Cancer 101
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The second part of my interview with Dr. Kristin Manning (part 1 here), expert radiologist at Seattle Radiologists, follows up on the basic principles of the cancer workup and turns to the limitations of our ability to clarify tough lesions. Understandably, many patients and caregivers are frustrated to learn that after multiple imaging studies, from a CT to a PET scan to an MRI and sometimes more, we still sometimes can’t say with certainty whether a questionable lesion represents cancer or something else. How could that be? Dr. Manning discusses how a tough lesion appears questionable despite plenty of good scans and smart radiologists trying to interpret them. Along with discussing the frequent benign lesions that cause anxiety for patients and their doctors as we try to sort them from cancer, she also discusses the still open question about risk from radiation involved in imaging for cancer.
As always, you’ll find below the audio and video versions of the podcast, along with the transcript and figures.
dr-manning-pitfalls-in-cancer-imaging-audio-podcast
dr-manning-pitfalls-in-cancer-imaging-transcript
dr-manning-pitfalls-in-cancer-imaging-figures
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Posted in: Imaging and Response Measurement, Screening Issues and ControversyDisclosure: There is only one company, Veridex, (a subdivision of J&J) that currently markets a commercial assay for circulating tumor cells. My research group is in the process of formally finalizing a research collaboration agreement with Veridex.
I receive and have no plans to receive payment of any kind, including salary, honorarium or research funding from Veridex.
What are circulating tumor cells (CTCs)? Leukemias as a case in point
Circulating tumor cells, or CTCs are just what they sound like: cancer cells that circulate in the bloodstream alongside normal cells such as white blood cells, red blood cells, and platelets. The classic examples of circulating tumor cells are the leukemias, or blood cancers.
As every criminal starts his or her life as a baby then crosses the line into criminality somewhere along the way, every cancer cell starts its life as a normal cell. Leukemia cells start as bone marrow cells. The normal job of bone marrow cells is to provide blood cells, so it’s no surprise that leukemia, by its very nature, circulates in the blood. This gives leukemia a unique property—it can be biopsied every day with extremely minimal risk to the patient, because the biopsy entails just a simple blood draw. For this reason, leukemias were the first cancer to have detectable CTCs — the technique is called flow cytometry.
Posted in: Cancer 101An article by Dr. Nancy Keating, from Harvard School of Public Health, in the journal Cancer discusses the issue of when physicians who treat patients with a terminal diagnosis discuss prognosis, preferences for extraordinary measures or a “do not resuscitate” (DNR) order, ideas about hospice, and where patients would prefer to have their death. Guidelines developed by the National Comprehensive Cancer Network recommend that physicians discuss these issues for patients who have a prognosis of less than a year, but what do physicians actually do? The relatively scant information on the subject suggests that physicians vary greatly in their styles.
To answer this question themselves, the investigators send out questionnaires that they received back from over 4,000 physicians, non-cancer physicians, medical oncologists, surgeons, and radiation oncologists. Specifically, they asked physicians when they would bring up the issues of prognosis, DNR preferences, hospice, and preferred location of death for a hypothetical patient with an estimated survival of 4-6 months but who felt well now. Options ranged from the time of the initial visit (”now”) to a point in the future when the patient was symptomatic, or there were no further feasible treatments, or when a patient was hospitalized, or not until the patient and/or family brought up these issues. The investigators also asked about physicians’ experience with managing terminally ill patients and how confident they were in their knowledge about managing terminal care issues for patients.
Posted in: GeneralDoctors interested in taking care of cancer patients must complete specialized training after their residency in internal medicine. This subspecialty training is called a fellowship and usually involves training in both hematology (study of blood disorders, including abnormal clotting and bleeding) and oncology (cancer). These two areas are pretty different, leading some to question why they are not split up into two completely different specialty training programs. For those of us who end up taking care of patients with solid tumors, we often question whether all of this hematology training has much value in our day to day practice.
Increasingly, though, links between clotting and cancer are emerging. As I result, I find myself going back to something that I found a lot less interesting during my training than I do now: the clotting cascade.
(click on image to enlarge)
Efficient clotting has been essential to our survival: without it, we would risk fatal bleeding with every scrape. Defects in this system lead to the disease hemophilia (Greek for loves to bleed), a disorder characterized by prolonged bleeding after minor trauma. Advances in the treatment of this disease have been a direct result of knowing which clotting factor (denoted by the roman numerals in the figure) is missing and then replacing it.
