National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
March 23, 2010 • Volume 7 / Number 6

Cancer Research Highlights

Many Older Colorectal Cancer Patients Do Not Receive Adjuvant Chemotherapy

Only half of patients age 75 or older with stage III colorectal cancer receive post-surgical chemotherapy, despite data from clinical trials showing that such treatment improves survival across age groups, researchers reported last week. Limited clinical trial data on older patients and toxicity concerns are often cited as the reasons those over age 75 aren’t always given potentially beneficial treatments, but in this study older patients who received chemotherapy were no more likely to have an adverse event than younger patients. The study, which was published in the March 17 Journal of the American Medical Association (JAMA), is part of the NCI-funded Cancer Care Outcomes Research and Surveillance (CanCORS) program.

The findings should prompt clinicians to more carefully consider adjuvant chemotherapy for older patients, as well as encourage the development of clinical trials involving older patients, said study co-author Dr. Robert H. Fletcher of Harvard Medical School during a JAMA-sponsored press briefing.

To conduct the study, Dr. Katherine L. Kahn of the RAND Corporation and colleagues analyzed data on 675 patients diagnosed with stage III colon cancer who had been treated at institutions across the country from 2003 through 2005. Overall, 75 percent of patients received any form of adjuvant chemotherapy, but only 50 percent of the 202 patients age 75 and older received the treatment, compared with 87 percent of younger patients. Older patients who did receive adjuvant therapy tended to be healthier, but they were also more likely to receive lower doses of chemotherapy and to discontinue treatment early. When the researchers adjusted for factors that differed between the younger and older patients, however, including the dose and type of chemotherapy received, older patients actually had fewer adverse events than younger patients, Dr. Fletcher said.

While the limited use of chemotherapy in older patients could be attributed in part to “wise clinical judgment,” Dr. Fletcher said, the study results “raise the likelihood that there is some element of undertreatment here.”

Drug Slows Progression of Cutaneous T-Cell Lymphoma

In a randomized trial of denileukin diftitox (ONTAK) for the treatment of cutaneous T-cell lymphoma (CTCL), a type of non-Hodgkin lymphoma that begins in the skin, patients who received the drug survived without progression of their disease for a median of more than 2 years, compared with just over 4 months for patients who received a placebo. Results from the trial, sponsored by Eisai, the pharmaceutical company that manufactures the drug, were reported March 8 in the Journal of Clinical Oncology.

Denileukin diftitox (DD) consists of a toxin derived from the diphtheria bacterium attached to human interleukin 2 (IL-2), a protein produced by the immune system. The IL-2 binds preferentially to CTCL cells, delivering the toxin to the tumors.

An international group of researchers led by Dr. H. Miles Prince of the University of Melbourne, Australia, enrolled 144 patients who had received three or fewer prior treatments for CTCL into the trial. Participants received one of two different doses of DD (either 9 micrograms or 18 micrograms per kilogram of body weight per day) or a placebo.

Each course of treatment consisted of once-daily infusions for 5 days followed by 16 days of rest, for up to eight courses (approximately 6 months). Treatment stopped if a patient’s disease progressed or if they experienced unacceptable side effects.

Overall response rates (either complete or partial tumor regression) were 49.1 percent in the group receiving the higher dose of DD, 37.8 percent in the group receiving the lower dose, and 15.9 percent in the placebo group. Patients receiving the higher dose of DD had a 73 percent reduction in the risk of disease progression or death compared with patients receiving the placebo. More patients receiving DD reported side effects, though the incidence of serious toxic effects was relatively low in all treatment arms.

Prognostic Marker for Hodgkin Lymphoma Could Improve Care

Researchers have identified a biological marker that could identify patients with Hodgkin lymphoma who are likely to relapse and could benefit from aggressive therapy early in their treatment. The biomarker is the number of white blood cells called CD68-positive macrophages present in a biopsy from a patient’s lymph nodes. Testing for this marker could easily be incorporated into clinical practice, the researchers reported in the March 11 New England Journal of Medicine.
 
Dr. Christian Steidl of the British Columbia Cancer Agency and his colleagues analyzed tumor samples from nearly 300 patients. They found that increased numbers of tumor-associated macrophages were strongly associated with shortened survival.

“These results will now allow us to design clinical trials that enroll only the high-risk patients with Hodgkin lymphoma, thereby accelerating the testing and validation of new therapies aimed at abnormal regulatory pathways in these tumors,” said co-author Dr. Louis Staudt of NCI’s Center for Cancer Research.

About 75 to 80 percent of patients with Hodgkin lymphoma are cured by their initial treatments, but the others relapse. Advances in treatment have stagnated for 20 years because researchers have lacked markers for predicting the response to therapy, according to an accompanying editorial. This lack of markers has also contributed to the overtreatment of many patients with Hodgkin disease, wrote the authors of the editorial, Drs. Vincent DeVita and Jose Costa of the Yale Cancer Center.

The new findings “appear to be the breakthrough we have been looking for by enabling the selection of patients with particularly poor prognosis (regardless of stage) for aggressive treatment, which can bring more logic to the treatment of this curable cancer,” the editorialists concluded.

Nanoparticle-based Therapy Triggers RNA Interference in Human Tumors

An experimental therapy designed to block the production of a protein in tumor cells through a mechanism known as RNA interference, or RNAi, has shown promise in an early-stage clinical trial. Cells use RNAi to regulate the activity of genes, and this mechanism could potentially be harnessed for turning off genes in the cancer cells of patients, according to findings reported online in Nature on March 21.

In a proof-of-concept study involving three patients with melanoma, the researchers injected targeted nanoparticles into the blood to carry small interfering RNA (siRNA) molecules into tumors. These nanoparticles were designed to bind to the transferrin receptor, which is expressed at high levels by cancer cells, and they included an siRNA directed against a subunit of ribonucleotide reductase 2 (RRM2). This protein is involved in DNA replication and is an important target for anticancer therapies.

Analyses of the patients’ tumors revealed that, once inside the cell, the siRNAs inhibited the production of the RRM2 protein by triggering the destruction of the protein’s messenger RNA. The researchers also detected a dose-dependent accumulation of nanoparticles; that is, higher doses of nanoparticles administered led to a higher number of nanoparticles in tumors. The researchers note that this is the first time that dose-dependent accumulation of targeted nanoparticles has been observed in human tumors. The researchers plan to present clinical results from the trial at the American Society of Clinical Oncology annual meeting in June.

“We were able to confirm both pieces of the puzzle—that the delivery vehicle got where it was supposed to go and that the observed effects occurred though the mechanism of RNAi,” said lead investigator Dr. Mark Davis of the California Institute of Technology, whose team has been working on the project for more than a decade. A primary challenge has been finding ways to deliver siRNAs, which degrade rapidly in the body.

“This study describes an effective way of delivering a fragile construct and represents a very important application for the use of nanotechnology in therapeutic delivery,” said Dr. Piotr Grodzinski, program director for the NCI Alliance for Nanotechnology in Cancer. “Nanoparticles may be one of the only effective ways to deliver siRNAs.”

Patients with other types of cancers are participating in the clinical trial, which was sponsored by a company started by Dr. Davis, Calando Pharmaceuticals. The analysis of tumors was supported in part by NCI.