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Selection Bias, Eligibility Criteria, and Interpreting Trial Results (or, a little cynicism can be a good thing)
My kids are right in the middle of that time when they watch SpongeBob and see commercials for toys, cereals, and music, nearly every one is puncuated at the end with, “Daddy, can we get that? I want that.” There comes a time in everyone’s life, hopefully early on, when we learn that we won’t actually find eternal bliss with every advertised item. Juicy Fruit gum loses its flavor in about 10 seconds, Pepsi doesn’t actually make you hip, and the urinating feature of the Betsy Wetsy doll actually loses its appeal (though anyone who changes real diapers probably don’t see the appeal of paying for this feature). Learning that advertising makes things seem better than they really are is a truism we all need to learn.
The harsh reality is that many press releases and newsroom puff pieces about supposed cancer breakthroughs are pretty akin to TV commercials. Some represent true, meaningful benefits, but there are a few valuable rules that can help us determine which ones are more sizzle than steak. Many of these stories are planted to manipulate people, specifically to generate buzz, to lead doctors to change their prescribing habits or to get patients to ask for a particular treatment. Here are two key caveats worth bearing in mind to help discriminate fool’s gold from the real deal:
Surveillance and Salvage Strategies
Or “What I Say vs. What I Do”
The current recommendations from the American College of Chest Physicians is for patients who underwent treatment with curative intent for lung cancer, and who are still healthy enough to be a candidate for any further aggressive treatment if needed, should undergo repeat doctor visits every six months for two years, and then annually after that. These surveillance visits should include a review of how they’re doing, physical exam, and some kind of chest imaging (chest x-ray or chest CT). Now, we know that chest CTs give a lot more detail than chest x-rays, and at least in theory more frequent visits and imaging could pick up a recurrence or new cancer earlier, but so far there isn’t any real evidence that patients who undergo very frequent surveillance do better than those who see their doctor rarely.
I personally tend to have visits about every 4 months after surgery for the first year, then every 6 months for up to four years, and then annually after that; after chemo and radiation, I will often follow patients with visits and scans every 3-4 months initially, although I can’t point to the evidence, but these patients are at high risk for recurrence, and occasionally we find a local recurrence after chemo and radiation that can undergo surgery for the solitary area of viable cancer. Is this in the guidelines? No. And I have just a couple of patients who are alive many years after initial treatment with no evidence of disease, after a surgery that followed chemo and radiation, and I honestly think they are now cured. Unfortunately, that applies to only a very small percentage of my surgical or locally advanced chemoradiation patients, but it motivates me to continue with a policy of close surveillance. And let’s be honest: even if an aggressive treatment isn’t curative, and the cancer returns in several locations after surgery or radiation to a focal area, I don’t know a patient who regrets pursuing an aggressive approach that we felt could be curative at the time.
I’ve mentioned in the limited literature on precocious metastases (prior post here) that there are associated with a minority of patients remaining alive 5 years later, after surgery for a single brain metastasis or adrenal gland metastasis, for instance. It may be that the aggressive, surgical approach is curative. The problems is that it may also be that there is something very different in the biology of a metastatic cancer that has only a single area of metastatic cancer vs. one that has spread all over. If the cancers that present with a single metastatic focus move far more slowly than other cancers that have multiple liver and bone or brain lesions, maybe we’re congratulating ourselves about what we’ve done, when really what we’ve done is just cherry pick the people who have the best prognosis and then take credit for how they’re doing.
Several people have asked about situations of aggressive salvage surgery or radiation on the Q&A Forum section. I think you need to balance hope and desire to be aggressive with reality. I don’t believe you can be “downstaged” from stage IV and then have surgery to residual areas of disease. The “great saves” have more commonly been people with a curable stage of disease that has a single area of residual disease, not metastatic. It also makes more sense if you’ve followed a patient for months or years and are only seeing one area of cancer over a long time. Seeing a good result for the first time could still mean that it’s coming back in multiple areas the next time you look. It makes much more sense to pursue aggressive salvage strategies if time has shown there isn’t anything new that will likely pop up before the patient has recovered from surgery or radiation. And I also think it makes 10 times more sense to be aggressive against a single area of viable cancer than to do surgery on two or three areas. We’re trying to thread a needle by acting as if a single area of metastatic disease represents the ONLY area of metastatic disease. This is very rarely the case. Finally, I think it’s much more reasonable to push the envelope if the treatment can be tolerated well than if it’s going to be a life-threatening challenge. Stepping outside of typical treatment patterns is less problematic for well-tolerated focal radiation than for a right pneumonectomy. And it’s much more problematic to consider that major surgery for an 85 year-old who had a heart attack last year and is on oxygen than it is for an otherwise healthy 55 year-old.
