A randomized phase II study of capecitabine-based chemoradiation with or without bevacizumab in resectable locally advanced rectal cancer: clinical and biological features.
ABSTRACT: Perioperatory chemoradiotherapy (CRT) improves local control and survival in patients with locally advanced rectal cancer (LARC). The objective of the current study was to evaluate the addition of bevacizumab (BEV) to preoperative capecitabine (CAP)-based CRT in LARC, and to explore biomarkers for downstaging.Patients (pts) were randomized to receive 5 weeks of radiotherapy 45 Gy/25 fractions with concurrent CAP 825 mg/m(2) twice daily 5 days per week and BEV 5 mg/kg once every 2 weeks (3 doses) (arm A), or the same schedule without BEV (arm B). The primary end point was pathologic complete response (ypCR: ypT0N0).Ninety pts were included in arm A (44) or arm B (46). Grade 3-4 treatment-related toxicity rates were 16% and 13%, respectively. All patients but one (arm A) proceeded to surgery. The ypCR rate was 16% in arm A and 11% in arm B (p =0.54). Fifty-nine percent vs 39% of pts achieved T-downstaging (arm A vs arm B; p =0.04). Serial samples for biomarker analyses were obtained for 50 out of 90 randomized pts (arm A/B: 22/28). Plasma angiopoietin-2 (Ang-2) levels decreased in arm A and increased in arm B (p <0.05 at all time points). Decrease in Ang-2 levels from baseline to day 57 was significantly associated with tumor downstaging (p =0.02).The addition of BEV to CAP-based preoperative CRT has shown to be feasible in LARC. The association between decreasing Ang-2 levels and tumor downstaging should be further validated in customized studies.Clinicaltrials.gov identifier NCT01043484. Trial registration date: 12/30/2009.
Project description:In locally advanced rectal cancer (LARC) preoperative chemoradiation (CRT) is the standard of care, but the risk of local recurrence is low with good quality total mesorectal excision (TME), although many still develop metastatic disease. Current challenges in treating rectal cancer include the development of effective organ-preserving approaches and the prevention of subsequent metastatic disease. Neoadjuvant systemic chemotherapy (NACT) alone may reduce local and systemic recurrences, and may be more effective than postoperative treatments which often have poor compliance. Investigation of intensified NACT is warranted to improve outcomes for patients with LARC. The objective is to evaluate feasibility and efficacy of a four-drug regimen containing bevacizumab prior to surgical resection.This is a multi-centre, randomized phase II trial. Eligible patients must have histologically confirmed LARC with distal part of the tumour 4-12 cm from anal verge, no metastases, and poor prognostic features on pelvic MRI. Sixty patients will be randomly assigned in a 1:1 ratio to receive folinic acid + flurourcil + oxaliplatin (FOLFOX) + bevacizumab (BVZ) or FOLFOX + irinotecan (FOLFOXIRI) + BVZ, given in 2 weekly cycles for up to 6 cycles prior to TME. Patients stop treatment if they fail to respond after 3 cycles (defined as ≥ 30 % decrease in Standardised Uptake Value (SUV) compared to baseline PET/CT). The primary endpoint is pathological complete response rate. Secondary endpoints include objective response rate, MRI tumour regression grade, involved circumferential resection margin rate, T and N stage downstaging, progression-free survival, disease-free survival, overall survival, local control, 1-year colostomy rate, acute toxicity, compliance to chemotherapy.In LARC, a neoadjuvant chemotherapy regimen - if feasible, effective and tolerable would be suitable for testing as the novel arm against the current standards of short course preoperative radiotherapy (SCPRT) and/or fluorouracil (5FU)-based CRT in a future randomised phase III trial.Clinical trial identifier BACCHUS: NCT01650428.
