Progression-Free Survival (PFS) as a Primary Endpoint: Pros and Cons

  There have been several good questions recently about the importance of progression-free survival (PFS) as a key endpoint in our clinical trials.  In fact, there have been more trials recently that have assigned PFS as the “primary endpoint”, the main variable that the trial is designed to test to see if there is a significant difference (as described here).  There are several advantages to PFS, including the fact that it takes less time to get an answer about whether your treatment changed the outcome.  Feedback is provided without a need to follow patients after the end of the treatment.  This also highlights another potential advantage of PFS as an endpoint: that it’s “cleaner” and not subject to the diluting effects of subsequent treatments given off protocol, after the end of the study treatment.

    But this is also a potential weakness.  Most oncologists, and I believe also many patients, report that the most important effect of a treatment is to improve survival, weighed against by the side effects of treatment.   So if a treatment improves progression-free survival for a first line treatment, but subsequent treatments make up the difference and overall survival (OS) is the same for both groups, it’s fair to question if it’s worth subjecting patients to a treatment with side effects and extra cost if it doesn’t improve OS. 

   Another key point is that PFS, like response rate, is defined with some rigid definitions based on measuring the dimensions of particular lesions, and the rules don’t always match perfectly with the more complex situation of the real world.  There is usually some discrepancy between the median PFS in a trial as measured by the investigators (who do tend to see their results through the prism of their expectations and hopes for a patient) and those of independent investigators.  Overall survival is far less controversial.

    But the other key issue is that, unlike overall survival, progression-free survival tends to be clustered in the times when you look for it on a scan.   As described in a recent paper (here), if scans are done every eight weeks and the actual progression takes place between scans, the time of the scans will overestimate the actual time of progression:

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The Myth of Targeted Therapy, or, Why are there side effects, anyway?

   Targeting cancer cells and missing all of the normal tissue is the Holy Grail of cancer therapy.  It is the cancer equivalent to the perfect diet:  eat everything you want, never exercise and stay perfectly skinny and fit.  Doesn’t happen in metabolics and doesn’t happen in cancer therapy.  Yet, to hear radiation oncologists or medical oncologists talk, you would think that all of our therapies are super precise.   Let’s consider each in turn, but being a radiation oncologist I will spend more time on that.

   Therapeutic radiation beams given from outside the body (as opposed to brachytherapy –otherwise known as implanted radiation or “seed therapy” in prostate cancer, which will not be considered here at all) are like visible light waves, but much higher energy.  Like visible light, the physics of therapeutic radiation beams has the same wave/particle duality that make theoretical physicists lay awake at night.  From a therapeutic perspective, though, the fact that the beam “travels in a straight line” is useful for it allows us to point the radiation beam at the tumor and miss the adjacent normal tissue (like using a knife to cut a bruised part out of a piece of fruit).  However, like that bruised piece of fruit, the knife has to start on the outside of the fruit and cut deep enough to get out the bruise—if the bruise is deep, all of the fruit from the skin down to the bruise will also get cut away.  In cancer therapy, this means that all the tissue from the skin down to the tumor “sees” the radiation beam. 

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Praying at the Altar of Statistical Significance

    One of the things that I found regrettable about the parallel universes in which information is provided for doctors vs. other information for patients is that there is a different language and frame of understanding that is used for these separate conversations.  Patients may be seeking opportunities and don’t need incontrovertible evidence that a fourth or fifth line therapy is valuable, while many oncologists strive to be data-driven and offer treatments with proven value.  This site is filled with example after example of me and other faculty members asking, “what is the evidence for one treatment approach over another?”  I’m a doctor, and I speak from the perspective of a doctor, but I think this is helpful for patients asking why their oncologist favors a particular treatment.   They can see the way the docs think.  I’m not saying that’s entirely right, but it provides a framework for reading off of the same sheet of music.

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Controversies about Screening, Not Just in Lung Cancer

   Although there are many controversial topics in the management of lung cancer, it’s hard to think of another issue that incites emotion as much as the debate about lung cancer screening.  After describing some of the pitfalls and arguments made by detractors in a prior post well over a year ago, I received multiple impassioned comments that made me feel as if I had described methods for torturing kittens, even though I was really more trying to just explain some of the cons as well as some of the pros of lung cancer screening.  And part of the issue is that there are relatively unquestioned screening programs for other common cancers like breast, colon, prostate, and cervical cancer, leaving many in the lung cancer community feeling singled out as a “less worthy” cancer for screening efforts.

   An article just out in the New York Times (here) that discusses some of the problems with cancer screening, and it actually doesn’t focus primarily on lung cancer, but rather more on prostate cancer, where a group of experts are now recommending against using the prostate-specific antigen (PSA) blood test to screen for prostate cancer in men over 75.  This is because of evidence that many patients with prostate cancer have an indolent form and competing medical problems that make it considerably more likely that the cancer will not limit their survival.  And the treatments for prostate cancer can cause erectile dysfunction, urinary incontinence, and other side effects, so it’s likely that many men undergo unnecessary procedures with risks of significant adverse effects.   And so while there continues to be controversy about the value of screening younger men, the conclusion of the experts is that men over 75 are not likely to be helped by PSA screening.

