Doctor David's Blog

Music Is Medicine

noreply@blogger.com (Doctor David) — Wed, 20 Mar 2013 02:58:00 +0000

No, the title is not a cliche. It's the name of a fabulous organization founded by the daughters of one of my colleagues here at Johns Hopkins. Leora and Ariella are musicians themselves, and they firmly believe that music can truly help in the healing process. Founded when the girls were still teenagers, Music is Medicine is now an organization with national reach. Quite a feat for two sisters from Baltimore.

Last year, I wrote about a visit one of my patients had from Drew Seeley, her favorite singer. He wrote her a song, and I'll never forget the look on her face when he showed up in her hospital room to sing it for her.

Yesterday, lightning struck twice, when my patient, Bo, received a visit from Savannah Outen, who flew to Baltimore to serenade him with a song she wrote just for him.

Bo is a musician himself. In fact, I've seen him play at a fundraiser to help raise money to cover some of his medical costs.

So after Savannah played, Bo picked up the guitar, and in a truly priceless moment, played for her as she sang his requests. Her version of Landslide (performed here by Fleetwood Mac and here by Smashing Pumpkins) was absolutely beautiful. Moments like this, unscripted and real, remind me of all that is good in people.

I was there to hear the music, but Bo and his family had a surprise for me, too. A framed picture of me and Bo... in one of my... uh... better moments in clinic. Yes, that's me, hard at work curing cancer!

The song Savannah wrote and sang for Bo, "Brave and True," will be available soon on iTunes. If you can't wait that long, check out this song to hear what a beautiful voice she has.

Related Posts:
Music Can Heal
Fishing, and the Kindness of Strangers
A Musical Wish

The Power of Social Media

noreply@blogger.com (Doctor David) — Thu, 14 Mar 2013 04:17:00 +0000

In the past, I've discussed the financial challenges facing those of us who conduct research on rare diseases and the important role private foundations play in facilitating our work. What I haven't mentioned before is the role social media can play in linking researchers with foundations.

As some of you may know, I'm on Twitter. Well... sort of. I've been on Twitter recently about as much as I've been posting on my blog.

But through Twitter, I found the Rally Foundation. Honestly, I'm not sure I would have found them otherwise. I'm sure glad I did, though. They're a fabulous organization. Founded by Dean Crowe, they have raised a ton of money to support childhood cancer research, and they have supported projects at 35 cancer centers across the country. I'm honored to be on their medical advisory board.

And today I was thrilled to learn that they are going to fund a new project in my lab.

We have been studying a gene called WT1, which is turned on in a large number of sarcomas, including many cases of Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma. The role of WT1 in childhood cancer is unclear. We have a theory -- that WT1 helps tumors to coax blood vessels into supporting their growth. Money from Rally Foundation will allow us to test this theory, and to begin the process of identifying drugs that will block the activity of WT1. Our hope is that, since WT1 is turned off in almost all noncancer cells in growing children, a drug that targets WT1 will be an effective treatment for childhood cancers with very few side effects.

We're obviously a long way from developing such a drug, but with the help of Rally Foundation, we're a step closer today than we were yesterday.

And every journey begins with a single step.

Welcome Back!

noreply@blogger.com (Doctor David) — Sat, 09 Mar 2013 17:27:00 +0000

It's a warm, sunny day today. Spring is finally here, from the looks of things. That means it's time for a new beginning.

On my way home from work last night, I stopped for a drink with an old friend of mine. When I say old... I've known this friend since we were kids. I can't remember a time when I didn't know him. We were joined by two of his other friends, who I was meeting for the first time. When I first meet people, and they ask what I do, my answer evokes either a blank look, a look of pity, or a lot of questions.

Thankfully, this time I got questions.

The two most common questions I'm asked are how I ended up doing what I do, and what is the most rewarding part of my job. I'd like to share my answers here, as a part of my new beginning.

How did I end up as a pediatric oncologist? I wasn't one of those kids who knew at age 5 he wanted to be a doctor. In fact, I went to college hoping to be a research scientist. It was only after my sophomore year that my father suggested to me that if I wanted to do medical research, a medical degree might be helpful. So I started medical school in the Medical Scientist Training Program, on a track to get both an MD and a PhD. Thankfully, just seven years later, I graduated with both degrees, ready to take the next steps.

Why oncology? I was attracted to the science. Understanding how cells work fascinated me, and when I realized that cancer is a perversion of the normal processes of cell biology, I knew what I wanted to study.

Why pediatrics? That's even easier. I love kids. I love their undying optimism, their boundless enthusiasm for life, they neverending need to explore the world around them, and their seemingly limitless ability to love those around them.

The choice to become a pediatric oncologist turned out to be pretty easy for me.

Source

What is the most rewarding part of my job? That's pretty easy, too. Earlier this week, I received an email from an old patient. He wrote to tell me that it was the 15th anniversary of the day we met and I told him he had cancer. He has now lived more time post-diagnosis than pre, and felt moved to tell me how much he loved his life and how happy he was to have met me.

I received a similar message two years ago. An old patient wrote to me on her birthday. She told me she had recently been researching her diagnosis... and realized that someone with her type of leukemia, who had the chromosome mutations that her leukemia had, ought to have died. Not only was she celebrating another birthday, but she was preparing for her wedding, and she wrote to thank me for taking such good care of her.

How could I ever have considered any other career?

It's spring. Time for new beginnings. Time to renew my efforts in the lab, so that even more kids will be able to look back on the day they were diagnosed and be thankful for the modern treatments, born of an intense research effort, that have erased the day when a childhood cancer diagnosis was a death sentence.

Related Posts:

Who am I, and why am I here?

Childhood Cancer Awareness Month

noreply@blogger.com (Doctor David) — Fri, 07 Sep 2012 02:54:00 +0000

September is Childhood Cancer Awareness Month. If you are a regular reader of my blog (even if I'm not a regular writer), you are already aware of childhood cancer. But perhaps you didn't know that cancer is the Number 1 disease killer of children. The only more frequent cause of death in childhood is trauma. Or perhaps you didn't know that 10,400 children will be diagnosed with cancer this year in the US, but that many women will be diagnosed with breast cancer every 2 weeks. This might be why a paltry 4% of the National Cancer Institute's annual budget goes to pediatric cancer research.

So now you're aware.

But here's a more important thing to be aware of: pediatric cancer is weak; although it can kill the body, it can't kill the spirit of childhood. Don't believe me? Check out the spirit of the kids I take care of every day.

A Challenge for Personalized Medicine

noreply@blogger.com (Doctor David) — Fri, 09 Mar 2012 04:43:00 +0000

Personalized medicine is the new Holy Grail of cancer therapy. The drugs we currently use are stupid. They don't actually target cancer cells, they target rapidly dividing cells. Cancer cells divide rapidly, which is why chemotherapy works, but plenty of other cells in our bodies divide rapidly, and that is why chemotherapy causes so many side effects.