Project description:BACKGROUND:In preclinical studies, the expression of vascular endothelial growth factor (VEGF) in hormone receptor-positive breast cancer is associated with estrogen-independent tumor growth and resistance to endocrine therapies. This study investigated whether the addition of bevacizumab, a monoclonal antibody against VEGF, to letrozole enhanced the antitumor activity of the letrozole in the preoperative setting. METHODS:Postmenopausal women with newly diagnosed stage 2 or 3 estrogen and/or progesterone receptor-positive, HER2-negative breast cancer were randomly assigned (2:1) between letrozole 2.5?mg PO daily plus bevacizumab 15?mg/kg IV every 3?weeks (Let/Bev) and letrozole 2.5?mg PO daily (Let) for 24?weeks prior to definitive surgery. Primary objective was within-arm pathologic complete remission (pCR) rate. Secondary objectives were safety, objective response, and downstaging rate. RESULTS:Seventy-five patients were randomized (Let/Bev n?=?50, Let n?=?25). Of the 45 patients evaluable for pathological response in the Let/Bev arm, 5 (11%; 95% CI, 3.7-24.1%) achieved pCR and 4 (9%; 95% CI, 2.5-21.2%) had microscopic residual disease; no pCRs or microscopic residual disease was seen in the Let arm (0%; 95% CI, 0-14.2%). The rates of downstaging were 44.4% (95% CI, 29.6-60.0%) and 37.5% (95% CI, 18.8-59.4%) in the Let/Bev and Let arms, respectively. Adverse events typically associated with letrozole (hot flashes, arthralgias, fatigue, myalgias) occurred in similar frequencies in the two arms. Hypertension, headache, and proteinuria were seen exclusively in the Let/Bev arm. The rates of grade 3 and 4 adverse events and discontinuation due to adverse events were 18% vs 8% and 16% vs none in the Let/Bev and Let arms, respectively. A small RNA-based classifier predictive of response to preoperative Let/Bev was developed and confirmed on an independent cohort. CONCLUSION:In the preoperative setting, the addition of bevacizumab to letrozole was associated with a pCR rate of 11%; no pCR was seen with letrozole alone. There was additive toxicity with the incorporation of bevacizumab. Responses to Let/Bev can be predicted from the levels of 5 small RNAs in a pretreatment biopsy. TRIAL REGISTRATION:This trial is registered with ClinicalTrials.gov (Identifier: NCT00161291), first posted on September 12, 2005, and is completed.
Project description:The aim of the present study was to compare the tumor volume reduction rate (TVRR), as determined by three-dimensional region-of-interest magnetic resonance volumetry, and Response Evaluation Criteria in Solid Tumors (RECIST) data for predicting the pathological tumor response (PTR) of locally advanced rectal cancer (LARC) following treatment with neoadjuvant chemoradiation (CRT). The current cohort consisted of 105 patients with LARC [clinical tumor stage (cT)3-4 or clinical lymph node stage (cN)+] from a prospective randomized trial who had undergone pre-operative CRT and radical proctectomy. Tumor volumes were measured prior to and following CRT to determine TVRR. Furthermore, receiver operating characteristic (ROC) curves of TVRR and RECIST were constructed to predict the PTR in terms of tumor regression grade (TRG) and downstaging. Values for the area under the ROC curve (AUC) were compared and TVRR cut-off levels were determined. RECIST was used to identify 5 (4.8%) cases of complete response, 44 (41.9%) of partial response, 55 (52.4%) of stable disease and 1 (0.9%) of progressive disease. The mean TVRR was 58.6±24.4%, and a good TRG (0-1) and downstaging occurred in 54 (51.4%) and 59 (56.2%) patients, respectively. In addition, TVRR and RECIST were significantly correlated with TRG and downstaging (P<0.01). The TVRR AUC was significantly larger than that of RECIST for TRG (P=0.020). For downstaging, TVRR also exhibited a larger AUC than RECIST, however, the difference was not significant (P=0.180). The sensitivity and specificity of TVRR in predicting a good TRG were 70.4 and 80.4%, respectively, therefore, the optimal TVRR cut-off value was determined to be 65%. TVRR appeared to be more accurate than RECIST in predicting PTR, particularly for TRG associated with survival. Thus, TVRR may be considered as a novel parameter for evaluating the efficacy of CRT for patients with LARC.
