Cancer 101
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Loading ...I’ve been impressed by many things about GRACE and its members. Among these many things are the thirst for new information and better treatments. I also admire the openness of the members both to new ideas, and to questioning these ideas.
Some new ideas succeed and, after careful evaluation, truly advance care. Others fail. As a clinical trialist, I regularly evaluate ideas to consider a clinical trial. Discussion with cards7up led me to realize that it might be helpful to share this thought process with this group—on behalf of yourselves and your loved ones, you vet ideas from the popular media, friends, family and the world wide web. I hope that these thoughts can help you to do so with more confidence.
This slide is from a talk that I gave a few weeks ago to a patient group in Philadelphia. It shows the four basic sources of ideas for a trial:
• Laboratory data
• Clinical observations
• Alternative Medicine
• Successes in other cancer
Some people might be surprised to see alternative medicine as an idea source. It is a common misperception that Western doctors are not open minded to alternative medicine. Taxol started as the bark of the Pacific Yew tree, ginger is gaining acceptance as a nausea treatment, and acupuncture has found a variety of roles in mainstream medicine. What I am closed-minded to is treating patients routinely with something whose efficacy and safety are unproven. So, new ideas are good, as long as they’re tested properly. We first take a new idea to the lab, and learn everything we can about how it might work. We test it on cancer cells in a dish. If it’s the next cure for cancer in a dish, we take it to animal testing where we test for efficacy, safety and dose. If it looks like the next magic bullet for rodent cancer (again, I can’t tell you how many times we’ve cured cancer in various rodent models) then the idea can start the clinical trials vetting process.
The vetting of a trial starts with a funding source. The investigator writes a proposal to the NIH, a pharma company, or a foundation laying out all of the data leading to the proposed trial and explains the basic structure of the proposed trial. If the funding source finds the idea promising and chooses to fund it, the investigator will next write a protocol. The protocol is a detailed guide for how a trial will be run. Once completed, it is submitted to a scientific review board. The job of this committee is to evaluate if the idea has sufficient scientific merit and promise and to ensure that the clinical rationale is sound. If they sign off, it next goes to the institutional review board (IRB) who ensures that the study is ethical and protects human subjects. If they approve the study, it may open, with either a data safety monitoring board (for large trials) or a medical monitor (for small trials) monitoring the trail to ensure subjects’ protection. Finally, at completion of a study, the results, positive or negative, should be presented and published.
Okay, so that’s how an investigator thinks. What about a practicing oncologist faced with an onslaught of new ideas published in various journals, presented at various conferences, and promoted in the media? How does a doctor, working a gazillion hours a week seeing patients choose what to read and what to believe? How does he or she evaluate a paper?
First, it is key to understand the idea of levels of evidence. Different ideas about how to treat patients have different levels of proof behind them. I’ve summarized these in the trial ladder below.
My next major point also answers the question of why your oncologist has never heard of the great new cancer therapy that you read about on the internet, or even the news. Given finite time, we want to read (and you should value most highly) the best, most proven papers. How do we know which ones they are? There’s a hierarchy of prestige levels in the cancer journal world, and authors try to get their papers accepted to the best possible journals. While I’m sure that oncologists will argue about which ones are best, , here’s my opinionated, very rough guide for clinical trials in lung cancer:
• Top tier: Journal of Clinical Oncology (JCO), New England Journal of Medicine (NEJM), Lancet, International Journal of Radiation Oncology Biophysics (”Red journal”)
• Second tier: Journal of Thoracic Oncology (JTO), Chest, Lung Cancer, Journal of the National Cancer Institute (JNCI), Clinical Lung Cancer, Journal of the American Medical Association (JAMA)
Often worth of reading: Other peer-reviewed, medline-listed medical journals
There’s also a hierarchy of conference presentations, with the American Society of Clinical Oncology (ASCO), the European Society of Medical Oncology (ESMO) and the World Lung Conference at the top. Note that findings usually first come out at conferences, then are published in journals — it should raise a red flag if a study is presented but never published.
So, to summarize, it might be worth reviewing brief criteria to know if an idea is worthy of routine implementation. We read high-quality journals. We then evaluate the findings presented and mentally place it somewhere on the trial ladder shown above. Finally, if we’ve accepted the idea that the data is true, we then start the more comprehensible process of asking if the difference is big enough and if it’s worth the toxicity.
In the end, properly vetting an idea is challenging even for trained oncologists. We meet in journal clubs to discuss new findings and we discuss them with colleagues. Those more pressed for time can turn to review articles and conferences. In these media, trusted experts summarize the data and give their interpretation. Time consuming? Yes. Difficult? Yes. But the stakes are high—failure to move a promising idea forward denies better therapy to patients in need. Treating patients with untested therapy denies them more promising therapy, risks toxicity, and denies the opportunity to move properly-vetted concepts forward to advance care.
