Several users on a recent thread have raised questions about whether exercise after surgery or chemo and radiation is harmful, beneficial, or has no effect on outcomes among people with lung cancer.  Unfortunately, this field has so few answers that it’s easy to imagine doctors filling in the void with half-truths or less.  I explained that I had seen so little information on this subject that I couldn’t shed much light, but I’d try to dig up some information.

   There is really little to nothing out there on exercise programs for patients with lung cancer specifically.  The American College of Chest Physicians put out a set of guidelines ten years ago (article here) that really focused on the value of exercise programs for patients with chronic obstructive pulmonary disease (COPD), or emphysema, but not cancer.  Overall, the findings of various trials suggest that lower extremity exercise (ambulating) is beneficial, in terms of improved exercise tolerance, but no significant improvement in pulmonary function, and no detrimental effects appreciated.  Many of these programs also include some upper extremity (or, you may know it as the arm) training, and breathing training, with some support for increased arm function in these exercise programs, but no improvement in breathing function. So these studies in aggregate show convincing improvement in exercise capacity, in activity levels, but also psychological benefits with improved quality of life as activity levels increase.  A summary table of results from the article is shown here (grade of evidence summarizes the strength of the evidence, from A for very strong to C for rather sketchy and only suggestive):

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   Hello again!  Some of you may have wondered why any patient would choose to see an oncology social worker.  I thought I would take this opportunity to explore the top reasons why patients come to see me in the first place.  These are not in any particular order, except for the first one, so I won’t dwell on each and every one.  I will just bring them up, and if any of them strikes you as information you would to hear more about, please add a comment, and we can discuss it further.

1. I would say that the top reason is the one I wrote about in my first column.  The anxiety, stress, and fear concerning the diagnosis and treatment of whatever cancer they have been diagnosed with.  Will they be able to tolerate the treatment? What about the side effects?  How will this new intruder effect their lives?  Will they be able to work?  And most of all, what about their family?

2. Family concerns are always right up near the top!  No matter if a person is the bread winner, or the caregiver for children or elderly parents, or is a working wife in a two income family with lots of other family responsibilities: everyone in the family is bound be caught up in the patients needs for downtime, rest, transportation, companionship, and assistance with many of the daily events we all take for granted.  Children are always an important concern.  How much to tell them about the parent’s cancer?  What is the appropriate amount of information and what kind?  How to normalize their lives as much as possible when everyone’s life around them is falling apart, at least temporarily?

3. Work and Disabillity Issues.  Many people are able to work at least part time while on treatment, but many others are told by their physician that they probably should not work during this time.  Even if patients have short term disability, it will most likely pay for only 60% of their earned income if they cannot work.  If the family is a two income family and one of the earners cannot work, that will eventually lead to financial concerns, and I have rarely met a family that doesn’t experience these during cancer treatment.  If medical insurance is tied to the job, that also presents a problem, since most of us cannot afford to purchase health insurance on our own.  Some companies provide coverage, often known as COBRA, but others require workers on disability to pay for this insurance, and it is pretty expensive.  Some families have no health insurance, and this is often the reason they are referred to see me by their health care provider, since it is rare for treatment to begin until a thorough assessment of the insurance issues is made and it becomes clear whether the person is eligible for Medicaid or charity care or both, if the institution provides some charity care.

4. Caregiver issues.  How to talk to friends about what is really helpful, and how to organize a helpful team, so that what needs to get done in the household actually does get completed without too many tuna casseroles being dropped off, while the laundry piles up , and the floors go unvacummed!  Most of us are conditioned to not ask for help or to refuse it if it is offered.  Now is the time to say yes, and to be directive about what you need help with.  People do much better with providing assistance if there is an actual menu of tasks to choose from.  Always assume that the people offering really mean what they say and are happy to help.  Honesty about the family’s needs at this time can be a real gift to friends and relatives!

5. Recurrence of the disease, which can be a very real risk.  This is everyone’s nightmare!  There are many people who never see a social worker during their first experience with cancer; but if a recurrence happens, then often the patient feels as though they need to talk to someone objective about their situation.  The social worker can become a wonderful mentor during this time and may continue the relationship for years if the patient so desires.  During one’s first experience with cancer, most patients have great faith that their treatment will work and they will never have to go through this trauma again.  If there is a recurrence, hope is often more difficult to keep ablaze: if the treatment did not work the first time, what is there to guarantee that it will work the second time?  Depression is common at this time and the patient may require medication to treat their depression for awhile.  It is absolutely normal to feel depressed if cancer returns, but most oncologists, and certainly oncology social workers are trained to distinguish between normal sadness and true depression.

