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Adriana's trial   Adriana Jenkins and her father, Adrian, say goodbye before her mastectomy at Brigham and Women's Hospital. After the surgery, doctors hope to be able to determine how well the experimental cancer drug has worked. (Globe Staff Photo / Suzanne Kreiter)

ADRIANA'S TRIAL

A cancer patient's longest wait

In experimental treatments,
test results don't always provide concrete answers

By Raja Mishra, Globe Staff, 4/29/2002

Second 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.


Anesthesia has kept a quiet smile on Adriana Jenkins's face for half an hour, but now she seems restless. Dr. Dirk Iglehart bends over her exposed right breast. An oval drawn in blue marker encircles it. He skims a just-sharpened scalpel over the pattern. Blue turns to crimson red.

A monitor chirps.

Iglehart stops and looks up: ''Is she all right?''

''She's just snoring a little,'' the anesthesiologist says.

''Snoring is good,'' says Iglehart, returning to the cut.

It is Oct. 19, 2001. The Brigham and Women's Hospital surgical team must remove Adriana's breast and her right armpit lymph nodes. These will be passed on to other doctors for closer examination. They will pass those results to yet more doctors, who will finally give her an answer. Did it work?

For four months, she has taken an experimental cancer drug in a clinical trial. And after four months of swelling uncertainty, Adriana Jenkins will finally have answers.

The Globe followed her for eight months to better understand clinical trials, the core of Boston's world-renowned medical community. Last year, at any given time, more than 3,000 trials were taking place here, converting the bodies of tens of thousands of patients into living, breathing laboratories.

The National Institutes of Health poured $1.6 billion into Boston last year, a substantial portion of it to fund trials. Hundreds of local doctors and scientists strive to advance medicine - and their careers - by running these trials. Drug companies watch nervously as their potential profit-makers, the products of massive investments of time and money, are tested.

For patients, clinical trials are unpredictable odysseys, excruciating ordeals, heroic fights, desperate last gasps. And despite the individual sacrifices, it takes hundreds of patients to prove a single drug works. Behind every medication and every breakthrough technique that spills from Boston's hospitals and medical schools are hundreds of anonymous patients. Patients such as Adriana Jenkins, a test subject in Dana-Farber Protocol No. 00-273.

Until this day, cancer treatment for her meant a single weekly appointment and mild nausea. She worked. She wed. She turned 32. But that is over. She has tasted the promise of the new - Herceptin. But because the drug remains unproven, her doctors must also provide the old treatments: mastectomy, chemotherapy, and radiation, known to breast cancer patients the world over as slash, poison, and burn.

One day, perhaps, some patients will only need Herceptin along with maybe one other drug. The treatment would be short. It would be painless. It would leave a woman's body unscarred. Adriana's trial might help make this reality. But first the drug must work in her. It must kill her cancer.

Iglehart fires up a cauterizer. He touches it to the cut encircling Adriana's breast. White sparks fly. The cut rips open, revealing spongy yellow breast tissue. This is where the answer - did the drug work? - lies.

Adriana stirs. The anesthesia is targeted to her chest area; she can awaken without pain.

''You OK?'' asks Iglehart.

''I'm fine. Yeah,'' mumbles Adriana.

Radical mastectomy

Three medical trainees watch Iglehart. One takes over the cauterizer.

''Whenever you guys find yourself doing nothing, pick something up,'' Iglehart tells the others, seizing a pair of tweezers and promptly dropping them. ''But don't do that.''

Adriana's half-severed breast hangs to the side. The surgeons have cut a moat of flesh around it. Now they can go underneath, to completely detach the breast from the chest. It takes digging. Iglehart uses a small hoelike tool to pull Adriana's skin back, then cut by cut removes the breast. Blood flows. Iglehart rams a cloth into the hole.

''Ow,'' says Adriana.

Iglehart promises to slow down.

The doctors extend the cut into her armpit, seeking lymph nodes. With a final snip, the breast comes off, trailed by a string of nodes. It's immediately wrapped in a blue towel, then placed in a plastic bag, then hurried by nurses out of Operating Room 29.

The team methodically mends the gaping red hole where her breast was, washing, stitching, applying bandages again and again.

Then, anesthesiologist Matt Posner whispers in Adriana's ear: ''All done. It's a quarter to one in the afternoon. Everything went smoothly.''

It took just under two hours. Within minutes, the breast - measuring 6.7 inches by 5.5 inches by 2 inches - is in a lab down the hall with pathologist Dr. Andrea Richardson. She cuts it into inch-thick slivers. She is looking for cancer. Or rather, no cancer. No cancer in the removed breast and lymph nodes means, in all likelihood, that the cancer has not spread anywhere else, that the Herceptin jammed the replication mechanisms of the cancer cells, causing her tumors to wither.