Next: PET scans for surveillance after curative treatment for lung cancer.
Treatment of Recurrences Detected with Surveillance
I have a remarkably delightful patient who initially developed a stage I NSCLC in 1998, and this was treated with standard surgery. Three years later, she was found on a routine follow-up scan to have disease in her mediastinum. This was biopsied and was found to look remarkably like her original cancer from several years earlier. At that time she received concurrent chemo and radiation, with curative intent. She did well with that, but unfortunately, a couple of years later she developed a single brain metastasis. This was treated with gamma knife stereotactic radiosurgery, and she hasn’t had any evidence of active disease since then.
Although I am tempted to steal credit for her remarkable story, I actually didn’t meet her until she came to me for follow up in 2003, when I started in my practice at Swedish Cancer Institute. I’ve always had the easy part. We obtain CT scans and head MRI scans, now just yearly, although frankly I’d prefer to see her more frequently because she’s a highlight of my day when she comes in.
I wish there were more patients like her. So how do we do with cancers detected after initial treatment?
As mentioned in my last post, most recurrences of treated lung cancer are distant metastatic disease, outside of the chest. But as in the case above, most recurrences in the chest are treated with a non-surgical approach, often radiation. There really isn’t much evidence on this issue, but it is possible to cure, just pretty unlikely.
Surgery is certainly an option for some patients and tends to be more feasible in patients who develop a metachronous second primary cancer (new cancer, later time vs. original), but it’s not common. After an initial potentially curative lung surgery, patients have considerably reduced pulmonary reserve and are less likely to be able to tolerate the loss of more lung tissue with another surgery. And it’s still hard to catch a cancer before it’s spread beyond the surgical range. If surgery is performed, it’s not associated with as good a prognosis as an original lung cancer of the same stage. However, the 5-year survival rates for resected stage I NSCLC in a patient being monitored for recurrence are in the 30-53% range, as shown in the table below:
(Click on image to enlarge)
These numbers are definitely not as good as a stage I patient with no history of prior lung cancer, but they still clearly illustrate that there’s a reason to follow patients after initial treatments. Recurrences and new cancers do develop, and they can be cured. Regardless, I find that most patients don’t need a lot of convincing that it’s worth keeping in close contact with their doctor for follow-up. It’s fair to say that there’s a huge amount of variability in practice styles about follow-up, and I think we all struggle to use good judgment even when we don’t have much evidence. But the few cases of the “great save” of a recurrence after initial treatment compels many of us to push aside the absence of data and do the best we can groping with good judgement and minimal data.
Follow-up Guidelines for Lung Cancer
I’ve had a series of questions about how frequent follow-up should be for LC after surgery for early stage disease, or potentially after chemo and radiation for stage III disease. The most appropriate answer to to say that there is really essentially no data on this subject, so people have made up guidelines based on little more than rationale and intuition. As you’d expect with this basis, the guidelines have differed substantially. One publication from the American College of Chest Physicians (ACCP) just came out on the subject (abstract here), in which they included a couple of tables to review the topic.
First, the goals of follow-up are worth reviewing. They basically include management of the acute side effects of the treatment, looking out for recurrent cancer, and surveillance for a new, different cancer.
We’ll go over things like the patterns of recurrence and the ability to treat recurrent cancer with curative intent, but it helps to start with the guidelines that have come out thus far. They are listed in the chart below, from the recent ACCP publication (click on it to enlarge):
The abbreviations are listed on the figure, but to highlight, the organizations are the Association of Community Cancer Centers (ACCC), the American College of Chest Physicians (ACCP), the American College of Radiology (ACR), American Society for Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and the National Comprehensive Cancer Network (NCCN). The most interesting points to highlight is that they don’t agree on the specifics, but they all weigh heavily in favor of checking the patient history (any new symptoms?) and performing a physical exam looking for problems. Several don’t even feature ANY imaging studies, some citing that there’s no evidence that a chest x-ray (CXR) or CT scan improve outcomes. The only ones that highlight regular use of a CT scan are ACR and the NCCN. Several others have guidelines that include NO regular imaging. Not surprisingly, they all take into account that the risk of recurrence is greatest early on, so the rate of follow-up is highest in the first 2 years, then drops to rather minimal by five years out.
