Reefer Madness

Last week, Delaware Governor Jack Markell put his signature to the state's first medical marijuana law. Of course, cancer is at the top of the laundry list of maladies that qualify patients for participation. I guess it's time to go shopping for a nice bong...

Kidding. For a state that trends to blue politically, Delaware is relatively socially conservative, and this is reflected in the fact that the law is substantially more restrictive than those currently in effect in, say, Colorado or California. Patients are not permitted to grow their own, and must obtain their smoke (a maximum of six ounces) from one of only three non-profit dispensaries (presumably one per county). Patients must have an on-going relationship with the prescribing MD; are supposed to have exhausted all the standard alternatives; and must obtain a state-issued ID card. It remains to be seen just how much of a problem there will be with people with nasty hangnails showing up at the dispensaries with ID cards and prescriptions, since there is an escape clause covering individuals with unspecified "chronic" and "debilitating" conditions. On the whole, it all sounds a lot more inconvenient than just driving to certain Wilmington neighborhoods on Friday night, but I guess that's partly the idea.

Huong asked me how interested I am in this. The answer is "Not Very", at least for now. I am not currently taking any kind of pain medication, not even any of the OTC varieties (OK, yes, I'm taking 81 mg aspirin, but that's for the heart, not for pain), and I'm hoping to avoid having to do so for as long as possible. The prescription opioids (e.g. Oxycontin) render me hopelessly constipated. I guess if it ever comes to the point where I'm pretty desperate then I'd consider smoking up. Actually, I'd prefer not to smoke it; I'd probably invest in a nice vaporizer.

Minus Aredia

The oncologist did not require much in the way of persuasion to call off the Aredia treatments for the time being, in honor of my recently discovered need for oral surgery. But he did question the need to order any CTX tests, indicating that it should only be necessary to wait a decent interval before proceeding. That was not the impression I had gained from what the endodontist had told me, so these two titans of medicine will consult, and presumably arrive at some kind of consensus on the subject.

This month, in addition to the usual blood tests (results as usual), I got a 24-hour urine test. This is really just looking for the same monoclonal proteins as the blood test, but is much more sensitive. It, too, failed to turn up anything. I also got a skeletal survey, which revealed little change since the last one I got, around a year ago. So everything is indicating stability at this point.

Recently it has seemed to me that the abdominal bloating has gotten worse, and I occasionally experience pains on the right side. Next week I am scheduled for an abdominal ultrasound, to check into this situation.

An Unexpected Complication

I seem to be specializing in Strange Maladies Of Indeterminate Origin. Last week, I visited my dentist for a routine cleaning and examination. I also got the annual full set of X-rays. The picture of one of the mandibular canines (tooth #27) caught the attention of the dentist, who forwarded it to an endodontist, who delivered a diagnosis of external root resorption. This is a poorly understood (especially by me) phenomenon, in which the tooth appears to be destroying itself from within, "apparently initiated by a peculiar inflammatory hyperplasia of the pulp", by one account. This could be an autoimmune disorder, but it is more commonly believed to be ultimately caused by trauma, where "trauma" is defined to include the wearing of orthodontic appliances -- which I did, back in the day. If the damage is not too advanced, the tooth can be rescued by means of a root canal; otherwise, it must be extracted and, nowadays, typically replaced by an implant. In my case, the endodontist would normally pass me off to an oral surgeon for extraction. But...

But I am receiving bisphosphonate therapy, to counteract the effects of the cancer on my spine. Normally, special cells called osteoclasts clean up old bone mass, making way for new bone created by the counterpart osteoblasts (a process known as "bone turnover"). Myeloma appears to overstimulate the osteoclasts, which begin to outperform the osteoblasts, creating many lytic lesions -- holes -- in the bone. This is obviously a Very Bad Thing, leading in my case to a greatly enhanced risk of spinal compression fractures. Bisphosphonates such as the one I am getting, Aredia, attempt to solve this problem by suppressing the osteoclasts, which is a mixed blessing, since bone turnover is as a result reduced everywhere, meaning that the bones are more brittle and are slower to heal than they should be. Apparently, this is especially a problem where surgical procedures performed on the jaw, such as a tooth extraction, are concerned, leading to a condition known as "bisphosphonate-related osteonecrosis of the jaw". The wounded jaw does not heal, and eventually the bone in the vicinity of the wound dies. This is another Very Bad Thing. So oral surgeons are understandably reluctant to perform extractions on patients receiving bisphosphonates.

