Is FCR up to par?

When I was diagnosed with CLL in 2003, the FCR bandwagon (fludarabine, cyclophosphamide, rituximab) was in full swing. I came rather close to jumping on board. After all, the MD Anderson Cancer Center in Houston was reporting that 70% of previously-untreated patients who had been given FCR had achieved a complete response.

To a newly-diagnosed patient who is told that he needs treatment, this is a tempting proposition. Only later did it sink in that “complete response” is never truly complete, and that depth of response may not correlate with how long you live, or what the researchers call “overall survival.”

Indeed, the central question about CLL therapy has not been answered: Given that one has a chronic disease that might span 20 or 30 years, will you live longer if you reduce the disease as much as possible at some point, even while taking on the additional toxicities of potent therapy, which might also lead to disease resistance to future therapy?

I hope to delve into that question soon, since it bears greatly on the treatment decisions that I am facing, and that all of us face. But for now, it is enough to look at the question of clinical trials. As a new patient, I had assumed that these trials are pretty much the same, and that the bigger the name of the institution, the more reliable the results.

Today I am older and wiser.

The question of how trials are conducted goes to the heart of the usefulness of the data we have on FCR. What I am learning is that, on one side, we have respected CLL researchers such as Dr. Terry Hamblin and the CLL team from Ohio State University, who argue that randomized, controlled, phase III trials are essential. And on the other side we have MD Anderson, equally respected, which regards them as unnecessary.

As in many things CLL, the experts disagree.

The traditional approach

Dr. Hamblin's article Are We There Yet? at CLL Topics argues in favor of randomized, controlled trials, or RCTs -- which is not the method used by MD Anderson in evaluating FCR.

States Hamblin: "The only way to satisfactorily compare two treatments is by a head-to-head, randomized, controlled clinical trial of sufficient power to distinguish between the treatments. . . . RCTs like this are called phase III trials. When there is no comparison, except with what went on in the past (so called historical controls) the trials are called phase II trials. The MD Anderson Cancer Center is a great champion of phase II trials. For CLL they have done large phase II trials of fludarabine combinations. Two in particular are important: fludarabine and cyclophosphamide (FC) and FC plus rituximab (FCR). . . . because the patients weren't randomized between the various types of treatment we do not know whether they were similar groups. All these studies do is provide justification for an RCT."

In an online post entitled "Clinical trials," Dr. Hamblin wrote:

"The randomized clinical trial is an invention as important as the airplane or the computer. . . . Both patients and doctors want the disease to be cured. No matter how objective we think we are, studies have shown that we have an unconscious bias towards certain results. This is why we randomize, to take away that unconscious bias. . . .

"With some of the drug combinations that we have today we have lots of information about short term effectiveness. We know that FCR, for example, produces a very high remission rate, and those remissions are quite long, on average. But because we have not had a randomized controlled trial, only comparisons with what has happened in the past, it remains a treatment that's not always available and one that hasn't really won its spurs. We don't know for instance, whether responses occur in patients with less severe disease, but less so with the more malignant forms, or what will happen to those patients who relapse (which probably means all of them, eventually). Will they respond a second time? Will they have a better overall survival than patients treated in other ways? Will there be long-term unforeseen side effects?

"Controlled trials of FCR are now taking place in Europe and worldwide, but not in America where the treatment was invented. I certainly hope that FCR proves as good as its supporters claim, but as of now, we don't have the evidence we should have."

The MD Anderson shortcut

MDA’s Dr. Michael Keating, the father of FCR, has not commented in much detail publicly on this question, but there was some discussion of it in a feature story that ran in MDA's Conquest magazine in 2004. The story, profiling Keating and MDA's CLL research team, can be found here. Some pertinent excerpts:

"In a period of 20 years, we've gone from an attitude of trying to control the disease with simple medications to gaining a more realistic expectation of curing some patients with these combination therapies," Keating says. "Since we have an outstanding natural history database that includes every M. D. Anderson patient treated for leukemia since 1965, we've been able to track and record treatment responses and survival among these individuals."

The “cure” question raised by Keating is the subject for another debate, but focusing on the question of trials, the author of the article goes on to state:

"Because the database has enabled Keating and his colleagues to better predict how well patients will respond to therapy, they have been able to move their clinical research forward without having to conduct any randomized, comparative studies.