''I see nothing,'' she says, holding the slices in her gloved hand. ''Looks normal ... I see something. Wait ... I don't know.''

Road to cures

Medicine begins with an idea. Some scientist studying some affliction decides some molecule or compound or technique can cure it. Then other researchers or drug companies take the idea, refine it, and run tests on animals, usually mice. But mouse cures do not mean human cures. And so clinical trials on human patients commence.

The goal is to prove the approach can be used day after day, patient after patient, anywhere, anytime, so that doctors can tell patients, Medicine X will heal Condition Y.

In 1998, the US Food and Drug Administration approved Herceptin for treating metastatic breast cancer, cancer that has spread. But doctors want to use it before the cancer has spread. Clinical trials on less-advanced cancers were launched. Trials like Adriana's, which seeks to answer a narrow question: Does Herceptin combined with another drug, Navelbine, help women with breast cancer that has spread to the lymph nodes but not yet farther? If Adriana's trial and a subsequent larger-scale test answer ''yes'' to this question, then the few thousand women a year diagnosed with similar breast cancers will have a powerful new treatment without harsh side effects.

The road has been hard for Adriana, as it will be for the 39 other women who will eventually take part in Protocol No. 00-273. And the drug trial could be in vain: At least 20 percent of the women must see their cancers disappear in order for the trial to succeed.

Boston's vaunted medical community thrives on trials. Most doctors practice medicine. But doctors running trials advance medicine. Boston doctors derive much of their reputation from running trials. And the city's hospitals, filled with these doctor-scientists, consistently outrank the rest of the nation in great part because of these trials. Boston medicine is anchored by Massachusetts General Hospital, the Brigham and Women's Hospital, Beth Israel-Deaconess Medical Center, Tufts-New England Medical Center, Boston Medical Center, Dana-Farber Cancer Institute, and three prestigious medical schools, at Harvard, Tufts, and Boston universities. Hot biotechnology companies also fill the area, their fortunes riding on the latest clinical trial results.

Few places on earth convert science into medicine at a more furious pace.

The doctor

The ritual of clinical trials is well known to Eric Winer. Winer holds a Yale medical degree and taught at Duke University Medical School before Harvard-affiliated Dana-Farber wooed him five years ago. At age 44, he runs the Breast Oncology Department. He has deep creases around his eyes and on his cheeks but moves with youthful energy, bounding from chair to exam room to conference room. Seventy-hour weeks are the norm. Tragedy is routine.

''One has to come to terms with the fact that people die,'' he says.

Over the years, he says, as patients slowly wasted away before him, he discovered an inner calm that allowed him to comfort during tragedy and remain optimistic afterward, a calm partially born in youth, when Winer's hemophilia caused numerous hospitalizations, familiarizing him with both medicine and empathy.

Winer is famous among his colleagues for encyclopedic breast cancer knowledge. He knows the science. He knows the disease. He knows the patients. Many a clinical trial started because Winer connected new science with patient needs. He has become expert at incorporating new therapies, such as Herceptin, into old treatment regimens, and at devising smart combinations of treatments from the crowded arsenal of cancer therapy.

Much of his reputation rests on the clinical trials he has overseen. When these studies come out, usually in agenda-setting medical journals, Winer's name is often at the end of a long list of authors, meaning he constructed the trial's intellectual framework, while his team handled the basics.

Winer will be last author on the paper documenting Adriana's trial.

The results

Six days after the surgery, Adriana sits in a Dana-Farber exam room. Her father, Adrian Jenkins, stares out the window. Her new husband, David Halligan, rocks silently in a chair. The surgery is over, the breast examined, and now, four months after starting this trial, Adriana will get answers.

Dr. Jennifer Ligibel, one of her physicians, walks in. This is the moment. Adriana will learn whether the drug worked, whether the cancer is gone, whether she can safely dream once again of a long life in a quiet town with Dave. She has waited months. She looks up.

Ligibel says Adriana's lymph nodes were clean. Only a few cancer cells were found scattered throughout the breast. In July, the cancer was a thick, mushrooming tumor. By the October surgery, when the breast was removed, it had shrunk to almost nothing. Herceptin worked.

''Absolutely great,'' says Ligibel, breaking into a wide smile.

The news seems spectacular. Only a few cancer cells left. It was a complete clinical response, in medical parlance. The therapy succeeded by the standards of the trial. But the announcement feels anticlimatic. It seems vague. Adriana has not yet heard what she wants to hear, that she can plan and dream without fear, that there is now much more than a 40 percent chance that she will be cancer-free five years from now.

Winer bounds in.

''I think to hope it could be better than that is completely unrealistic,'' he says.

Then Adriana asks her question: ''So one number I was hoping you could change for me is, or tell me what it could be, is this 40 percent, five years survival.''