Project description:AIM: The treatment of recurrent glioblastoma remains an open issue and the role of BEV has been largely debated since only few data compared this agent with the standard agents. METHODS: A multicenter, open-label, randomized (2:1), non-comparative phase II study (EudraCT:2011-001363-46; AVAREG-ML25739) with BEV 10 mg/m2 iv every 2 weeks or FTM 75 mg/m2 iv day 1-8-15 followed, after a 35 days interval, by FTM 100 mg/m2 every 3 weeks, was conducted. Primary endpoint was overall survival at 6 months (OS6). RESULTS: 91 pts with recurrent GBM were enrolled among 10 Italian centers between 11/2011 and 9/2012. Median age was 57 years (range:28-78), PS was 0/1/2 in 42/35/14 pts. All pts were treated with RT/TMZ accordingly with EORTC 26981-22981/NCIC-CE3. Time from diagnosis to 1st recurrence was 331 days in the BEV arm and 460 days in the FTM arm. At time of recurrence, 21 pts (23.1%) received re-resection before the study inclusion (13/8 pts in BEV/FTM arms). Fifty-nine pts were enrolled in the BEV arm and 32 pts in the FTM arm. OS6 was 62.1% (95%CI:48.4-74.5) and 73.3% (95%CI:54.1-87.7), OS9 was 37.9% (95%CI:25.5-51.6) and 46.7% (95%CI:28.3-65.7) in the BEV and FTM arms, respectively. Median OS was 7.3 months (95%CI:5.8-9.2) in the BEV arm and 8.7 months (95%CI:6.3-15.4) in the FTM arm. PFS6 was 26.3% and 10.7%, respectively. In the BEV arm, OS6 and OS9 were 77.8% (95%CI:57.7-91.4) and 59.3% (95%CI:38.8-77.6) in pts =55 yrs, and were 48.4% (95%CI:30.1-66.9) and 19.3% (95%CI:7.4-37.5) in pts >55 yrs. HR for OS in BEV group for pts >55 yrs compared with pts =55 yrs was 2.0 (95%CI:1.0-4.1, p = 0.05). G3-4 toxicity: thrombocytopenia 0% vs 21.9%, neutropenia 1.7% vs 12.5%, intestinal perforation and cerebral ischaemia/hemorrhage 3.4% vs 0%, pulmonary thromboembolism 1.7% vs 0%, and acute myocardial infarction 1.7% vs 0%, in the Bev and FTM arms respectively. CONCLUSIONS: BEV in recurrent GBM showed survival rates superimposable with FTM.
Project description:Background:Chemoradiation (CRT) or short-course radiotherapy (SCRT) are standard treatments for locally advanced rectal cancer (LARC). We evaluated the efficacy/safety of two neoadjuvant chemotherapy (NACT) regimens as an alternative prior to total mesorectal excision (TME). Methods/design:This multi-centre, phase II trial in patients with magnetic resonance imaging (MRI) defined high-risk LARC (>cT3b, cN2+ or extramural venous invasion) randomised patients (1:1) to FOLFOX + Bevacizumab (Arm 1) or FOLFOXIRI + bevacizumab (Arm 2) every 14 days for 6 cycles prior to surgery. Patients were withdrawn if positron emission tomography (PET) standardised uptake value (SUV) after 3 cycles failed to decrease by >30% or increased compared to baseline. Primary endpoint was pathological complete response rate (pCR). Secondary endpoints included adverse events (AE) and toxicity. Neoadjuvant rectal (NAR) scores based on "T" and "N" downstaging were calculated. Findings:Twenty patients aged 18-75 years were randomised. The trial stopped early because of poor accrual. Seventeen patients completed all 6 cycles of NACT. One stopped due to myocardial infarction, 1 poor response on PET (both received CRT) and 1 committed suicide. 11 patients had G3 AE, 1 G4 AE (neutropenia), and 1 G5 (suicide). pCR (the primary endpoint) was 0/10 for Arm 1 and 2/10 for Arm 2 i.e. 2/20 (10%) overall. Median NAR score was 14·9 with 5 (28%), 7 (39%), and 6 (33%) having low, intermediate, or high scores. Surgical morbidity was acceptable (1/18 wound infection, no anastomotic leak/pelvic sepsis/fistulae). The 24-month progression-free survival rate was 75% (95% CI: 60%-85%). Interpretation:The primary endpoint (pCR rate) was not met. However, FOLFOXIRI and bevacizumab achieved promising pCR rates, low NAR scores and was well-tolerated. This regimen is suitable for testing as the novel arm against current standards of SCRT and/or CRT in a future trial.