“Such progress is due, in large part, to the work of Susan Lerner, manager of clinical protocol administration, and her team of 11 research data coordinators. She has worked on CLL with Keating since he began his studies in 1983.”

So the difference in positions could not be more stark. Is MD Anderson right to be thinking outside the box, as it were? And should I -- or should you -- bet my body on it? To put it another way, which is more trustworthy, Sue and her team, or a RCT?

MD Anderson is in Texas, where they like to think big, and MDA is known for its aggressive and varied clinical trials. We patients owe our heartfelt thanks to those who enter trials, at MDA or elsewhere, to help pioneer new therapies. There is no doubt that research progresses faster, and gets to market sooner, if one avoids the lengthy process of phase III trials. If one can leapfrog ahead, one may stumble upon useful things sooner, but one may also make more mistakes, and the unconscious bias Dr. Hamblin talks about might enter the picture.

So, is FCR really a chemo star?

Dr. Keating and the MDA team published two articles about FCR in the Journal of Clinical Oncology last year. One dealt with chemo-naive patients and the other with relapsed patients.

Their conclusions?

For naïve patients, “FCR produced a high CR rate [70%] in previously untreated CLL. Most patients had no detectable disease on flow cytometry at the end of therapy. Time to treatment failure analysis showed that 69% of patients were projected to be failure free at 4 years (95% CI, 57% to 81%).”

For previously-treated patients, “The FCR regimen was an active and well-tolerated treatment for previously treated patients with CLL. Myelosuppression was the most common toxicity. FCR induced the highest CR rate [25%] reported in a clinical trial of previously treated patients with CLL. Furthermore, molecular remissions were achieved in a third of patients achieving CR.”

Sounds good, right?

These studies were accompanied by an editorial written by Drs. Thomas Lin, Michael Grever, and John Byrd, all of Ohio State. The full text of the editorial is available here, and I highly recommend it to anyone considering FCR or the like.

The authors have some good things to say about the potential of FCR and combination chemoimmunotherapy. But they also have some direct warnings about the MDA data and against jumping to conclusions about new therapies before they are proven (boldface mine).

“The first report by Keating et al summarizes the results of fludarabine, cyclophosphamide, and rituximab (FCR) in 224 previously untreated CLL patients. Extraordinary clinical activity was observed, with CR in 70% of patients, nodular partial response (NPR) in 15% of patients, and partial response (PR) in 15% of patients. The OR rate was 95%, though the percentage of stage I and II patients was higher than in most earlier studies. It is unclear what proportion of these early-stage patients had symptoms.”

That last sentence is telling. One wonders at the implication. Could some of the MDA results be based upon early stage patients who, it might reasonably be argued by other doctors, did not really need treatment? (And beyond this, what are the results by disease profile --mutated v. unmutated, 13q v. 11q? Do “Bucket A” patients respond better or longer than those in “Bucket C,” and is there a preponderance of one or the other in the study? How were patients chosen, if not by a randomized method? Was there any “unconscious bias,” as Hamblin puts it?)

The Ohio State authors go on to discuss data from MDA as compared to that on FR from trials in the Cancer and Leukemia Group B (CALGB):

"Although the M.D. Anderson report by Keating et al and the CALGB comparison study both report highly encouraging results, one must remember that these findings still represent phase II, noncomparative data. The difference in patient demographics between these two studies, with younger, earlier-stage patients being enrolled onto the M.D. Anderson study, could be a major contributing reason for the difference in complete response rates between these two studies. At the present time, PFS [progression-free survival] between these two studies seems to be similar. With respect to both trials, one only needs to recall the excitement generated by highly aggressive combination treatments in the treatment of aggressive NHL in the 1980s. Similarly distinguished institutions reported phase II results that seemed superior to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), yet a phase III study by the Southwest Oncology Group showed that all three regimens were no better than CHOP. The value of multi-institutional, prospective, randomized phase III studies should never be underestimated.”

When the risks are potentially as great as the rewards -- not all patients gambling on FCR are winners -- and one has the luxury of doing something less risky (which I fully recognize that not everyone has), I believe it is wise to wait until the proper trials are done.

