Leucovorin, a modified B vitamin, has been a key ingredient in chemotherapy regimens for 30 years, ever since studies found it tripled the number of patients whose tumors shrank when given another drug, called 5-flurouracil. A drug cocktail of 5FU and leucovorin is now a backbone of colon cancer chemotherapy. Newer drugs like Erbitux and Avastin have never been tested without it.

But leucovorin, which is generic, is made by only two companies: Teva Pharmaceuticals of Jerusalem and Bedford Laboratories, a Bedford, Ohio, subsidiary of the German drug giant Boehringer Ingelheim. In November, the Food and Drug Administration said that both companies were unable to make an adequate supply, but hard information about the shortage has been difficult to obtain, beyond what is posted on the FDA Web site.

More than 140,000 Americans are diagnosed with colorectal cancer annually, but it is not clear how many are affected by the shortage, as the degree of rationing varies. M.D. Anderson Cancer Center says it anticipated the shortage and just received a bulk shipment, but at the University of California, San Francisco, "the average patient" is not getting leucovorin, says UCSF oncologist Alan Venook, and a committee meets weekly to decide how to use the existing supply.

"This is a very serious and scary situation for patients," says Kate Murphy, director of research communication for the Colorectal Cancer Coalition, a patient advocacy group. Murphy has personally survived three bouts of colon cancer over a 25-year period, the most recent last year.

"There are no answers at the FDA, and there are no answers at the manufacturers as to what is causing the shortage or how soon it might be resolved." Murphy says. "With no leucovorin in the pipeline, patients are just faced with no good alternatives."

Multiple requests for comment by Forbes to Teva were unanswered, and Boehringer had no immediate comment. The FDA is "aware that leucovorin injection is in shortage due to manufacturing delays," says Karen Riley, an FDA spokeswoman. "Bedford and Teva are both releasing product currently, and we are continuing to monitor this situation," she says.

But the Web site of the American Society of Health-System Pharmacists says that leucovorin powder for injection from both Teva and Bedford is on back order, that the companies "cannot estimate a release date," and that "the manufacturers will not provide a reason for the shortage"

On an Internet chat room support group called the Colon Club, one patient wrote of not receiving any leucovorin at a scheduled infusion of the cancer drug Eloxatin, made by Sanofi-Aventis. "Neither the distributor nor the manufacturer had any in stock." Another patient reported being switched from Eloxatin to Xeloda, a pill made by Roche that does not require intravenous leucovorin. Camptosar, a competing drug from Pfizer, is also administered with leucovorin. Sanofi-Aventis is "aware of the situation," says spokeswoman Noelle Boyd. "We are currently looking into the implications both from a research and a commercial perspective."

The Eastern Cooperative Oncology Group (ECOG), an independent group of academic cancer doctors that has played a key role in testing new cancer medicines, started hearing from hospitals that they were almost out of leucovorin.

"We've been fielding phone calls from institutions that are running out," says Albert Benson, head of clinical investigation at the Robert H. Lurie Cancer Center and chairman of an ECOG committee that oversees colon-cancer drug studies. "There may be institutions that have a good supply, but it is getting harder and harder to find. This is going to affect a lot of people, and we need to have some answers."

ECOG and other similar clinical trial groups are holding an emergency conference call Tuesday to try to figure out how to handle ongoing clinical trials if more leucovorin does not emerge. These groups are running 100 studies of cancer drug regimens that might improve on current cancer drug regimens. Genentech says the shortage is not yet affecting research on its drug Avastin.

"This is starting to be an issue nationally," says Leonard Saltz, a leading colon cancer doctor and researcher at Memorial Sloan-Kettering Cancer Center in New York. He warns that there is short supply for "a number of drugs," including vinblastine for lymphoma, and dexraxozane, used to protect the heart from another chemotherapy, doxorubicin.

In a blog post on the Web site of HemOnc Today, a trade publication for cancer doctors, oncologist Noelle LoConte of the University of Wisconsin writes that there are ongoing shortages of other drugs, including cyclosporine and doxorubicin.

"There is no clear endpoint in the shortage," she writes, "and clearly some patients need it without question." She adds that as rumors of the shortage spread, some doctors have stockpiled the drug. "One of my partners was at a site yesterday which had two years of leucovorin stored! The drug will likely expire before they can use it all!"

UCSF oncologist Venook says he is not sure leucovorin is necessary. It was added when 5FU was a new drug, and its not clear whether there will be a real impact from removing it. Still, the shortage is leading to general fears about access to generic cancer drugs.

"I've never heard of anything like it," says Michael Katz, a cancer survivor who is chair of a committee of patients that advises ECOG. He worries that the leucovorin shortage is a "red flag" that the cheap generic drugs cancer doctors use in addition to the pricey drugs like Avastin, made by Genentech and Roche, and Erbitux, from Eli Lilly and Bristol-Myers Squibb.

"This could be something that could occur much more frequently with generic drugs, because the margins of generic drugs are so thin. And many of the drugs that are the most important drugs in the cancer armamentarium are the drugs that have gone off patent," says Katz. He wonders why there is no system to catch such shortages and prevent them from harming patients or halting clinical trials.

Katz asks, "How many drugs are out there that are just being produced by the grace of God?"