Vitamin B12, Folic Acid Supplements Reduce Pemetrexed Toxicity

SAN FRANCISCO—Adding vitamin B12 and folic acid to chemotherapy with pemetrexed disodium (Alimta) reduces the incidence of severe life-threatening toxicities, according to research presented at the 37th Annual Meeting of the American Society of Clinical Oncology (ASCO abstract 300).

Pemetrexed disodium is an investigational, novel, multitargeted antifolate with inhibitory activity against multiple enzymes involved in non-small-cell lung cancer (NSCLC), mesothelioma, and breast, pancreas, colorectal, gastric, cervical, and head and neck cancers, said lead investigator Paul Bunn, Jr., MD, University of Colorado Health Sciences Center, Denver.

It offers convenient administration (10-minute intravenous infusion every 21 days) and can be combined, often at full dose, with other active drugs.

Unpredictable, severe toxicities, however, have been a problem with antifolates and antimetabolites in general. These have included neutropenia, thrombocytopenia, mucositis, and febrile neutropenia—all significantly correlated with drug-related death, Dr. Bunn said.

"When you have falling blood counts together with mucositis, infection is very common. There has never been a good way to predict who will get these toxicities, especially the severe ones, or to prevent them, again especially the severe ones," Dr. Bunn said in an interview with ONI.

Dr. Bunn and his colleagues observed that folate and vitamin B12 nutritional status affect the toxicity of antimetabolites, particularly those targeting thymidylate synthase. Specifically, they had seen that B12 and folate pools, as assessed by plasma homocysteine and methylmalonic acid, correlated with severe toxicity, with high homocysteine levels indicating folate deficiency.

The tip-off, according to co-investigator Paolo Paoletti, MD, director of clinical research, Eli Lilly, was that in multinational early trials of pemetrexed disodium, baseline levels of homocysteine were higher among European patients than among American patients. "We knew that the USDA requires vitamin supplementation in US diets and that many Americans take multivitamins," Dr. Paoletti said.

The objective of the current study, therefore, was to assess whether low daily doses of folic acid and periodic vitamin B12 injections would reduce severe toxicity and drug-related death in patients given pemetrexed disodium.

Investigators proceeded with supplementation with folic acid (350 to 1,000 µg daily by mouth) and vitamin B12 (1,000 µg IM every 9 weeks) in 220 patients receiving chemotherapy with pemetrexed disodium. Findings among those patients were compared with findings from 246 previously treated patients who had not received vitamin supplementation.

Analysis was conducted after two and seven cycles of therapy to evaluate acute and longer-term effects. Also, the investigators separately assessed patients with high baseline homocysteine levels (greater than 12 µm/L) vs those with low levels (12 µm/L or less).

From the start, in patients receiving supplementation, homocysteine concentrations dropped and continued to decline steadily over the course of the first three cycles of therapy, from a mean of 8.3 µm/L to a mean of 6.9 µm/L, and remained at that level.

Differences among patients with and without supplementation were significant within about 1 month and remained so throughout 126-day follow-up. The mean change in homocysteine levels was greater (-3.2 µm/L vs -1.1 µm/L) in patients with higher homocysteine baseline levels (mean, 15.6 µm/L) than in those with lower levels (mean, 8.0 µm/L).

In patients receiving supplementation, after both two and seven cycles, all severe toxicities were significantly reduced. Grade 3-4 hematologic and nonhema-tologic toxicities fell from 37% of patients without supplementation to 6.4% with supplementation (P = .001). Grade 4 neutropenia fell from 32% to 2.6% (P = .001); grade 4 thrombocytopenia from 8% to 0% (P = .0053); and toxic deaths from 5% to 0% (P = .026).

Grade 3-4 mucositis, diarrhea, and infections (with grade 4 neutropenia) were all reduced. Reductions in toxicities were greater in patients with higher baseline homocysteine levels.

Dr. Bunn concluded that folic acid and vitamin B12 supplementation significantly reduces the number of episodes of grade 4 hematologic or grade 3-4 non-hematologic toxicity associated with pemetrexed disodium use. This may be attributed to decreases in homocysteine levels. The effect appears to be more pronounced in patients with baseline homocysteine levels 12 µm/L or higher.

Dr. Bunn noted that many cancer patients do take multivitamins and that alternative practitioners may advocate megadoses. "In this study, we used just 400 to 500 µg per day of folic acid, not megavitamin doses. So this should not be taken by the alternative medicine people to suggest that high doses should be recommended."

Dr. Bunn said that the finding raises further questions: Could vitamin supplementation be helpful among patients receiving cisplatin (Platinol)? (This is currently under review.) Would supplementation be helpful in reducing side effects of other chemotherapy agents? Should patients have their vitamin status tested before beginning chemotherapy?

Dr. Bunn noted that alcoholics generally are folate deficient and that smokers, in general, have poor vitamin status.

Phase III trials with pemetrexed disodium have been completed in mesothelioma (analysis is ongoing). Currently in progress are phase III trials of pemetrexed disodium as second-line treatment for NSCLC and trials in pancreatic cancer of gemcitabine (Gemzar) alone vs gemcitabine plus pemetrexed disodium, Dr. Paoletti noted.