   Now I realize that the vast majority of people reading here are more focused on the risk of lung cancer.   The reason I highlight this article is that it describes concerns about screening in general, not just in lung cancer, and it emphasizes that while it is counter-intuitive to even consider not doing everything possible to detect a cancer earlier rather than later, there can be negative consequences of screening.  The article even mentions that we may look back at PSA screening as having done a real disservice to the screened population.  I have previously noted that while we generally think of lung cancer as aggressive and threatening, the more complex reality is that there are some cancers that are far more indolent, and it may not be necessary or even beneficial to chase these down in every patient, particularly those with significant other medical problems.   I have a few 80+ year old patients who underwent a lobectomy for a very tiny (few mm) BAC lesion that grow by 1-2 mm over a couple of years, and though they continue to do well from a cancer perspective (and I may be more than happy to take credit for it), I think they would have likely continued to have done well even with the cancer still there and growing incredibly slowly while they contended with other, more threatening medical problems.

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Developing an Index of Abbreviations and Glossary of Terms in Cancer Medicine

I try to describe the terms in posts and comments, but some people had suggested a glossary of cancer terms and abbreviations that are commonly used here, on slides, doctor’s notes, etc. This is my first attempt to develop something fairly comprehensive, but I’m sure this isn’t everything. Please add your suggestions for terms or topics that would be helpful to add to this.

Once we get it pretty settled, we’ll make it a permanent link from throughout the site that people can access if they encounter an abbreviation or term that they don’t know.

Common Abbreviations/Glossary of Terms in Oncology

ADLs - activities of daily living

ANC - absolute neutrophil count, the absolute number of bacterial infection fighting blood cells – low means notably higher risk for infection

BAC – bronchioloalveolar carcinoma, a unique and uncommon subtype of lung cancer

CR – complete response (after treatment), leading to no evidence of disease (NED)

CT – computerized tomography, “cat scan”, a detailed look at the body at varying levels internally, “slice by slice”

CTCs – circulating tumor cells, in blood

CT/PET – a combined scan that does a simultaneous CT, which measures the shape and size of body structures, with PET, which measures metabolic activity. The images can then

CXR – chest x-ray

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Recommended Books for Cancer Information?

One of the members of GRACE’s Board of Directors who isn’t an oncology person asked me for a recommendation for a general book on cancer for the public. I didn’t have a good answer, because most of my reading has been for physicians, but it’s a great question. I like to think that we and the internet provide a lot of very helpful information for patients, but there are some books that can provide a very good overview of multiple cancers, a huge range of cancer topics, and also some books dedicated just to specific cancers like lung cancer.

Because I actually haven’t read these in any detail, I’d consider them more of a wish list of books I’d like to get to, and/or get some opinions from people who have read these carefully. I’d like to learn what books people have found the be the best resources, and perhaps we can add them to the sections on “other resources” in the new website, so please add your comments (they’re back up):

Everyone’s Guide to Cancer Therapy (5th Ed) is written by specialists on each topic, largely at Univ. of California, San Francisco. It has received great reviews on Amazon, and my read of much of the lung cancer chapter (at least, a good skimming) really showed that it was a very good general review, with less detail than we’d include here, but a very nice, brief summary — and I think pretty easy to find a few pages on what you’re looking for. Probably a great resource if you want a book of general cancer information and have family members affected by different types of cancer. Read the rest of this entry »

Survivorship by Dr. Jeannine McCune

Hello everyone, I wanted to follow-up on Dr. West’s post about cancer survivorship a few days ago. The term “cancer survivorship” can mean lots of different things to different people. In this post, cancer survivors are those patients who finished their cancer treatment and are now being followed to see if their cancer returns and if they have any long-term side effects to the cancer treatment.

One important thing for all cancer survivors is to have a summary of your cancer treatment. A one page summary about your specific treatments - surgery, radiation, and chemotherapy. There is no established guidelines for what the summary should state for lung cancer survivors. This summary will help you as time goes on and you get further away from your cancer treatment. It will also help other health care professionals taking care of you as it’ll be a quick summary of your treatment. Another important thing is to get the contact person and number for medical records of where you received your cancer treatment. That way, if you need to get your medical records, you’ll already know who to talk to.

In terms of what you can expect, there is very little information about long-term side effects to cancer treatments for lung cancer. Most of the information about cancer survivorship is obtained from adults who survived highly childhood cancer or from breast cancer survivors. Especially as we have more lung cancer cancer survivors, it will be really important that we get more information about their health after the treatment to try to keep healthy. A great example is the “how to quit smoking” post.

This is my first post, so please tell me if you need more information or explanation. I look forward to working with you all!

-Dr. McCune

Introduction to Paraneoplastic Syndromes

The topic of paraneoplastic syndromes has been on my “to do” list, but it has taken far too long… so let’s get to it.

