Although it’s uncommon, hypertrophic osteoarthropahy, or HPOA, is an odd and therefore memorable syndrome that can be a side effect of lung cancer. It features an abnormal proliferation of skin and bone tissue, primarily in the hands and feet. Patients can develop clubbing, which is most commonly associated with NSCLC (up to 1/3 of patients) more than SCLC (only about 5%), and adenocarcinoma in particular. Here’s what it looks like:

Other features include a buildup of bone in the ends of long bones, and sometimes an effusion (fluid collection) in the joints, particularly large joints.

   Patients will often feel painful joints (arthritis/arthopathy), which can look a lot like typical arthritis, particularly when the pain precedes clubbing.  But in some cases, that joint pain is an early symptom of lung cancer.   What’s interesting is that if patients with an early stage NSCLC and HPOA undergo surgery, their joint pain can resolve pretty much as soon as they come out of surgery (imagine coming out of lung surgery with less pain than you started with!).

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   One of the basic concepts of oncology is that you treat patients with different drugs once they’ve shown progression on a treatment, rather than continue that a patient has presumably become resistant to.  However, there are some exceptions to this: many or most women with breast cancer continue the antibody herceptin (trastuzumab) even after progression, adding it to one chemo and then the next, and the same is often done with avastin in colon cancer and sometimes lung cancer as well.  In the past few years, there has been interest in whether the patients who respond well to an EGFR inhibitor like tarceva (erlotinib) or iressa (gefitinib) should continue on it for a while or even forever after showing the first evidence of progression on an EGFR inhibitor.

    It may help for us all to take a step back and remember that the goal of improving survival and slowing the progression of a tumor may occur not only if the cancer is shrinking or even if it’s holding steady.  If the cancer might potentially be growing quickly, even slowing the progression may translate to an improvement in how a patient does.  In the lab, basic scientists examine the growth of a cancer in lab animals and consider it beneficial if the cancer progression is slower over time when a new treatment is added, compared with a placebo or some alternative approach.   But in the grading system oncologists use, we don’t discriminate between slow progression and faster progression — it’s just considered a disappointment and time to move on.

 (Click to enlarge)

  The point is that imperfect brakes is better than no brakes.   In fact, in some settings of especially effective treatments for other cancers, some investigators noticed that patients who were progressing slowly on a previously very effective treatment showed a rapid rebound progression when they stopped the treatment (as if they jumped from the blue line to the yellow line in the figure above).  So a few years ago, the folks at Memorial Sloan Kettering Cancer Center (MSKCC)studied a small number of patients with either EGFR mutations or a prolonged response to EGFR inhibitors who were showing some progression (abstract here).  They did CT scans and PET scans right before and right after patients took a planned three week break from their EGFR inhibitors, and they also assessed how these patients were feeling.  After restarting their EGFR inhibitors and repeating scans and checking patient symptoms, they added another novel agent called everolimus, an mTor inhibitor (see prior post for discussion of the novel agent approach of mTor inhibitors alone and combined with EGFR inhibitors).  For the more visually oriented, this is the overall design of the complicated trial:

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   In my last post I wrote about the prognostic value of molecular markers like EGFR and K-Ras that have generally been studied in patients with advanced NSCLC and treated with EGFR inhibitors, but these studies looked at prognosis in patients with early stage NSCLC who underwent surgery.  These studies also provided some interesting results on the prognostic value of some clinical variables as well.

   The Japanese surgical series of 397 patients with resected adenocarcinomas (abstract here) reported several associations of survival with clinical variables, as shown in the figures below:

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Some of these findings are very intuitive.  In the top right, we see that patients with stage I adenocarcinomas have a far superior survival to patients with higher stage cancers.  Since staging is designed as a method to predict prognosis, these results corroborate what we’d expect.  I’ve also written a prior post about more poorly differentiated cancers being associated with a worse prognosis than better differentiated cancers, as is shown in the bottom right panel.  And there has been a growing collection of evidence that, as a population, women with lung cancer have a more favorable prognosis, stage for stage, than men (see prior post), as shown in the panel on the lower left.

