3rd Annual CCA Conference (April 2003) - Review

by Keith Altman
(dx Stage IV March 2001)

I recently got back from the 3rd annual Colon Cancer Alliance conference which took place over the weekend (April 5 and 6, 2003). Overall I think the meeting was quite good, especially the two keynote speakers (Saturday), Dr. Paul Sugarbaker and Dr. John Marshall . Both gave excellent talks and by themselves made the trip to attend this conference worthwhile. There was also a quite interesting presentation by Patty Delaney from the FDA. Lunch was free, the food was good and I even ate a few of the yummy cookies they put out for snacks during the breaks (yes, the sugar is bad for you, but the enjoyment was worth the couple days survival time they may have removed from my lifespan!). Met a few people whose names I recognized from the listservs and online support groups, but most there I didn't know. The CCA should be commended for the fine job they did in organizing the conference and obtaining quality speakers.

Some people have asked me what was said in these key presentations, so I thought I'd give a brief review along with a few references which might be of interest. I'll also give some of my own interpretations (may be bit different from those of many CCA/ACOR attendees!).

To understand where I'm coming from, the starting point for this review is an article (never mentioned by any of the speakers so far as I am aware) which summarizes (in my opinion) the unfortunate truth about most cancer research. It was written by Dr. David F. Horrobin, published in the Feb. 22, 2003 issue of the Lancet and entitled Are large clinical trials in rapidly lethal diseases usually unethical? . Unfortunately you can't view the full article online unless you subscribe to the Lancet, but there were two online summaries I saw - here is one by Ralph Moss and here is one from The Sunday Herald newspaper.

I apologise to those readers who don't like Ralph Moss (there is a large contingent in the colon cancer community who view anyone involved with "alt med" as being "tainted"), but he is only giving a summary of what he read in his newsletter and I must point out that Dr. Horrobin cannot easily be dismissed as a nut. He has been involved in mainstream biomedical research for a long time, having degrees from Oxford and being a founder of the biotech company, Scotia Holdings PLC (1979) and currently Executive Chairman of Laxdale Ltd., a company that specializes in the development of new drugs for psychiatric and neurological disorders.

Briefly, Horrobin says that most clinical cancer research is a waste of time. You can easily tell whether there is much expected benefit from a particular clinical trial by looking at planned enrollment:

"If a trial has to be large, say more than 100 patients, it is large only because the expected effect size is very small. That means that most patients entering the trial have little or no chance of receiving benefit. With the toxic nature of many oncology [tumour] treatment regimens, there may well be a substantial chance of harm. Although the risk of harm is usually well described in patient information leaflets, almost nothing adequate is ever said about the assumed effect size and the real chance of benefit. Almost all patients volunteering for most trials in oncology are doomed: at best they can expect little benefit. They are not usually being properly told about this low expectation."

For those concerned with "trial ethics" (whatever that means), this would be translated into saying the Informed Consent is not being done properly.

What does this mean in practice? See the Tennessean's excellent series, Life Inside a Cancer Trial for real life examples - heartbreaking stories of patients forcing themselves to stay on experimental regimens in hopes of benefiting future patients, when in fact the research benefited no one.

The truth is, if you need a statistican to "interpret" the results of a clinical trial, you are probably in trouble. A truly significant result would be obvious to all - what I would call the "duh test". What's that? Well, the answer to the question "Does this treatment help?" is so obvious and so clear that all one could say in reply is "well DUH!!!". Unfortunately, there are few cancer therapies that pass the "duh test", but incredibly enough, the developer of one such (Dr. Paul Sugarbaker) was a speaker at the CCA conference.

Before I get into Dr. Sugarbaker's presentation, I will give a simple example of a "Horrobin's Horror" style clinical trial specifically for colon cancer. This past October, there was a meeting of the European Society for Medical Oncology. Some of the attendees were discussing the benefit of giving Camptosar or Oxaliplatin to stage II patients following colon resection. They concluded:

"At best, the incorporation of irinotecan or oxaliplatin into modern adjuvant therapy regimens will increase absolute survival in stage 2 disease by approximately 5%. If the addition of biologic agents can eke out another 5% absolute survival advantage, the trials designed to confirm this will need to enroll upwards of 6000 patients, making the current trial enrollments quite pitiful indeed"

AT BEST a 5% increase in survival. Optimistic indeed considering the ZERO percent increase in survival seen thus far with 5-FU/LV chemotherapy. As noted in the abstract,

Conclusions: We found that in real world practice a substantial minority of stage II colon cancer patients receives adjuvant chemotherapy; but there appears to be no evidence that the treated patients realize survival benefit.

