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Adriana's trial   A monitor is attached to Adriana Jenkins's chest to measure her heart's pumping action after she experienced a fluttering sensation during her clinical trial. (Globe Staff Photo / Suzanne Kreiter)

ADRIANA'S TRIAL

Balancing benefits and risks

Cancer patient's side effect forces a difficult decision

By Raja Mishra, Globe Staff, 4/30/2002

Last of three parts

   
 THE SERIES

Part 1
An experiment begins

Part 2
A cancer patient's longest wait

Part 3
Balancing benefits and risks

Follow-up
Cancer drug's link to heart ill probed
Trials continue in different form

 PHOTO GALLERY

Photos from Adriana's experience

By Suzanne Kreiter / Globe Staff

 TIMELINE

Herceptin's history

 CLINICAL TRIAL

To gain FDA approval for widespread use, a new treatment must successively pass three phases of clinical trials, each seeking to answer different questions:

Phase I: Is a new treatment safe? What are safe dosage levels? Usually small trials, often with less than a dozen patients.
Phase II: How well does the treatment work? What are its side effects? (Adriana Jenkins is in a Phase II trial.)
Phase III: Does the treatment heal more effectively than standard treatments? Does it work consistently in a large group of patients? This phase often involves hundreds of patients in many hospitals.

 HERCEPTIN

About 30 percent of breast cancers produce excessive HER-2 proteins, which makes cancer cells proliferate. Herceptin disables HER-2. It hits only HER-2 producing cancer cells, not normal cells, minimizing side effects and earning it the title "smart" drug. UCLA's Dennis Slamon spent 13 years developing Herceptin. San Franciso-based Genentech Inc. sells it. The first large-scale clinical trial results came out in May 1998: 78 percent of patients on Herceptin plus chemotherapy survived one year; compared to 67 percent on chemo alone. The FDA approved Herceptin for treating metastatic breast cancer, where the cancer has spread. Doctors now seek to extend its use to earlier stages of cancer through clinical trials, such as the one involving Adriana Jenkins.

 RESOURCES

Dana Farber research advances
ClinicalTrials.gov
CenterWatch
CRnet from MGH and Harvard
Clinical trials search
NEMC: The Cancer Center

 ABOUT THIS SERIES

The Globe followed breast cancer patient Adriana Jenkins through a clinical trial at the Dana Farber Cancer Institute in Boston for eight months. A reporter and photographer were given access to most medical events and records. All conversations reported were witnessed. The lengthier exchanges that appear in the stories were recorded on audio tape. Jenkins' writings, as well as representations of her thoughts, were taken from contemporaneous notes written by her and supplied to the Globe on a regular basis throughout the eight months.


The fuzzy spots did not belong. Not in the checkout at Star Market. Yet Adriana Jenkins saw them. And then, the familiar counter at the familiar Allston store blurred. Her husband distantly stood smiling. She would fall over. Right there. Adriana rushed away, to the safety of a bench, regaining her bearings after several minutes.

Had she eaten enough that day? Yes. Had the cancer treatments simply worn her out? Maybe. Was the episode somehow connected to the strange new flutterings of her heart? Oh, no.

The experimental cancer drug she had taken for almost three months listed congestive heart failure as a possible side effect. She had signed a consent contract acknowledging this risk. It seemed remote at the time.

The Globe followed Adriana Jenkins for eight months through a clinical trial for an experimental breast cancer therapy. Clinical trials determine whether a new medicine or treatment works, but in the process side effects sometimes are revealed. Every side effect listed on every drug is the product of some trial patient's suffering. Or injury. Or death.

More than 3,000 clinical trials were conducted in the Boston area last year. Puzzles of biology were solved. Cures inched closer. But there were unexpected rashes and strange spells of dizziness. Patients doubled over with mysterious pain or were racked with surprising seizures. Sometimes, severe problems forced doctors to halt trials. More typically, the side effects were dutifully recorded, a warning for future patients. Trial patients shoulder the risk of the unknown so other patients will not have to.

Doctors running clinical trials routinely engage in an ethical balancing act: When are side effects too much? When should a trial be stopped? There are no textbooks for this. Each doctor must decide alone. These are among the most difficult decisions made by the thousands of white-coated men and women in Boston's hospitals and clinics. And just such a decision would soon determine Adriana Jenkins's fate.

