Calcium Plus Vitamin D Does Not Reduce Colorectal Cancer Risk, Study Finds

Taking daily supplements of calcium and vitamin D for 7 years did not reduce the risk of colorectal cancer in postmenopausal women, a large, randomized clinical trial has found. The supplements did, however, provide a modest benefit in bone health by preserving bone mass and preventing hip fractures, particularly in women over age 60.

The primary goal of the study was to test the effects of taking 1,000 mg of elemental calcium plus 400 IU of vitamin D₃ daily on bone health and, secondarily, on colorectal cancer risk. The trial included 36,000 women aged 50-79 from the Women's Health Initiative study; half took the supplements and the others took a placebo.

"The lack of an effect on colorectal cancer risk after 7 years was remarkably consistent overall and in all subgroups we examined," says Dr. Jean Wactawski-Wende of the State University of New York at Buffalo, who led the study. The only adverse effect of the supplements was an increase in kidney stones, according to findings in the February 16 New England Journal of Medicine (NEJM).

The researchers will follow the women for another 5 years. Colorectal cancer can develop slowly, and the study might not have been long enough to show the effects of the supplements. The trial ended just as the women were reaching the peak high-risk age for colorectal cancer, notes an accompanying editorial.

The researchers would have expected a difference in colorectal polyps during the trial if the supplements were thought to affect later colorectal cancer outcomes, says Dr. Wactawski-Wende. However, there was no difference in the number of self-reported colorectal polyps between the groups during the trial.

Response to Immunotherapy for Melanoma Tied to Autoimmunity

Patients treated for melanoma skin cancer with adjuvant interferon alfa-2b who developed clinical signs of autoimmunity were significantly more likely to respond to the treatment than patients who did not, a clinical trial has found. Autoimmunity occurs when the immune system begins to attack the body's own tissues.

Dr. Helen Gogas of the University of Athens Medical School and colleagues enrolled 200 patients in a substudy of an ongoing trial. They prospectively evaluated the presence of autoantibodies and clinical manifestations of autoimmune disorders in melanoma patients who received adjuvant therapy with high-dose interferon alfa-2b.

The development of autoimmunity was associated with an approximate reduction by a factor of 50 in the risk of recurrence of melanoma. The benefit of interferon alfa-2b was primarily restricted to patients who showed signs of autoimmunity, the researchers report in the February 16 NEJM.

Efforts to identify biological markers for predicting which patients might respond have generally not been successful.

Although the new findings do not provide biological markers for patients who may have "immune-sensitive tumors," the results suggest a mechanistic connection between autoimmunity and the benefit from interferon alfa-2b in melanoma patients, says an accompanying editorial.

The study provides "the strongest data to date connecting the development of autoimmunity with a favorable antitumor effect of immunotherapy," write Drs. Henry Koon and Michael Atkins of Beth Israel Deaconess Medical Center.

MRI Dye Exhibits Anticancer Effects

Researchers from the Université Paris-René Descartes in France report in the February 15 Journal of the National Cancer Institute that mangafodipir, a contrast dye used in magnetic resonance imaging, can both protect normal cells against chemotherapy-induced damage and amplify the effect of those drugs on cancer cells.

Leukocytes taken from healthy volunteers and exposed to paclitaxel, oxaliplatin, or 5-fluorouracil and simultaneous doses of mangafodipir experienced significantly less cytotoxicity than leukocytes exposed to any of the chemotherapy drugs alone. When paclitaxel alone was administered in vivo to BALB/c mice, the investigators recorded a significant decrease in blood counts. Co-administration of mangafodipir and paclitaxel abolished the hematologic toxicity.

The investigators next looked at the effect of co-administration of mangafodipir and chemotherapy drugs on cancerous cells. The combination of mangafodipir and any of the three drugs used in the in vitro experiments significantly increased the toxicity to cancer cells. In vivo, mice implanted with CT26 tumor cells developed smaller tumors when treated with both mangafodipir and paclitaxel than with paclitaxel alone.

Mangafodipir belongs to a class of compounds that can protect normal cells from hydrogen peroxide-induced apoptosis. Exposure of tumor cells to paclitaxel, oxaliplatin, and 5-fluorouracil can, among many other effects, increase intracellular levels of hydrogen peroxide (H₂O₂). The investigators postulate that the opposite effects of mangafodipir seen in normal and cancerous cells are due to different baseline levels of reactive oxygen species, including H₂O₂ in tumor versus normal tissues. To follow up on these positive results, the authors have planned clinical studies in humans to evaluate the safety and efficacy of the compound as an adjuvant to paclitaxel-based chemotherapy.

In an accompanying editorial, Dr. James Doroshow, director of NCI's Division of Cancer Treatment and Diagnosis, seconds the need for clinical studies, stating that "the optimal study venue for agents that target the intracellular oxidant milieu of tumors may well be early-phase clinical trials." This is due to both the biological variability found in different model systems and the need to test drugs at concentrations actually used in treatment, as "the concentrations of paclitaxel, oxaliplatin, and 5-fluorouracil used for these experiments were far in excess of those achieved in routine clinical practice," explains Dr. Doroshow.