The effect of bisphosphonates on bone turnover is typically gauged by a serum CTX test; patients getting bisphosphonates will show much lower than normal CTX numbers. A sufficiently lengthy drug holiday might return serum CTX to a range acceptable to an oral surgeon; a temporary root canal might be necessary to stave off disaster in the interim. The question is whether the oncologist can be persuaded to declare such a drug holiday. I was on track to continue receiving Aredia until at least the end of this year, for reasons of course completely unrelated to dentistry. My next visit with the oncologist should be much more interesting than usual, for this and certain other reasons, which I will discuss in due time.

The Safety and Effectiveness of Revlimid

A few weeks ago, the FDA issued a safety announcement concerning Revlimid, indicating its concern that longer-term exposure to the drug increases the risk that the patient will develop additional hematological malignancies (translation: leukemias and lymphomas). This isn't exactly shocking new news, but it does betoken a heightened level of concern and awareness of the problem. Of course, in my case, "longer-term exposure" is exactly what we are hoping for, since the idea is that I will continue to take Revlimid as long as possible, until it stops working.

But we already knew that the answer to the "how safe" question is "not very". Lenalidomide (Revlimid's chemical name) is a derivative of thalidomide, which was originally introduced in the 1950's as a sedative. Thalidomide was prescribed to large numbers of patients, among them pregnant women, who proceeded to produce tens of thousands of babies with severe birth defects, until the drug was withdrawn in the early 1960's. It was one of the most spectacular failures in the history of the pharmaceutical industry. But in the 1990's, thalidomide was resurrected as a chemotherapeutic agent effective against none other than our old friend, multiple myeloma. Subsequently a derivative, lenalidomide, was introduced for the same purpose, but with better responses and fewer side effects for many patients. Today, both thalidomide and lenalidomide are being prescribed for myeloma, but they are distributed in a tightly controlled fashion. Every 28 days my oncologist generates, and the insurance company approves, a prescription for Revlimid capsules, quantity 21, in 25mg strength. Eventually I am contacted by the specialty pharmacy, and I receive the same "counseling" from a pharmacist every time: I am warned against donating blood or sperm, and against engaging in sex with "a woman who is pregnant, or who could become pregnant", unless I use a condom. The pharmacist then transfers me to a patient service line at Celgene, the manufacturer of Revlimid, and I take a "survey", which is the same every time: I answer questions about whether or not I have donated blood or sperm, and whether or not I have engaged in unprotected sex with "a woman who is pregnant, or who could become pregnant". Only after I have successfully jumped through all of these flaming hoops can I be shipped the goods.

Beyond this, Revlimid carries warnings regarding, among other side effects, deep vein thrombosis (blood clots) and tumor lysis syndrome (TLS), which covers a grab bag of metabolic disturbances, the most dangerous-sounding of which is acute renal failure.

So Revlimid is a dangerous drug, maybe more dangerous even than we were thinking. Given the risks, definite and possible, should I be "allowed" to take it? In the binary world of mass media health and science reportage, drugs are either "safe" or "unsafe". No gray areas, please. No nuances allowed. And the FDA is the God of this Manichean religion, sitting in judgement over which may enter the Heaven of Safe Drugs and which are consigned to the Hell of Unsafe Drugs. For many drugs, the end of the line comes in the Phase I clinical trial. The Phase I clinical trial has nothing to do with assessing the efficacy of the drug under test. The question "Does Revlimid do anything good for multiple myeloma patients?" was not asked, let alone answered, in the Phase I clinical trial. The only objective of the Phase I clinical trial is to determine whether or not the drug is going to hurt or even kill people. Those laundry lists of "possible side effects" that come with prescription medications are generated by the Phase I clinical trials. If a patient in the non-control arm of the trial (the group of patients actually getting the drug under test, rather than the placebo) gets a nose bleed during the trial, then "nose bleed" is going to appear in the list of "possible side effects" for this drug -- whether or not the drug actually had anything to do with the nose bleed. Because, in fact, there's no way to know for sure. And if patients in the non-control arm die during the trial? Then the drug is pretty much done for. And in fact quite a few promising drugs have not survived their Phase I trials for precisely this reason. Pharmaceutical industry professionals of my acquaintance assert, with the utmost seriousness, that should it have been subjected to the FDA's approval process, aspirin would not be available in the United States today. It's simply not "safe".

And given its litany of problems, no doubt many people would be surprised to learn that the FDA has approved the use of a drug such as Revlimid for any purpose whatsoever. Probably, it is flying under the radar: few are the patients who want or need to use it, and these few are sufficiently desperate to resort to it in spite of the dangers. In all probability, they are more likely to die without it than with it. So the all-powerful FDA has allowed this, calculating that repercussions will not return to haunt it. But now it's getting nervous about it, as the safety announcement shows.