Adriana took the promising new drug Herceptin, along with a more conventional medication, to combat her aggressive breast cancer. After removing the breast, her doctors determined the drug combination destroyed much of her cancer. But she still had to suffer the nausea and hair loss of standard chemotherapy as a precaution. After this misery, however, would come the payoff: The last part of the clinical trial meant 40 more weeks of Herceptin. Adriana was increasingly convinced the drug was healing her. She volunteered for this trial, quite simply, to get as much of the drug as possible. Now there were just eight weeks of chemo to get there.

So she began biweekly infusions of Adriamycin, an older chemotherapy. Soon she was feeling something that was not quite pain and not quite discomfort but that deeply fatigued her. And there was her oddly fluttering heart.

Adriamycin

Adriana had felt her heart stutter within minutes of receiving the first infusion of Adriamycin. The nurse thought it might be nerves. Adriana had been dreading the drug for months. An electrocardiogram was scheduled. The test measures electric pulses in the heart, which correspond to beats. It can detect heart damage, abnormal beats, and other defects. Adriana's test detected nothing.

Adriamycin pummels the DNA of cancer cells, causing them to die. But it hits normal cells as well, producing often-vicious side effects. In contrast, Herceptin targets only cancerous cells. Some doctors hailed it as the first smart cancer drug. By developing it, researchers hoped to eliminate the need for harsh drugs such as Adriamycin.

Three days after her first Adriamycin treatment, Adriana, out on a walk with a friend, could not maintain even a leisurely pace.

That week, she would return home exhausted from work, plopping on the couch, refusing phone calls, then off to bed. She felt terrible. Sleep would last nine hours, 12 on weekends. This is not the way to start off a marriage, she thought. But she was not in pain. Medication staved off nausea. The treatment was bearable.

The day after the second Adriamycin infusion, however, was different. It felt like a car wreck. Everything was sore. Adriana got to work late; she missed an important meeting.

A few days later, she was running her hand through her hair. Out came a clump. It was happening. She had already lost a breast. Now the hair. Two days later, the shower drain collected more. That was it. Adriana decided on a preemptive strike: Wielding scissors, in front of a mirror, she cut off most of her hair. About two inches remained. She began wearing her wig.

David Halligan, her husband, took to calling her Telly, after bald ''Kojak'' star Telly Savalas. If her rapidly changing appearance bothered him, he didn't show it. Their married life continued unaffected.

''He is a saint and every d ay I am thankful that he is in my life,'' she wrote. Days later came the Star Market incident. Her fatigue was increasing and the worrisome heart fluttering continued. The Dana Farber team sent her to Dr. James Fang, a Brigham and Women's Hospital cardiologist with expertise in the side effects of cancer drugs.

In Fang's office, Adriana donned a hospital gown and was placed on a treadmill for 10 minutes. She wore a tiny monitor on her chest that measured her heart's pumping action.

Later, Fang examined the results. He quickly called her Dana Farber medical team. There was something wrong.

Disturbing data

In Washington, at roughly the same time, government scientists began noticing some troubling Herceptin data. The National Cancer Institute, an arm of the National Institutes of Health, coordinates and monitors cancer clinical trials around the country, serving as a clearinghouse for doctors and cancer patients.

One trial under the institute's jurisdiction was a massive phase III trial similar to Adriana's: About 250 breast cancer patients around the country were given Herceptin combined with chemotherapy. The researchers had expected that some cases of congestive heart failure - when the heart loses blood-pumping ability - would develop, as they had in previous Herceptin trials.

But as the data from Trial N9831 started filtering in, it appeared that more women than anticipated showed signs of the potentially fatal condition. The women had taken a combination of Herceptin and Taxol, another cancer drug, following Adriamycin chemotherapy. Adriana was in Adriamycin chemotherapy. In a few weeks, she was scheduled to take Herceptin and Taxol.

None of the women in the Trial N9831 died. In early January, however, the National Institutes of Health decided to freeze the trial. No more women would be enrolled. The women already enrolled, and their doctors, received a detailed explanation and the option to drop out. It was unclear how many were exiting.