I think many members will be surprised to find how minimal the recommended follow-up is, particularly in terms of imaging (no group recommends CT scans more than every 6 months, and NOBODY is recommending PET scans in the follow-up setting.
We’ll review some of the justification, or at least what little is known about recurrence risks and survivorship in some upcoming posts.
Stable Disease: Is the Glass Half-Empty or Half-Full?
Over the past several years, oncologists have experienced an evolution in the way we think about stable disease, at least in the context of lung cancer. Historically, oncologists have graded our work by looking at response rates, or the percentage of patients with tumor shrinkage of 50% or more of their lesions as measured in two dimensions. We considered a drug or combination to be “active” if it had an “objective response rate” (ORR) of 15% or more, and we generally discarded approaches that had a lower ORR than that.
But largely as a response to the recognition that some targeted therapies may potentially halt tumor growth but not significantly shrink or kill a cancer, we’ve come to acknowledge that achieving stable disease can translate to a valuable clinical benefit for patients (as in, patients are likely to live signfiicantly longer). Of course, we all want to see tumors melt away, but at least in the setting of advanced lung cancer, having the cancer shrink just a little or just stay the same for several months at a time is a real improvement over the natural history of what the cancer would do, which is grow steadily over time. We also often see that patients who have chemo with or without radiation before surgery sometimes show no significant tumor shrinkage, but after surgery we find that the tumor contains mostly or only dead tumor cells. So again, stable disease underestimated clinical benefit of treatment. Continue reading
Using PET Scans to Predict Response to Chemo in Advanced NSCLC
PET scans have become well established in initial staging of lung cancer and many other cancers, but another setting in which they may emerge as useful is in assessing response to treatment. Some oncologists and patients are already doing this, but the standard test most commonly used for measuring response is the CT scan, which is widely available and has the benefit of years and years of experience. We grade our work in oncology by looking for tumor shrinkage. The percentage of patients who have an “objective response” of tumor shrinkage by 50% is one of our key endpoints when we describe a treatment for cancer, but we now know that it is definitely very possible to have patients live longer without having major tumor shrinkage. Cancer without any treatment is definitely going to grow, so even keeping it stable in size can appropriately be considered a relative improvement. I’ll describe the evidence showing survival benefit in the setting of stable disease in a dedicated post soon.
But the issue here is the concept that either before a CT scan is able to detect changes in size, or in the event that there is no obvious change in the size of a cancer mass on CT, the PET scan may detect decreased or increased metabolic activity that can help us determine whether the treatment is helpful or futile. Even if nobody wants to learn that a treatment is ineffective, if it is causing side effects without the real promise of benefit, it makes sense to abandon that futile treatment earlier rather than later. And now that we have a growing number of treatments available for advanced NSCLC, we might consider it increasingly important to not waste our time, strength, and money on treatments that aren’t going to provide a benefit. Continue reading
Molecular Signatures in Lung Cancer: A Growing Trend of Individualizing Treatment
Today we cannot predict the behavior of individal patient tumors and need to overtreat some patients and undertreat others. However, the science behind lung cancer has now moved a step forward by identifying a “molecular signature” of key genes that may predict patient survival. This week’s New England Journal of Medicine (NEJM) included a very provocative manuscript by a group in Taiwan that studied tumor tissue from a series of patients who had surgery for NSCLC and identified five key genes that could help them separate those with a good prognosis from those with a poor prognosis. Similar to a prior NEJM article from a research group at Duke that identified a large collection of genes that distinguished better prognosis and worse prognosis patients with early stage NSCLC, the article this week by Chen and colleagues out of Taiwan was designed to do a better job than just relying on our current staging system to predict clinical outcomes for patients with lung cancer.
Their technique was complex, and these results need to be reproduced widely before this approach becomes established and incorporated into clinical decision-making. But there were certainly robust differences between the two groups they identified by molecular signatures. The median survival was twice as long in the low-risk group as in the high risk group (40 months vs. 20 months), and there was a more than doubling in the median relapse-free survival (29 vs. 13 months for high- vs. low-risk, respectively).
I’ll review some of how they came to this point, but even trying to simplify this, it’s pretty scientifically complex. You may want to take some Tylenol in advance. Continue reading
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