This is not a drill!

 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

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...

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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.


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Entering the Fray

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?

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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My name is FDA, and I approve of this message

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.

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Managing Pain

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

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

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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!

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

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The Emperor's New Book

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.

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