Beyond Fluorouracil and Radiation in Rectal Cancer Therapy: The Potential of Molecular Biology
Lawrence
Leichman, M.D.
Roswell Park Cancer Institute, Buffalo, NY, USA
Summary: Surgery, radiation, and chemotherapy are the basis for current treatment for rectal cancer. Given improvements in identification of families at risk and in general screening methods, it is likely that the number of cases of rectal cancer, especially those caught at an early stage, will increase. Dr. Leichman discussed how molecular biology might play a role in improving clinical care through the establishment of molecular tissue markers useful in establishing prognosis or predicting sensitivity to therapy for individual patients.
It is likely that rectal cancer will be discovered in younger patients and at earlier stages in the future because of improved understanding of the familial genetics of colorectal cancer and widespread use of efficient screening methods. Thus, both survival and quality-of-life issues such as urinary and bowel continence and sexual function become increasingly important in developing new treatments.
In his presentation, Dr. Leichman summarized published data on several intracellular markers, including the K-ras gene and the kinase inhibitor called p21, that have shown sufficiently intriguing results in small, pilot studies to merit further research as possible markers of prognosis or predictors of sensitivity to radiation or chemotherapy.
The K-ras gene encodes a protein that plays a pivotal role in transduction of mitogenic signals. Mutations that result in greater gene activity are common in patients with colon cancer (present in roughly 40-60% of cases), although less so among patients with rectal cancer (present in roughly 15% of cases). Clinical significance is unclear, and retrospective studies have had mixed results. However, one study in patients who had preoperative radiation and neoadjuvant chemotherapy found that tumors with K-ras mutations at time of resection were at a significantly lower stage than tumors that did not demonstrate K-ras mutation (Ntotal= 37, p=0.05). Furthermore, after a median follow-up of three years all of the patients with mutations (N=12) were alive, whereas only 14 of 25 patients were alive (p=0.03). Dr. Leichman asserted that this data warranted a prospective study with tissue obtained before any therapy is administered.
The changing paradigms for rectal cancer treatment (shown in the circles) have included an increasing number of local excisions for clinically staged T1 and T2 lesions and preoperative radiation, chemotherapy, or both for patients with more advanced lesions. New tools to noninvasively measure tumor depth and the availability of tumor tissue make rectal cancer an ideal translation model for studying the prognostic and predictive molecular factors (shown in the center) that may assist in making clinical decisions to both treat disease and maintain quality of life (shown in rectangles).
The kinase inhibitor called p21 is another example of an intracellular marker that might have clinical usefulness. It normally induces G1 arrest in cells exposed to DNA-damaging agents. Multiple studies have shown that mutation-induced alteration in p21 correlates with a decrease in radiation-induced apoptosis. One study that examined possible markers (including vascular endothelial growth factor, proliferating cell nuclear antigen, p53 gene status, and Bcl-2 expression) for response to radiation found that only p21 was predictive of radiation sensitivity (p=0.03). Dr. Leichman noted that further research with a prospective study might clarify the significance of p21 as a marker of radiosensitivity and enable it to be used in clinical practice.
In closing, Dr. Leichman noted "The clinical utility of one or a set of rectal cancer intracellular markers for prognosis or therapeutic predictions in rectal cancer has yet to be prospectively identified. Nevertheless, the recent emphasis of clinical and bench scientists in this arena suggests that we will soon move beyond the current paradigms in the therapeutic strategies for treating rectal cancer."
2001 by DOL Inc. All rights reserved.