The ethics of clinical trials for terminally ill cancer patients

After chilling out for part of the weekend, yesterday I became so engrossed in writing my part of a training grant for my postdoc that, before I knew it, it was way too late to provide you with the Insolence you crave. Oh, well. Tomorrow for sure. In the meantime, I’ll post a couple of bits of “classic” (if you can call it that) Insolence. This particular bit of insolence dates back nearly four years, all the way back to November 2006. Remember, if you haven’t been reading at least four years, it’s new to you! Besides, it’s always fun (or disturbing) to me to see how well some of my older material has aged. See you tomorrow.

A few days ago, I posted a response to another physician who was not happy with me, no, not happy with me at all. What made him unhappy was the vociferousness with which I criticized the creeping infiltration of woo that is insinuating itself into medical school curricula and expressed dismay at the threat that I see to evidence-based medicine (EBM) from it. He interpreted this vociferousness as “anger,” but in reality it is more frustration, a dismay that was exacerbated by his defense of including unproven therapies in his practice. I did not respond so harshly somuch because I think that in his specific case his use of acupuncture does harm, but rather because of the attitude behind it, an attitude that can (and in too many cases does) open the door to less benign forms of woo.

At the risk of turning this into the Solo Practitioner rebuttal blog, I thought I’d have one more go at it because of one further comment he made. SP’s misguided analogy does, almost in spite of itself, bring up a a difficult issue, although I resent it a bit that he did so in the context of labeling me and those who have little tolerance for woo as “fanatics”:

Let’s talk about false hope. Apparently “conventional” medicine is immune from providing this to its patients; however, a study a few years ago found that less than 50% of terminally ill patients with cancer at one of the nation’s leading cancer centers, Memorial Sloan-Kettering Cancer Center, were approached with discussions about end-of-life issues, such as a DNR (Do Not Resuscitate) order and a Living Will. Furthermore, most of the therapies used for terminal cancer patients at MSKCC are not EBM, because there hasn’t been enough time to study the efficacy of these therapies, or perhaps because these “conventional” doctors have decided that there is little “harm” that can be done with potentially toxic chemotherapy if the person is going to die anyway (as long as the patient consents to a potentially toxic, life-threatening treatment. But what would make a patient consent to such an unproven treatment? Could it be that it provides some hope of a cure?). It seems these doctors believe that they can try experimental, unproven therapies because these patients come to them from other referral centers where their cancers were determined untreatable. These patients are coming for another answer and for HOPE. So are these doctors at MSKCC “quacks” for slipping outside the confines of EBM to try to help the terminally ill? According to Orac, it sounds like no other medicine should be practiced other than EBM.

“Sorry, you’ve got Stage IV Ovarian CA, go home, get your affairs in order and die, because there are no evidence-based treatments that work,” is perhaps what they should tell their patients. That way we’re all living in realityland. How is it ok for “conventional” medicine to expose these patients to harmful, toxic treatments that are unproven? It doesn’t stand up according to Orac’s arguments.

Logical fallacies piled on top of nonsequiturs piled on top of straw men. These have to be dealt with before we get to the issue that he brings up almost by accident, namely the ethics of clinical trials in which terminally ill cancer patients are enrolled.

Let’s start with the tu quoque logical fallacy, which basically means “nah, nah, nah, you too!” Fine, I’ll concede that conventional medicine often does not do a good job of dealing with end-of-life issues. In fact, I’ll even go SP one further, even if it is at the risk of offending my fellow ScienceBlogger The Cheerful Oncologist, and tell an oncologist joke that goes along these lines:

“Why is it a good idea to nail shut the coffin of a cancer patient who’s died?”

“To stop the oncologist from trying to give him more chemo.”

OK, it’s a bad joke, but it has a point, which is that there is a subset of oncologists who never give up and keep treating hopeless cases, rather than facing reality and changing the focus to palliative therapy, to trying to make the patient’s remaining time as comfortable as possible. Not infrequently are the times when I’ve been consulted on a patient with metastatic cancer and a bowel obstruction due to peritoneal carcinomatosis (in essence, a belly full of tumor lining the peritoneal membranes covering the abdominal organs) who is clearly at death’s door to be considered as a surgical candidate, despite the fact that in a patient in such a debilitated state surgery has only a very small chance of accomplishing even the palliative goals of enabling him to eat solid food again, and the morbidity and mortality due to surgery are high. Patients operated on under such circumstances seldom make it out of the hospital alive, and they often suffer many complications before they die, observations that suggest that a very selective approach is called for in choosing whom to operate on. (I discussed this very issue in one of my very first blog posts.) It’s also been a not infrequent occurrence over the years that such patients often do not have “do not resuscitate” orders that clarify what level of care they want (full code, ICU transfer, intubation, medication drips to support their blood pressure, etc.) if they should suffer a cardiac arrest, leaving me in the awkward position of having to broach the topic with a patient whom I’ve never met before in the context of discussing what surgery can (or, more frequently, cannot) do for him. Most of the oncologists that I’ve work with range from pretty good to fantastic at addressing these issues, but not always, and sometimes even the great ones don’t settle the issue because the patient isn’t ready to discuss it.