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  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:

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   As I introduced in my last post, the superior vena cava SVC syndrome occurs in about 2-4% of lung cancer cases, and lung cancer is the leading reason for it.  One of the most important factors in managing it is to determine, usually with CT imaging, the cause of the SVC syndrome — generally whether it’s caused from tumor or a blood clot, such as around a catheter. 

   To recap, the appearance of a CT scan may look like this, with the large vein known as the SVC compressed between the tumor (in the lung, which is black) and the mass of lymph nodes toward the middle of the chest:

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   If this is an initial presentation and there is no diagnosis yet, it’s important to get tissue as one of the first steps.  The symptoms usually develop over weeks, and studies have actually shown that it’s rare for there to be significant consequences in taking the time to complete the workup and figure out the cause, rather than just frantically start treating without knowing what you’re treating.  The treatment of choice depends in part on whether this is SCLC, NSCLC, lymphoma, or something else.   And just jumping in with something like radiation can make it hard to determine the actual diagnosis later.

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Warning: this symptom can be a little gross, so the delicate flowers out there should skip this post.

One of the more unusual but quite vexxing symptoms we sometimes see in lung cancer is called bronchorrhea, which is the copious production of watery sputum, specifically at least 100 ml per day. The setting in which it’s most frequently seen is in bronchioloalveolar carcinoma (BAC), and we typically think of it as being a manifestation of the mucinous subtype. In its worst form, patients can drain vast amounts of phegm each day, typically worst in the morning. Patients have told me that they lean their head down off the bed to drain a half a liter or more at a time before starting their day. Though rare, there have been frequently cited cases that have been life-threatening because of severe electrolyte imbalances that develop from losing so much fluid and salt (case report here). Interestingly, there’s a sheep virus that appears clinically remarkably similar to BAC (though there hasn’t been a human form of the virus ever isolated, despite searching), and I’ve seen video footage of researchers demonstrating bronchorrhea by lifting the hind legs of the sheep into the air, putting a beaker under its nose, and letting the watery mucus drain out for several minutes. Sorry, I told you this post has some indelicate moments. I don’t think that video’s on YouTube yet.

Unfortunately, bronchorrhea is a very difficult symptom to treat effectively. Among the things that have been tried and were written up as possibly successful in individual cases have been steroids (abstract here), inhaled indomethicin (a non-steroidal anti-inflammatory drug)(abstract here and here), a drug called octreotide (reference here), radiation therapy to the most “consolidated” area of lung (reference here), and most recently EGFR tyrosine kinase inhibitors like iressa (full text here, another abstract here, and there are several other reports out there).

The ideal situation is to treat the underlying cancer effectively, rather than just the symptom.   In that sense, the EGFR inhibitors are pretty unique in being the best treatment if a particular person’s BAC happens to respond.  Based on the fairly large phase II studies that have been done with iressa and tarceva in BAC, the response rate with this class of drugs is in the 15-25% range (see prior post for review).  So for the patients who respond to an EGFR agent, it’s a potentially dramatically helpful treatment for a long time.  For the majority of patients who don’t respond to one of these agents, the others are things that can be tried, but most of what’s been reported is a single case of a treatment that worked, not a trend of multiple cases.  In truth, it’s probably never going to possible to run a study and enroll 20 patients to get a particular treatment, because bronchorrhea is an uncommon symptom of an uncommon disease.  But these are a few things that people may try, and I’d be very interested if there are people out there who have had success with any of these approaches.  Another one I’d be inclined to try, although I’ve never seen mention of it being done before, is inhaled lasix, the effective diuretic, which is an approach I’ve heard of hospice folks using to treat secretions.

In the meantime, bronchorrhea is often unpleasant, sometimes scary, and potentially life-threatening complication that nobody sees enough to become an expert at managing.

