Scientific process: Useless treatments found to be useless (2)

Last month [August 2009], a major study whose results had been anticipated by the alt-med community, as well as those of us who consider it to be highly unethical pseudoscience, were reported. However, they were reported without fanfare, without press releases, without any sort of publicity whatsoever. Only a handful of bloggers who have paid attention to the issue (myself included) even noticed, and even I wouldn't have noticed if someone hadn't forwarded the journal article to me and asked me what I thought of it. So under the radar is this important paper that not a single alt-med website that I've been able to find has commented on it, even nearly four weeks after its release.

I wonder why.

I suspect that you'll soon understand why. The study is of an "alternative" medical therapy for pancreatic cancer, one of the most lethal, if not the most lethal, cancer there is. There are several reasons for the lethality of pancreatic cancer. …

Because the outlook for pancreatic cancer, particularly unresectable pancreatic cancer is so grim (the median survival has barely budged from less than six months for decades. Median survival for untreated metastatic pancreatic cancer is on the order of 3-4 months, although gemcitabine chemotherapy regimens combined with radiation) can result in median survivals of six months or more. For locally advanced pancreatic cancer that cannot be resected but has not metastasized, the median survival is on the order of 6-12 months depending on the study. Thus, we can rightly say that pancreatic cancer is one of those cancers for which science-based medicine has frustratingly little to offer that can cure it. That's not to say that science-based medicine doesn't have a lot to offer for palliation, but no one wants just palliation. We all want to live to a ripe old age, not just have our pain and nausea palliated for a few months before cancer claims us. Even scarier is that pancreatic cancer usually produces few or no symptoms until it is fairly advanced. Usual symptoms include vague upper abdominal discomfort, loss of appetite, and post-prandial nausea from intermittent gastric outlet obstruction, you know, the sorts of symptoms that nearly of us have from time to time and that primary care doctors see in their practice every day. By the time a pancreatic cancer causes severe pain or obstructs the bile duct leading to jaunice, it's usually unresectable or metastatic. (Often the reason it causes such severe pain is because it invades a plexus of nerves just posterior to the pancreas.)

It is the very deadliness of pancreatic cancer and the lack of effective life-saving or life-prolonging treatments for it that make pancreatic cancer a ripe condition for quackery. Rising above most other quackeries to attract a lot of attention about a decade ago is a quackery known as the Gonzalez protocol. It is described on Dr. Nicholas Gonzalez's website as involving dietary changes, supplements, the replenishment of pancreatic proteolytic enzymes, and "detoxification," including coffee enemas. It is not an easy therapy to undergo.

For example, Dr. Gonzalez states:

Overall, cancer patients will consume 130-175 capsules a day, including nutrients as well as enzymes. Non-cancer patients might consume in the range of 80-100 capsules a day, the exact number depending on their health status and medical problems.

I know of no science-based cancer protocol that requires a patient to consume 150 pills a day. There are also the dietary alterations that can be quite hard to follow, as well as the frequent coffee enemas. All in all, the Gonzalez protocol is an arduous regimen for a debilitated pancreatic cancer patient to follow. Still, for some reason, it gained some popularity in the "complementary and alternative medicine" (CAM) community, so much so that, based on poorly designed case series of eleven patients, Dr. Gonzalez managed to get a clinical trial funded by the NIH to study his method versus standard chemotherapy, a sordid story that Dr. Atwood has chronicled in detail in a long series of blog posts. That trial ended in 2005.

So why is it 2009 before we have the results of this trial, which show that the Gonzalez protocol is worse than useless? As Gollum would say, "It makes us wonder, yes it does." …

Sadly, the "scientific" rationale behind the Gonzalez protocol, with its megadoses of supplements and pancreatic enzymes plus "detoxification" by coffee enemas, is a perfect example of what Harriet Hall terms "Tooth Fairy science." The Gonzalez treatment is basically a modification of a protocol known as the Kelley Treatment, which in turn was very similar to the Gerson protocol. In any case, it's all an example of how alties have this conception that disease is caused by "toxins" and "contamination" that must somehow be purged in a religious ritual of colon cleansing. I've joked about this before as being an example of when mere regularity is not enough and mocking late night infomercials about colon cleanses, but, totally serious, Chabot writes in the introduction to this study:

The Scottish embryologist John Beard first proposed pancreatic proteolytic enzyme treatment in 1906 and soon after published a monograph, entitled The Enzyme Therapy of Cancer. In 1981, Nicholas Gonzalez began to evaluate the use of proteolytic enzyme therapy. Twelve years later, in 1993, he was invited to present a series of cases at the National Cancer Institute (NCI), which led him to undertake a case series of alternative medical therapy that included proteolytic enzymes, diet, nutritional supplements, and detoxification procedures. Among 11 patients with inoperable, biopsy-proven, stages II to IV pancreatic adenocarcinoma, he reported 81% survival at 1 year and 45% at 2 years. Four of the 11 patients survived for 3 years.

