Yes, I know it’s a cliche, but it’s really true this time. Last month, 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. Less than 5% of all patients diagnosed with pancreatic
cancer are alive five years after diagnosis. To put it another way, pancreatic cancer is the tenth most commonly diagnosed cancer but number four in the list of cancer killers. That’s because most (at least 80%) are diagnosed with unresectable and/or
metastatic disease, for whom surgery cannot be performed. Given that the only currently known possible chance of long term survival in pancreatic cancer comes from a complete surgical resection of the cancer with negative surgical margins (i.e., no tumor at
the margins of the surgical specimens and a rim of normal tissue between the margin and the tumor), any pancreatic cancer patient who is not a candidate for surgery has incurable disease. Of the minority of patients who do have their cancer completely resected
surgically, the five year survival rate is better, perhaps in the range of 15-20% or so, but still the vast majority will be dead within five years, usually
much less. Moreover, known as a pancreaticoduodenectomy or Whipple procedure, the surgery necessary to remove a pancreatic cancer in the head of the pancreas (the most common location) is a huge operation that involves removing the head of the pancreas and
the duodenum and then reconstructing the connections between the bile and pancreatic ducts and the GI tract and establishing continuity between the stomach and small intestine. It’s a tour de force operation that often takes 8 hours or more and is fraught
with the potential for complications, both short term and long term. However, for someone with a potentially resectable pancreatic cancer in the head of the pancreas, it is the patient’s only hope. Even so, after surgery, median survival times still
only range from 12 to 19 months.
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:
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.” The trial, begun in 1999, is known formally as Prospective Cohort Study of Gemcitabine Versus Intensive Pancreatic Proteolytic Enzyme Therapy With Ancillary Nutritional Support (Gonzalez Regimen) in Patients With Stage II, III, or IV Adenocarcinoma of the Pancreas. The results were finally reported in an E-pub ahead of print manuscript for the flagship journal of the American Society of Clinical Oncology, the Journal of Clinical Oncology, and entitled Pancreatic Proteolytic Enzyme Therapy Compared With Gemcitabine-Based Chemotherapy for the Treatment of Pancreatic Cancer, written by John A. Chabot, Wei-Yann Tsai, Robert L. Fine, Chunxia Chen, Carolyn K. Kumah, Karen A. Antman, and Victor R. Grann. It is a clinical trial studying fairy dust versus science in treating a horrific disease.
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:
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. Nor is there any evidence that this discription of the rationale behind the Gonzalez protocol, cribbed straight from the NCI website, has any relationship to reality:
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. Some patients with pancreatic cancer do survive longer than a year. Indeed, actor Patrick Swayze is one such patient, who has now been alive over a year and a half since being diagnosed with stage IV pancreatic cancer with liver metastases. Without knowing the denominator (i.e., how many patients Gonzalez treated to produce those 11 patients with significantly better than average survival for pancreatic cancer), his case series is meaningless. Indeed, back in my old Usenet days in the late 1990s and early 2000s, I would frequently comment that if I were to apply for a grant at the NIH to fund a clinical trial based on such a thin gruel of preliminary data, my application would have found its way to the cylindrical file. The trial for the Gonzalez protocol did not. Selection bias is a wonderful thing if you’re peddling unscientific cancer therapies, where patients who actually could undergo the rigorous Gonzalez protocol would be more likely to be doing better and thus more likely to continue to do better than average, therapy aside.
So what was this trial? These were the objectives:
The two arms of the study were described thusly:
Arm I is the very epitome of Tooth Fairy science. Indeed, it’s pure fantasy. How such a study was ever approved by an Institutional Review Board, I’ll never know. It is to the shame of medical academia that it ever was.
