Stories about progress in the war on cancer have been falling like artillery
shells in recent months. The world had barely recovered from the Angiostatin/Endostatin flap,when news emerged of a sensational
new drug called Herceptin. The story was announced at the American Society
for Clinical Oncology (ASCO) meeting in Los Angeles and like the Angiostatin
was ballyhooed in the New York Times (although not on the front page).
According to a University of California at Los Angeles news release,
a new study on Herceptin represented "a significant medical breakthrough."
Dr. Larry Norton, chief of the breast service at Memorial Sloan-Kettering
Cancer Center in New York (the same scientist who claims that vitamin C
is harmful to cancer patients undergoing chemotherapy) waxed enthusiastic
about the treatment in the New York Times.
"This is the biggest difference I have ever seen in advanced
breast cancer," he said. It is "a big effect, not a small,
minor effect." This treatment "is not like anything we have
ever seen before" in cancer therapy, he added. The Food and Drug
Administration (FDA) has said that it will decide by November 4 whether
or not to allow Genentech to market Herceptin. But Genentech mounted a huge
display at ASCO, announcing that the drug would in fact be approved and
available by November. This has created near pandemonium among breast and
ovarian cancer patients desperate to get the latest "cure."
EXPERIMENTAL DRUG
So what's all the shouting about? Herceptin is an experimental immunological
drug of a new and promising kind that homes in on a defect in one particular
type of breast cancer. These are the cells that express the HER-2/neu gene.
The gene is not inherited but develops for unknown reasons during a woman's
lifetime. It then produces a protein which is present on the cell surface.
HER-2/neu is found in about 30 percent of breast cancer cases and 20 percent
of ovarian cancer cases. Weekly intravenous injections of Herceptin in a
clinical trial were added to standard chemotherapy in women with stage IV
breast cancer.
In the chemotherapy-alone group there were 32 percent remissions (partial
or complete tumor shrinkages for a month or more). In the Herceptin-added
group there were 49 percent remissions. After one year, there was an
11 percent difference: 67 percent of those receiving chemotherapy-alone
were still alive while 78 percent of those also receiving Herceptin were
still alive. About 14 percent of patients receiving chemo alone did not
show evidence of progression compared with 28 percent of those receiving
chemo plus Herceptin. The median duration of the response--which is a measurement
from the time the cancer shrank to the time it began to enlarge or spread--was
six months in the chemotherapy group compared to nine months in the chemo-plus-Herceptin
group, a three month improvement.
Herceptin by itself had unspectacular effects. There were remissions
(partial or complete) in 16 percent of patients. The median duration
of responses was also nine months.
Scientists said that the side effects of Herceptin was minor, although
they conceded that it could cause heart damage when combined with other
drugs.
TELEVISED CURES
Before the meeting I was astounded to see on television a woman talking
about her long-term cure following this treatment. It turns out that there
are in fact precisely two cases in the country with apparently long-lasting
effects of Herceptin. One of them is a patient of Dr. Dennis Slamon at UCLA,
the other of Dr. Norton. The patient of Dr. Slamon has lived six years after
taking Herceptin for 18 weeks, but none of the drug since. The patient of
Dr. Norton is still on the drug five years out. According to Larry Altman,
M.D. of the New York Times, "Statistically, the women would have been
expected to die in less than a year without such treatment...." (May
18, 1998).
When such "poster child" cases are publicized by alternative
practitioners they are universally derided as "mere anecdotes."
But apparently a different standard applies when such stories are related
by top doctors at major medical centers. Then they become valid case histories,
worthy of publication in the New York Times.
The problem with such reasoning is this: no particular individual performs
according to statistical norms. According to the government's own statistics
(SEER Cancer Statistics Review, 1973-1991) the five-year relative survival
rates for women with distant metastases (stage IV disease) ranged from 11.0
in older black women to 21.8 percent in younger white women. If we just
look at the latter group for a moment, more than one out of five women
with "incurable" breast cancer survives five years or more.
These women, needless to say, did not receive Herceptin and some of them
probably did not receive chemotherapy at all. So, if you treat a cohort
of such women with Herceptin it is statistically inevitable that some of
them are going to be alive at five years, as will untreated patients. We
would expect, in fact, about a 20 percent survival. So how can you tell
in the case of these particular individuals whether it was the Herceptin
that caused the prolonged survival? Even if there is no sign of the tumor
in their cases this fact may not be the cause of their prolonged
survival, but merely an epiphenomenon. They might have survived anyway,
with or without visible tumor.
PROBLEMS WITH CLINICAL TRIALS
Clinical trials theoretically offer a way out of this dilemma (although
the ethics of having a control group are highly debatable). But such clinical
trials have to be conducted by people who do not have any vested interest
in the outcome of the trial. This is difficult, since a positive outcome
alone is a tremendous career-booster.
There are many pitfalls to conducting clinical trials which I and many
others have pointed out repeatedly (See my book Questioning Chemotherapy.)
For example, it sometimes happens that patients receiving more toxic regimens
seem to do better than those receiving less intensive treatments. Through
a kind of medical Darwinism, the healthiest patients tend to survive the
clinical trial itself, while sicker patients drop out due to toxicity or
death. These patients are then sometimes eliminated from the final tally
as "unevaluable." This bit of bookkeeping makes the intensive
treatment look better than the control treatment, since it was precisely
this hardy group of patients that was most likely to survive longer anyway.
As a general rule, it takes great care and moral scruples to design a
study in a way that does not bias the results in a direction that promotes
the personal interests of the investigators.