Not only that, but not every tumor of the same type responds similarly to the same chemotherapy. For breast cancer, some tumors respond well to cyclophosphamide and doxorubicin, but others do not.

Cancer is, at its root, a genetic disease... meaning that changes in the genes within a cell cause it to transform from normal to cancer. A lot of recent work has gone into identifying the specific mutations that lead to a particular tumor type, and using this information to gauge risk and make treatment decisions.

A by-product of this work has been the development of so-called targeted therapies... drugs that interfere with the abnormal function of a mutated enzyme, for example. Because these drugs act only in cells that have that particular mutation, which presumably only happens in tumor cells, they are thought to be more specific and less prone to side effects. The ultimate goal, then, of personalize cancer medicine would be to identify mutations in an individual's tumor and prescribe a regimen of targeted therapies that are specific for that tumor. Not for the type of tumor... for the individual tumor.

An article in today's issue of the New England Journal of Medicine makes it clear that this approach is going to be more difficult than previously believed.

Most work aimed at identifying mutations in a specific tumor is based on a single biopsy of the tumor, the idea being that the important mutations will be present in every cell in the tumor. Today's article addressed this issue directly by comparing the mutations found in multiple different biopsies from the same tumor. What they found raises serious concerns. Only about 1/3 of the mutations this group identified were present in every biopsy specimen from the same tumor. The other 2/3 were found in only a subset of the biopsies.

At one level, this is not news. Cancer scientists have been aware for years that tumors are heterogeneous... that is, not all of the cells are the same. It stands to reason, then, that not every cell will have all of the mutations. That there will be some cells with fewer mutations, and some with more. And today's article does suggest that some mutations, probably the ones important for the original development of the tumor, are found throughout the mass. However, if only a single biopsy is performed and used as the basis for making treatment decisions, most of the identified mutations will NOT be common throughout the tumor.

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It's not the end of the world, but it does mean that developing and testing this kind of treatment approach is going to be a lot messier than people have previously believed.

Related Posts:

A Smarter War on Cancer
Is the Medical Community Complicit?
Genomic Medicine -- The Hope and The Hype

Music Can Heal

noreply@blogger.com (Doctor David) — Tue, 06 Mar 2012 20:23:00 +0000

Well, maybe music can't cure cancer, but it can certainly heal the spirit.

Drew Seeley released a new song today that he wrote for my patient.

Watch the video here.

If you buy the song on iTunes, the proceeds go to support childhood cancer research. Even if you don't buy the song, watch the video and enjoy the bliss on Brooke's face when Drew came to sing for her.

Priceless.

This is not a drill!

noreply@blogger.com (Doctor David) — Thu, 16 Feb 2012 04:34:00 +0000

Today was the day.

I recently wrote about chemotherapy shortages. They've been in the news more and more over the past 12 months. But until today, at least in my practice, they were worries.

But now the drug in short supply is methotrexate.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Cancer is the most common cause of death (other than trauma) in children. Upwards of 80% of children with ALL are cured with modern treatment regimens.

But I don't know how to cure ALL without methotrexate.

Or osteosarcoma.

Or lymphoma.

There are several companies that supply methotrexate in the US, but all are experiencing production or distribution delays or suspensions. The net result? We had a meeting today to figure out if we have enough methotrexate to treat our current patients. And, if we have a shortfall, to figure out who gets treated... and who doesn't.

The good news is we found a few vials we didn't know about yesterday, and for at least the next 2 weeks, all current patients can get treated on schedule. But, if we don't get another shipment in 2 weeks, or if an adult-sized patient is diagnosed with Burkitt's lymphoma presents to the hospital tomorrow? We won't have enough drug.

And someone won't get treated.

I have already discussed the many reasons for drug shortages. The list of drugs in short supply is mind-bogglingly long. But we can work around a lack of Zofran. We can find alternatives for Gentamicin.

But I can't cure ALL without methotrexate.

What's Sauce for the Goose May Not Be Sauce for the Gander

noreply@blogger.com (Doctor David) — Thu, 26 Jan 2012 02:36:00 +0000

Avastin has been in the news a lot lately, and most of the press has been negative. In November, the FDA revoked its approval of Avastin to treat newly diagnosed metastatic breast cancer. Then, in December, Genentech, who manufactures Avastin, announced it would not seek FDA approval for the treatment of ovarian cancer, based on studies showing an improvement in progression-free survival but not overall survival. Of course, whether Avastin helps women with ovarian cancer remains a controversial question, depending how you value progression-free survival. Compare this report with this one, for example.

In tomorrow's New England Journal of Medicine, there are two reports of clinical trials evaluating Avastin for patients with newly diagnosed HER2-negative breast cancer. In both this study and this one, women with newly diagnosed breast cancer were given chemotherapy with or without Avastin. The women with HER2-negative tumors had a higher rate of "pathological complete response" if they received Avastin. "Pathologic complete response" means that when it was time for surgery, not living tumor could be found. Women with a "pathologic complete response" tend to live longer than women who do not respond as well.

What does all this mean? Will these studies "reignite the debate" about Avastin in breast cancer? I guess that depends on who is doing the debating. I think the role of Avastin in breast cancer, indeed the role of Avastin in treating any cancer, remains unclear. In the end, I believe it will be shown that Avastin helps some cancer patients and not others, and it will all depend on the biology of each tumor type. Clearly, not all breast cancer is the same, and breast cancer is not the same as ovarian cancer, let alone osteosarcoma or lymphoma. Today's studies simply reinforce the fallacy of extrapolating from one tumor type to another. A drug may be very helpful for one type of cancer, and useless for another.

That's why we do clinical trials like this one, sponsored by St. Jude Children's Research Hospital, in which we are participating, trying to see if Avastin helps osteosarcoma patients.

These studies do raise another important point, which I will discuss very soon. These studies relied on a "surrogate end point." That is, the studies were designed to see an effect on "pathologic complete response," but only because that is thought to correspond with improved overall survival. Only time will tell whether the women who received Avastin do actually live longer.

More to come...

Related Posts:
My name is FDA, and I approve of this message
Yes, we have no...Zofran?
Access to Experimental Drugs for Dying Patients

Yes, we have no...Zofran?

noreply@blogger.com (Doctor David) — Mon, 23 Jan 2012 02:47:00 +0000

Photo Credit

The issue of chemotherapy drug shortages has made the news a lot over the past 6 months or so, including an OpEd piece in the New York Times last August that pointed out that the situation is so bad that, in effect, cancer care is being rationed in the US.

How did this happen?

Well, the situation is quite complex, but much of what is going on was summarized beautifully by my colleague Michelle Hudspeth, Director of Pediatric Hematology/Oncology at Medical University of South Carolina (and graduate of our residency and fellowship programs), when she testified before Congress (her testimony is here). Briefly, the problem can be traced, in part, to a rule by The Centers for Medicare and Medicaid Services (CMS) called the ASP + 6 Rule. This rule limits what a private oncologist can charge for a chemotherapy drug to the Average Sale Price plus 6%.