   One issue that everyone with lung cancer faces, but that we haven’t covered before, is the duration of a lung cancer work-up.  I’ve worked in a range of treatment settings and see patients for second opinions who come from very different backgrounds and receive their work-ups through completely different medical systems.  In that process, you see some patients who receive a stunningly fast series of tests and a short interval from first suspicious finding to diagnosis and ultimate treatment of cancer.  Reading the documentation of someone coming for a second opinion, it pains me a bit to see that someone was first found to have an abnormal x-ray 9 months before their diagnosis, because they were told it was likely nothing, or they were told nothing at all, only to lose 40 pounds before someone realized somthing might really be wrong.  On the other hand, it’s impressive to see patients who have a brisk workup and initiate treatment rapidly.  It’s certainly pretty common to have someone get a course or two of antibiotics for a few weeks after an ambiguous chest x-ray before any alarm bells go off, but how long is too long?

    A couple of recent studies are now reporting some observations from different health care systems.  One comes from the Veteran’s Administration (VA) system here in the US, which is the closest our country has to a single payor health care system, which lends itself to collecting a broad array of data from many institutions.  The report (abstract here) describes the results from a huge chart review of 2463 patients with newly diagnosed lung cancer in around 2005 from 133 different VA hospitals.   They found that there was a median of 72 days  from first imaging finding to the start of treatment, with one quarter going out more than four months.  There was a trend toward much shorter intervals between first imaging and treatment in patients with advanced (Stage IV) disease, at 48 days, compared with 95 and 98 days for stage I and II, respectively.  Stage III patients had a median interval of 69 days before treatment started.

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   My name is Robert Resta, and I’m a certified genetic counselor working at the Hereditary Cancer Clinic at Swedish Cancer Institute in Seattle.  Dr. West asked me if I might provide a few general comments about the genetic contribution of lung cancer. 

   In truth, this is a complicated question. There is little doubt that more than 90% of lung cancer can be directly attributed to tobacco use.  The tendency to smoke cigarettes runs in families, and relatives of smokers often have greater exposure to second-hand smoke, making it very difficult to tease out genetic factors from environmental influences.  Research studies on genetic and familial factors have produced conflicting results and conclusions.

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   Some members had previously asked about a breath test to detect lung cancer, and at the time I was not familiar with this work.  But research has been ongoing with a new test designed by Menssana Research to detect lung cancer (LC) by noting a pattern of volatile organic compounds (VOCs), essentially chemicals in exhaled breath, that characterizes people with lung cancer but isn’t seen in other people (recent summary papers here and here).  In fact, VOCs are present in the air around us, and in the exhaled breath of people who don’t have cancer, but the technique used by the company involves using a complex computer analysis to detect patterns of VOC concentrations that are common to LC patients but not seen in people without cancer.   Here’s the summary of their hypothesis for this work:

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   I’ve been involved in a wide range of discussions, both here and in my own clinical, about the fairly common situation of how to approach a situation in which the story on paper and what you see actually happening are incompatible.  For instance, last week I and several of my colleagues participated in a journal club (a group discussion of a new and/or controversial journal article or two), in which the topic was the potential utility of doing surgery for unusually early small cell lung cancer tumors.  We’ve also had several recent questions about patients in whom the diagnosis of bronchioloalveolar carcinoma (BAC) is being considered, and it’s not clear whether to treat this sometimes very indolent cancer as a full-fledged NSCLC, a non-entity that might sometimes be ignored, or as a separate category worthy of being managed differently from the standard approaches for other NSCLC subtypes.

It’s important to highlight that the discrepancy between the expected outcome based on a pathology report and the clinical picture in front of you can cut both ways.  In some cases, you may have a biopsy of a lung nodule that shows no cancer, but if it’s growing and continues to grow, that’s not very reassuring, and you’d suspect that the biopsy missed the diagnostic part of the tumor that would confirm viable cancer.  In other settings, a biopsy of a lung nodule might diagnose cancer, leading down a path toward the typical management with surgery, etc., but if you happened to have old films that showed that the nodule was actually minimally changed over 3 years or more, it might be reason to take a step back and wonder whether you haven’t already been furnished with some valuable information that might lead you to individualize and change your treatment plan.

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