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Dr. Weiss,
Thank you for an interesting and informative post. Though we are all anxious for the next breakthrough treatment, your post helps me stay grounded amid the media hype and “not ready for prime time” preliminary results of new therapies.
It also makes me appreciate just how difficult it is for oncologists to stay at the breaking edge of new treatments without adopting a new idea to soon or too late.
Jim
JimC
Dr. Weiss -
Thank you for an interesting, informative post. It’s good to get an idea of how oncologists think. Your list of trustworthy journals is useful. I hope that my oncologist follows a similar strategy. I agree with Jim: It must be difficult for practicing oncologists to stay at the “breaking edge of new treatments.”
- Catharine
Catharine
Great post, very helpful. Thanks!
Andy
Andy
Dr Weiss,
Very Informative and well presented.
Barry
Great info!
Can you tell me how long the vetting process takes place? For example: On average, how long does it usually take to get approval to do the clinical trial, how long do the clinical trials phases I, II, and III take to complete and publish, and how long does it take to get FDA approval?
Overall this process sounds very time consuming before a promising “Animal tested” drug can be used by an oncologist. In incurable cancers like SCLC (after relapse and Chemo-resistance), can an oncologist use a drug that shows promise (such as a case study, or do they still have to wait for Phase II, Phase III trials, and/or FDA approval to use it?
rachelk
It’s quite variable, but the short answer is that it’s typically a matter of many years to go from animal models to late clinical trials and FDA approval. It depends on how quickly trials can get enrolled and how dramatic the benefit of treatment proves to be, but it’s going to be 8-15 years or even more to go from lab to widespread patient use.
Short of that, if an agent is already commercially available, an oncologist or other physician can potentially prescribe it, and physicians will have varying degrees of inclination to pursue ideas that are still unproven and not standard. There is a real risk that these treatments may be harmful. There is also the question of whether insurance companies will pay for unproven treatments, especially ones that are expensive and that will, therefore, compete with many other potential treatments to be covered that are more likely to be beneficial to patients.
Thank you Dr. West. If a treatment doesn’t exist that is known to benefit a patient, like relapsed Chemo-resistant SCLC is it unethical or illegal to try unproven treatments or do patients have to enter clinical trials if they want to pursue that line of treatment? Another question that I have is about clinical trials. Do patients actually have to move to the place carrying out a clinical trial or can the patient’s oncologist prescibe the medication that is being tested in the clinical trial and follow the procedures etc. so that the patients can still remain at thier current treatment facility?
Thanks, Rachel
rachelk
These are all great questions. Some drugs take longer to go from science to popular treatment than others. In part, it depends on how good the treatment is. The recent story with EML4/ALK and PF-02341066 (covered extensively on GRACE) is a good example of a fantastic treatment going through this process much faster than typical. Drugs with small benefit (say, the cetuximab story, also covered on GRACE) tend to move slower.
Unproven drugs that are FDA approved for some other indication are easier to use than non-approved drugs. Obviously the decision to do so requires careful consideration and patient education to decide together that this is the right thing to do. Here, the major obstacle is getting the drugs for the patient–insurance often balks.
You ask about both legality and ethics of giving unproven therapies when there are no other options. I do believe in offering this to patients. However, I think that the above vetting process should still be done so that what is given is the most promising available thing. And it should be done in a trial (typically, this kind of conversation centers around phase I trials, which are often first in man). My reasoning for feeling this way is that we should learn if the drug is truly safe and if it truly works. If so, having done it in the phase I trial allows us to know that we need to move forward with phase II, then phase III, and ultimately using the new therapy to help everyone to whom it applies. If the drug does not work, and especially if it is harmful, then we want to learn and disseminate that too–no one else should get the drug, and we should move onto new ideas.
You also ask about locations of trials. Some trials can only be done at large centers with the capacity to do special kinds of infusion, run special kinds of tests, and be ready to quickly address complications during infusion. Other trials can be opened at other centers. I just opened a head and neck trial simultaneously at my hospital and two others and it may soon open at two additional sites, giving patients there access to the drugs. As more of the new drugs are oral, it becomes easier and easier to open the trials at more hospitals, speeding accrual time and providing access to more patients.
Finally, you ask about payment on trials. Many trials have some aspects that are identical to guideline standard of care (some of the drugs in the regimen, blood counts, imaging) and one or two elements that are unique. Typically insurance pays for everything that is part of standard of care (and yes, they actually do in practice) and the trial pays for everything else (the experimental drug as well as any tests needed for the trial that are not normally part of standard care).
Dr. Weiss,
To clarify regarding the location of trials, is it generally true that if one wishes to remain at their current treatment facility then the trial must be opened at that facility?
Jim
JimC
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