SAFETY ISSUE, Cumulative Dose Monitoring


Big Doses of Chemotherapy Drug Killed Patient, Hurt 2d


Published: March 24, 1995

Two patients receiving experimental treatment for advanced breast cancer at one of the country’s most prestigious cancer hospitals were given massive overdoses of two chemotherapy drugs. One patient died, and the other suffered permanent heart damage.

The incidents occurred at Dana-Farber Cancer Institute in Boston, a Harvard teaching hospital, late last fall. Officials at the hospital said they were at a loss to explain how such a serious medical error, which apparently resulted from a mistake in an order by a doctor last November, escaped attention until a clerk picked it up in a routine review of data last month.

The patient who died, Betsy A. Lehman, was an award-winning health columnist for The Boston Globe. The news of the mistake, detailed today in an article published in the Globe, was all the more unsettling because Ms. Lehman, as a health reporter, was presumably knowledgeable about her treatment and would have chosen her hospital with care. Ms. Lehman, who was 39, died on Dec. 3 at the hospital.

Doctors apparently refused to heed her warnings that something was drastically wrong and ignored the results of tests indicating heart damage. Her death came as she was preparing to go home to her two daughters, ages 7 and 3, and her husband, Robert Distel, a scientist who works at Dana-Farber. A pathologist who did an autopsy did not spot the overdose. He also found no visible signs of cancer in her body.

The other patient was a 52-year-old woman who is seriously and chronically debilitated from irreversible heart damage, Dana-Farber officials said. She is now being treated at Beth Israel Hospital in Boston. Her name was not released for reasons of patient confidentiality.

Dr. David M. Livingston, physician-in-chief at Dana-Farber, said his institution “profoundly regretted what has occurred, assumes full responsibility for these tragic events and has taken additional precautions to ensure that they do not happen again.”

“It’s an extremely sad time here,” Dr. Livingston said in an interview.

The overdoses occurred two days apart. Both patients were cared for by the same medical team. Two doctors involved in their care have been suspended from clinical care and are now working full-time in administration pending completion of an independent investigation. The names of the doctors were not released and their patients have been reassigned to other staff members.

Both patients were being treated with an experimental procedure known as autologous stem-cell transplant, a variation on a bone marrow transplant. The therapy involves removing stem cells from the blood instead of the marrow, and holding them in reserve until treatment with high doses of chemotherapy have ideally killed all the cancer cells in the body. Then the stem cells, which form new blood cells, are reinjected to repopulate the blood and replenish the immune system.

Each patient received large amounts of the chemotherapeutic drug cyclophosphamide, or Cytoxan. The amount was supposed to be calculated according to the amount of the patient’s body surface. For Ms. Lehman, the correct dosage would have been 1,630 milligrams each day for four consecutive days. Instead she received 6,520 milligrams a day for four days, four times the intended dose. The other woman received a similarly miscalculated dosage. Each woman also received four times the standard amount of another marketed drug, Mesna, which is used to counter the adverse irritating effects of Cytoxan on the bladder.

The Globe said the error was detected only as part of a routine data check performed when a protocol, or blueprint for treatment, is considered experimental.

The original medication order was filled out by a physician who is believed to have been working as a research fellow, the Globe reported, and “who apparently misinterpreded the study protocol.” At least five other doctors and nurses countersigned the order including the leader of the team, Dr. Lois J. Ayash. “It was a blunder compounded or overlooked by at least a dozen physicians, nurses and pharmacists, including some of the institution’s senior staff,” the Globe said. Dana-Farber said the article in the Globe was fair.

The overdoses were repeatedly documented in Ms. Lehman’s hospital record.

The experimental protocol involved only Dana-Farber and not other hospitals. The experimental plan was not under the supervision of the Food and Drug Administration, Dr. Livingston said.

Dana-Farber has 57 licensed beds, is one of 20 Federally designated regional cancer centers and is a recipient of $35 million in Federal funding and $25 million in charitable contributions annually. It was founded in 1947. Dr. Livingston said that “in the recorded history of the institution, we can’t find any evidence of an overdose induced death.”