Dr Paul Sugarbaker "Surgical Treatment Advances"

Dr. Sugarbaker is well known in the medical community for his pioneering work in the use of Heated Intraperitoneal Chemotherapy

Does it work? Well, according to this paper in the Japanese Journal of Clinical Oncology 31:573-583 (2001) Sugarbaker is getting 5 year survival rates of 50% with colon cancer patients who historically are well known to have a zero 5 year survival rate. DUH!!! See what I mean? Do you really need a 6000 patient trial to tell what is going on?

There is actually an online article by Dr. Sugerbaker that parallels his presentation very closely - It's What the Surgeon Doesn't see that kills the patient! Key point: "It is likely that surgical skill is a more important determinant of prognosis than the aggressive nature of the cancer or its stage at diagnosis".

Elaborating on this, Dr. Sugarbaker discussed the wide range of varibility in surgeons when it comes to recurrence rate for colorectal cancer. He showed a graph of recurrence rate by surgeon - which differed by as much as 50% (Sugarbaker dubbed the guy on the high end "Dr. Death")! He suggested that one might want to inquire about recurrence rates for your particular surgeon before agreeing to an operation - and that you might want to be SURE that your surgeon uses Total Mesorectal Excision for his rectal surgeries.

You are more likely to get a good surgeon at a major, NCI cancer center. Local hospitals are much more iffy, especially if the surgeons there are not board certified and/or have not performed rectal surgeries on MANY patients with successful outcomes. Going to a major cancer center can help you avoid the sort of disasters experienced by patients such as Ann Lory Pawelski who was unfortunate enough to be treated by "local doctors" without a clue which end is up.

Some surgeons view chemotherapy as a remedy for "bad" surgery; Sugarbaker sees this as totally wrong. As discussed below, chemotherapy just isn't good enough to make up for surgical mistakes (e.g. failure to get good margins, tumor spills during surgery, etc.).

Takeaway message from Sugarbaker's talk? "The most important prognostic factor is the surgeon!".

Dr. John Marshall "Advances in Treatment: Oncology"

Dr. Marshall is an oncologist at the Lombardi Cancer Center (Georgetown University in Washington).

Oncology is kind of a strange profession - in the grand scheme of things, I'm not sure what benefit oncologists have been for most stage IV colon cancer patients. After all, 5-FU chemotherapy has been the "mainstay" of colon cancer therapy for 40 years, but it cannot cure stage IV disease - except in an exceedingly small number of patients. It has around a 1% 5 year survival or "cure" rate, as was noted in this ASCO 2002 abstract 693 .

Even in stage III patients, there is only about a 10 to 15% improvement in "cures" caused by 5-FU/Leucovorin as has been noted in many peer reviewed articles, e.g. see Abstract PMID: 11441937 .

This can be interpreted as follows: if 100 stage III patients have their tumors surgically removed, then 50 of them are cured outright with no further treatment. Of the remaining 50 who are NOT cured, 10-15 would be cured if they take 5-FU/LV chemo, and 35-40 will NOT be cured even if they do take the chemo. In other words, all 100 patients are "supposed" to take the chemo, but only 10 get any benefit from it. Surgery is thus the most efficacious treatment for any stage of colon cancer, and chemotherapy is the least. Surgery is the easiest therapy to recover from, and chemotherapy is the hardest.

The "new" Camptosar and Oxaliplatin (which, incredibly enough, was "discovered" in 1969) have not to my knowledge changed this basic fact but may have extended the survival in stage IV by a couple months.

Despite the dismal efficacy of chemotherapy in treating colon cancer, there is little understanding among the general public about this fact as noted at the ASCO 2001 meeting. Consider for example the following ASCO 2001 Abstract 1542 ("The Goal of Chemotherapy: Little Agreement Between Patients and Their Doctors") and the sanitized version here

"When doctors identified the goal as palliation, 67% of patients thought that the goal of treatment was cure. However, in those cases where the doctors identified the goal as cure (20%), agreement with their patients was high (93%). When the doctor and patient agreed on the goal (45%), patients had higher expectations for success than their doctors - 80% vs 60% (p<.001). Twenty-three percent of patients did not know the likelihood of achieving the identified goal of the chemotherapy. Sixty percent of patients did not know how long they might live without chemotherapy, or how much longer they might live with chemotherapy"

NOTE: There are certain cancers such as testicular which can be cured even in late stage by chemo a la Lance Armstrong, but they are the exception and not the rule.