Why does that matter? An article by the Director of the National Library of Medicine, and one in the New England Journal of Medicine, outlines the financial issues. Because so many of the older chemotherapy drugs are available as generics and are consequently very inexpensive. Consider the case of carboplatin. A vial of carboplatin once sold for $125, but recently the cost has fallen to $3.50. Add 6% to that, and you certainly don't recoup the cost of administering the drug in your office. Similarly, paclitaxel costs $312 per vial, while Abraxane (albumin-bound paclitaxel) costs $5,824 (all cost data come from this article in the New England Journal of Medicine). There is almost no financial incentive to pharmaceutical companies to make generic chemotherapy drugs, nor is there a financial incentive to private oncology practices to use generics.

But this is just part of the problem. There is currently a nationwide shortage of Doxil (liposomal doxorubicin), which is not a generic. Why? Through industry consolidation, there are fewer and fewer plants that manufacture these drugs, so when something happens at even a single plant, the entire market is affected. Quality control issues at the only plant in the world that makes Doxil shut the plant down and with it, all drug production.

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So, it seems that industry consolidation, downward pressure on pricing of generics, as well as contamination, other quality control problems, and shortages of raw materials have conspired to create a perfect storm.

The consequences of these shortages go beyond just drug availability. As the New York Times article discussed, and Dr. Hudspeth mentioned, medication errors are increasing as oncologists are forced to use less familiar drugs. Research is affected, too. This article, published in the scientific journal Nature in October, discusses the effect of drug shortages on clinical trial enrollment. Closer to home, the clinical trial I am running looking at Doxil and temsirolimus for sarcoma patients is on hold because Doxil is unavailable. We haven't enrolled a new patient in months, and there is no end to the shortage in sight.

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The shortages are not limited to chemotherapy drugs (which, of course, is evidence that the problem is not due to the inability of oncologists to make a profit giving drugs to patients). Drugs for ADHD, the components for iv nutrition, anesthetics, and many others are affected. In fact, on Friday I was told our hospital has only a 5 day supply of Zofran, the mainstay anti-nausea drug used for patients receiving chemotherapy.

I sure hope they get more. I'm not looking forward to giving chemotherapy without it.

Related Posts:
My Name is FDA, and I Approve of this Message
A Smarter War on Cancer
When Translational Research Really Translates

Entering the Fray

noreply@blogger.com (Doctor David) — Fri, 13 Jan 2012 23:38:00 +0000

The vast majority of biomedical research conducted in the United States is funded by taxpayers through grants distributed by the National Institutes of Health. This includes investigator-initiated laboratory research (the work we do in our labs) as well as clinical trials, both large and small (NIH is a large supporter, for example, of the Children's Oncology Group). In the not-too-distant past, the results of all of this research were published in scientific journals which were available to anyone who could gain entrance to a medical library. With the rise of the internet, journals began publishing online, and charging a fee for viewing these articles on their websites. Those of us who work at academic centers generally have free access to most (but not all) of these websites because our universities buy institutional subscriptions. Others, including people who work at smaller centers and the general public, have less (or no) access to this work.

All of this changed in 2008, when the NIH instituted a Public Access Policy that stated, in brief, that results of research funded by the NIH had to be made freely available to the general public. Along with NIH's Public Access Policy came the advent of the Public Library of Science, a non-profit organization co-founded by Michael Eisen, a professor at UC Berkley (and blogger), dedicated to open access to scientific research. I have published in one of their journals, PLoS ONE. I am a strong supporter of open access to the results of research, mine and everyone else's.

This concept of free access to taxpayer-funded research is under attack by a bill introduced into the House of Representatives last month, the Research Works Act. In essence, this bill would forbid the NIH to require that its grantees provide copies of their papers to the National Library of Medicine for online, open access. There are innumerable reasons to oppose this bill, and Dr. Eisen discussed them far more eloquently than I ever could in an Op-Ed piece published in the New York Times.

If you agree that the results of research paid for by your tax dollars should be freely available, please contact your congressperson and express your opposition to the Research Works Act. As the PLoS journals have demonstrated, high quality research can be published online and made freely available to all, and the research enterprise will flourish because of this, not suffer.

"We need a better test"... or do we?

noreply@blogger.com (Doctor David) — Tue, 10 Jan 2012 19:26:00 +0000

A study, published online January 6 in the Journal of the National Cancer Institute, claims to show that screening men 55 years old or older for prostate cancer does not significantly decrease mortality from the disease.

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This study made headlines, in large part because it runs contrary to conventional wisdom -- that cancer screening tests, by detecting the disease at an early stage, save lives. A number of things struck me about this study and the way it was reported.

This is one of several relatively recent studies that has called into question the premise behind cancer screening tests. Two years ago, I had a post about a revision of the US Preventive Services Task Force's position on Pap smears and mammograms. In that post, I talked more about how screening tests might be applied to particular patient populations. But cervical cancer and breast cancer are very different from prostate cancer. Women rarely die WITH breast cancer... they die OF breast cancer. In contrast, many men die WITH prostate cancer, but not because they had prostate cancer. This is a key difference, and strongly influences thoughts about screening tests. KevinMD did a great job addressing this issue, highlighting the idea that screening tests are not without their costs.

This episode also demonstrates that it is important to read the whole article, not just the headline. (Reading the original research is best, but only if you know how to interpret it appropriately). The Washington Post's headline, for example, reads, "Routine prostate cancer testing does not save lives." Only if you read deep into the article does it become clear that one group of men was screened by the study doctors with PSA blood tests and digital rectal exams, while the other group of men were cared for by their regular doctors. Of course, the regular doctors were allowed to do PSA tests and digital rectal exams, too. But those data were not recorded, making it challenging to know how different the screening of the two groups really was. This is important, because the "screened" group had a higher rate of cancer than the "unscreened" group, but no difference in the rate of death from prostate cancer.

How can that be?

The answer may come from pediatric oncology. Neuroblastoma, the most common solid tumor (other than brain cancer) in children, can be detected by a simple urine test. Since neuroblastoma primarily strikes kids less than 3 years old, a population of children who see their pediatricians quite frequently, it seems sensible to do a urine screening test for neuroblastoma as part of routine well child care. In fact, that was the routine in Japan for many years. In the beginning of this century, though, two large studies showed that screening for neuroblastoma increased the rate of diagnosis, but did not change the death rate. On the basis of those two studies, Japan no longer screens children for neuroblastoma.

How can a screening program increase detection but not decrease the death rate, especially if there are effective treatments available?

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In the case of neuroblastoma, we believe the answer lies in the biology of the tumor. Some tumors are very aggressive, grow rapidly, and kill a high proportion of patients, while others are more slow growing and can be cured pretty easily, often with surgery alone. If screening detects more of the low grade tumors, but the high grade tumors end up being detected because they cause symptoms, then screening programs won't change the rate of detection of the aggressive tumors... the ones that cause most of the deaths.