''I think it's a lot higher, but I don't think I can honestly give you a number,'' Winer says.

He explains that the initial prognosis was based on decades of breast cancer survival data. There is no similar collection of data yet for Herceptin treatment. In fact, Adriana's trial itself will help establish that data. Winer cannot give her new numbers; any guess would be an extremely uninformed guess.

''OK,'' she says.

Winer senses her disappointment.

''I think it's better than 50-50 and I think it might be a lot better than 50-50,'' he says. ''My assumption is you're going to get through this and you're going to go on to live a long, healthy life. And I know I can't guarantee that, but in my head that's how it's gonna be.''

She stares blankly. He continues: ''It's very, very likely you're going do well ... I wish that I were in a position to say that there were a 96 percent chance that five years from now you were going to be fine.''

''OK,'' says Adriana.

''I think you're going to be fine in 20 years, so plan your life, don't give away your retirement funds,'' he says.

Adrian Jenkins interjects: ''When the treatments are all over, and you have better idea if they worked or didn't work ...''

''We will never have a better idea of how you will do,'' interrupts Winer.

''Be happy,'' he says.

''OK,'' says Adriana.

She smiles. But she is not happy. Since the first day, 40 percent, five years has become a pessimistic mantra. It has come to mean that cancer can strike anytime - as it did in her mother, who was given a year to live but was dead from lung cancer in six weeks. She wonders if Winer is hiding something.

''My greatest fear is that these results are not a true indication of how I will do in the future, hence Dr. Winer's reluctance to change my initial statistical prognosis,'' she writes in a journal. ''All I was looking for was that info to translate into a better long-term prognosis for me. And while Dr. Winer was willing to up it to 50/50, he was not definitively willing to up it any higher, which frightens me.''

It is quite possible that Herceptin plus Navelbine therapy has vanquished her cancer. And when data on the 39 other women in the trial come in, and more data on hundreds of other women in the next stage of the trial come in, Winer may have enough evidence to say to a woman that her odds have improved by some specific increment. But he cannot do so right now. So he relies on 50-50, a casual formulation meaning, basically, he cannot offer any guarantees.

She has been stoic, even cheerful, to this point. The Herceptin therapy was a breeze. She gracefully juggled it with her marriage and her job and her social life. It was her friends who cried when she first told them about her cancer. She would simply smile, and they would marvel at her fortitude.

After all, she would say, I'm taking this incredible new drug. She had hope. And now, with the results in, her heart sank. Outside she appeared hopeful. Inside, doubt metastasized.

''I hate to be so negative and always look at the glass as half-empty, but that is part of my personality,'' she wrote. It is Nov. 29 and Adriana has just finished a one-month respite from the trial with no treatments and Thanksgiving in New York and pigging out at restaurants and enjoying the new bliss of married life with a husband who doesn't care if she has only one breast.

But now it is time for Adriamycin, part of the old-style chemotherapy. And that means hair loss, fatigue, nausea, vomiting, sores, and diarrhea. It was all listed on the consent contract she signed months ago. She has been dreading it. In fact, she'd asked, only half-jokingly, if she could skip this part. The trial contract gave her the right to drop out anytime. But she never really considered it.

Dana-Farber nurse Kathryn Clarke brings in three syringes filled with a thick cherry-red syrup. Adriamycin. She hands Adriana eight antinausea pills to take all day tomorrow.

`Is that normal?'

Adriana is scheduled to receive four doses, one every other week. The drug will impair her body's ability to make white blood cells, leaving her more vulnerable to infection. So Clarke shows her how to take G-CSF, an immune system booster. Adriana must inject it into her thigh every day for eight days between Adriamycin infusions.

Clarke hooks Adriana to an IV line and the drug oozes through, into her body.

''You will lose your hair in a week,'' Clarke says.

''What about my eyebrows and eye lashes?'' Adriana asks.

''That's very individual. You might not. Eyebrows can be more resilient,'' Clarke replies.

Adriana has purchased stencils for drawing in eyebrows. And she has picked out a wig at Dana-Farber's wig shop. It is the same color as her hair, but she could not find one without bangs. A new style, she plans to tell people.

''When you wake up, there will be a ton of hair on your pillow,'' says Clarke, who has tended to hundreds of cancer patients. ''And when you shower, there will be a ton in the drain.''

The Adriamycin continues to course into her. She is quiet. Then a question.

''I feel like my heart is kind of pounding. Is that normal?'' asks Adriana.

Clarke pauses, then, ''Maybe.''

She suggests drinking extra water all day. Perhaps you're fatigued, she offers. Adriana nods. At the moment she is unconcerned.

But that will soon change.

PART 3:  A side effect takes center stage

This story ran on page A1 of the Boston Globe on 4/29/2002.
© Copyright 2002 Globe Newspaper Company.

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