Anyway, going into this talk I thought Dr. Marshall might be discussing the new TRICOM vaccine (see also here and here ) that he has been experimenting with recently at Lombardi, and although briefly mentioned this was unfortunately not his main focus. I found Dr. Marshall to be a good speaker, gave an entertaining talk and he even brought up some of the key reasons I don't like oncologists in his discussion!

The presentation began with a slide of an old "Far Side" cartoon (Gary Larson), I recognized it right away as one of my all time favorites. It depicts his main character Doreen studying her textbook for vet school. The textbook is open to chapter 12, "Equine medicine", which has a long list of "ailments" and following each the same remedy: "shoot the horse!"

Marshall pointed to the cartoon and said "This is what colon cancer oncology USED to be", referring to the fact that 5-FU has been the primary treatment for over 40 years until the recent Camptosar and Oxaliplatin approvals. He then attempted to put a cheery spin on these new drugs, but personally I find it hard to get enthused about the 2 and 3 month "improvements" in stage IV survival time they apparently offer. He presented the survival curves you can see in figures 1 and 2 of the Camptosar Package Insert , which compare Camtosar as a second line therapy to "Best Supportive Care", or BSC. BSC means "doing nothing", or no treatment.

Now, Marshall didn't say it, but I have always wondered if there might be a type of Nocebo Effect going on in these trials, i.e. the BSC arm is really a Nocebo arm. After all, in a true placebo controlled trial, the patient does not know if he is getting study drug or placebo, but obviously in this Camptosar trial the patients knew whether or not they were on BSC. You tell patients in the BSC arm that they are being "sent home to die", and think that has no effect on their psycological state and will to live? It is well known among those who work with the dying that they can to some extent chose when to die , i.e.

"We know that many people can chose the actual moment of their death. Everybody can talk about a grandmother who waited for a grandson to come, or a grandparent who waited for their grandchild to be born. Dying people are very focused on particular dates, they may choose to avoid Christmas or wait for a wedding anniversary, that sort of things. Dying people can also speed up their dying and die sooner than we thought because the time is right for their family"

and it would not be unreasonable to think that this could add or subtract a couple months from their survival. If you wanted to remove the Nocebo Effect from the trial, what you would have to do is give the BSC arm some sort of actual placebo pill, telling them that it was a "powerful nontoxic cancer drug" which might be able to help. Of course, that would be viewed as highly unethical (although in practice I would question whether it is really any more "unethical" than other stuff they apparently think is "ok").

That being as it may, Marshall didn't spend long on the recent "advances" in colon cancer oncology. The parts of his talk which really perked my attention were his discussions of cancer politics, stuff which is not usually obvious to Cancerworld new arrivals. Specifically, Marshall mentioned the so called "Chemotherapy Concession", also the topic of an extensive article in the NY Times (Jan 26, 2003) . The basic problem is this:

"Typically, doctors give patients prescriptions for drugs that are then filled at pharmacies. But cancer doctors, known as oncologists, buy the chemotherapy drugs themselves, often at prices discounted by drug manufacturers trying to sell more of their products, and then administer them intravenously to patients in their offices"

The reason this is a problem is that it causes a conflict of interest between the doctor and the patient. It is in the doctor's financial interest to administer as much intravenous chemo as possible. Does this influence his/her decisions about how long patients will be continued on chemo that is not working? Would it influence the scan schedule to determine whether or not a chemo is working? Is it the reason why "Sixty percent of patients did not know how long they might live without chemotherapy, or how much longer they might live with chemotherapy" in the ASCO abstract discussed above (doctor has no motivation to explain to a stage IV patient that Camtosar will extend survival by a couple months so they don't do it?). Would it influence a doctor's decision about whether a patient should be given a new oral chemo such as Xeloda instead of IV 5-FU/LV? Well, this has already been suggested in journals aimed at oncologists, for example the Medscape article Oral Oncology Products: Barriers to Successful Adoption

Another topic Marshall spent some time on is the differences in colon cancer treatment between US and European oncologists. A good reference is Chapter 3 of Michael Lerner's book "Choices in Healing" ( Full Text Free Online here ). He noted that European oncologists have been experimenting with continuous infusion regimens (chemo delivered by pumps worn by the patient instead of the "bolus" shot given in the oncologists office), but oncologists in the US have shied away from this because of the unpleasantness they perceive in patients having to carry around the pump/be permanently attached to it. Trials have shown CI to have fewer side effects and hinted at possible improved efficacy (stage IV survival time), but Marshall observed you cannot compare survival times between US and European trials. He noted that Oxaliplatin was available to European oncologists as a "salvage therapy" (2nd line), whereas US patients had nothing (Camptosar had not yet been approved). This may have inflated the European survivals and given the illusion that CI is "better".