If this same biological principle applies to prostate cancer, the findings of the screening trial make sense. Which brings me to my last point: at the end of the article in the Post, Dr. Jonathan W. Simons was quoted as saying, "We need a better test than PSA." That may be true, but it needs to be better not because it can detect prostate cancer even earlier, but because it can detect aggressive prostate cancer earlier. Screening for that may change death rates. Maybe we don't need a "better" test... we need a different test.

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More What You'd Call "Guidelines" than Actual Rules
Is the Medical Community Complicit?
HPV, STI's, and Teenaged Girls: What does 1 in 4 mean, and what can be done?

My name is FDA, and I approve of this message

noreply@blogger.com (Doctor David) — Thu, 29 Dec 2011 18:10:00 +0000

As the new year begins and election season accelerates, we will be hearing phrases like that more and more. In the context of a political commercial, it is often pretty clear what is being approved and the basis for the approval.

But what about new drugs? How does the FDA decide whether or not to approve a new cancer drug, and what exactly is being approved? In the era of targeted therapies, which are incredibly expensive to develop, and therefore incredibly expensive for patients and their insurance companies, these are crucial questions.

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I think the case of bevacizumab (Avastin) is a perfect example. Avastin was the first of a new class of drugs that treats cancer not by directly killing tumor cells, but instead by attacking the blood vessels that feed a growing tumor, essentially attempting to starve the tumor of oxygen and nutrients. Avastin was approved by the FDA for the treatment of renal cell carcinoma (kidney cancer) based on its ability to prolong the life of patients with this disease. Avastin was given a provisional FDA approval to treat metastatic breast cancer, based on its ability to delay progression of the tumor. It was big news last month, however, when further studies failed to show an improvement in "overall survival" (meaning how long the patient lives from the time she begins treatment) in women with metastatic breast cancer, and the FDA withdrew its approval.

Avastin is in the news again today. In today's issue of the New England Journal of Medicine there are two reports (links here and here) showing that Avastin prolongs Progression-free Survival (PFS; the time from beginning treatment until the tumor gets worse) but not Overall Survival (OS) in women with newly diagnosed ovarian cancer. Based on these results, Genentech, the manufacturer of Avastin, declared that they will not seek approval from the FDA to treat women with ovarian cancer using Avastin, because they know approval will not be granted without an effect on OS.

Overall survival, an extension of life expectancy, is clearly the ideal for a cancer drug. I certainly treat all of my patients with drugs that I expect will allow them to live longer (hopefully to cure, but even in patients who are not likely to be cured, I would like them to live longer). But is that the only goal of cancer treatment? Perhaps there is a benefit to an increase in PFS. If I told you that your child was going to die in 10 months no matter what I did, but that there is a treatment that will keep his tumor from growing for 7 of those months, and that during those 7 months he would develop no new tumor-related symptoms, would you want him treated with it? Probably that would depend on the side effects the drug causes, right? If the drug was very toxic, you might decide that treatment isn't worth it, but if all that happened to your child was high blood pressure that was easily controlled by medication, you might say yes.

The primary result the FDA wants to see before approving a new cancer drug is an improvement in OS. Although FDA guidelines do allow for approval based on an improvement in PFS, the degree of improvement required for PFS-based approval is much more strict than what is required for OS-based approval. I believe that there may be cases where even a modest change in PFS would be a more appropriate standard. Demonstrating a change in OS requires large studies enrolling many patients. For rare diseases, studies like this may not be feasible. In that circumstance, FDA approval based on a change in OS may be an unattainable standard, and PFS may be a reasonable alternative.

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Some may ask whether lowering the standard will change the entire drug approval process, because PFS is an easier standard to reach. Concerns could be raised that no pharmaceutical company will ever try to reach the OS standard (which is more expensive and more time-consuming) if PFS is sufficient to be granted FDA approval, and thus we will never know which, if any, drugs prolong patient survival.

These are valid concerns, but I believe they can be addressed. Perhaps a two-tiered approval process, with a lower tier for drugs that affect PFS and a higher tier for drugs that affect OS, with financial incentives for reaching the OS standard, would be a solution. I'm sure there are others. But the status quo gives the impression that if a drug doesn't change total survival time, it has no benefit. And I'm quite sure that's not true.

Related Posts:
Access to experimental drugs for dying patients
Medicine from the Sea
I Can Buy it Over the Counter: FDA Followup

Managing Pain

noreply@blogger.com (Doctor David) — Sat, 24 Dec 2011 17:01:00 +0000

Pain.

Little scares a new oncology patient as much as the idea of pain. Unfortunately, pain permeates my practice. Often, pain is the initial symptom that leads to a new cancer diagnosis. Cancer patients undergo frequent painful procedures -- biopsies, bone marrow aspirates, surgeries ... even a simple blood draw involves a small amount of pain. Because of this, managing pain is something I have some experience doing.

So I was surprised when I read this article in The Washington Post this morning and discovered that "some [pain doctors] began decrying the increasingly widespread use of opioids and questioned whether the drugs worked." Really? There are pain doctors who question whether opiates (morphine, for example) work?

Over the years, I have seen a variety of pain management styles. From doctors who prescribe intramuscular injections of pain medications to small children recovering from surgery, through sophisticated regimens involving patient-controlled analgesia and the use of non-drug techniques designed to specifically combat different types of pain. Pain management skills vary widely, and careful use of appropriate therapies can make all the difference to a suffering child.

Unfortunately, because the drugs which are the mainstay of pain treatment, opiates, are highly addictive, their use is politicized. The article in today's Washington Post, for example, was focused on a patient advocacy group, the American Pain Foundation, which gets the lion's share of its funding from the pharmaceutical industry. Unfortunately, this creates the appearance of a conflict of interest when the group strongly advocates for the use of specific narcotic pain medications (such as OxyContin) to control chronic pain. And the appearance of a conflict of interest, whether or not the conflict exists, is sufficient to cast doubt on everything the Foundation has to say, even when what they say is spot on.

The use of narcotic pain medications is clearly expanding, and as a result, overdoses are an increasingly common cause of death in this country. That doesn't mean these drugs should not be used. They are highly effective at controlling acute, and even chronic, pain. But like all medications, they need to be used appropriately, under medical supervision, prescribed by doctors who are experienced in their use, know how they work, know what kinds of pain they help, and know the risks and limitations of their use.

The diseases I treat cause pain. One of the most common fears among cancer patients is the fear of dying in pain. The treatments I use cause pain. Some of the procedures we perform to monitor the progress of my patients cause pain. Without highly effective drugs to treat pain, I could not do my job. Rather than politicizing these drugs, we should be advocating for increased education about their proper use, about choosing the right drug for the right type of pain, and increasing research into the mechanisms of pain so that newer, more effective, safer drugs can be developed.

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Special Kids

noreply@blogger.com (Doctor David) — Sun, 26 Jun 2011 02:40:00 +0000

All of the kids I take care of are special. Is that cliche? Maybe so, but it's true. I truly have learned something from each and every one of them -- though not always what I thought I would learn.

Some kids stand out.

