperative SCRT (5 fractions each of 5 Gy, on days 1 to 5) combined with (a) capecitabine alone (increasing dose levels: 500-825 mg/m2/bid), on days 1-21, or (b) capecitabine as above plus VPA (oral daily day -14 to 21, with an intra-patient titration for a target serum level of 50-100 microg/ml) followed by surgery 8 weeks after the end of SCRT, in low-moderate risk RC patients. Also, a randomized phase-2 study will be performed to explore whether the addition of VPA and/or capecitabine to preoperative SCRT might increase pathologic complete tumor regression (TRG1) rate. A sample size of 86 patients (21-22/arm) was calculated under the hypothesis that the addition of capecitabine or VPA to SCRT can improve the TRG1 rate from 5% to 20%, with one-sided alpha = 0.10 and 80% power. Discussion: This project aims to improve the efficacy of preoperative treatment of LARC and to decrease the inconvenience and the cost of standard long-course RT. Correlative studies could identify both prognostic and predictive biomarkers and could add new insight in the mechanism of interaction between VPA, capecitabine and RT.
KW - FDG-PET
KW - HDAC inhibitors
KW - Preoperative chemo-radiotherapy
KW - Rectal cancer
KW - Short-course radiotherapy (SCRT)
KW - Valproic acid (VPA)
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UR - http://www.scopus.com/inward/citedby.url?scp=84920840486&partnerID=8YFLogxK
U2 - 10.1186/1471-2407-14-875
DO - 10.1186/1471-2407-14-875
M3 - Article
C2 - 25421252
AN - SCOPUS:84920840486
VL - 14
JO - BMC Cancer
JF - BMC Cancer
SN - 1471-2407
IS - 1
M1 - 875
ER -