There is also a version of continuous infusion called Chronomodulated Therapy where chemo is delivered by a continuous infusion pump but according to body circadian rhythms. CT has been studied in Europe for some time but has only recently appeared in the US (e.g. Dr. Block , Chicago). Marshall briefly touched on Chronomodulated therapy, but apparently thinks there is still a lot of uncertainty surrounding the "correct" timing of chemo delivery. Seemed to me the medical literature suggests otherwise (as shown here ), but that's just my opinion.

And finally, I will mention a passing statement Marshall made about whether Camptosar or Oxaliplatin "should" be used as first line colon cancer therapy. He came right out and said it probably makes NO DIFFERENCE! In which case, Oxaliplatin "ought" to be used first because it seems less toxic for most patients (neuropathy being the main side effect, whereas Camptosar causes a lot of GI problems for many).

Patty Delaney (Associate Director, Cancer Liaison Program for the Food and Drug Administration)

Patty Delaney is a Stage IV Hodgkins Lymphoma survivor whose life was saved by an NCI trial. Undoubtedly being a cancer patient herself has given her a perspective different from most at the FDA. As is true for many things, the FDA is neither all good nor all bad. For example, on the positive side I am sure the FDA has been a major reason for the increased quality of clinical trials seen during the last 20 years or so. But on the negative side, there are a lot of things about the way cancer research is currently being conducted (driven by the FDA) that need to change, and Patty seemed to recognize that.

Patty's talk opened with a cartoon showing a waiting room at the FDA with a big sign on the wall saying something like "Please wait here and a jack-booted government thug will be with you shortly". Of course, there are some who might not find that funny, thinking it hits a bit too close to home (but I'll just leave it there for this review!).

Anyway, the key problem with the FDA has been its rigidity in creating and forcing on others "rules" which have not always been in the best interests of cancer patients. A big fan of the type of large scale clinical trials Horrobin criticizes, the FDA has failed to recognize that the kind of research that works great in lab rats has often not helped patients. For example, see FDA Trials Cost Lives and Harvard oncologist Jerome Groopman's article from the New Yorker magazine, The Thirty Years War .

Given the unlikely prospect of a "silver bullet" which can cure cancer in a majority of patients, what is needed is precisely the type of individualized approach to cancer therapy that Horrobin took. But that's not in the interests of big business which drives most cancer research, as noted in Cancer Super Drugs 'Might Cost Too Much to Make' . What is even worse, as Horrobin said there may already exist drugs on the market or other nonpatentable compounds which could be successfully used in cancer therapy, but the clinical trials needed to prove this will never be run if a profit cannot be made by the trial sponsor.

"Personalized therapy" is the way to go. And there are several patient stories similar to that of Horrobin of which I will mention here.

One such story is that of a colon cancer patient, Dr. William Fair, head of the Urology dept. at Memorial Sloan Kettering for many years. According to Jerome Groopman, a Harvard oncologist who wrote a lengthy article about Dr. Fair in the New Yorker magazine, Dr. Fair refused (the then experimental) Camptosar chemotherapy in favor of multiple surgeries and alternative medicine. Although eventually dying of his cancer, he survived far longer (5 years metastatic) and with a MUCH higher quality of life than expeienced by most patients who follow "FDA recommended therapy", e.g. see this obituary by Ralph Moss.

Another cancer survivor who has a lot of interesting comments is Ben Williams , diagnosed with "terminal" Glioblastoma in March of 1995. He wrote a very good book about his experiences (especially see the customer review by James Dabbs III at the Amazon site).