My first "real" patient, who was 13 at the time, and is now, at the advanced age of 27, joining the military.

The patient who got a transplant for her horrible leukemia... who was so sick going into her transplant that I said to her during her "consent conference"... "Well, if your kidneys fail during the transplant, at least your donor can give you one of his, too, and since your immune system will be his, you won't have to worry about rejection." Not only did her kidneys not fail, but she is alive, well, in remission, and sometimes takes her hormones.

Marta also stands out. Marta was a teen mother before I met her, though she was finishing her freshman year of college. That, alone, impressed me. But as I got to know Marta, first during her initial treatment, and then while we were unsuccessfully treating her relapse, I got to know a warm, caring, wonderful mother. A young woman who faced adversity with grace, never complaining about her fate. A young woman who made mature decisions, including continuing college through all of her treatment. A young woman who accepted hospice care when she needed it, but continued to do what she could to extend the time she would have with her child.

From some kids, I learn about a disease. From some kids, I learn compassion. From some kids, I learn grace. From Marta I learned how to face life, no matter what life has in store.

I'll miss her.

Another Kind of Tears

noreply@blogger.com (Doctor David) — Thu, 10 Mar 2011 03:14:00 +0000

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Tears are a fact of life in my business. Parents cry when I tell them their child has cancer. Children cry when they undergo painful procedures. We all cry when a child dies.

But sometimes the tears are tears of joy.

Jade came to my clinic for another opinion. She has a benign tumor, but it's in a bad place. As I have shared before, sometimes it isn't better to have a "benign" tumor. In order to remove Jade's tumor, she would need disfiguring surgery. She and her father were told there was no choice.

Thankfully, they were told wrong.

Even though Jade's tumor is benign, it can be treated with chemotherapy. It's a small tumor, and it's not causing her any symptoms right now. Even if we can't make it go away, if we can keep it from growing, she will be fine.

After discussing her options, I asked Jade and her father if they had any questions. Her father started crying, and then Jade did, too. They were so relieved to have non-surgical options!

Photo Credit

How nice to make someone cry tears of joy for a change.

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The Emperor's New Book

noreply@blogger.com (Doctor David) — Wed, 23 Feb 2011 04:44:00 +0000

It may not be a new book anymore, and I actually read it a few months ago, but I would like to share my thoughts on Siddhartha Mukherjee’s The Emperor of All Maladies. Dr. Mukherjee subtitled his book, “A Biography of Cancer.” Much has been made in other reviews about the significance of this subtitle, and what it means to the approach he took to his topic – the history of cancer therapy.

I am fascinated by the history of medicine. When I teach residents about current sarcoma therapy, I always teach them the history of how we got to where we are. Dr. Mukherjee took this approach to its logical extreme, beginning with the first known record of the disease in ancient Egypt all the way to the present.

The main theme coursing its way through the book is the evolution of our therapies from radical to targeted. Mukherjee starts with the 4^th century BC Persian Queen Atossa, who commanded her servant to cut her breast from her body, and traces the evolution of surgery up through Halsted’s radical mastectomies in the early part of the 20^th century and then to our current practice of lumpectomy, showing along the way how medicine is shaped by the personalities of those who set the standards of care.

Dr. Mukherjee gives chemotherapy a similar treatment, tracing the evolution of systemic therapies from the use of single chemotherapy drugs (beginning with nitrogen mustard-derivatives and anti-folates), through high dose chemotherapy with stem cell support, and back to the current vogue of molecularly targeted therapies.

Reading the novel as a oncologist who treats children, I was, of course, thrilled with the center stage given to pediatric oncology, especially the focus on childhood acute lymphoblastic leukemia as the first example of the successful use of chemotherapy to cure cancer. Given the importance cooperative groups have played in the development and dissemination of cancer therapies over the past 40 years, I was a bit disappointed at how little attention was paid to the role of these organizations in advancing cancer treatment. Reading this book, you would get the impression that most important clinical trials were run by small groups of physicians at their own hospitals. The staggering successes seen in pediatric oncology over the past 30 years have come about almost entirely as a result of pediatric oncologists working together across the country to perform the kind of trials that would otherwise be impossible.

My other problem with the book is a common problem among medical oncologists – a marginalization of the successes of pediatric oncology. In his effort to support the thesis that radical treatments (radical surgery, high dose chemotherapy…) are of little value, and that the future of cancer treatment is molecularly targeted therapies, Mukherjee substantially downplays diseases where high dose chemotherapy has been shown to make a difference. Randomized trials have demonstrated superior survival for children with neuroblastoma if they have high dose chemotherapy with stem cell support compared with standard chemotherapy. Neuroblastoma is the most common solid tumor of childhood, so this is not an insignificant finding. High dose chemotherapy clearly improves the survival of both children and adults with relapsed leukemia. Sure these diseases are not as common as breast cancer, but they serve as stark examples of how in some cases, the radical treatments Mukherjee deplores clearly improve survival.

Certainly childhood cancer is biologically distinct from the common adult tumors (breast, prostate, lung, colon), and what works for kids may not work for adults. But the paradigm pioneered by pediatric oncology – the cooperative group – is responsible for some of what Mukherjee proposes are the most important advances in adult cancer (such as the National Surgical Adjuvant Breast and Bowel Project). As I have said before, I think the medical oncology world has a lot to learn from the advances made in treating and curing cancer in children, and I wish that high profile works like this one did more to emphasize that point.

Nevertheless, I really enjoyed this book. It makes the history of medicine an easy read, and its focus on the personalities of some of the giants in our field was truly fascinating. If you have even a passing interest in oncology (and if you’re reading my blog, you must), you’ll enjoy this book.

A Smarter War on Cancer

A New Old Remedy for Nausea

Why Study Rare Diseases?

noreply@blogger.com (Doctor David) — Fri, 18 Feb 2011 03:23:00 +0000

The times they are a-changin’! When I began my career as a scientist, NIH funded 25% of the applications they received. That number is now down to less than 10%, and if there really are radical cuts in the discretionary federal budget, that number could fall even further. Many of my colleagues (including myself) are concerned that this would lead to an emphasis on funding projects directly related to common problems (heart disease, breast cancer, emphysema) at the expense of less common diseases (like childhood cancer).

An article published on my birthday by Science: Translational Medicine demonstrates the danger in cutting off funding for rare disorders.

In this study, Dr. Jaime Guevara-Aguirre and his colleagues published the results of their 22 year study of an isolated population of individuals living in a remote village in Ecuador. The 99 subjects all have Growth Hormone Receptor Deficiency, or Laron Syndrome. This is not a public health menace, even in Ecuador. This article states that there are only 250 known people with Laron Syndrome worldwide.

Photo Credit

So why study such a rare disorder? Well, interestingly, people with Laron Syndrome don’t get cancer (they also don’t get diabetes, but this is a blog about cancer, so we’ll focus on that). This interesting observation raises a really obvious question: Why not?