Paraneoplastic means alongside cancer, and that’s because they are weird manifestations not of the cancer that are caused directly by the tumor but at distant sites from the cancer, such as by the cancer turning up the production of a protein or peptide (piece of a protein). They really aren’t being mass-produced as part of the cancer’s needs, but more of a side effect, just copying these genes that happen to be innocent bystanders. Another potential mechanism of these syndromes is stimulation of an antibody response by the body, and these antibodies against the cancer cross-react against normal body cells, turning the immune system against the body (causing an auto-immune disease). This is commonly against neurons in the setting of SCLC. The cells of origin for SCLC are neuroendocrine cells, so deranged cells starting as neuroendocrine can have features that look similar to the immune system to neurons, and the endocrine portion means that these cells have differentiated to have a good ability to package proteins and peptides. With that background, it shouldn’t be a surprise that SCLC is the most common form of cancer to be associated with paraneoplastic syndromes. And these can be associated with a HUGE range of symptoms from low serum sodium levels (caused from a syndrome of inappropriate anti-diuretic hormone, or SIADH) to neurological disorders like Lambert-Eaton myasthenic syndrome, and everything in between. Read the rest of this entry »

General Comments on Clinical Trials

In the past, we’ve covered some issues in clinical trial design and statistics, but it’s appropriate to take a few steps back and talk more generally about the clinical trials process. Clinical trials are the main and nearly only way for new drugs and approaches to be approved by the FDA and similar agencies around the world and become commercially available. Drugs are added to our standard treatment or compared head to head against them, and if the new drug looks significantly better and/or has fewer side effects, it is generally viewed favorably and may be approved for widespread use. This means that trials and their underlying process are a gatekeeper in development of new treatments for clinical use.

Over the past 10-20 years, cancer clinical trials in the US have gone from being conducted largely with government support to being primarily supported by private industry. The good part of this is that we have so many new drugs that are being generated by companies with a financial incentive (and arguably also a humanitarian one, but we can leave that debate for another time) to develop a great new cancer treatment. The cancer community wants and needs this as well. The bad part is that there are also many clinical trials done that aren’t designed to lead to cutting edge new treatments, but often to serve as marketing questions (asking if drug X should be given weekly or every three weeks is not especially interesting in most cases and is akin to me conducting a poll asking whether people would consider me to have boyish good looks or rugged good looks).

The sad fact is that there are many disincentives for oncologists in offering clinical trials these days. Generally under great time pressure already, oncologists need to spend more time discussing clinical trial options than recommending an “off the shelf” treatment. Extra meetings generated from the company overseeing a trial are also common. Clinical trials are often not profitable and sometimes are money losers for a clinical practice, when you factor in the extra people needed to support the infrastructure of the trials — nurses, data management people, etc. They also generate an insane amount of CYA paperwork — this is a highly regulated field, replete with crazy bureaucacy. It’s quite typical for me to need to sign 10-40 forms daily, like spending every day buying a mortgage. And trials force doctors to be less flexible than they would otherwise be in selecting doses and modifying treatments. Despite these factors, many oncologists do try to enroll patients on trials, as a labor of love if not in the financial best interests of the doctor or the practice. But if it’s a daily struggle to find the time to take care of all of the patients you need to see, clinical trials usually make it harder, not easier.

For patients, clinical trials often include several visits, tests, and often some paperwork. Patients may object to having multiple blood draws or EKGs over the course of a day or a week. And they often impose a delay in the start of treatment, because patients need to complete several extra criteria to enroll. For some patients (and oncologists), being forced to wait an extra week or two in order to obtain a test only needed for the study, or to “washout” the last drug given, is a deal-breaker. Read the rest of this entry »

Energy Machines as 21st Century “Snake Oil”: Anecdotes vs. Clinical Data

I have expressed a good deal of skepticism about certain aspects of complementary and alternative medicine (CAM), but I’d emphasize that CAM is a diverse array of approaches, some becomingly increasingly studied and accepted by more conventional (acupuncture, massage, potentially some supplements), while others (far more likely to be alternative than complementary strategies) continue to evade scientific scrutiny and probably should because they’re fraudulent and expensive.

The Seattle Times just ran a series of articles on energy medicine machines that was highly critical of these approaches as a modern day “snake oil”, a successful money-making scan without medical merit and that could be harmful directly or in keeping people from pursuing more conventional and proven helpful conventional medical treatments. This is pretty much a verbatim assessment of my take on this industry, but I would extend my skepticism and concern about opportunism (including any anticancer bracelet or other jewelry) and some brick and mortar alternative medicine centers.

This is also a topic that was covered in the ACCP guidelines about CAM approaches for lung cancer (abstract here). Specifically, the relevant evidence-based guideline reads as follows: For lung cancer patients, therapies based on manipulation of putative bioenergy fields are not recommended. Simple enough, and this is based on an absence of any evidence of a medical benefit from either biofield or electromagnetic energy fields. The idea behind biofield approaches is that these can modify the energy fields that surround and penetrate the body. Electromagnetic field therapies, as the name implies, are designed to use electrical fields and/or magnetic fields in novel ways. This work is based on research on how electromagnetic fields alter cancer risk, related to questions of whether exposure to power lines or cell phones increases risk of cancer (abstracts here and here).

The take home message is that there’s never been any evidence from any study that treatments aimed at manipulating biofield or electromagnetic energy improves survival. Read the rest of this entry »