Dr. Eric Winer, Adriana's doctor, sat on the panel that made the call. He backed the decision. And he began wondering if the new development had any bearing on his patient.

Trial and error

These are nervous times for researchers conducting clinical trials. In 1999, 18-year-old Jesse Gelsinger died during a gene therapy clinical trial at the University of Pennsylvania, shaking the medical world. The trial was halted. An investigation blamed researchers for numerous ethical and safety lapses. All clinical trials around the country were subjected to heightened government scrutiny. For a time last year, federal regulators shut down clinical trials at the prestigious Johns Hopkins University Medical School after a test subject there died.

Clearly, clinical trials mean risk. Doctors know it. They are acutely aware of it. Patients also know it, although their understanding depends on an able explanation from a doctor and their own ability to comprehend.

Adriana signed a consent form, a legal document, that clearly outlined the possible side effects of the treatment. They filled four pages. Under the heading of ''Less Likely'' risks of Herceptin was congestive heart failure. The consent form also noted that combining drugs could produce ''unknown and potentially life-threatening side effects.''

In her journal, Adriana wrote that the risks were explained to her ''fairly well.'' After she weighed them against the possible benefits of Herceptin, her choice to enter the trial was easy.

Adriana's trial was approved in advance by Dana Farber's Institutional Review Board, a 15-member panel, split among doctors and educated lay people, that monitors all trials there. Every hospital and research university has one. These boards report to the federal Office of Human Research Protections, based in Washington, which establishes the rules for protecting trial patients. These rules grew out of the horror of Nazi medical experiments, as nations sought to prevent patients from exploitation.

The review board must balance possible risks with possible benefits. Patients headed for certain death can take larger risks. Those with minor sicknesses cannot. Adriana fell somewhere in between, as do most trial patients.

The Dana Farber review board had greenlighted her trial. Now it was about to get involved again.

Vital questions

Dr. Fang's tests had detected extra heart beats. In the time a normal heart would beat twice, Adriana's produced three beats - premature ventricular contractions, or PVCs. The PVCs were sporadic but frequent enough for concern.

PVCs are not on their face worrisome. Many people get them after drinking coffee. In fact, the tests indicated that the strength of Adriana's heart muscle was normal. There was no sign of congestive heart failure. But the PVCs could be an early warning of heart damage.

The results triggered a delicate ethical debate for Fang. Right now, Adriana's heart was healthy. And, according to her records, the cancer therapy worked quite well. But he also knew that Herceptin occasionally produced congestive heart failure. He'd seen it in other patients referred to him from Dana Farber, especially those who took the drug just before Adriamycin, as Adriana had. He knew that congestive heart failure could be a death sentence. Yet there was no test to determine whether Adriana was developing it or simply having harmless extra heartbeats.

Argument and counter-argument raged in Fang's mind. There was no chart to consult, no computer program to run. It was a gut call for Fang, who describes himself as conservative doctor. Pull Adriana from the trial, he told Winer. It wasn't urgent, he advised, but she should not receive any more Herceptin.

Winer considered his advice, then engaged in his own moral calculus, through his own personal prism. In the end, it would be his decision alone. Winer had seen, first-hand, how well the Herceptin worked. Adriana's cancer had been proliferating like mad but now was reduced to tiny millimeter specks. He wanted her back on Herceptin. And it was clear that Adriana was in no immediate danger.

Yet none of the 14 other women in the trial thus far had developed PVCs. In fact, almost all of them responded quite well to the treatment. He felt confident the trial would be a success. He felt confident Herceptin, in these cases, worked.

But there was the data coming out of Washington on Trial N9831. In that case, Winer voted to freeze the trial. Now he, too, had to decide from the gut, negotiate between the scientist in him and the doctor, the optimistic researcher and the cautious caretaker.

In the end, he drew on the first lesson he'd learned in medical school: ''Do no harm.''

On Jan. 16, Adriana was removed from Protocol No. 00-273.

The Dana Farber team drafted a letter to the review board explaining its call. The board agreed. But what would this mean for the trial data? Winer and the board knew Adriana's PVCs must be recorded as a possible side effect. They decided her results thus far, showing Herceptin worked well, could also be included. But she would contribute no more to the trial results.