At first blush, there could be a very simplistic answer: IGF-1 makes your body grow. For you to grow from the size of an infant to the size of an adult, your cells have to divide many, many times. Each time a cell divides, it risks developing a mutation, and the accumulation of mutations leads to cancer. If you don’t grow any larger than a 7-year old, there are fewer cell divisions. Fewer cell divisions means fewer mutations.

But if that were the answer, people with Laron Syndrome would have a lower than average rate of cancer. That is not what was observed, however. What was observed was an almost complete lack of cancer. This must tell us something profound about how cancer develops.

It turns out that Growth Hormone Receptor Deficiency results in low circulating levels of insulin-like growth factor-1 (IGF-1; also called somatomedin C because it mediates the effects of growth hormone, or somatotrophin). IGF-1 has been in the news a lot recently because its receptor appears to be important for the growth and survival of a wide variety of tumors, making it a darling of drug developers. The fact that people with Laron Syndrome don’t get cancer suggests that IGF-1 signaling through its receptor probably plays a role in cancer development, not just the survival of cancer cells once the tumor develops. More importantly, this must be a general property of cancers, because it’s not the case that people with Laron Syndrome are protected from just one or a few types of cancer. They don’t develop cancer at all.

This sort of insight could never have come about from a focused study of a particular tumor type, nor could it have been derived from studying cells in a lab. Only because someone was interested in the biology of a rare disorder was this discovery made. I can only hope that the people in charge of the federal government’s medical research budget consider this when deciding how much research we can afford, and whether to focus on the common disorders, or whether we can let scientists study what is interesting… because we never know where the next important discovery will come from.

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David's First Book Review: The Immortal Life of Henrietta Lacks

noreply@blogger.com (Doctor David) — Tue, 21 Dec 2010 03:14:00 +0000

I've discovered reading again. Or maybe what I've done is made a conscious decision to set aside time to read. Some books I've recently read have nothing to do with cancer, like Cloud Atlas. Then there's The Immortal Life of Henrietta Lacks.

Rebecca Skloot did a marvelous job telling the story of Henrietta Lacks, a woman from Baltimore whose cervical cancer cells became the very first immortalized cell line. I think this book is a "must read" for anyone engaged in cancer research, if for no other reason than it reminds us that every cell line we work with was once a tumor growing in an individual... a person who had a family and friends, a person who suffered and probably died of cancer. Each of these people has a story, and knowing that story can inspire us to work harder to find better treatments with fewer side effects.

But aside from the human interest angle, the book is an interesting study in the evolution of medical ethics. When Mrs. Lacks was treated, in 1951, there was nothing "unethical" about taking some of the cells that were removed from her during the course of her treatment and trying to grow them in the lab. She did not give informed consent for her cells to be cultured, but the very concept was not a part of medical research at the time.

Times have changed. Just last week I was getting informed consent from a woman one of whose children was going to donate bone marrow to another. Our cancer center has a "leukemia bank," a freezer full of bone marrow removed from patients with leukemia, frozen away for future research. As I explained to her, it can be hard to tell what is abnormal about the leukemia cells if we don't have normal cells to compare them to. So we ask each normal bone marrow donor to allow us to freeze a teaspoon or so of marrow for comparison studies. In order to do this, we have to get approval from an Institutional Review Board and the donor (or the donor's guardian, in the case of a minor) has to sign a statement asserting that he or she consents to having this normal marrow stored away.

And that is just to STORE the marrow. If we want to use the marrow for research, we have to get approval from the Institutional Review Board for the research project and use the marrow anonymously. If we need clinical information about the marrow donor (or the leukemia donor), we need to either track that person down and get informed consent for the specific experiment or we have to convince the Institutional Review Board that doing so would be an undue burden (if, for example, the patient has subsequently died or has left no contact information or the study will involved hundreds of samples and the data will be used anonymously).

None of these safeguards were in place in the 1950's.

Another fascinating question raised by Ms. Skloot is the question of intellectual property and a patient's rights to his or her own tumor. Ms. Skloot contrasts Mrs. Lacks, whose family received nothing in exchange for her cells (although, to be fair, neither Johns Hopkins nor Dr. Gey, the man who cultured her cells, received any money for her cells, either.... they were distributed freely to any interested lab anywhere in the world), with Ted Slavin and John Moore. Mr. Slavin was a man with hemophilia who sold his serum because it had extremely high levels of antibody against Hepatitis B and then supplied serum to Baruch Blumberg, a virologist who discovered the link between Hepatitis B and liver cancer and created the first vaccine against Hepatitis B. Mr. Moore's spleen was removed as treatment for Hairy Cell Leukemia, and his physician grew a cell line from the spleen, which he then patented and licensed to biotechnology companies to "commercially develop." In each of these cases, something of value was taken from a patient, sometimes with their knowledge and consent, sometimes not. In each case, the material contributed to the development of the nascent biotechnology industry, eventually being used to generate profit.

I would love to hear my readers' thoughts on the ethics of these situations. After all, it seems wrong for someone to profit from cells taken from my body, but the cells are not inherently valuable... it's how they are used that is valuable. Without intellectual input from a scientist, they are just cells. But does this mean that, as the California Supreme Court ruled, I don't have any right to profits generated from tissues removed from my body?

One final note: Ms. Skloot speaks eloquently about how Mrs. Lacks was treated by Johns Hopkins (and subsequently seemingly forgotten). Just recently, the Johns Hopkins Urban Health Institute announced the Henrietta Lacks Award for Community-University Collaboration, a prize of $15,000 to a community entity that collaborates with Hopkins to work to improve the health and well-being of the residents of the City of Baltimore.

Thanks to Ms. Skloot, Van Smith, and Mike Rogers (all of whom have written about her), Henrietta Lacks will achieve some level of immortality beyond the HeLa cell.

Photo Credit

What is Life?

noreply@blogger.com (Doctor David) — Fri, 03 Dec 2010 04:47:00 +0000

Life is hard to define. Perhaps former Supreme Court Justice Potter Stewart summed it up best (though he was referring to hard-core pornography, not living organisms) when he said, "I shall not today attempt further to define [it]... and perhaps I could never succeed in intelligibly doing so. But I know it when I see it."

Erwin Schrodinger gave a series of lectures in 1943 that were published under the title "What is Life?"

NASA has an Astrobiology group that is charged with searching for evidence that there is life on other planets. Key to that mission is understanding what life is. How else would they know what to look for?

Up until today, living organisms were thought to require four elements: oxygen, carbon, hydrogen, nitrogen, sulfur, and phosphorus. A paper published today by the NASA Astrobiology group has challenged that belief. NASA scientists discovered a bacterium that can live without phosphorus, using arsenic instead.

The bacterium, designated GFAJ-1, can build the molecules of life, including DNA, proteins, and the energy molecule ATP, with either phosphorus or arsenic. This is very handy, considering the organism was found in a lake with an extraordinarily high concentration of arsenic in its water.