Project description:BACKGROUND:This study was designed to explore whether an intensified chemoradiotherapy (CRT) led to a better clinical outcome in locally advanced rectal cancer. METHODS:Patients with stage II/III rectal cancer were randomly allocated to receive either pelvic intensity-modulated radiation therapy (IMRT) of 50?Gy/25Fx concurrently with capecitabine and oxaliplatin (Arm A), or pelvic radiation of 50?Gy/25Fx with a concomitant boost of 5?Gy to the primary lesion, followed by a cycle of XELOX 2 weeks after the end of CRT (Arm B). All patients were planned to receive a definitive operation 8?weeks after the completion of CRT and a total of six perioperative chemotherapy cycles of capecitabine and oxaliplatin regardless of pathological result. Pathological complete response (ypCR) was the primary endpoint. RESULTS:From February 2010 to December 2011, 120 patients from three centers were enrolled in this study. Ninety-five percent patients completed a full-dose chemoradiotherapy as planning. Then 53 and 57 patients received a radical surgery, and 8 and 14 cases were confirmed as ypCR in two groups (P?=?0.157). The other 10 patients failed to receive a definitive resection because of unresectable disease. Similar toxicities were observed between two groups and more incision healing delay were found in Arm B (3 vs.13, P?=?0.011). No statistical differences were observed in local-regional control (P?=?0.856), disease-free survival (P?=?0.349) and overall survival (P?=?0.553). Mesorectal fascia (MRF) involvement was an independent prognostic factor for survival in multivariate analysis. CONCLUSIONS:A concomitant boost to oxalipatin-combined preoperative chemoradiotherapy demonstrated a slightly higher pCR rate but delayed incision healing after surgery. The impact of MRF involvement on survival merits further investigations. TRIAL REGISTRATION:NCT01064999 (ClinicalTrials.gov).
Project description:Using Human WG CodeLink microarrays, we established the expression profiling of 26 LARC without metastasis to gain insight into the molecular signatures associated with response to treatment after CRT. The study initially included a total of 35 consecutive patients with locally advanced rectal cancer (LARC) treated at Virgen de las Nieves Hospital from 2008 until 2010. Written informed consent was obtained from all the patients, and the study protocol was approved by the local Clinical Research (Ethics) Committee. They were distributed in two subgroups following a histological classification of response to treatment. Pretherapeutic staging was performed, including complete medical history and physical evaluation, digital rectal examination, endorectal ultrasound, rigid rectoscopy, colonoscopy, PET/TC and chest x-ray. Tumor samples were prospectively obtained during the rectoscopy. All patients subsequently received a total dose of 50.4Gy of radiatio (28 fractions of 1.8Gy) associated with capecitabine or capecitabine and oxaliplatine. Standardized surgery was performed, including total mesorectal excision, after an interval of 8 weeks after chemoradiotherapy. Tumor response was assessed in surgical specimen by semi-quantitative pathological examination (regression grade) including UICC stage. Histopathological tumor regression was graded based on the semiquantitative 5 point tumor regression grading (TRG) system: TRG1 or a TRG2 scores were considered Responders, whereas TRG3, TRG4, and TRG5 scores were classified as Non-Responders. In addition, the tumor regression or radiotherapy effects were assessed by positron emission tomography (18F-FDG PET). Tumor samples of LARC were collected from 35 patients. Nine patients were finally excluded due to the poor quality of the RNA or contradictory results of Mandard´s criteria and histopathological downstaging, resulting a total of 26 patients. Complete clinical data regarding, age, sex, stage of disease, response to therapy, and overall survival from 26 patients (10 responders and 16 non-responders) was provided in the sample characteristics field. CRT: Chemoradiation; Cap: Capecitabine; Capox: Capecitabine and Oxaliplatine; cTN: clinical stage; Surg: surgical technique; LAR: Low anterior resection; APR: Abdmino-perineal resection; HART: Hartmann, TRG: Tumor Regression Grade; Downst: Downstaging; Downs: downsizing, Resp: response, CPR: complete pathologic response