However this misbegotten parody of a clinical trial came into existence and somehow managed to slime its way into being funded and accruing patients, a word needs to be said about the design of this study. It is not randomized, and it is not double-blinded. It was originally designed as a randomized but not blinded study, given the difficulty in blinding which group is getting coffee enemas, for example, and which were not. (I can see how placebo enemas would be a problem.) Even so, because placebo effects would not be evident in the objective outcome, namely survival, this would not be a major problem in a study of this sort, although the lack of blinding could conceivably affect the quality of life measurements. Unfortunately, investigators could only accrue three patients between 1999 and 2001; so in 2001, the trial protocol was converted from a randomized phase III design to an open label observational design. Basically, patients picked which therapy they wanted, and the investigators prospectively studied how they did. The figure below shows the ultimate flow of patients:
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:
Moreover, the quality of life, as measured by standardized surveys, was actually worse for the Gonzalez therapy group:
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. Not only was the median survival of patients in the Gonzalez therapy group worse than it was for the standard chemotherapy group, it was three times worse. At one year, 56% of the chemotherapy patients were alive; only 16% of the Gonzalez protocol patients were. But it’s still even worse than that for the Gonzalez therapy. Not only did Gonzalez therapy patients do worse than those receiving standard therapy, but they did worse than the “average” pancreatic cancer patient as determined by the survival curve derived from data from the SEER Database. The most likely reason to explain such a result is that the Gonzalez therapy is not just inferior to gemcitabine but is probably completely biologically inactive against pancreatic cancer. What we are looking when we examine the survival curve for the Gonzalez protocol group is, most likely, indistinguishable from a survival curve of untreated pancreatic cancer versus treated.
Is this study a slam dunk? Is the Gonzalez therapy, for all intents and purposes, as dead as the parrot in a Monty Python sketch? Or is it still pining for the fjords? Personally, I’d say that this study is proof positive that, as far as having any use whatsoever in pancreatic cancer, the Gonzalez protocol has shuffled off ‘its mortal coil, run down the curtain and joined the bleedin’ choir invisible.
That’s not to say there aren’t a few problems. First and foremost, the nonrandomized nature of the trial makes it possible that biases crept in. As I mentioned before, that is always a potential problem with a nonrandomized study design, especially one in which the patients can select which group they want to be in. Fortunately, the patients in each group ended up being reasonably well matched in age, gender, and other demographics. There was, however, at least one relevant difference that no one discussed. Indeed, I’m surprised that the investigators didn’t mention it, as it could have at least partially suggested a reason why the Gonzalez group might have done so poorly early on. It’s unlikely to have made a difference big enough to have explained the huge difference between patient groups, but it would at least have been a straw to grasp at. Specifically, the serum albumin levels in the Gonzalez group were statistically significantly lower than they were in the control group. Albumin is a rough estimate of nutrition (although there are better parameters) and we surgeons know that lower albumin levels are associated with increased early mortality in pancreatic cancer. I doubt that this is anywhere near enough to explain such a huge difference in mortality between the two groups, especially since the difference between the albumin levels in the two groups was relatively small (4.3 g/dL versus 4.0 g/dL), with the Gonzalez group still having albumin levels within the normal range, but it is one difference that caught my eye. It is also likely (but not well explained) that there were differences in supportive care, such as the rate of inserting biliary stents to relieve bile duct obstruction or aggressively treating infections such as ascending cholangitis, which is one of the most common causes of death in pancreatic cancer patients. The obstructed bile duct causes bile to back up; the bile gets infected; and the patient develops a life-threatening infection. The primary treatment is biliary drainage, either through a tube inserted endoscopically into the bile duct or inserted through percutaneously into the bile ducts in the liver. Antibiotics are necessary, too, of course, but they don’t do much good without biliary drainage. Also, if there was a difference in palliative care between the two groups, that, too, would be yet another example of the unethical nature of this trial.