There is no way that a mass-market drug like Lipitor or Viagra would be permitted to reach the market with a rap sheet as long as Revlimid's. That sounds right, except that there are bound to be gray areas in which certain drugs could benefit a relatively large number of patients, but the FDA has ruled that out, because it doesn't want to be raked over the coals by the media and by Congressional sub-committees later, if it guesses wrong. Better to keep this stuff away from the unwashed, who don't know what they're missing anyway. The FDA is rarely made to suffer for keeping dangerous drugs out of the hands of people who might be helped by them.

Which brings us to the topic of "effectiveness", which is the subject of the later-phase trials. This is where the gray areas become very murky indeed. Technically, Revlimid is approved, in combination with dexamethasone, only for myeloma patients who have failed at least one prior therapy. I have now been prescribed the drug not once but twice in circumstances that do not fit this description: once with dexamethasone as induction therapy for a stem cell transplant; and once without dexamethasone as post-transplant maintenance therapy. When this inconvenient truth is brought to their attention, oncologists merely shrug. This kind of thing is routine, universal practice in American medicine. Once a drug has been approved for any purpose whatsoever, it will never again be approved for any other, irrespective of any subsequent research that may support such usages. Formal clinical trials done in support of an application for FDA approval are so expensive and so drawn out that no one ever does more than one set of them for a given drug, if they can avoid doing so. Physicians feel free to dispense a drug for unapproved uses if current research supports them. But they, not the FDA, make these decisions. Hence my experiences with Revlimid to date. As one of the aforementioned pharmaceutical industry professionals commented to me: "You're in the real clinical trial, right now."

The thalidomide disaster gave birth to the FDA's existing approval process for drugs. But the problem with thalidomide wasn't the absence of this approval process, the problem was a lack of adequate testing. There can be no doubt that drugs like Revlimid need to be tested and retested, early and often. What I question is the FDA's power to arbitrate what drugs can or cannot be made available as a result of these tests. Why aren't the results of drug tests simply made available to the physician community, so that they can decide whether and how to use the drugs? They are doing this job anyway, for drugs that have managed to successfully negotiate the FDA's highly politicized approval process, as my experience with Revlimid shows. To me, the FDA's control of this process appears to be less about assuring safety and efficacy than it is about control.

Geraldine Ferraro's 12-Year Benchmark

With the death of Geraldine Ferraro, multiple myeloma claimed its most prominent American victim in recent memory -- perhaps ever. Huong asked me whether I was bothered by this. I suppose she guessed that I might consider it to be an unwelcome harbinger of some kind. Anyway, the answer is "No", and not because I'm an insensitive lout (although that could be another reason).

When Ms. Ferraro was first diagnosed, in the late 1990's, her chances of surviving five years were deemed to be slim; her chances of surviving ten years were, for all intents and purposes, nil. In the event, she managed to hopscotch past the Devil for even longer than that, on the backs of powerful new therapies that became available in the intervening years.

Short of a cure -- and curing myeloma would require the kind of breakthroughs that merit Nobel prizes -- the goal of clinical oncologists today is to render this disease as manageable as, say, Type II diabetes. The gallows humor version of this says that "success" is lodged in making the patient survive long enough to be killed by something else. That remains a goal, as Ms. Ferraro's demise makes clear, but there is every reason to believe that I will be able to live a relatively normal life for many years to come, by shifting from one therapeutic regime to another over time, following her example. Yes, I will likely have to battle undesirable side effects. There will be uncomfortable moments when Plan N is found to be no longer working, and Plan N+1 has not yet succeeded in replacing it in a stable manner. I may eventually have to resort to something previously untried. But on the whole, it would really be a little surprising, to me, if I cannot do better than Geraldine Ferraro's 12 years before I'm done, since I should have access to options not yet conceived in her time.

Boosters

Yesterday my immune system advanced to "adolescent" status, at least in terms of childhood immunizations. I made my way to the office of my primary care doc to receive boosters for four of the five vaccines I received during my most recent visit to Johns Hopkins, in January. My primary care doc is of course not a pediatrician, but she does have patients young enough to need these boosters, so she had them on hand. I will get the last installment of these when I return to Hopkins for the last time (well, the last time related to the transplant, at least), for my 24-month checkup.

Cancer Research: Vital To The Nation's Defense?

Apparently so, since Congress has continued to fund it via Dept. of Defense budgets for almost 20 years, and will do so again for fiscal 2011, according to this Washington Post article. Of course, this is in addition to the usual avenues of funding for such research, such as the NIH. Money quote: "Breast cancer is a 'huge issue' for women in the military." Yeah, I get it, but...