Unresectable Cancer Of Concurrent Chemoradiotherapy For Clinical Research And Efficacy Evaluation Of Prediction Methods Discussed

Part I:Phase II study of neoadjuvant concurrent radiation with Capacitabine/Oxaliplatin and Celecoxib in the treatment of unresectable rectal cancerPurpose:Neoadjuvant concurrent chemoradiation has become the standard treatment in locally advanced rectal cancer. This study is to investigate the efficacy and toxicity of neoadjuvant concurrent radiation with Capacitabine/Oxaliplatin and Celecoxib in the treatment of locally advanced unresectable rectal cancer.Material and methods:Forty patients (median age 56 years; m/f:34:6) with unresectable rectal cancer were treated in Cancer Hospital, Fudan University from June 2006 to Dec.2007. All patients were evaluated as unresectable by at least two surgeons and staged IIIB-C based on MRI and endorectal ultrasound examination. Of them,27 patients were staged as T3N1-2M0 and 13 were T4N1-2M0. Numbers of patients whose tumor location from anal verge were 33 (0-6cm) and 7 (6-10cm), respectively. All patients underwent pelvic irradiation of 45Gy/25fx/35day. The regimen of concurrent chemotherapy is Capacitabine 625mg/m2, bid (Mon-Fri.); Oxaliplatin 50mg/m2, weekly and Celecoxib 200mg bid. The patients were operated 5-8 weeks followed by concurrent chemoradiation and Celecoxib. Tumor response was evaluated by weekly diffusion weighted MRIs combined with digital physical examination. Tumor regression grading was evaluated according to the criteria by Rodel.Results:After chemoradiation,35 patients initially unresectable underwent radical resections (R0) and five patients did not. Of these five patients, one patient was with liver metastasis in restaging workup and one patient found renal failure due to tomor progress before surgery. Two patients underwent exploratory laparotomy and one patient accepted Rl resection. Pathologic complete response (pCR) was observed in 4 of 40 patients (10%). Downstaging with respect to the tumor stage was observed in 40% patients and downstaging with respect to the nodal stage was observed in 50%. The tumor regression grades after CRT were grade 0-1 in 37.5%, grade 2 in 12.5%, grade 3 in 37.5%, grade 4 in 12.5%. Six patients whose tumor locations were within 6cm from the anal verge got sphincter preservation after neoadjuvant chemoradiation and Celecoxib. The more common grade 3 toxicities were diarrhea. Two patients had wound infection (5%) and one patient had anastomotic leakage (2.5%).Conclusion:This study showed neoadjuvant concurrent chemoradiation with Celecoxib increased resectability and sphincter preservation and gained the encouraging rate of pCR, pathologic downstaging and tumor regression in unresectable rectal cancer. Toxicities were tolerable and surgical morbidity was not increased.Part II:The role of Cox-2 expression in locally advanced rectal cancer treated with neoadjuvant concurrent radiation with Capacitabine/Oxaliplatin and CelecoxibPurpose:Neoadjuvant concurrent chemoradiation has become the standard treatment in locally advanced rectal cancer. The target therapy combined with chemoradiation also showed encouraging results. However, there are about 20-30% patients who couldn't get benefit from tumor downstaging due to radio resistance. COX-2 may be involved in tumor radio resistance mechanism. The application of selective COX-2 inhibitor Celecoxib in combination with chemoradiation is appealing in the aspects of overcoming the radio resistance and acting as a potential target therapy. This study is to investigate the COX-2 expression and its significance in locally advanced rectal cancer treated with neoadjuvant concurrent radiation with Capacitabine/Oxaliplatin and Celecoxib.Material and methods:Forty patients with locally advanced rectal cancer were treated in Cancer Hospital, Fudan University from June 2006 to Dec. 2007. All patients were staged IIIB-C based on MRI and endorectal ultrasound examination. All patients underwent pelvic irradiation of 45Gy/25fx/35day. The regimen of concurrent chemotherapy is:Capacitabine 625mg/m2, bid (Mon-Fri.); Oxaliplatin 50mg/m2, weekly and Celecoxib 200mg bid during the whole course. The patients were operated 5-8 weeks followed by concurrent chemoradiation and Celecoxib. Tumor regression grading was evaluated according to the criteria by Rodel.35 pretreatment biopsies and 25 surgical specimens of COX-2 expression were examined using immunohistochemistry method. Of all specimens, there were 20 patients who had both pretreatment and surgical specimens.Results:COX-2 expression increased in 80.0%(n=16/20) of the patients from a median of 0% before to 40% after chemoradiation (p=0.006). COX-2 expression in pretreatment biopsies was not significantly correlated with tumor regression (p=0.315) and tumor downstaging (p=0.499).Conclusion:This study showed COX-2 expression in pretreatment biopsies is not associated with tumor regression or tumor downstaging. Elevated expressions of COX-2 post treatment were observed in