Posted in: Cancer 101, Cancer TreatmentsThere was a time when oncologists learned the latest information about potential risks of cancer and new treatment ideas at major cancer meetings. Nowadays, we’re likely to first learn about these issues from a news report (and often in the business section!) or from patients directly. What’s particularly challenging is that these stories are often reported in extreme terms: Is coffee an amazing anti-cancer treatment or a deadly toxin today? What’’s the miracle cancer treatment of the week?
Most oncologists, including those offering insights here, probably seem very conservative in their responses when patients and caregivers come into the office or write in with breathless excitement about the latest report in the mass media about the newest treatment (see Dr. Weiss’s post on “How to Vet a Treatment Idea” for a balanced perspective). Yes, the person on 60 Minutes (or the 11 o’clock news, or Oprah, or whatever) said it was incredibly promising, but the regular reports of miracle treatments have been far more likely to be mirages than revolutionary treatments.
Posted in: Cancer 101, GeneralI’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
I treat cancer for two and only two reasons. I want my patients to live longer and with a higher quality of life. All other measures are surrogates, and that includes cancer growth or shrinkage. For years, oncologists focused on survival as the primary outcome of trials. We assumed that any therapy that could knock down cancer would also make patients feel better. In fairness to the older trials, this assumption often was right. When cancer grows, it can cause such terrible symptoms that even a therapy with bad side effects can lead to a better quality of life than if the cancer was left untreated. However, as our drugs have improved, we have become pickier and now demand that new drugs not only knock down cancer better, but also have fewer side effects. Most new trials incorporate robust measures of both side effects and quality of life. Some trials even seek improvements in quality of life as their primary endpoint.
Every patient has different priorities and values, but I keep hearing the theme of “quality over quantity” from a sizable portion of my incurable patients. I think that most of my colleagues, including trialists, now acknowledge the importance of quality of life in palliative therapy. However, this recognition has lagged in potentially curable disease, whether the cure is attempted via chemoradiation or surgery plus adjuvant chemotherapy. With this issue in mind, two recent trials in the Journal of Clinical Oncology (JCO) are heartening.
The first study is derived from RTOG 9801. This trial randomized patients receiving chemoradiotheray with curative intention to receive amifostine or placebo. The goal of the trial was for amifostine to decrease the toxicity of radiation. Unfortunately, the trial was negative, with no difference between the amifostine or placebo group in survival, toxicity, or any other measure. However, the trial did teach us an unexpected but very important lesson.
Since the trial was negative, the amifostine and placebo groups are equivalent and all patients in the trial can be evaluated for other prognostic factors without regard to assignment to receive amifostine or placebo. When this is done, the most important prognostic factor predicting for survival is patient-reported quality of life at the beginning of the trial. The yellow curve below represents patients with an above average quality of life at study initiation and the blue curve patients with below average quality of life. You could drive a Mack truck between the survival curves with the yellow curve representing survival of patients with a score above the median, and the blue curve representing patients with a less than average score.
(Click on image to enlarge)
I learned long ago that one case well-studied can be worth much more than a number studied less well. A case in point: some years ago, a fellow oncologist was caring for a man with advanced non-small cell lung cancer. The patient was then lost to follow up, then later presented to the hospital in coma from very low thyroid function, which is termed myxedema coma. After he was given thyroid hormone [TH] and awakened, it was found that there was no evidence of his lung cancer [!]. Subsequently he died a few years later of unrelated causes. My friend became curious and has since, for the past 25 years, dedicated himself to finding if there was a cause and effect.
His efforts have been rewarded because there is now a growing body of literature showing that TH, while not actually causing cancer, may act in a permissive manner on existing cancers. It seems that many cancers have on their outer cell membrane a great number of receptors for TH. When TH is present in the system, it attaches to this receptor. What are called growth signals are then sent from the receptor through the cytoplasm to the nucleus, allowing the cancer cell to multiply by dividing. Such receptors are, in addition, found in abundance on the blood vessels which feed the cancer. This, too, leads to more cancer because more blood vessels feeding the cancer is the result, leading to progression of that cancer. Normal cells also have such receptors but in far lesser numbers.
Now, in this country, many patients, more often women than men, are given TH for a number of reasons, including fatigue, weight reduction, or a clinically insignificant degree of low thyroid function. This is usually discovered by a routine blood test called TSH [thyroid-stimulating hormone]. Any level more than 5 is considered abnormal. When the level is 5-10, many doctors feel that it is necessary to give TH in order to get the TSH level back below 5. The American Thyroid Association, however, does not feel this is necessary because almost no one has any symptoms at a level of 5-10. In fact, many individuals feel just fine with TSH levels much higher than that. When they are then given TH, they feel no different.
