Ashwani Rajput

Factors Associated With Sphincter-Preserving Surgery for Rectal Cancer at National Comprehensive Cancer Network Centers

Objective:To determine rate and predictors of sphincter-preserving surgery (SPS) for rectal cancer patients treated at specialty institutions. Summary Background Data:SPS has been considered a surrogate for surgical quality, and sphincter preservation is tremendously important to patients. Evidence of association between case volume and SPS rate has prompted recommendations that all rectal cancer patients undergo surgery at specialty institutions. However, rates of SPS, and the factors associated with ability to perform SPS, have not been well-characterized. Methods:A prospective registry of all colorectal cancer patients treated at 7 National Comprehensive Cancer Network institutions was used to identify patients with clinical stage I-III rectal cancer undergoing surgery (n = 674) between September 2005 and October 2007. Patient, tumor and treatment factors were abstracted; patients clinical characteristics with and without SPS were compared using descriptive statistics and multivariable logistic regression. Results:Of 674 identified patients (median age, 58.2; 60% male), 520 (77%) had SPS. Of these, 240 had low anterior resection with coloanal anastomosis, 268 low anterior resection without coloanal anastomosis; 12 had other SPS procedures. Sixty-two percent had a temporary diverting stoma. On multivariable analyses, independent predictors of SPS included younger age at diagnosis, proximal location in the rectum, nonfixed tumor, and institution. Conclusions:SPS rates at National Comprehensive Cancer Network institutions exceed those seen in population-based samples and clinical trials. In addition to expected variation in SPS rates based on patient and tumor characteristics, we identified variation among institutions. Although the optimal rate of SPS remains unknown, this provides areas for further research and potential performance improvement.

Identification of DNA methylation in 3′ genomic regions that are associated with upregulation of gene expression in colorectal cancer

Restriction Landmark Genomic Scanning (RLGS), a method for the two-dimensional display of end-labeled DNA restriction fragments, was utilized to identify genomic regions of CpG island methylation associated with Human Colon Cancer. An Average of 1.5% of the RLGS loci/spots are lost or significantly reduced in sporadic primary colon tumors relative to normal colon mucosa from the same patient. This may represent tumor specific methylation of about 400 CpG islands in sporadic colon cancer. A number of RLGS loci exhibiting frequent loss associated with colon cancer were cloned. DNA sequence analysis indicated that the RLGS loci identified genomic regions characteristic of CpG islands. A number of methods including bisulfite genomic sequencing as well as quantitative MassARRAY methylation analysis (www.sequenom.com) confirmed tumor specific methylation at several of these loci. DNA database searches indicated that candidate genes associated with these loci include transcription factors and genes involved in signal transduction (52%), and genes of unknown function (37%). Expression analysis using quantitative real time RT-PCR indicates that methylation of some CpG islands located in non-promoter regions were associated with up-regulation of gene expression in colorectal cancer. These results indicate that alterations in methylation status within CpG islands in colon tumors may have complex consequences on gene expression and tumorigenesis, sometimes resulting in up regulation or ectopic gene expression that may involve novel regulatory mechanisms.

Phase II Study of Weekly Intravenous Oxaliplatin Combined With Oral Daily Capecitabine and Radiotherapy With Biologic Correlates in Neoadjuvant Treatment of Rectal Adenocarcinoma

PURPOSEnTo evaluate the efficacy of a combination of capecitabine, oxaliplatin, and radiotherapy (RT) in the neoadjuvant treatment of Stage II and III rectal cancers.nnnMETHODSnCapecitabine was given at 725 mg/m(2) orally twice daily Monday through Friday concurrently with RT. Oxaliplatin was given intravenously at 50 mg/m(2) once weekly five times starting the first day of RT. The radiation dose was 50.4 Gy in 28 fractions (1.8 Gy/fraction), five fractions weekly. Endorectal tumor biopsies were obtained before treatment and on the third day of treatment to explore the effects of treatment on thymidine phosphorylase, thymidylate synthase, excision repair cross-complementing rodent repair deficiency complementation group 1 (ERCC1), and apoptosis.nnnRESULTSnA total of 25 patients were enrolled in this study; 6 patients (24%) had a complete pathologic response. T-downstaging occurred in 52% of patients, and N-downstaging occurred in 53%. Grade 3 diarrhea was the most common Grade 3-4 toxicity, occurring in 20% of patients. Only 2 patients experienced disease recurrence, with a median of 20 months of follow-up. Thymidylate synthase, thymidine phosphorylase, ERCC1, and apoptosis did not vary significantly between the pretreatment and Day 3 tumor biopsies, nor did they predict for T-downstaging or a complete pathologic response.nnnCONCLUSIONnCapecitabine at 725 mg/m(2) orally twice daily, oxaliplatin 50 mg/m(2)/wk, and RT at 50.4 Gy is an effective neoadjuvant combination for Stage II and III rectal cancer and results in a greater rate of complete pathologic responses than historically shown in fluoropyrimidine plus RT controls.

Meeting the 12 lymph node (LN) benchmark in colon cancer

Examining ≥12 LN in colon cancer has been suggested as a quality metric. The purpose of this study was to determine whether the 12 LN benchmark is achieved at NCCN centers compared to a US population‐based sample.

Chemotherapy-Induced Carcinoembryonic Antigen Surge in Patients with Metastatic Colorectal Cancer

Objectives: To investigate the incidence of carcinoembryonic antigen (CEA) surge in patients with metastatic colorectal cancer (MCRC) and its implications on clinical outcome. Methods: A retrospective chart review of patients with MCRC treated with chemotherapy at Roswell Park Cancer Institute from January 2000 to May 2004 was conducted. A CEA surge was defined as an increase of >20% from baseline followed by a >20% drop in one or more subsequent CEA levels compared to baseline. The incidence of CEA surge and its association with clinical outcome was investigated. Results: Eighty-nine patients were evaluable for CEA surge. A CEA surge was documented in 10 patients. The CEA surge lasted <4 months in all 10 patients and was associated with a clinical benefit. No significant correlation was noted between CEA surge and site of primary tumor, site of metastatic disease, or tumor differentiation. Conclusions: CEA surges can be observed in patients receiving chemotherapy for MCRC and are often associated with a clinical benefit. None of the CEA surges satisfied the American Society of Clinical Oncology definition of CEA progression. A rise in CEA after initiation of chemotherapy, unless lasting >4 months, cannot be used as an indicator of progressive disease.

Effect of lymph node retrieval rates on the utilization of adjuvant chemotherapy in stage II colon cancer

Failing to meet the benchmark of 12 lymph nodes in resection specimens is an indication for adjuvant chemotherapy in stage II colon cancer.