Unfortunately, MDA's reputation in the patient community, and among local US oncologists, can lead people to leap without thinking. It is assumed that the data is sound. In fact, the idea that some experts would find fault with it is almost inconceivable. But to err is human, and removing the human component from pivotal studies such as FCR is not only wise, it can also be a matter of life and death for patients.

When leaving medicine is the best medicine

Why does a doctor hang up her stethoscope and quit?

I don’t mean a doctor who reaches their 60s or 70s and wants to retire. I mean a doctor in her 30s, who not long ago spent countless hours and uncountable sums of money learning her craft. One with a long and potentially bright career ahead.

This question is on my mind because my hem/onc has decided to quit her practice as of the end of May. She doesn’t exactly say why in her letter to her patients, but her office staff provides a little more information: She wants to “go in a new direction in her life.” She “may do some traveling.”

“Doing some traveling” is sometimes a catchphrase for “finding yourself.” I never got the impression that my doctor -- we'll call her Dr. Chopin -- was particularly unhappy with her work. Not that we discussed her situation too much when I visited. She was usually focused on palpating my lymph nodes, knocking on my rib cage to check the liver, and having me breathe deeply so she could go in search of my spleen.

“I can feel a spleen tip,” she would say more often than not. Sometimes we would discuss treatment options, and we once had a long discussion of what we CLL patients talk about all the time: If I use therapy X, am I burning bridges, so how do I control the disease incrementally, as it were. At the end she termed this an “esoteric” discussion, which surprised me, because it was composed of the down-to-earth considerations that patients deal with.

But I liked her general manner, which was businesslike in an easygoing, friendly sort of way. She hid nothing from us (for Marilyn was always there with me) and we felt comfortable being honest with her. If we disagreed about a treatment, we agreed to disagree. I have a feeling that, had she been our neighbor and not our doctor, we might have been gotten along pretty well.

She did let slip an occasional frustration. Once she complained about a health insurance company reviewing her and finding that she had “prescribed too much.” As I recall, she said, “Either the patient needs the drug or they don’t.” Another time she spent much of our appointment talking about the frustrations of dealing with some patients, probably the ones we had seen as we passed by the open door of the examination room next to us. They looked frozen, blank, in shock. There was only so much a doctor can do, Dr. Chopin told us. A doctor cannot make happen what nature has decided cannot happen. Another time, perhaps a year ago, when she may have started entertaining thoughts of leaving her profession, she mentioned that she had seen a movie she liked called “What the BLEEP Do We Know?” It’s a New Agey picture about the meaning of life, and Dr. Chopin declaimed briefly about life's mysteries. Most recently, our always-busy doctor pointed out that she had done the unheard of on a Saturday -- slept in until 11 a.m.

In her bedside manner, Dr. Chopin was not the touchy-feely type. But perhaps she was, inside, and just wasn’t able to let it out -- until now. There must be great frustrations as well as great rewards in hematology/oncology. One saves lives, and one also sees them lost. Dr. Chopin had a lot of breast cancer patients, women her own age, some of whom met their ends well before their time.

Perhaps this left an impression of life’s shortness, and perhaps being in the trenches for six years or so left my doctor with the feeling that there was something else she could be doing, something less consuming and more personally fulfilling. (I do know she is not married and does not have family obligations, which can sometimes lead to career changes and reassessments.)

I cannot really complain -- well, yes I can, because I know it won’t be easy to find a doctor with whom I will get along as well -- but I once did something similar. I gave up a promising journalism career in my 30s when it became apparent that I was going to end up as an editor for the rest of my life. Reporters are a dime a dozen but editors are hard to come by. Still, I knew I had the soul of a writer. Writers act and editors largely react (and being city editor of a newspaper is like herding cats of varying levels of competence.) I remember looking down the long road one day, wondering how it would end. It would have ended in a position of some importance at a newspaper we’ve all heard of, and this would have impressed my family and friends. But my heart sank whenever I thought of it.

Dr. Chopin was just named a “Top Doctor” by Phoenix magazine, an annual event in which doctors vote for their best colleagues. So I suppose it can be argued that she is quitting at the top of her game. I hope we are losing her because her heart brightens at the thought of doing something else, and not because the grind of her work is making her want to scream and run away.