Up until this discovery, life forms were the stuff of science fiction novels. I've read novels about silicon-based life forms, based on the idea that silicon, being just below carbon on the periodic table, could take the place of carbon in the building blocks of life. This is actually the basis for how GFAJ-1 uses arsenic. Arsenic is just below phosphorus on the periodic table of the elements. So the bacterium just substitutes arsenic for phosphorus.

This finding has important implications for the search for life away from earth. Clearly phosphorus is not a requirement for life. Perhaps neither is carbon. Maybe not even oxygen is needed. Life can take many forms, so finding it is going to require knowing it when we see it.

Question to ponder: if ATP is the main energy molecule in a cell, and the P stands for phosphate, does GFAJ-1 have ATA instead?

You're Kidding, Right?

noreply@blogger.com (Doctor David) — Thu, 02 Dec 2010 03:58:00 +0000

(Another of David's rants about insurance companies)

I've written many times about the absurdities I've encountered dealing with insurance companies. I've had another experience that I'd like to share.

The patient came into clinic for chemotherapy. The PA examined him and heard an irregular heartbeat. Neither of us know the patient well, so we looked through his chart to see if anyone has ever noticed an irregular heartbeat before. No one had. We ordered an EKG, and it showed an abnormal rhythm. The patient has had several EKGs in the past, and this rhythm was a new finding. One possible explanation for the new abnormal rhythm would be if the patient's central line had moved a bit and was irritating the right ventricle of his heart. The best way to figure out if that could be happening is to get a chest x-ray to see where the catheter tip is.

We ordered a chest x-ray, only to learn that the patient's insurance company doesn't cover radiology procedures at Johns Hopkins. Since an abnormal heart rhythm can cause sudden death, diagnosing a cause is an emergency, so we called the insurance company for "permission" to order the x-ray.

You may think this is a "no brainer." After all, a chest x-ray is cheap, and we could discover the cause of the patient's abnormal heart rhythm and fix it relatively easily. The insurance company, however, needed to authorize the x-ray. So I was told the nurse would review the case and get back to us.

Once again, I find my judgment about a case under review by someone with a financial stake in the decision. In this case, a nurse, sitting in an office in another state, not able to see my patient, was going to decide if my decision to order a chest x-ray was justified.

No. I'm not kidding.

But if you ask, insurance companies don't make medical decisions, they make coverage decisions.

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Rare But Serious

noreply@blogger.com (Doctor David) — Wed, 29 Sep 2010 14:58:00 +0000

The patient and her parents were hardly focused on what we were saying. Not surprising, since she was still recovering from the news that the pain in her leg was not from a sports injury, but from osteosarcoma.

Kameron was a high school athlete, and now, instead of anticipating a college scholarship to play hockey, she was anticipating a year's worth of chemotherapy and a major leg surgery. She and her parents were in the office, listening (but probably not hearing) to the side effects she should expect from her upcoming chemotherapy. At the end of the conference we discussed some of the "rare but serious" side effects, like fertility loss and heart failure.

Fertility loss is something that catches people's attention. To some extent, so does heart failure. But for adolescent patients, somehow infertility feels more "real." So we talked about her possible future fertility problems much more than we talked about her heart.

Throughout her therapy, we monitored heart function with regular testing. All of the tests were reassuring. But one day, soon after her treatment was done, Kameron developed chest pain. When treatment for reflux and then for infections didn't make things better, she came to the emergency room, and that is when we discovered she was in heart failure.

These side effects, the "rare but serious" ones, are some of the hardest for us to deal with. Kameron's cancer prognosis is excellent. I am optimistic she will become a survivor. Unfortunately, she paid a huge cost to survive her cancer. When she leaves the hospital, she will be on heart medicine for the foreseeable future. She may even end up needing a heart transplant. This is not a problem that is just going to go away, and for the rest of her life, Kameron will not only be a cancer survivor, but also a heart patient.

This is what drives us to work hard in the lab for treatments that won't come at such a high price to our patients.

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How Much Time Do I Have?

noreply@blogger.com (Doctor David) — Sun, 27 Jun 2010 16:29:00 +0000

I think that is the hardest question I have ever been asked. The emotional weight that goes along with asking how many days are left in a child’s life is staggering. I have been asked this question many times during my career, and I still don’t know how to answer it.

Some doctors answer this question based on disease-specific statistics. For example, since most patients diagnosed with a brainstem glioma die within a year of diagnosis, some will tell the family of a patient who receives this diagnosis that the child has less than a year to live.

Photo Credit

Some doctors answer this question based on personal experience. It is personal experience that has led me to dread this question the most. I would like to share two of these experiences to illustrate why.

It was a Monday night. I was home having dinner with my family when I was paged by the resident covering our inpatient unit. My patient had just completed an MRI, ordered to help us determine why he had lapsed into a coma. The MRI had just been read, and the radiologist had called the resident with the result: not only had my patient’s tumor grown substantially, but it was causing an “uncal herniation” (this is when a part of the brain is compressed, often by blood or a tumor, cutting off the blood supply to vital structures and often rapidly leading to death). Since the family had already decided not to pursue further treatment of their child’s cancer, the progression was not a surprise, but I went back the hospital immediately to talk to them about the herniation, since that was a sign that their child could die as soon as that very night. The previous week, when asked how long they had left, I had estimated several weeks, so this change would come as quite a shock.

Picture Posted By Permission

When I got to the child’s room, we spoke at length about his prognosis. His parents asked me how long they would have with him. I answered honestly that I thought he would die within days, and that he could possibly die within hours. The next morning, when he was still alive, we started to arrange a discharge with hospice care. It was Friday when he was finally able to go home.

That was 52 days ago, as I type this. Since discharge, my patient has regained consciousness, resumed eating, and is considering an exercise program to regain some strength. He is on his second hospice company. My estimates of his lifespan were both way off base.

Picture Posted By Permission

Two weeks after my Monday night conversation, another patient of mine was admitted to the hospital for end of life care. After a couple of days in the hospital, his mother asked me how long he had left. I told her that I had no idea, and shared with her the story of the patient with the herniation, who I thought would die within days and who was still alive almost 3 weeks later (at that point). I told this mother that, based on my experience, the best I could do was to guess how long she had with her son. She really wanted an answer, though, so I guessed for her. I told her that her son’s lifespan could be measured in weeks. Probably not days, certainly not months or years, but weeks. He died three weeks later.

I suppose sometimes I do guess correctly.

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Yoga – Not Just for Skinny, Pretty Women Anymore?

noreply@blogger.com (Doctor David) — Wed, 16 Jun 2010 03:10:00 +0000

This post is dedicated to a close friend of mine, a budding scientist with an aversion to yoga.

The benefits of yoga for cancer patients were plastered throughout the popular press recently, in anticipation of a presentation by Dr. Karen Mustian from the University of Rochester Medical Center at this year’s meeting of the American Society for Clinical Oncology in Chicago. This study enrolled 410 cancer survivors (96% female, 75% had breast cancer) suffering from moderate or worse sleep disturbance. The participants were randomized to standard monitoring versus a 4 week yoga intervention. Participants in the yoga program had improvements in sleep quality, fatigue, and various measures of Quality of Life compared with the control arm (no intervention). The benefit was significant enough to be covered by mainstream media outlets like CNN as well as web-based media like Breastcancer.org. ASCO president Douglas Blayney, MD, stated that the results are “readily applicable” for a huge patient population.