So - what is wrong with the FDA? Well, it has been Too Slow To Approve New Medical Drugs And Devices - also see The Cancer Drug Delay . During Delaney's discussion, someone in the audience brought up the fact that Oxaliplatin had been approved by dozens of countries before it was available in the US. There was the usual hemming and hawing about "why" this happened (yes I know, its "complicated"), but the bottom line is that there was evidence out there that oxaliplatin WORKED as part of a curative strategy in a large percentage of patients - see e.g. this abstract abstract (Ann Oncol 1999 Jun;10(6):663-9 PMID: 10442188)

Specifically:

"RESULTS: In 151 patients, the size of liver metastases decreased by > 50% in 89 patients (59%) and median overall survival was 24 months , with 28% surviving at five years (20%-35%). Surgery with curative intent was attempted in 77 patients (51%), complete resection of liver metastases was achieved in 58 patients (38%). The median survival of the 77 operated patients was 48 months (25-71), with a five-year survival rate of 50% (38-61)"

DUH!!! That means you can use it to HELP cure people. But the FDA focused on "Horrobin's Horror" large scale trials of CUD ("Chemo Until Death") patients, many of whom probably weren't considered for potentially curative surgery, even when possible. For a more complete list of Oxaliplatin links ,see here Also see the related articles For Officals at the FDA, Drug tests can be a trial (discusses the history of Oxaliplatin from the FDA reviewer viewpoint) and FDA Must learn to use common sense

Delaney attempted to counter by bringing up the fact Iressa was recently approved in Japan (but not US), and has had "a number of patients die because of it". Of course, what she negleted to mention was the PERCENTAGE of patients dying from the drug - 39 out of 10,000 as of Oct 2002? Compare that to 5-FU, which has mortality rates between 2-7% !

Other FDA stupidity involves the forcing of "1 drug at a time" testing. For example, even though Judah Folkman had little success without combining angiostatin and endostatin in animal testing during the 1990's, to this day he has not been allowed to combine these drugs in patients as noted here . Given that drug cocktails are usually far more effective than any of the ingredients for most chronic diseases (e.g. AIDS), one might think that could be tried a bit sooner. But no, that would violate the "rules"! Dr. Folkman says:

"we found the most dramatic effects in mice when endostatin and angiostatin were used in combination, but the FDA will not allow to use both drugs together before the end of phase II, maybe early phase III [large-scale, with many human patients] of the trials. Moreover, we have evidence that the drugs would work better if given at an early stage of the tumor"

Note too the point made in the second sentence - referring to the "rule" that patients must "exhaust all conventional options" (e.g. FDA approved chemotherapies) before being allowed to try far less toxic experimental therapies, even though the approved chemos only extend survival by a couple months as shown in clinical trials. By the time a patient has gone through standard therapy, his/her cancer has become highly chemoresistant and unlikely to respond to any further therapy.

Another big problem is that FDA policies are shifting the focus of innovative cancer treatments outside of the US and into Europe. This report, The FDA and Radiology by the Radiological Society of North America goes into some of the details. Some examples are:

Hyperthermia.

Hyperthermia has long been known to Intensify the Effect of Chemotherapy and Radiation , however it has not been applied much in the US for "deep seated" tumors (abdomen/pelvis) as would be seen in colon cancer patients . The first location for BSD's new 3-D MRI hyperthermia machine was Erlangen University in Germany. In 2000, other European cancer centers got BSD 2000 machines . Went to Japan in 2001. See the pattern? Other BSD references may be found here BDS Press Releases

Stereotactic Radioablation

Long used in Sweden, Stereotactic Radioablation is similar to the "gamma knife" precision radiation for brain tumors. There are only a few centers in the US which know how to do this type of therapy. Here are some recent articles about the use of SR for Liver tumors and Lung tumors .

Whole Liver Irradiation

Italian researchers are trying new techniques such as removing, irradiating, and replacing the Liver which have the potential to CURE disease limited to that organ.

There are many who bemoan the lack of participation in clinical trials by cancer patients, but the reasons really aren't too hard to figure out. The trials are terrible! Until you go outside the paridigm of "Horrobin's Horror" or what I have heard referred to as "Coke vs Pepsi" testing of one ineffective chemo regimen against another, this is unlikely to change.

Most patients do not have the resources, knowledge, and abilities of a Dr. Fair, a Ben Williams, or a Dr. Horrobin to seek out nonstandard, individualized treatments which may be far less toxic and have a far better chance of "working" than the "FDA recommended and approved" therapy. By its rigid rules and red tape, the FDA has contributed significantly to the lack of choices for cancer patients. I think that that this control needs to be loosened so that "terminal" cancer patients are freer to go outside the box and choose the therapy THEY think is best instead of what OTHERS think they "should" do.

Gail Inderwies "End of Life Issues"

No great revelations here, but thought I'd give a few references in addition to those of the presenter. See Death and Dying links

Conclusion

All in all, a great conference! Everyone I spoke with was very favorably impressed. My only suggestion for future conferences might be that at least one dinner (say on Saturday night, mid conference) be included, even if it increases the registration fee a bit.