6. Marital or Relationship Conflicts.  A family that was dysfunctional prior to the cancer diagnosis will definitely need counseling, a group, or some additional attention by health care professionals, since whatever their dysfunction is about; it will be increased by the stress of the cancer experience.  Sexuality and intimacy issues will surface if they were not there already.  Certain types of cancers, such as those impacted by hormone treatment carry with them the probability of loss of libido, and chemotherapy and radiation both increase the patients fatigue levels to such an extent that just getting through the day may be all that the patient is able to manage.  If clear and open communication is lacking in the relationship, the couple may need some coaching in talking about their real feelings relative to how they are coping with the cancer in their family.  This is a huge topic and one I have barely skimmed the surface of, and even the most well-adjusted, loving couple may experience problems in coping, and are often embarrassed to discuss it.  However, it is also one of the most important!

7. Finally, people come in to talk about the whole spectrum of death and dying issues.  From the legal papers necessary to be completed, such as the Directive to Physicians, or the Durable Powers of Attorney, both Medical and Legal, to Hospice Care, or questions about what their dying process is going to be like – if the patient is thinking in this way, they will often come in to ask the questions that are troubling them.  Generally, patients will come in alone to discuss these issues, sometimes because they believe their loved ones are not ready to talk about this topic, or because they want to hear the answers themselves first, and then invite the family in for further discussion.  It is always interesting to see how many people try to protect their loved ones from this discussion, choosing to believe that the loved one is not already worrying about it.  Nothing is usually further from the truth, and most people are immensely relieved to talk openly and honestly about their end of life worries.

   Of course, the reasons that patients choose to see an oncology social worker are as varied as the patients themselves, but these are the most common topics of discussion. 

   What do you want to hear more about? 

   Let’s talk! 

-Leah

I asked Dr. Carolyn Dressler, a terrific expert on nicotine addiction and smoking cessation, to write a general post on how to approach quitting.  She’s actually a lung surgeon who also obtained a Masters in Public Health and now works as Branch Chief for the Tobacco Cessation and Prevention Program for the Arkansas State Governent.  She is deeply committed to helping people, and I think she’d also be illing to answer questions people may leave.  Here’s her guest post:

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   So, you’ve decided to stop smoking? It is probably the most important step you will take in your life! Your doctor has probably told you that one of the most important steps you can take to help with your diagnosis or to improve your health is to stop smoking. This post will help to guide you on how to do it! 

   First of all, let us review a few facts. In the above paragraph, we talked about stopping using tobacco – whether it is from smoking or smokeless tobacco. In the United States, the most common form of tobacco use, and its most deadly, is from smoking tobacco, usually in the form of cigarettes. Cigarettes have more than 4000 different chemicals in them and these include more than 60 cancer causing chemicals. It is no wonder your surgeon told you the most important thing you can do to help yourself is to stop smoking!

   Stopping smoking is usually a very difficult task.  You should know that what you are about to do is one of the hardest things you have ever tried. People smoke cigarettes because of the drug nicotine which is one of the most addictive drugs we have in our society.  You probably already know how hard it is, since most smokers have already tried to quit at least once or twice.  If it was easy, you would have done it already! (more…)

   Getting back to the issue of differences in side effects and efficacy of treatments based on differences in individuals and populations, let’s continue the story of how different populations appear to have significant differences in how the do on the same treatment regimen.  In a recent prior post I described the SWOG-Japanese research collaboration to compare treatment with the carbo/taxol combination for patients with previously untreated advanced NSCLC and the same eligibility requirements – these results demonstrated superior survival despite significantly greater hematologic toxicity in Japanese compared with North American patients.  Is this an isolated occurrence, and do we have any potential explanations for why we might see population-based differences? 