But wait. As we scientists often ask, do the results support the conclusions?

I think the answer is a resounding “Maybe.”

There is mounting evidence that cancer survivors benefit from participating in yoga programs. Although this study is the largest thus far reported, it is certainly not the first to show a benefit to yoga. Back in 2003 a study presented at the ASCO meeting showed that participation in a yoga intervention improved the Quality of Life of women newly diagnosed with breast cancer.

But is it yoga, per se, that helps? So far none of the studies have compared participation in yoga with any other exercise program. This study, for example, published in 2001, demonstrated that a home-based walking exercise program improved fatigue and other Quality of Life measures in women being treated for breast cancer. The studies cited on this page of the American Cancer Society’s website demonstrate a benefit to using a treadmill or an outpatient wellness program involving aerobic exercise, strength training, flexibility and relaxation. So maybe it’s exercise in general, and not specifically yoga, that helps cancer survivors live better.

Are the results of the yoga study “readily applicable” to a huge patient population, as suggested by Dr. Blayney? Again, I think the answer is “Maybe.” It depends on how you define “a huge patient population.” Dr. Mustian’s study is certainly applicable to the very large number of women diagnosed with breast cancer every year, but her study involved essentially only women with breast cancer. Given the variety of ways various cancers are treated, it may be premature to conclude that because yoga helped these women, that it would make a difference for young adults being treated with intensive chemotherapy for leukemia.

So what can we conclude? I think it is safe to conclude that some degree of exercise is beneficial for cancer patients, probably regardless of where they are in the course of their therapy. But before we can state that yoga is the best form of exercise, the right study has to be performed: patients need to be randomized to various forms of exercise, and research participants need to include men as well. Perhaps for a relatively inflexible man like me, the frustration of not being able to do “downward dog” will make yoga a poor choice, while the feeling of accomplishment associated with being able to last 5 more minutes on the treadmill will make that form of exercise a much better choice. Only a well-designed experiment can tell us for sure.

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Genomic Medicine – The Hope and the Hype

noreply@blogger.com (Doctor David) — Mon, 14 Jun 2010 02:59:00 +0000

Ten years ago this month, President Clinton, along with Drs. Craig Venter and Francis Collins, announced the completion of the Human Genome Project – the complete DNA sequence of the human genome. As is typical of such announcements, there was much pomp and circumstance, as the President declared it a “day for the ages.”

Why the excitement? It was fully expected by participants in the struggle to sequence our genome that achieving this goal would rapidly lead to a new understanding of the genetics of common disease, and would yield new genomic treatments that would revolutionize the practice of medicine. In fact, Dr. Collins predicted that the genetic diagnosis of disease would be accomplished within 10 years, and treatments would begin to appear 5 years later.

This, sadly, has not happened.

So does that mean the Human Genome Project was a bust? Hardly. While medicine has not been revolutionized, basic biology has been. The complete sequence of the human genome has shed tremendous new light on a variety of ways that genes are regulated, especially by RNA, which would never have been understood without sequence information.

So why has the sequence of the human genome not revolutionized medicine? As discussed in an article from The New York Times, there are several reasons. One reason cited by The Times is that many of the sequence variations associated with common diseases are not found within genes. This raises the possibility that these sequence variations are a statistical fluke, not really associated with the disease at all… or by anything other than chance. More disconcerting, if your goal is to develop a new treatment, is that common diseases may be caused by a large number of very rare sequence variations, so that individuals with a particular disease may have very little in common with each other, and nothing amenable to a drug.

Is this result entirely a surprise? To any serious student of human genetics, the answer has to be, “Not really.”

The First Genetic Disease

After reading any article in the popular press about genomic medicine, one would get the impression that the genetics of human disease is a new field, and that before the human genome was sequenced, there was nothing known about how gene mutations cause disease. This, however, is not true. In a paper published in Science in 1949, Linus Pauling and his colleagues demonstrated that sickle cell anemia is caused by a mutant form of hemoglobin, the protein that carries oxygen in red blood cells. In 1956, Vernon Ingram and his colleagues proved that this mutation was at the 6th amino acid of the protein. This change was soon shown to be the result of a single DNA base pair change.

For more than 50 years now, physicians and scientists have understood Sickle Cell Disease in molecular detail. Nevertheless, we are still unable to explain how this molecular defect causes any of the symptoms of the disease, and we are unable to do anything about it. To this day, despite how long we have understood the molecular biology of the disease, treatment remains supportive (meaning prophylactic antibiotics, pain medicine, and transfusions) or aimed at changing the way the hemoglobin genes are controlled (using a medicine called hydroxyurea). There is no treatment available that is directly related to the genetic cause of the disease, the mutation at amino acid 6.

I think this should be a warning to those who think that the path from the molecular understanding of a disease to a treatment will be straightforward. The era of genomic medicine may be upon us, but it is probably going to be a very slow change, not an overnight revolution.

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Another Ethical Dilemma

noreply@blogger.com (Doctor David) — Fri, 21 May 2010 21:44:00 +0000

The ethics of modern medicine has always fascinated me, and Pediatric Oncology has provided me with more than my fair share of ethical issues to contemplate. I want to share today’s, and see what people think about this particular, emotionally charged, situation.

I received an email today from a colleague in another state. He trained under me, and I guess he thinks I did a good job, since he emails me for advice from time to time. He met a new patient today – a 23 year old woman with a new diagnosis of osteosarcoma. Unfortunately, she is 20 weeks pregnant.

One of the mainstays of osteosarcoma treatment is high dose methotrexate. Methotrexate is a very effective drug for terminating pregnancies, and this is where the ethical dilemma begins. The patient has a choice to continue her pregnancy or not. Except that the state in which she lives does not allow medical assistance funds to be used to terminate a pregnancy, and she has Medicaid as her sole source of health insurance. She cannot afford to pay for an abortion herself. If she chooses to continue the pregnancy, either out of necessity or out of desire to do so, giving her methotrexate will be fatal to the baby inside of her.

If the patient chooses to remain pregnant, my friend has some very difficult decisions to make: should he wait to treat her until the baby is born? This would give the tumor as much as 4 months to spread before treatment, a huge risk to the patient. Should he begin therapy early, maybe once the third trimester begins, and just not use methotrexate? This would allow the baby to develop to full term prior to delivery, and only delay beginning chemotherapy a few weeks, but would provide less than optimal care to his patient. Could an obstetrician ethically deliver the baby early, say at 30 weeks, a time when the child’s development is likely to be normal (but, of course, may not be) despite being premature? This would allow him to use methotrexate almost 3 months earlier than if the baby is delivered at full term.

I told him what I think I would do, but I’m glad that for me this is just an ethical puzzle, instead of a real situation where I have to make real decisions.

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