Of course, just because conventional oncologists more often than we like do not do a great job at dealing with end-of-life issues, however, is not an argument against EBM or for woo. That’s a nonsequitur. That conventional oncologists could do better with end-of-life issues is an argument for finding ways to get physicians to do better in that area within the context of EBM. That should be, but apparently isn’t, obvious to SP. Doesn’t he realize that quacks who prey on terminally ill cancer patients do a far, far worse job of dealing with end-of-life issues than even the most incompetent conventional oncologist? Indeed, quacks deal with end-of-life issues, in essence, by ignoring them entirely. After all, discussing the possibility of the patient’s death would require admitting to the patient the possibility that their treatments won’t work, something we as physicians ethically must do but quacks don’t. Given that the quacks’ sales pitch is that they can cure cancers that conventional medicine cannot, discussing end-of-life issues is bad for business. In any case, it’s a straw man to claim that I advocate telling terminally ill patients to “get their affairs in order and die” in a manner as callous as described. Just because a cancer is no longer curable does not mean that it is no longer treatable or that effective palliation does not exist. SP seems to be a victim of all-or-nothing thinking; either a physician treats for cure or he is telling his patient to go home and die (that is, it would seem, while he isn’t busy preying on the patient’s hope by experimenting on him with toxic chemotherapy). Whether he realizes it or not, SP is in essence using the failures of EBM-practicing physicians in counseling patients as a defense of cancer quackery.

In fact, SP’s nonsequitur/tu quoque combination really irritated me. (If it didn’t, I wouldn’t have responded with a second blog post to his ramblings.) SP actually makes an analogy between the hope that patients entering clinical trials of new cancer medications have and the “hope” that quacks give such patients, implying that there’s no real difference and that physicians offering experimental therapeutics to terminally ill cancer patients are somehow going outside the bounds of evidence-based medicine. He’s astoundingly incorrect, of course, when he seemingly implies (actually, all but states explicitly) that oncologists at Memorial Sloan-Kettering Cancer Center who use experimental treatments on terminally ill cancer patients prey on patients’ hope the same way that quacks do.

The reason why is just as obvious as why his tu quoque rhetoric was a logical fallacy. It’s a little thing called informed consent. Before a patient who meets the enrollment criteria and doesn’t meet any of the exclusion criteria is enrolled in a clinical trial of an experimental therapy, several things have to happen: (1) what is known and not known about the therapy being tested has to be explained in detail to the patient in lay terms; (2) the risks, as far as they are known, have to be described; (3) the patient has to read and sign a detailed informed consent form without duress, signifying his or her agreement to participate and understanding of the protocol and risks. In fact, before such a study can even be opened to patient accrual, it first has to pass two committees, the Scientific Review Board (SRB), which looks at the scientific design of the proposed trial to verify that it tests an important question and that the design is scientifically sound; and the Institutional Review Board (IRB), which verifies that the protocol does not subject patients to undue risks compared to its potential benefits, that it provides truly informed consent, and that it does not subject the patient to undue pain (excessive blood draws, invasive tests, etc.). Finally, clinical trials are not somehow outside the rubric of EBM because the very rationale for them must be based on sound preclinical scientific evidence, often coupled with small amounts of clinical data (case reports, small case series) that suggest that the therapy being tested might be efficacious.

I think you can see the difference between a clinical trial as described above and how quacks operate. Quacks promise desperate patients for whom no curative therapy is available from “conventional” medicine that they will be cured with little pain or suffering, even though there is no evidence to support such claims. Consider the Hoxsey treatment, which its main adherents claim to be able to cure 80% of patients with cancer who take it. Of course, if it didn’t work, Mildred Nelson, who took over the BioMedical Clinic in Tijuana after Harry Hoxsey died, would blame it on the patients, saying the patient “didn’t believe enough” in the treatment. And that’s just one example. There are many, many more.