Adriana would now only get Taxol. The Herceptin doses were canceled.

Precious life

Adriana wanted as much of the Herceptin as she could possibly get. She had originally been scheduled to get 40 more doses. Twelve doses seemed to shrink her cancer. Imagine what 40 could do! She would take it forever if they'd allow it. But she trusted Winer. She accepted his decision.

The final week of Adriamycin had been tough. Twice sudden fevers came on, and Dave rushed her to the emergency room. She lost 10 pounds. Her hair completely fell out. It wasn't as miserable as she expected, but it was bad enough.

A heaviness, a weariness, settled on her. There was the physical ordeal, the suddenly absent Herceptin, the fact that Winer refused to give her significantly better survival odds. And beneath it all, there was the reality that she could still die.

Her husband, Dave, had been a pillar of support but steadfastly refused to discuss the possibility of death. No sense in dwelling on it, he said. Her father felt the same. Adriana attended a breast cancer support group, only to find 60-year-olds talking about their shattered lives. She just wanted to live to 60. Only one percent of breast cancer patients are her age or younger. She could find no one.

Adriana began meeting with her former therapist. Years ago, they discussed love and ambition. Now it was all about death. Adriana found no solace in traditional religion. But her outlook took on a new cast. Life could be short. Life should be precious.

She wrote: ''This situation, as bad as it is, has had the benefit of making me view life in a different way. That work is work and not life. That I should not be thinking `I'll do that one day,' or `I've always wanted to do that,' but to do things now and not wait. To appreciate the people in my life as much as possible. To appreciate everything as much as possible. Who knows what the future will bring? It really puts in perspective the concept `yes, we are all going to die someday.' And, maybe I'll die within a year, maybe I won't. Maybe I'll get hit by a car in the meantime! Maybe I'll live to 80 years old. Regardless, this situation has afforded me the unique opportunity to live my life with a new perspective, and has given me the time to make sure I have as few regrets as possible.''

She drew up a must-do list: Visit Iceland, Winnipeg, Italy. Buy a Toyota MR-2 Spider sports car, learn to ride a motorcycle, slide down a fire pole.

And she thought often of her mother, Georgeanne, who was given a year to live from lung cancer and died in six weeks, gasping for breath, unable to arrange her affairs, unable to say goodbye.

Adriana began transferring funds into Dave's name. She spoke to a lawyer about drafting a document that would give permission to turn off life support if she was close to death.

She thought of writing a will. But that made her cry. So she did not.

Sunnier climes

It is a chilly March morning in Boston, but it's warmer, much warmer, in St. John in the US Virgin Islands, and that's where Adriana and Dave are headed. Four days on the beach await.

''We're just going to sit,'' says Dave.

Adriana has packed a new bathing suit, a Dana Farber special, a navy blue one-piece with a pocket on the right breast she can stuff to create the illusion of a breast. The two are all smiles.

Adriana is taking Taxol. The side effects have been mild. In fact, in retrospect, none of the drugs' side effects were unbearable. And losing a breast was not as emotionally difficult as she had expected.

The PVCs stopped days after she was pulled from the trial. The cause remains a mystery. Winer will continue to monitor her heart. The most recent heart test turned up nothing. He plans to eventually give her more Herceptin, later in the year. In a few weeks, she will begin daily radiation treatments.

The 14 other women in the trial have fared quite well. The trial has already surpassed expectations. Once 40 women have been tested, Winer will publish the results, probably in 2003. And thousands of women will be one crucial step closer to a powerful new treatment.

But Adriana's trial is over. She has no regrets. She believes the Herceptin, even with a limited dose, may have saved her life, though the cancer could still resurface. She believes her heart is fine and her marriage stronger and her dreams still a distinct possibility. And now, Adriana Jenkins will get on a plane, close her eyes, and fly off to somewhere warmer.

''Yeah, we're just going to sit,'' she says.

Raja Mishra can be reached at rmishra@globe.com.

This story ran on page A1 of the Boston Globe on 4/30/2002.
© Copyright 2002 Globe Newspaper Company.

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