    When we look for it, we can also see racial/population-based differences in the setting of extensive disease SCLC.  In fact, racial differences may be very relevant, because several years ago a Japanese trial by Noda and colleagues was published in the New England Journal of Medicine (abstract here) as a potential change in the standard of care.  This study closed early, with only 154 patients enrolled, after showing highly significant improvements in response rate and, more importantly, survival for recipients of cisplatin/irinotecan vs. the older standard of cisplatin/etoposide (see prior post for further discussion).  Following this publication, the cisplatin/irinotecan combination for ED-SCLC was widely considered to be a standard of care, an appropriate option, but many and probably most US-based oncologists wanted to learn whether the superior results with cisplatin-irinotecan would hold true in a North American trial.  This wasn’t due to xenophobia, but rather a recognition that a trial with just 154 patients that stopped early is pretty small to change the standard of care for more than a decade, and irinotecan might be more challenging and/or less effective outside of Japan.  This could be based on the longer experience of Japanese oncologists with irinotecan – the drug was developed there – or it could be from population-based differences. (more…)

  I’ll get back to the storyline of our growing understanding of the differences of individuals based on pharmacogenomics very soon.   But I wanted to give people some breaking news that just came out.  The first line ESCAPE trial of chemo with the anti-angiogenic and multi-kinase inhibitor nexavar (introductory post here) or placebo is apparently negative according to a press release, and it even shows a harmful effect of the study drug in patients with squamous cancers, who were included in the trial.

  The trial was designed very similar to the ECOG trial with avastin that led to its subsequent FDA approval.  Over 900 first line, previously untreated patients with advanced NSCLC were randomized to receive standard carbo/taxol chemotherapy IV every three weeks for up to six cycles, with either nexavar (introductory post here) by mouth twice daily or a placebo on the same schedule.  As in the avastin trial, patients who did not progress after six cycles of chemo continued on “maintenance” nexavar or placebo until progression or prohibitive side effects.  The trial design is summarized here:

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   While the differences in anticipated clinical benefits from EGFR tyrosine kinase inhibitors like tarceva and iressa are well known (summarized in prior post), less well appreciated is the potentially significant differences in results with garden variety standard chemotherapy.  These differences are likely to be very relevant as the US has a harder time getting large trials completed, especially placebo-controlled ones, as we look more to trials done in other parts of the world to prove what agents are beneficial and well tolerated.  For instance, the original trial of alimta in mesothelioma (abstract here) was a worldwide effort, and the BR.10 trial of tarceva vs. placebo (abstract here) was led by NCI Canada but really conducted throughout the world, with a very minimal contribution of patients from the US.  So we really need to know whether conclusions can be generalized from one race to another, one continent to another, or whether we might get very different results in the US than they see in Japan, even if both places conduct their clinical research well. 

    To test whether there really are meaningful differences in outcomes when different racial/genetic/geographic populations receive the same chemotherapy, Dr. David Gandara and the SWOG Lung Cancer committee collaborated with leaders of lung cancer trials to ensure that both North American and Japanese groups would develop trials using the same chemo regimen (carbo/taxol at identical dose and every three week schedule) in trials done in the US or Japan for patients with the exact same eligibility.  This would then allow for comparison of the results across different trials that were run essentially concurrently (many years of difference in timeline could have led to differences over time in supportive care or subsequent treatments available), producing a “common arm analysis”.  The carbo/taxol arms from three different trials have been compared, two from Japan (abstracts here and here) and one from the US (abstract here).  As you’d hope for trials with the same eligibility, the enrolled populations were quite comparable to each other:

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While you’d expect this, it’s not a foregone conclusion.  Social patterns, or differences in the characteristics of NSCLC on one continent vs. another could lead to significant differences in factors like age, balance by patient sex, and definitely histology.  For instance, European trials have historically had more patients with squamous NSCLC than adenocarcinoma, unlike the US and definitely Asian trials; they also typically have 70-90% men, which may be from lung cancer still being a very disproportionately male disease in Europe, and perhaps from men being more likely to be recommended for or agree to participate on European clinical trials.  Regardless, as shown above, the common arms in the Japanese and US trials included similar patients by demographic and basic cancer features. (more…)

    The issue of population-based differences in response to lung cancer treatments was essentially introduced with the EGFR inhibitors, so it’s appropriate to introduce racial differences overall with this work.  Mention of more favorable results with EGFR inhibitors iressa and tarceva emerged with the earliest clinical studies and have since become a well established truism.  Let’s explore what we know now and how we got here.