the majority of tested patients with small samples. More patients with prolonging duration or escalating the dose of celecoxib may need further investigated.Partâ…¢:Diffusion-weighted magnetic resonance imaging for prediction of tumor response of rectal cancer to neoadjuvant concurrent chemoradiationPurpose:Neoadjuvant concurrent chemoradiation has become the standard treatment in locally advanced rectal cancer. However, there are about 20-30% patients who couldn't get benefit from tumor response due to radio resistance. Nowadays, functional non-invasive Diffusion-weighted magnetic resonance imaging (DW-MRI) studies are increasingly applied to add information about changes in tumor pathophysiology, acting as a surrogate marker for early assessment of tumor response of rectal caner to neoadjuvant chemoradiation. This study is to evaluate the clinical value of diffusion-weighted magnetic resonance imaging (DW-MRI) to predict tumor response of primary carcinoma of the rectum to neoadjuvant chemoradiation by measuring tumor apparent diffusion coefficient (ADC).Material and methods:Fifteen patients (median age 56 years) with locally advanced rectal cancer were treated in Cancer Hospital, Fudan University from June 2006 to Dec.2007. All patients were evaluated as stage IIIB-C based on MRI and endorectal ultrasound examination. All patients underwent pelvic irradiation of 45-50.4Gy/25-28fx/35-38day. The regimen of concurrent chemotherapy is Capacitabine 625mg/m2, bid (Mon-Fri.); Oxaliplatin 50mg/m2, weekly and Celecoxib 200mg bid. The patients were operated 5-8 weeks followed by concurrent chemoradiation and Celecoxib. Diffusion-weighted MR images were obtained prior to and at constant intervals once weekly during the course of neoadjuvant chemoradiation and ADCs calculated from acquired tumor images.Results:Comparison of the mean pretreatment tumor ADC showed increase of the mean tumor ADC during the course of neoadjuvant chemoradiation, especially at the 2nd week (P=0.004). We found a strong negative correlation between mean pretreatment tumor ADC and tumor response after neoadjuvant chemoradiation (P=0.021). In the T downstage and tumor response groups, we found a significant increase of mean ADC at the 2nd week (P=0.011; 0.004).Conclusion:This study demonstrated tumor ADC changed via detection of therapy-induced alterations in tumor water mobility during the course of neoadjuvant chemoradiation. The mean pretreatment tumor ADC was inversely correlated with tumor response after chemoradiation in locally advanced rectal cancer. ADC values at the 2nd week of therapy showed a significant correlation with tumor response. Our results indicated that diffusion-weighted magnetic resonance imaging might be a valuable clinical tool to predict tumor response of rectal cancer to neoadjuvant concurrent chemoradiation. Part IV:CT perfusion imaging for prediction of tumor response of rectal cancer to neoadjuvant concurrent chemoradiationPurpose:Neoadjuvant concurrent chemoradiation has become the standard treatment in locally advanced rectal cancer. However, there are about 20-30% patients who couldn't get benefit from tumor response due to radio resistance. Nowadays, functional non-invasive perfusion computed tomography studies are increasingly applied to add information about changes in tumor vascular physiology, acting as a surrogate marker for early assessment of tumor response of rectal caner to neoadjuvant chemoradiation. This study is to evaluate the clinical value of CT perfusion to predict tumor response of primary carcinoma of the rectum to neoadjuvant chemoradiation by measuring tumor perfusion parameters.Material and methods:Nineteen patients (median age 55 years) with locally advanced rectal cancer were treated in Cancer Hospital, Fudan University from June 2006 to Dec.2007. All patients were evaluated as stage IIIB-C based on MRI and endorectal ultrasound examination. All patients underwent pelvic irradiation of 45-50.4Gy/25-28fx/35-38day. The regimen of concurrent chemotherapy is Capacitabine 625mg/m2, bid (Mon-Fri.); Oxaliplatin 50mg/m2, weekly and Celecoxib 200mg bid. The patients were operated 5-8 weeks followed by concurrent chemoradiation and Celecoxib. CT perfusion images were obtained prior to and after neoadjuvant chemoradiation and the data were analyzed by using commercial software to calculate tissue blood flow (BF), blood volume (BV), time to start (TTS), time to peak (TTP), permeability surface (PS) from acquired tumor images.Results:After chemotherapy and radiation therapy, tumors showed significant reduction in BF (P=0.003). There was a significant difference in baseline BF between the group of well-regression and poor-regression (P=0.027).Conclusion:This study demonstrated perfusion CT has potential for monitoring the effects of combined neoadjuvant chemoradiation and predicting the response of rectal cancer to neoadjuvant concurrent chemoradiation. In this small patient sample, tumors with initial high BF value tended to respond poorly to chemoradiation.