Project description:Background:Patients with locally advanced rectal cancer (LARC) have an improved prognosis if achieved a pathological complete response (pCR) on account of neoadjuvant chemoradiation therapy (nCRT). However, the proportion of patients achieving pCR is only 8-24%. The purpose of this study was to explore whether the addition of consolidation chemotherapy to nCRT could improve pCR rate in patients with LARC. Materials and Methods:The subjects were 144 individuals with clinical stage II (T3-4, N0) or III (any T, N1-2) LARC who had received neoadjuvant CRT followed by total mesorectal excision (TME). Eighty-three patients in the consolidation chemotherapy group received two cycles XELOX between CRT and TME, while 61 patients in the standard treatment group without consolidation chemotherapy. The pCR (ypT0N0), tumor downstaging (ypT0-2N0) after TME and adverse events (AEs) during and post treatment were compared between the treatment groups using multivariable logistic regression analysis. To adjust the unbalanced variables for the primary endpoint, logistic regression analysis and stratified analysis were performed. Results:The consolidation chemotherapy group improved pCR rate (19.3% vs 4.9%, p = 0.01) and tumor downstaging rate (45.8% vs 24.6%, p = 0.009) compared to the standard treatment group. After adjustment for clinical tumor stage, clinical nodal stage and time interval to surgery, patients with consolidation chemotherapy were more likely to reach pCR (adjusted odds ratio 4.91, 95% CI [1.01-23.79], p = 0.048). AEs during and post treatment in the two groups were 54.1% vs 49.3% (p = 0.57), respectively. In addition, the incidence of any grade 1-2 AEs in the two groups was 93.4% vs 95.1% (p = 0.93), while the incidence of grade 3 AEs was 1.6% versus 2.4% (p = 0.74), respectively. No grade 4 AEs occurred in two groups. Conclusions:The addition of neoadjuvant consolidation chemotherapy after CRT significantly increased the pCR rate and did not increase the AEs during and post treatment and in patients with LARC.
Project description:To date, no effective method exists that predicts the response to preoperative chemoradiation (CRT) in locally advanced rectal cancer (LARC). Nevertheless, identification of patients who have a higher likelihood of responding to preoperative CRT could be crucial in decreasing treatment morbidity and avoiding expensive and time-consuming treatments. The aim of this study was to identify signatures or molecular markers related to response to pre-operative CRT in LARC. We analyzed the gene expression profiles of 26 pre-treatment biopsies of LARC (10 responders and 16 non-responders) without metastasis using Human WG CodeLink microarray platform. Two hundred and fifty seven genes were differentially over-expressed in the responder patient subgroup. Ingenuity Pathway Analysis revealed a significant ratio of differentially expressed genes related to cancer, cellular growth and proliferation pathways, and c-Myc network. We demonstrated that high Gng4, c-Myc, Pola1, and Rrm1 mRNA expression levels was a significant prognostic factor for response to treatment in LARC patients (p<0.05). Using this gene set, we were able to establish a new model for predicting the response to CRT in rectal cancer with a sensitivity of 60% and 100% specificity. Our results reflect the value of gene expression profiling to gain insight about the molecular pathways involved in the response to treatment of LARC patients. These findings could be clinically relevant and support the use of mRNA levels when aiming to identify patients who respond to CRT therapy.
Project description:Objective: Although preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer (LARC), the clinical efficacy differs among patients. This study was conducted to determine the association between genetic variations in the PI3K/PTEN/AKT/mTOR pathway and clinical outcomes in LARC patients. Methods: Sixteen tagging single-nucleotide polymorphisms (SNPs) in five core genes (PIK3CA, PTEN, AKT1, AKT2, and FRAP1) were genotyped. The associations of these SNPs with tumor response to preoperative CRT, postoperative disease-free survival (DFS) and overall survival (OS) were identified. Crude odds ratios (ORs) and hazard ratios (HRs) were adjusted by age, sex, clinical stage, tumor differentiation, tumor location, cycles of preoperative chemotherapy and time interval from CRT completion to surgery. Results: In an analysis of 97 LARC patients, the G/T+G/G genotype of AKT1:rs2498804 was associated with an increased tumor response rate (adjusted OR = 2.909, 95% confidence interval (CI), 1.127-7.505, P = 0.027). At a median of 65.7 months of follow-up, the G/C+C/C genotype of AKT2:rs8100018 was associated with a reduced risk of postoperative recurrence (adjusted HR = 0.414; 95% CI, 0.187-0.914, P = 0.029). Patients carrying the G/C+C/C genotype in AKT2:rs8100018 presented a higher 5-year DFS rate than those with the wild-type genotype (79.2% vs. 62.3%, P = 0.038). None of the SNPs were significantly associated with pathological complete response (pCR) or 5-year OS. Conclusions: The current study indicates that genetic variations within the PI3K/ PTEN/AKT/mTOR signaling pathway are associated with the clinical outcomes of LARC patients undergoing preoperative CRT followed by radical surgery.