I will miss the sound of her clompy black shoes as she approaches the examination room and pulls my file from the plastic holder on the outside of the door. That task will fall to someone else now. I wish Dr. Chopin luck, and I wish it for myself, too.

P.S.

There was a hilarious abstract on PubMed from Harvard Medical School called "Leaving medicine: the consequences of physician dissatisfaction." The conclusion? "Our findings demonstrate that dissatisfied physicians were 2 to 3 times more likely to leave medicine than satisfied physicians." I wonder how much money it took to figure that one out.

Here they come . . .

Sometimes, with my warped sense of humor, I see the various drugs used to treat CLL parade before me in a rather grotesque and unsettling beauty pageant. I sit as the judge, flanked by my white-coated medical advisers.

There’s Miss Rituxan, comely and alluring, though some say she’s a bit mousey. Too bad her solo talent is a little too limited. But she’s definitelty going to be one of the winners; for in this pageant there will be a minimum of two and perhaps even a third, that will steal my heart with their combination of talent and beauty. Or what passes for beauty in these things.

Miss Fludarabine comes trotting out again, a contender in every pageant so far, and always an also-ran. She’s big-boned and can belt out quite a tune, but I wish she’d find one besides “You’re My Refractory Baby.” Plus, she’s covered with skin cancers. Somehow, I just can’t open my heart to her.

Her sister, Miss Pentostatin, is a little more demure, a little more petite, perhaps a little less able to hit the high notes, as well as the low notes. Somehow she is getting lost in the blur as the contestants tromp across the stage in formation singing: “This is our time, and we’re gonna make it fine!”

I can’t take my eyes off Miss Campath, or as she prefers to be called, Mistress Alemtuzumab. Not every contestant comes attired in black boots and carrying a whip. This isn’t my thing, but she does stand out. She has a certain authority, and is effective in the talent portion, but I do wonder how severely she might kick my ass.

Miss Chlorambucil has been in so many of these that she is going to appear with a Rhinestone-covered walker someday. Her baton twirling act is the best in the land, if you like baton twirling. But it’s coming back in fashion, and some of Miss Rituxan’s glow has rubbed off on her. Maybe she’s wearing her hair differently. All I can think is, “Why, Miss Chlorambucil, I never thought of you like THAT before.”

The show stealer is Miss High-Dose-Methyl-Prednisolone. The name wouldn’t even fit on the sashes that the other contestants are wearing, but Miss HDMP is a lot taller than the others, and so her sash is a great deal longer. She also has biceps as big as a tree trunk. Dig those washboard abs! No swollen spleen or nodes in there. She reminds me of those pumped-up East German female athletes of yore, and she is winking at me a lot.

Somewhere back in the crowd is that perennial contestant, Miss Cyclophosphamide. She usually blows it during the question-and-answer part, when I inquire about her views on the 17p deletion. Just talk about world peace, girl! Maybe your day will come, but don’t get your hopes up too high this time.

Tripping all over herself is Miss Vincristine. Must be the peripheral neuropathy she’s suffering. I do believe Miss Mitoxantrone is having a heart attack in the back, as we speak. Or is that Miss Doxorubicin? Hard to tell from here. They’re among that group that always gets eliminated shortly after they’re introduced. Chief among them is Miss Mini-Allo. She can puff out her chest all she wants; it ain’t going to help. Still, it’s nice to see she’s there.

I hear there may be some interesting contestants in future years. There’s a lot of buzz about Miss Humax, but she’s still learning how to walk and smile at the same time, and as much as I might want to fantasize about other contestants -- stop the show, it’s Miss Cure! -- I am left with the group that I am left with.

It’s quite a circus -- er spectacle -- er pageant. And I can’t wait for the finale. I have some white-coated advisors to consult, but I’ll let you know who wins.

Customer disservice

It happened again the other day. I heard Marilyn, down the hall, talking on the phone.

"Customer service," she said.

Then a little louder: "Customer service!"

Then screaming into the phone:

"CUSTOMER SERVICE!
CUSTOMER SERVICE!!
CUSTOMER SERVICE!!!"

Marilyn was trying to navigate one of those automated voice menus that you reach almost every time you call a credit card company or a bank or a department store. This one was voice-responsive, or so it claimed.

"Which department do you want?," the disembodied voice had asked her. "For 'customer service,' say 'customer service'. "

Which Marilyn was trying to do, and the irony of the situation was not lost on me.

