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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   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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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 »

Several members here have asked questions on the discussion/Q&A forum over the last several months about the potential value of continuing treatment, usually tarceva, in the setting of mild progression. Our general rule in oncology is that if someone shows that a tumor is growing (in trials, generally defined as any new cancer lesions or a 25% increase in the size of measured lesions being followed for response) you stop that treatment and consider it ineffective. In actual clinical practice, we don’t usually make precise measurements and usually just discontinue a chemo regimen or other strategy any time the progression is convincing, not looking for a 25% increase. But there are a few exceptions that we make routinely in oncology. Patients with breast cancer who have tumors that overexpress HER2/neu, the protein target of the antibody Herceptin, usually continue on Herceptin from one line of chemo to another and another when they demonstrate progression on a chemo/Herceptin combination. Men with prostate cancer who are on lupron, a hormone therapy that blocks testosterone production, are generally continued on lupron to reduce the rate of progression even after their PSA is consistently rising on lupron alone, generally adding new treatments to the lupron. And patients on Gleevec for GI stromal tumors may respond initially to one dose, then become resistant, and again respond to a higher dose level of the same agent. So there are exceptions to the rules, but we generally haven’t operated that way in lung cancer. Read the rest of this entry »