Despite Dana-Farber’s high reputation, it has a troubled past. The hospital often has been criticized by doctors elsewhere for aggressively marketing its scientific expertise.

When Paul E. Tsongas, the former Senator from Massachusetts, ran for President in 1992, two of his doctors at Dana-Farber repeatedly said Mr. Tsongas had been cancer-free since undergoing a bone marrow transplant in 1986 for a lymphoma, a cancer of the lymph system. But in 1987 Dana-Farber doctors found evidence of the disease in a lymph node in Mr. Tsongas’s armpit. Mr. Tsongas, who is a trustee of Dana-Farber, suffered a relapse in late 1992.
After Mr. Tsongas said he had erred in not providing full disclosure, Dr. Livingston said that he and Dana-Farber “made a bevy of mistakes” in connection with the way the candidate’s health was described by his doctors. A review of the episode led to a new policy of disclosure from the hospital about the illness of patients who are public figures.

Dana-Farber has investigated five allegations of scientific misconduct by its scientists over the last five years. Two cases were dismissed in the inquiry phase, a spokeswoman for the hospital, Gina Vild, said. One researcher, whose name was not released because Federal officials have not completed its investigation, fabricated laboratory work and was fired. Another scientist, Dr. Mark Kowalski, plagiarized. A fifth scientist is currently under investigation for falsification of data, Ms. Vild said.

Both the Board of Registration in Medicine, which issues medical licenses in Massachusetts, and the Division of Registry, which issues licenses to nurses and pharmacists, are launching investigations into allegations of malpractice at the hospital, said Terry Ann Knopf, spokeswoman for the Office of Consumer Affairs, which oversees both agencies.

“The Board of Registration in Medicine will initiate an investigation concerning the double tragedy,” Ms. Knopf said. “The investigation will focus both on the hospital’s systemic safeguards — what safeguards are supposed to be in place it and if those safeguards were indeed in place — and also take a look at the question of physician competence.”

Ms. Knopf said the agencies first learned of the two deaths at Dana-Farber from yesterday’s report in The Boston Globe.

Dr. Livingston said that Dana-Farber has begun an internal investigation of the circumstances surrounding the overdoses and has appointed Dr. Vincent T. DeVita, a former director of the National Cancer Institute, a Federal agency in Bethesda, Md., who is now in charge of the cancer center at Yale, to head a panel of outside experts to review the overdose problem at Dana-Farber.

Dana-Farber has also installed a new computer program similar to those in use elsewhere to signal pharmacists when a doctor orders an unusually large amount of a drug.

Dr. Livingston said that the existing system has built-in checks and balances.

“Why it didn’t work is what I want our investigators to tell me,” Dr. Livingston said. “I am deeply troubled by that.”

Another internal group is auditing the records of all patients in the experimental therapeutic program. A report of the audit is to be sent to the National Cancer Institute, which paid for the research with taxpayer money.

Within 24 hours of learning of the overdose, Dr. Livingston, doctors involved in the care of the two patients, and other staff members directly informed both families of the error.

“Those two meetings, which took place within hours of each other, were the two saddest individual occurrences I remember. I looked into their eyes and all I could see was abject grief and misery. It was the kind of misery that was penetrating.”

At one point, the article also misstated the harm done. The overdoses caused one death and one case of permanent heart damage, not two deaths. In some editions, the article also incorrectly described the dosage given to Betsy Lehman, the patient who died. It was four times the intended dose, not four times the lethal dose.

Photos: The Dana-Farber Cancer Institute’s physician-in-chief, Dr. David M. Livingston, answering questions yesterday at a news conference about the death of a patient because of a chemotherapy overdose. Dr. Livingston said the institute accepted full responsibility for the error. (Associated Press); Betsy Lehman.

Use this Calculator to Quickly Estimate the Price of your Order