Posted in: Cancer 101, Cancer Treatments, Multikinase inhibitors, Supportive careOK, I hope you all aren’t bored to tears by this topic by now, given two related posts in April and again earlier this month describing the “broken” clinical trials system and the challenges to performing clinical research in the current environment. However, I thought this would be a good follow up post to let all of you know that the laughably obstructionist policies in place that prevent timely processing of clinical trials are being recognized, and that something is being done to fix it.
Clinical trials designed to test new cancer therapies are the only way that potentially effective drugs can make if from research labs into cancer patients in dire need of help. In April I talked about a couple of recent papers (see link above) that documented the complicated process of opening a clinical trial, involving hundreds of distinct processes in the bureaucratic morass of review, and taking multiple years from submission to trial opening.
In an early release publication in the Journal of Clinical Oncology, a group led by Dr. Razelle Kurzrock at the M.D. Anderson Cancer Center in Houston describes a new streamlined process for getting a phase I trial approved and the first cancer patient enrolled in what must be a record time (aptly called “Project Zero Delay”). This paper begins with a very interesting review of the myriad problems with the current system. For example, the authors note an average of 4-5 years for a company to take a new drug from the lab through enough initial safety studies in animals to get to clinical trials. After that, there is another 7.5 years before a promising drug makes it to FDA approval! All of this while over half a million people per year are dying of cancer in the USA, and of course millions elsewhere. The group then describes many of the same details I mentioned in my initial post about the delays in getting a specific trial opened.
Project Zero Delay focuses just on this aspect of the problem, namely getting a single new trial open. MD Anderson took it upon itself to also look at the exorbitant delay in opening trials, and designed a plan to fix it. The first step MD Anderson took was to negotiate a master agreement with a particular pharmaceutical company that would cover all trials over a 3-5 period, designed to overcome the months of budget and contract negotiations that normally take place for a new trial.
Most of the remaining problems with this process can be related to sequential levels of bureaucracy. In other words, drug companies, academic institutions, and the federal government each have an enormous amount of steps necessary to produce what is known as an Investigational New Drug (IND) application and then to open the trial, and these operations are usually done sequentially (one after the other) rather than simultaneously to be efficient. Project Zero Delay was designed to have all regulatory processes happen in parallel rather than sequentially, so that when the final OK came from the FDA the trial could open immediately.
The protocol described in the paper was designed cooperatively with the company and the MD Anderson principle investigator (PI). As the PI of a number of trials myself, I can tell you that the way it normally works is I write a protocol and then send it back to the company for review. This can then start a back and forth review and re-review process that can literally take years. In this paper, the authors were able to streamline this by having the company and PI cooperate at the inception of the concept so that the protocol could be completed fast. Read the rest of this entry »
Posted in: Cancer 101, Current Clinical TrialsThanks to GRACE member speedpuppy for highlighting the link to a New York Times article on the one of the key obstacles to meaningful progress in cancer management being the difficulty of getting clinical research completed. It discusses challenges from both the patient and physician perspective. Only about 3% of patients in the country enroll on clinical trials, and in lung cancer it’s lower than that. Not suprisingly, clinical trial participation is heavily skewed toward academic centers, so many community practices participate in little or no clinical research.
There are certainly challenges from the physician perspective. The leading one is that clinical research is generally a financially disadvantageous option for a physician and a practice. Clinical trials tend to take much more time per patient than managing patients outside of clinical research. They often provide the same or less money than the cost of running the trial for each patient. They also require more attention to following the precise treatment plans of a protocol. Larger research centers require extra nurses and administrative staff to oversee the details of clinical trials, and this is a significant investment. And the paperwork involved is a royal pain, requiring time that many docs just don’t feel that they have.
From the patient perspective, some people are very wary of being a “human guinea pig” in clinical research (a mindset fostered by some media outlets trying to generate controversy), and in the US in particular, patients are often extremely wary about participating in clinical trials with a placebo for some patients, even though a placebo-controlled trial is often the best way to really learn how effective vs. toxic a new treatment is. In truth, many of the most important trials in cancer are now done outside of the US, where more patients are willing to accept some uncertainty, and partly because the alternatives may be less favorable. Importantly, trials may require considerable effort to find, and they often entail travel to participate, for unclear benefits. Finally, it’s also important to note that many patients who want to participate in trials are unable to do so because they aren’t eligible, often due to prior treatments or other medical problems. A recent study that did a chart review in the Kaiser system in California found that only 15-30% of patients there were eligible for various clinical trials in advanced NSCLC.
The idea for restricting eligibility is to provide a more homogenous population of patients with an anticipated similar prognosis. However, trials often include restrictions that are unnecessarily limiting. This can leave patients without options and slows the pace of our progress in the field.
Posted in: 3
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