Fortunately, there is a website out there run by people who have gotten fed up with having to suffer through endless menus that ask us to "say or press 1" for this and that, with the result of being navigated to even more menus, all of which become an annoying blur and raise one's blood pressure.

So, as a public service, allow me to present http://www.gethuman.com/. The site has a database of workarounds for various companies, as well as some tips on how to get through to a human being wherever you call.

And, yes, this is health-related. Stress has been shown, anecdotally at least, to raise one's lymphocyte count. High blood pressure can lead to heart attack or stroke. Think of this as a medical necessity.

The other foot

“Some memories are realities,
and are better than anything that can ever happen to one again.”
--Willa Cather, My Antonio

My CLL diagnosis has, among other things, made me aware of mortality in a way that I was not before. I used to live in one realm, the everyday, mundane world where the sun always rises. But now I also live in another, a realm in which I know that one day I will not live to see it set.

Sometimes I wonder: Is this a curse, or a blessing, or both?

My wife, Marilyn, says the body is like a ticking time bomb, that everything seems OK until it goes off. In good health, life seems endless. Death is a vague intellectual concept, not a visceral reality. It’s hardly a concern at all, really.

Perhaps we humans are hard-wired not to think about our demise; perhaps Western society, with its endless fascination for youth and progress, does not like to consider that those entertaining features will come, for every last one of us, to a screeching halt.

But when that time bomb goes off, one must live, at least on occasion, outside the comfort zone that most of us spend a lifetime building. Even with cancer we still live mostly in the mundane world, attending to our daily doings, but we are sometimes forced out of that coccoon into a fearsome new place.

This new realm is awesome, in the traditional sense of the word; we enter it with gaping jaws, dumbstruck in the presence of the mysteries of life and death. So long as we live we cannot completely know these mysteries, but in this realm we accept their palpable presence and our connection to them. Sometimes we enter this realm with a thought, or a passing emotion, or a memory, or after hearing some bad medical news. Sometimes it steals upon us like a breeze, and then passes. If you are living every day with leukemia, it is never far away.

In this realm one can sense the eternal cycle of creation, shrouded in a cloak of uncertainty, promising us just one thing for sure: the loss of the world we have known. It is the realm where our greatest fears must be faced as rites of passage. And yet, this is the place of our most profound hope: To live after, to be connected again to those we love. For lack of a better term, and to differentiate it from the everyday world, I call it the Realm of Life and Death.

When one of those bodily time bombs explodes, it can shake up the world of loved ones, too. This is especially true where the bond of love is deep, as with Marilyn and me. Now she must learn to live without taking anything for granted except that the harrowing second realm is close by.

As with many cancer patients, my diagnosis came like a tornado, picking up everything in its path. In the beginning, both of our energies were sucked into the dark cloud, and our focus become what to do, how to cope. This can become the normal state of affairs after awhile, a new reality in which the patient’s progress becomes the marker by which a family unit measures time. CLL becomes the sun around which the planets rotate.

And yet, we patients need to guard against becoming self-centered, or allowing the center of attention to drift too much toward our own needs and away from those of our loved ones. For I have come to know in the Realm of Life and Death that Marilyn, too, will one day wake and not live to see the setting sun.

This was driven home to me recently as I sat in the waiting room of a doctor’s office for more than two hours while a an emergency colonoscopy was performed on the love of my life. When it came to care, the shoe was now on the other foot, and I was reminded of what it is like for Marilyn to cope with my CLL: the anxiety, the fear, the mix of tears and prayers, the challenge of holding it together enough to think rationally in a world that has suddenly become arational.

For several days Marilyn had had severe abdominal cramping, along with a number of other nasty symptoms, which only seemed to be getting worse. The office of our primary care doctor insisted that she see the nurse practitioner, since the Great Man Himself was booked solid for two weeks. This nurse practitioner is a nice person, but her level of skill as it applies to any given condition is not unlike that which one can acquire in an hour of searching the internet.

So I fired our doctor and found another, who has an interest in gastroenterology and agreed, after hearing about the symptoms, to see Marilyn that very day. After he saw her, he scheduled a colonoscopy for the next afternoon.