Still, even though SP’s intent in what appears to me to be a criticism of MSKCC for abusing patients’ hope seems to be to imply by comparison that woo isn’t so bad because it gives hope, almost by accident he manages, in spite of his bad arguments, to raise an important issue; i.e., the ethics of clinical trials on terminally ill cancer patients. We do indeed have to be careful about using hope to sell new drugs in clinical trials. I would argue that this is not so big a problem in Phase III clinical trials. These are large randomized studies enrolling significant numbers of patients, in which a new drug is compared with the standard of care. (The reason that new drugs are compared to standard of care rather than placebo in phase III oncology trials is because, under most circumstances, it would be unethical to treat a cancer patient with a placebo.) Both groups are getting what is viewed as effective therapy, because a drug wouldn’t make it to a phase III trial if it didn’t show evidence of efficacy in Phase I and Phase II trials.

More care has to be taken in Phase I trials. Phase I trials usually represent the first time that a drug is ever given to human beings. The patients enrolled almost always have terminal cancer for which no further potentially curative therapies are known. It has to be remembered that the purpose of a phase I trial is not to determine if a drug is effective against cancer, but rather to evaluate its safety, determine the maximal tolerated dose, and measure toxicity. It’s nice if tumor shrinkage is observed, but not essential for the drug to be taken to the next stage, phase II trials. It’s true that patients enroll in these studies because they have some hope that they might be helped by the drug being tested. However, IRBs are very insistent that it must be emphasized to patients enrolling in phase I trials that they are unlikely to benefit from the new drug.

So, knowing this, why do patients enroll in phase I trials? Certainly, altruism is one major reason, the desire that their deaths have meaning in contributing to knowledge that might help future patients. Also, as this editorial explains, as long as careful respect for patient autonomy and informed consent is maintained, phase I clinical trials are not unethical, nor do they abuse a patients’ hope:

Investigational drug trials are ultimately the result of a complex scientific and ethical balancing act very familiar to the investigators involved in the studies that Dr Slyter cites. It is unfortunate that new treatments cannot be developed without risk, but we do not believe that the principle of “do no harm” should be translated into “make no attempt to help unless risks can be eliminated.” Virtually all forms of treatment involve risks. A physician’s role is to try to assess the benefit-to-risk ratio. Most commonly accepted therapies can have side effects ranging from serious injury to death, and many patients do not respond to a given form of treatment. If avoiding harm was the only objective of physicians, it would be a logically defensible position that we should not treat anyone.

The purpose of a phase 1 trial is not to prove the efficacy of a new agent, and one can predict with near certainty that some patients will suffer adverse events. This is inevitable in almost any drug development program, because the tolerability limits of a new form of treatment must be explored to define its safety profile. Initial estimates are derived from preclinical testing, but the final determination must come from human studies. It is not more ethical to expose healthy volunteers to potential side effects than to conduct these trials in patients who have at least the possibility of benefit from the investigational agent…

The potential for drug-induced injury must be explained to prospective study patients in a manner that is specified and approved in advance of the trial. These plans are reviewed by institutional review boards (IRBs) that include physicians who are not directly involved in the clinical testing, as well as other patient advocates. It is, however, impossible to inform patients fully of the risk-benefit ratio during a drug development trial, since that information is derived ultimately from the entire drug development process. If a patient does not wish to assume unknown risks, he or she can simply refuse to participate in a trial, and many do.

The difference between a well-designed clinical trial and quackery in terms of dealing with patient hope and expectations could not be clearer. Yes, like any human endeavor, clinical trials are not always carried out according to the ideal, and, because doctors are human, sometimes oncologists will sell such trials by playing up the possibility of patient benefit more than is warranted. But contrast this with quackery, where no attempt to be realistic about the risks and the possibilities of benefits is even made, and I think you’ll see just how inappropriate SP’s analogy is. It’s a shame that SP is so persistent about defending woo and seems fairly hostile to EBM, because he actually does have other things to say that are interesting, such as his description of how insurance companies sometimes stealthily try to cut reimbursements to physicians without notice. On the other hand, his reading list, which includes books like Deepak Chopra‘s Quantum Healing, and you know what I think of Dr. Chopra. (Maybe his referring to himself as “Shaman” or “Medicine Man” is not meant entirely ironically.) I just wish that SP would apply the same level of critical thinking skills to the evaluation of alternative medicines and his perception of the evils of conventional medicine as he does to chicanery by his insurance company.