CURE SINGLE CANCER PATIENT

CURE SINGLE CANCER PATIENT

DID NOT HAVE THE LUXURY: of focusing on just one issue as president
of Memorial Sloan-Kettering, or even of focusing on one issue at a time. I
was required to help plan and run important fund-raising affairs, such as the
annual gala at Radio City Music Hall, hosted for several years by Frank
Sinatra. I helped in recruiting key staff members. I was involved in the
expansion of some facilities and planning new construction. I had to coordinate
our response to emergencies, such as the time one of our surgeons operated on
the wrong side of the brain of a patient with brain cancer and had to immediately
recruit a surgeon from New York University capable of correcting the error. I
served as a liaison to our board and the New York business community, and I
communicated regularly with senior officials in Washington at the National
Cancer Institute and the National Institutes of Health. In addition, I felt a
personal responsibility to stay informed on developments in the biology of
cancer and new cancer treatments.
And, of course, there was my own research into hexamethylene
bisacetamide, or HMBA, the possible new cancer drug I had been working on
with colleagues from Columbia. It had taken a backseat to my other activities at
first, but then was jolted back to life with a surprising encounter I had in early
1982 with Charles Young, a senior medical oncologist at Memorial Sloan-
Kettering. He had read the articles in scientific publications that my colleagues
and I had written on HMBA and was interested, he said, in the promise of a drug
that appeared to stop cancer cells without killing healthy cells, too. He suggested
that, based on what he had read about our progress, it was time to conduct a
clinical trial of HMBA with Memorial Sloan-Kettering patients.
My initial reaction was amazement bordering on disbelief. I told Young that
I was reluctant to pursue a trial because our Columbia experiments had
demonstrated that HMBA was extremely effective in stopping a range of human
cancer cells from growing, but only in test tubes; the drug, to our great
disappointment and surprise, had failed to stop tumors from growing in mice. I
wanted to be optimistic about the drug, but those initial results with mice had left
me skeptical.
But as Young explained his thinking, it became clearer that one of the
impediments to successful drug development in the campaign against cancer in
those years was that medical centers like Columbia had been slow to test
innovative prospects. Only about 3 percent of the cancer patients at Columbia
who were no longer responding to standard treatments—the usual candidates for
drug testing—were entered into clinical trials. By contrast, about 60 percent of
similar patients were in drug trials at Memorial Sloan-Kettering, based on the
proven theory that testing on mice was only moderately predictive for how drugs
would work in humans.
Developing trials with new and hopefully better drugs was an integral part of
the mission at Memorial Sloan-Kettering. At Columbia, in comparison, most of
the oncologists were in private practice, and the truth is, drug trials produce little
income relative to the extra commitment of time and monitoring. They are not
moneymakers, and, of course, the success rate is generally low.
I gave Young’s proposal some thought and, getting over my initial
reluctance, agreed to move forward. He obtained approval from the Food and
Drug Administration to begin a Phase I clinical trial. The agency agreed to
permit the trial based on evidence from our earlier testing at Columbia that
HMBA had not been toxic when administered to mice and had demonstrated
anticancer activity against malignant cells in test tubes. Today, the FDA has
more stringent rules on approving human trials, but at that time, the evidence
that we were, at least, unlikely to harm the patients was enough to take the initial
steps.
Young and I sifted through records and consulted with doctors and identified
thirty-three candidates with different types of advanced cancers—twenty-two
men and eleven women, ranging in age from twenty-one to seventy-eight. Most
were no longer responding to chemotherapy or chemotherapy and radiation, and
in all cases their conditions appeared to be deteriorating. Traditional treatments
had simply stopped working, and, in each case, the anxious patients and their
families were willing to try something new.
We calculated that in order for the patients to receive therapeutic doses of
HMBA, they had to take intravenous (IV) infusion continuously for up to ten
days. And so we began. In five of the thirty-three patients, the HMBA caused a
dangerous drop in their platelet counts, which could have led to internal
bleeding, so for them the drug had to be discontinued. For the remaining patients
who tolerated the drug and showed preliminary indications of improvement, we
repeated the ten-day infusions every twenty-eight days for six to eight months.
Having had little experience with trials, I found the process anxious and
exciting, particularly when we began assessing the initial results some months
later. Five of the patients—three with breast cancer, one with colon cancer, and a
fifth, a fifty-year-old woman with a serious form of lung cancer called large-cell
carcinoma—showed measurable improvement, evidenced by shrinkage of their
tumors on X-rays or in physical examinations and the relief of some symptoms.
Four of those patients had what turned out to be transient improvements—their
tumors stopped growing for some months, or shrunk, but then resumed their
deadly spread. Further treatments with the HMBA failed to improve their
conditions. We documented those results in an article in the academic journal
Cancer Research in 1988.*
In such trials, no matter how well designed and how close the monitoring, it
is often difficult to understand initially why one patient responds to the drug,
while others show little or no therapeutic benefits. The answers to such questions
can determine whether the next step is follow-up research, further efforts to
refine or adjust the chemistry of the drug, or dropping the experiments and
moving on. Adding to the puzzle of evaluating the results of the HMBA trial was
the fact that one of the patients, the fifty-year-old woman with lung cancer,
responded differently from all the others. She had a stunning and inexplicably
positive response. This was my first opportunity to observe firsthand what
amounted to a magic bullet in action. The positive results were particularly
intriguing because her condition had been dire.
By the time this patient had entered the trial, her disease had spread to both
lungs and the lymph nodes in her chest. Her diagnosis of lung cancer had been
confirmed by examination of a biopsy of her tumor cells. The tumors had made
her breathing difficult, and she had suffered substantial weight loss. In the
preceding eighteen months, she had received combinations of chemotherapy
drugs, but the cancer was not responding. She was probably months from death
when we began the HMBA trial.
After her first six months on HMBA, we identified no obvious improvements
in her condition, but, and this was important, her disease had not progressed.
That was a modestly positive sign. Because she was tolerating the doses of
HMBA well, we continued to administer the drug, and we monitored her closely.
I heard little further on the case for many months. Then one morning Dr.
Young called and asked that I come to the X-ray viewing room as soon as
possible. He said he was “excited,” something I had not heard from him before.
I rushed down to the X-ray room, where Young showed me four films on a
light box, each taken roughly four months apart. He said nothing, only waited for
me to see for myself what his enthusiasm was about.
The first X-ray, on the left, was taken on the day the woman had started on
HMBA, and the fourth, on the far right, was dated the previous day. The masses
in the early X-rays had simply melted away. Even to my inexpert eye—I’m no
radiologist—the change from the first to the last X-rays was dramatic. It was
hard to believe we were looking at the same patient. The most striking changes
had occurred in just the previous four months.
Young explained that some of the patient’s more troubling symptoms,
wheezing, weight loss, and constant fatigue, were disappearing, too. She was
breathing easily, and her energy was returning. It was stunning. Doctors do not
frequently exhibit much emotion in the laboratory, but Young and I clasped
hands as we both looked through what seemed a window of opportunity. “You
realize this could never have happened if I had not come to Memorial and you
had not come to my laboratory with your ‘insane’ idea of doing a clinical trial
with HMBA,” I told him. “Before this, we could not even show that it stopped a
tumor growth in a mouse!”
We had saved a life. What greater good can you do in medical science? It
was, nevertheless, one out of thirty-three. We had a lot more work to do.
By chance, Memorial Sloan-Kettering’s board was meeting that afternoon. It
was an opportunity I did not want to pass up.