And so I found myself in the waiting room, hoping that whatever it is is easily fixable, not really serious, nothing that will blindside us like my leukemia did. After a cancer diagnosis, one can never again count on all being well. The body is a time bomb, the immutable truth of the second realm awaits.

I sit in the waiting room writing these notes as the colonoscopy drags on; in the corner a TV attached to the wall lords over the array of chairs, blasting forth a fluffy talk show that entertains, and perhaps sometimes annoys, its captive audience.

I look up when there is a segment about pets who look like celebrities. People sent in pictures for this. “She thinks her dog ‘Poochie’ looks like Jack Nicholson!,” giggles the host. I watch, I smile. Some of them are pretty dead on. I sit there, one foot in the breezy, mundane realm of laughter and forgetting, one foot in the Realm of Life and Death.

Soon I am back to finding nothing to smile about, for it is in some ways harder to be the mate of the sick person than to be the sick person. The threat of loss -- of an end to everything that makes life a joy, and to be left with nothing but the memories of what was, with no prosepct of having such joy again in this life -- is more fearsome than death itself.

If I die of CLL, leaving Marilyn behind, I go from one journey to the next (perhaps), leaving her to live what could only be described as a purgatory on Earth, in which half of her is missing. It would be easier, I think, to be the one who passes on.

Out of love for her, I do not want to leave her in this condition. I remember having a nightmare once, about ten years ago, when Marilyn had another medical problem that at first appeared extremely serious: I was alone, in a spacesuit, floating eternally and aimlessly in the black space between the stars. It brought with it a gnawing feeling of despair and loneliness that I will never forget.

And so this is a powerful force in my life, to live for her, to spare her a long purgatory, to stay alive for us, and to continue to enjoy our life together. This is a drive, subconscious and unconscious and superconscious, of such significance that I have no doubt that it will help prolong my life.

But I know, perhaps, that this will only put off the inevitable. One day, one of us may go before the other. If it happens when we are old, it might be just a little easier, for the time in purgatory would be shorter, the day of reunion -- or the bliss of forgetting -- closer. If it happens sooner, it will be that much harder, bringing with it the prospect of unbearable and prolonged pain.

There was a German composer named Louis Spohr, who lived from the time of Beethoven through that of Schumann. He dearly loved his wife, Dorette, and his early works, written in the atmosphere of their completeness and love, were touched with the genius of the great composers. At Beethoven’s death, he was considered to be the next great man of music. And then, unexpectedly, his beloved mate died, and his inspiration, his very abilities, began to lessen. He recognized this and wrote about it in his autobiography. Here was a man who, in the flower of love, made music; without it, he could do no more than assemble notes.

Not that this is true for everyone. Beethoven never married and wrote great music to the end. But for some souls, who thrive on love, the death of a mate is the same as removing the cosmic feeding tube, the very nourishment of life.

I wondered today, holding Marilyn’s hand in the waiting room as she nervously awaited her colonoscopy, what was my lesson in this life? There are those who believe in reincarnation, and who posit that we are sent back to life to learn what we failed to learn before. Accepting this as a fact (for the moment, at least), what lesson did the powers-that-be want to teach me?

This has always mystified me, for while I have learned lessons about this and that, I never saw an overarching theme.

Until today, tears welling up, I realized: To know what love is.

I have come to know it by its absence, when I was very young and my parents broke up at exactly the wrong time in my life. By abandonment and fear and loneliness I have missed love profoundly. As an adult, I have come to know it by its fullness, by its tenderness and acceptance and by its remarkable depth.

Marilyn and I used to joke that we would both die together, sometime in our eighties, in a car accident. It was our way of not thinking about life without the other, of accepting that our journey is, from here on out, made together.

But what if there is no accident? What if one of us does die first? Marilyn recently said she sees no purpose in dwelling on the matter, nothing to be gained from it. I think she is right.

It is enough to wake each day and put one foot in front of the other, hand in hand. And from the vantage point of the Realm of Life and Death, to appreciate the beauty of the act, the faith it represents, and the joy it sustains.

Epilogue: We were granted a reprieve. The colonoscopy turned out OK, and showed nothing cancerous or life-threatening.

The photo above dates from ten years ago, the year I had a blood test that showed an elevated white count, and which I now suspect was the beginning of my CLL. The time bomb was going off, quietly.