This is the very example of an implausible hypothesis. True, it's not as implausible as homeopathy (few hypotheses are), but it goes against everything we know about cancer in general and pancreatic cancer in particular. There is no evidence that pancreatic enzyme deficiency has anything to do with pancreatic cancer, for example. …

Here's the problem. These "toxins" are never identified, nor is there any evidence that the Gonzalez regimen actually removes them. It's not that environmental exposures don't have an effect on cancer susceptibility. Smoking can cause lung cancer and, ironically enough, increase the risk of pancreatic cancer as well. "Detoxification" quackery like the Gonzalez protocol takes science and turns it into Tooth Fairy science by giving near magical characteristics to these "toxins." In any case, cancer is primarily a genetic disease. Even heavy smokers who smoke for 50 years "only" have about a 25% lifetime risk of developing lung cancer, which means more smokers don't get lung cancer than do. In any case, think about it: Let's say there is this host of unnamed, undefined "toxins" that give you pancreatic cancer. Remember, the toxins from tobacco smoke that predispose to lung cancer are largely known and quantifiable. Why would one think that coffee enemas would remove those "toxins"? Certainly there is no scientific basis to think that the special diet, the dozens of capsules of supplements and pancreatic enzymes, or the other aspects of the regimen would "detoxify" anything. Basically, the Gonzalez protocol appears to derive from a prescientific notion of disease that is almost religious in its nature blaming "contamination" as the cause of all disease and that one must "purge oneself" of this "contamination" to cure the disease.

But, say Gonzalez supporters, what about the case series of 11 patients with stage II to IV pancreatic cancer from the 1990s reporting 81% survival at 1 year and 45% at 2 years, with 4 of the 11 patients surviving for 3 years? As Dr. Kimball Atwood pointed out, this was a nonconsecutive case series, a so-called "best case" series. Basically, it's a cherry-picked series, and I've criticized "best case" series before because they in essence intentionally look at outliers for whom the therapy may or may not have made a difference. …

So what was this trial? These were the objectives:

1. Compare the survival of patients with stage II, III, or IV adenocarcinoma of the pancreas treated with gemcitabine versus intensive proteolytic enzyme therapy and adjunctive dietary and nutritional support.
2. Compare the quality of life in patients treated with these regimens.

…
One serious problem with a nonrandomized design like this is the likelihood of selection bias. In this case, it would be "self-selection" bias in that investigators would have to worry whether patients who were either worse off or better off might opt preferentially for one arm of the trial over the other. I will address that point after we look at the results, which are quite striking:

In words:

At enrollment, the treatment groups had no statistically significant differences in patient characteristics, pathology, quality of life, or clinically meaningful laboratory values. … At 1 year, 56% of chemotherapy-group patients were alive, and 16% of enzyme-therapy patients were alive. The quality of life ratings were better in the chemotherapy group than in the enzyme-treated group (P <.01).

In all my years in medicine, surgery, and surgical oncology, I have never seen a study with such a striking difference in outcome between the two groups. No wonder the Office for Human Research Protections (OHRP) issued a determination letter stating that it was appropriate to terminate the study before the full 72 patients were enrolled due to the study having reached its "predetermined stopping point." These days, clinical trials are designed with periodic assessment of results and predetermined stopping points. These stopping points are invoked to shut down the trial in the event that one group is doing so significantly better than the other that enrolling the remaining patients could not possibly change the result. The purpose of such a stopping point is to protect clinical trial subjects from being enrolled in a study that no longer has clinical equipoise; i.e., the groups can no longer be predicted to have roughly equivalent outcomes based on what we know. Usually, it's the experimental group that does better than the control group. At least that's the intent. Sometimes, however, as in the case of the Gonzalez protocol, it's the experimental group that does much worse, so much so that the study has to be halted before reaching its full accrual.

But it's even worse than that.

Read it all!

The moral of the story: Even if evidence based science hasn't much to offer for your illness, you can be much worse off by trusting untested treatments.

… Given the striking difference between the two groups and the fact that the Gonzalez group did more poorly than historical controls, from this study we can confidently say that the Gonzalez protocol is almost certainly no better than no treatment.

In fact, it's probably worse. Go back to Dr. Atwood's post on this issue and consider the story of an unfortunate 40 year old man who enrolled in the trial and chose the Gonzalez protocol arm. This man was told to have his fillings removed and afterward tried as hard as he could to continue the regimen to the letter and suffered horribly as he did. At one point he was even told that increasing pain might be an indication that his tumors were "dissolving."

Oh, this reminds me of the "die off" myths with regards to antiviral and antibiotic drug (ab)use.

Finally, the most disturbing issue that this trial raises is the question of why it took nearly four years after the trial was stopped to publish the results. Dr. Atwood has speculated why this might be the case, namely to cover up the results that were unfavorable to Gonzalez. There is now no doubt that this trial was completely unethical right from the very beginning, but that lack of ethics was compounded by not having the results reported right away. In this, after having had a few days to think about it, I am going to have to strongly disagree with Dr. Atwood when he asserted, "A compelling argument can even be made that the JCO should not have published the report--as paradoxical as that sounds."
…

I can understand where he's coming from. This study clearly violates the Helsinki Declaration, to which JCO requires the clinical trials that it publishes to adhere. However, I find an it equally, if not more, compelling to take the view that the patients who suffered in the Gonzalez group will have suffered in vain if the results of this trial were not published. I also tend to take the view that shining a light on such a trial, in the form of publication, is a good thing in this particular case because it eliminates the uncertainty over whether the results were as bad as we know them to be. Let's put it this way: If the results were not published in a peer-reviewed journal but rather announced or mentioned in a report, they would seem less credible to shruggies. It is these people who need these bad results rubbed in their noses, the better to let the stench waft into their nasal passages and make them retch. When they ask, "What's the harm," we can tell them in no uncertain terms what the harm is. The same would apply if they were simply announced on ClinicalTrials.gov or mentioned in a report. It's just not the same as a peer-reviewed publication in one of the highest impact oncology journals there is. This is truly a case where the greater good can be served by disseminating this data far and wide as soon as possible by the most scientifically credible means necessary.