Colorectal Cancer -- Clinical Research Program

Our colorectal cancer research team includes medical oncologists, pathologists, radiation oncologists, and surgeons who are at the forefront of developing the latest treatments for cancers of the colon and rectum.

Research conducted here helped to establish the efficacy of several drugs that are now the standard of care for colorectal cancer patients. Our surgeons have pioneered many preservative and reconstruction techniques. We also have an ongoing program to pinpoint new genetic mutations responsible for colorectal cancer, and we have established registries for tracking patients with hereditary forms of the disease.

Among our recent research accomplishments:

Molecular Pathology

  • Studies utilizing Memorial Sloan Kettering’s Colorectal Cancer Family Registry, which has registered more than 500 patients with hereditary colorectal cancer syndromes, have identified the increased frequency of an APC mutation (A636P) in individuals of Ashkenazi descent with early-onset disease. The result of a collaboration among the Colorectal, Gastroenterology, and Clinical Genetics Services at Memorial Sloan Kettering, this finding has had a significant impact on patient care. Two other Center studies are being developed using data from the registry. The first is an investigation of genotype-phenotype correlations of APC gene mutations in patients with familial adenomatous polyposis (FAP). The second is a study of the genes involved in early-onset colorectal cancer.
  • We are engaged in efforts to identify molecular determinants of response and resistance in the RAS-RAF-MEK signal transduction pathway. Expanding on recent evidence that KRAS wild-type gene status is necessary but not sufficient for response to anti-EGFR therapy, we are exploring downstream mutations that may confer resistance in KRAS wild-type patients. We are also using the Sequenom platform to initiate large-scale molecular analysis of patients’ tumor tissue in order to rationally select patients for investigational targeted therapies.

Imaging

  • Our work with endorectal ultrasound (ERUS) in the preoperative staging of early-stage disease is currently directed at developing a treatment-oriented staging system and assessing the ability of ERUS to stratify tumors by substaging. An IRB-approved pilot project, “Evaluating the Response to Preoperative Chemotherapy and/or Radiation Therapy for Rectal Cancer Using Three-Dimensional Transrectal Ultrasound (3-D TRUS),” has been initiated.
  • Several members of our team are collaborating in an active IRB-approved protocol, “A Pilot Evaluation of Radioimmunodetection of 124-Iodine-Labeled Humanized A33 Antibody (124-I-huA33) in Patients with Colorectal Cancer.” The protocol has assessed the safety of a single 10 mg IV dose of 124-I-huA33 for tumor targeting in colorectal cancer patients for the purposes of staging, detection of recurrence, evaluation of response to therapy, and, possibly, for delivering tagged therapeutic agents directly to a cancer via radioimmunoguided surgery. Patients have been accrued, and preliminary data have been analyzed.
  • We are engaged in an NCI-sponsored prospective trial comparing the accuracy of positron emission tomography (PET) and computed tomography (CT) in evaluating rectal cancer response to preoperative chemoradiation, based on pathologic assessment of tumor in surgical specimens. Long-term follow-up of patients has been undertaken to determine if PET findings are predictive of outcome and if patients with complete pathologic response to preoperative chemoradiotherapy have an improved prognosis. Our team is also conducting an innovative study of ex-vivo molecular polyp imaging using fluorodeoxyglucose (FDG) PET imaging that aims to determine the protein and gene expression signatures of premalignant colorectal polyps.