The one thing that surprised me about this study was not so much that the Gonzalez group had the same mortality and median survival as, in essence, untreated pancreatic cancer patients (which they are), but rather that the survival in the gemcitabine group was so long (14 months). This is better than most studies of gemcitabine-based regimens from the time period during which patients accrued to this study (although results of more recent trials have been better). This suggests a possibility of some unexpected selection bias. Alternatively, it could be that this is simply an outlier group. However, it’s highly unlikely that it invalidates the study. 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.” Although it may be that the Gonzalez protocol didn’t make his pain worse, it’s quite clear that the man’s pursuing the therapy kept him from persuing effective palliative care that might have made his last few months on this earth a lot less unpleasant. Indeed, this makes me wonder what the investigators did after the trial was closed. From an ethics standpoint, every patient in the Gonzalez arm should immediately have been informed of these results and been strongly encouraged to give up the Gonzalez protocol and undergo standard gemcitabine chemotherapy.
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.
One thing that is most remarkable is that this study was released without any fanfare whatsoever. You can bet that, had the results been positive, it would have been trumpeted with press releases. I bet that even if the results had shown that the Gonzalez protocol was no worse than “conventional” therapy, it would have been trumpeted as “Gonzalez therapy as good as conventional chemotherapy!” to the press. Yet, here we have exceedingly striking results, results far more striking that we usually see in any clinical trial, cancer or otherwise and what do we hear?
Well, not quite nothing. H. Kenneth Schueler, writing for Ralph Moss, who is a booster of the Gonzalez therapy and was involved in the genesis of this clinical trial, has commented in a post entitled Clinical Trial of Pancreatic Enzymes: One View. He actually seems to accept the trial results, sort of. After pointing out that it is not surprising that an advanced cancer would require chemotherapy, he tries to rationalize away some of the differences in quality of life observed in the trial but in the end more or less accepts the trial results. More typical to me is how Schueler sidesteps the horrific disaster that is this trial and starts complaining that it’s wrong to view its results as scientific medicine trumping “alternative” medicine (which is actually exactly right; scientific medicine did trump alternative medicine in this trial):
Ah, yes, the old Galileo/Semmelweis/Marshall/Warren gambit. As if we haven’t heard that before. Of course, it’s a myth that Marshall and Warren were treated so poorly. In fact, the acceptance of H. pylori as a major cause of duodenal ulcers happened in record time. Within less than a decade, the standard of care for duodenal ulcers radically changed. I lived through this transition. It was fast, and it was based on overwhelming evidence. In other words, it was a triumph of science-based medicine. Compare that to CAM, where centuries-old concepts still prevail, unaffected by a hundred years of scientific medicine.
Schueler’s conclusion? To try to coopt the language of science:
No duh. That’s what real oncologists are increasingly beginning to believe, too. That does not mean that “integrating” pseudoscience with science will necessarily result in better outcomes. I know where Schueler’s going with this. He’s going to argue that various forms of woo target different tumor growth mechanisms or that herbal remedies are better because there’s more stuff in there, again, to target different tumor mechanisms, but his is an evidence-free assertion. As I’ve said many times before, show me the evidence, or, as I put it when I’m in one of my cruder moods, evidence talks, bullshit walks, and Schueler’s assertion, without solid evidence to back it up, is nothing more than bullshit.
It is a smelly load that I suspect we’ll be seeing and hearing a lot of once CAMsters finally figure out that they can’t ignore this study any more. I suspect that will happen when the study actually sees physical print. It’s fairly easy to ignore an E-pub that comes out weeks or months before the physical article, but harder to do so when the article comes out. I’ve seen articles where no press release accompanied the electronic publication but did accompany the print release, and I’ve even seen articles where press releases were issued months after the study was published.
My guess, however, is that there will be no press release and no accompanying editorial. The authors, I suspect, are embarrassed by the results that they want as little attention as possible, which is why I plan on keeping an eye out for the print publication and updating this post when that happens.
John A. Chabot, Wei-Yann Tsai, Robert L. Fine, Chunxia Chen, Carolyn K. Kumah, Karen A. Antman, & Victor R. Grann (2009). Pancreatic Proteolytic Enzyme Therapy Compared With Gemcitabine-Based Chemotherapy for the Treatment of Pancreatic Cancer Journal of Clinical Oncology : 10.1200/JCO.2009.22.8429 (E-pub ahead of print).