Local and Regional Treatment

  • We are continuing our work evaluating the pathologic features, surgical management, and treatment outcomes of T1 adenocarcinomas of the colon and rectum. We have shown that there is a greater prevalence of lymphatic dissemination in T1 rectal cancers than previously thought, quantifying the higher risk of tumor recurrence when conservative treatment is used instead of radical resection. Our publications on this topic have defined the standard of care in surgical management of early rectal cancers. Ann Surg. 2005 Oct; 242(4):472-7; discussion 477-9. [PubMed Abstract]; J Gastrointest Surg. 2004 Dec 8; (8):1032-9. [PubMed Abstract]
  • A study by Memorial Sloan Kettering researchers shows that a large majority of patients who present with stage IV colorectal cancer do not require immediate surgery to remove the primary tumor in the colon. For this population with metastatic disease that cannot be cured by surgery, undergoing colon surgery is not always necessary. And by moving directly to chemotherapy, patients can avoid the risk of surgical complications and can start treatment for all sites of disease without delay. For this retrospective study, a multidisciplinary team looked at 233 metastatic colorectal cancer cases treated at Memorial Sloan Kettering from 2000 to 2006. Their analysis showed that 217 of the 233 patients, or 93 percent, did not have complications that required resection of the primary tumor. Only 16 patients required colon surgery for symptom management.
  • We have published a nomogram for predicting recurrence of colon cancer, and we are currently completing work on a rectal cancer nomogram. This tool enables clinicians to more accurately determine the risk of recurrent disease and death based on any number of clinical and pathological variables.
  • Our preliminary studies confirm that the minimally invasive (laparoscopic) surgical approach is associated with quicker recovery than the conventional open approach. A related area of study focuses on the oncologic equivalency of laparoscopy to open surgical techniques.
  • We are exploring the hypothesis that modern chemotherapy has advanced to the point where the toxicity and expense of radiation therapy may no longer be necessary. Our ongoing trial is exploring the use of neoadjuvant chemotherapy, without radiation therapy, for the curable management of rectal cancer. Initial data are encouraging, showing that a high degree of pathological complete responses has been seen after preoperative chemotherapy. A follow-up trial, currently in preparation, will explore the use of neoadjuvant chemotherapy in colon cancer. Pretreatment and post-treatment tissue is being analyzed for molecular signatures relevant to sensitivity and resistance.
  • A recently completed phase I study evaluating hepatic arterial FUDR/dexamethasone plus systemic oxaliplatin and 5FU-leucovorin after resection of hepatic metastases defined the optimal treatment dose and revealed a four-year survival of 88 percent for the entire cohort, making this an attractive regimen for possible future randomized studies.
  • New findings by our colleagues in the Department of Epidemiology and Biostatistics for a Decision Analysis for the US Preventive Services Task Force (USPSTF) suggest that routine colorectal cancer screenings can be stopped in patients over the age of 75. The results are based on patients who began screenings at age 50 and have had consistently negative screenings up to the age of 75. Ann Intern Med. 2008 Nov 4;149(9):659-69. [PubMed Abstract]

Targeted Therapies

  • We are exploring cMet as a target in refractory colorectal cancer. Phase I investigation of the cMet inhibitor MK-8033 is ongoing. Plans include a trial of this agent in refractory colorectal cancer, with pre- and post-treatment biopsies to evaluate for relevant molecular signatures.

Immunotherapy

  • The Colorectal Disease Management Team has completed the first investigation of anti-Insulin-like Growth Factor Receptor monoclonal antibodies in colorectal cancer.

Symptom Control and Quality of Life

  • We are conducting research to determine whether the American Medical Systems Acticon Neosphincter prosthesis can be used to reconstruct the anal sphincter mechanism in rectal cancer patients requiring abdominoperineal resection who would otherwise require permanent colostomies.
  • A member of our team surveyed rectal cancer patients and found that there are significant changes in bowel, bladder, and sexual function following rectal cancer therapy. (One of the surveys developed, the MSKCC Bowel Function Instrument, is now used by several major institutions.)
  • We are studying patient quality-of-life and decision-making issues and developing novel instruments that will enhance measurement of postoperative function and outcomes. For example, we developed a decision-analytic model to evaluate the relative benefits of surgery versus observation in rectal cancer patients who achieve clinical complete response after neoadjuvant chemoradiation. The model suggests that surgery is beneficial for the average patient with rectal cancer with a clinical complete response after neoadjuvant therapy. Dis Colon Rectum. 2009 May;52(5):863-71. [PubMed Abstract]
  • We have led research on treatment and predictors of treatment outcome in patients with anal squamous cell cancer. Sphincter-preserving therapy is possible in most patients presenting with stages I to III of the cancer, and tolerance of chemoradiation seems to be an important predictor of treatment success. Dis Colon Rectum. 2008 Feb;51(2):147-53. [PubMed Abstract]