   The first demonstration of more favorable results in Asian patients came with the phase II Iressa single anent dosing studies called IDEAL-1 (conducted largely in Japan and Europe) and IDEAL-2 (conducted largely in the US) (see review post of this work).  The response rate in IDEAL-21 was in the 18-20% range, approximately twice that seen in IDEAL-2.  One hand-waving argument was that the eligibility requirements were slightly different between the two trials: the trial that included Asian patients required only a single line of prior therapy for advanced NSCLC, while the US-based trial required two or more lines of therapy.  So while you could argue that the less extensively treated patients in the IDEAL-1 trial would be expected to have a higher response rate, this doesn’t explain the difference in response rate within IDEAL-1 of 27.5% vs. 10.4% (p = 0.0023) for Asian vs. non-Asian patients, all on the same trial and with the same eligibility requirements.   And the same trend was seen in the BR.21 trial with tarceva, in which the response rate was 18.9% vs. 7.5% for Asian vs. non-Asian patients, respectively (p = 0.02), with everyone sharing the same eligibility and receiving the same treatment.  Similarly, although the ISEL trial of iressa vs. placebo in patients with refractory advanced NSCLC was negative overall, there was a three month difference in survival that was statistically significant in the pre-specified subset analysis of Asian vs. non-Asian patients (9.5 vs. 5.5 months, p = 0.01).
  
   Of course, the explanation for this difference came from the groundbreaking work on the activating mutations of the EGFR molecule that exist right in the part of the target protein where iressa and tarceva bind and where the subsequent signal cascade is activated. 

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That story broke in the spring of 2004, and shortly after that it was demonstrated that collections of tumor tissue showed a frequency of EGFR mutations from Asian patients that was 2-3 times that in Caucasian patients.   Since then, I and other experts have described how many of the clinical factors identified with favorable response to EGFR inhibitor therapy has really been largely due to the tight correlation of these variables with the frequency of EGFR activating mutations in patients with particular clinical characteristics, such as a higher frequency of EGFR mutations (which themselves appear to be closely associated with higher likelihood of response to EGFR inhibitors) among Asians vs. non-Asians, women vs. men, never-smokers vs. current or prior smokers, and/or patients with adenocarcinomas (including bronchioloalveolar carcinoma (BAC) tumors) vs. squamous histology tumors. (more…)

  One piece of news in the oncology news today was a celebratory announcement by Merck that they will be collaborating with researchers at the Dana-Farber Cancer Center, part of the Harvard medical system and one of the most influential cancer centers in the world, in drug development.   As part of this agreement of developing a team approach, “Merck will provide up-front and research support funding to [the Dana Farber Cancer Center} as well as milestone and royalty payments upon market approval.”

    Umm…great.  Merck is happy to have buy-in of one of the world’s leading research institutions.  Stockholders are happy, too: the stock went up $1.22 (2.69%).  Woohoo!

    Now I’m not anti-business, and I’m certainly not against advancing the cancer field, but I’m just taking a moment here because we’re rightly focusing on potential conflict of interest among researchers and speakers.  I just wrote a post (here) in which I’m trying to convey that we’re struggling with even the perception of conflict of interest in having an educational grant with no strings attached that would be provided to GRACE from a pharmaceutical company.  When I give a talk to oncology colleagues, I consistently report that in the past two years certain companies have paid me to speak on their behalf or consult with them (and this information will also be available on the GRACE website for every board member and faculty writer).  So I’m just wondering, shouldn’t we maybe be a bit concerned if our academic centers are becoming the Research and Development Division for the world’s largest pharmaceutical companies? 

   The argument for this is that it’s hard to bring new cancer drugs through clinical trials and into commercial use: I appreciate this and have also written about this in past posts.  But personally, I would be a little concerned if my oncologist, let alone the entire department or institution in which s/he practices, had systematic incentives to develop novel drug X for a company that is in ongoing collaboration and providing large amounts of research funds and then potential royalties to our academic institutions that are also receiving our support.  I’m not saying Merck is alone here, either.  There are many other academic-industry collaborations that are uncomfortably friendly.

   I’m not trying to be sanctimonious here: I work closely with industry and have made money consulting with and speaking for various companies.  And I don’t want to hold up progress.  But I’m troubled if we have wild double standards of tarring and feathering individual investigators who made $1500 for speaking on behalf of one company, while congratulating a revered institution that may compromise its credibility in the name of a systematic “partnership” with another company.  Do people not mind their oncologist earning royalties from Merck (or even if the royalties go to the cancer center, are we confident that there would be no influence on management habits?)?  Are people at all concerned that this may influence patient care in a detrimental way?

   Infused throughout the website is a constant recognition that “patients are different”, but while we know this intuitively, we’re really not moved to a point of individualizing treatment on the basis of this.  There are many lines of clinical research that are moving in that direction, and one of the key elements is pharmacogenomics, the study of the genetic underpinnings of the differences among people in response to a medication, both in terms of response and side effects.  The slides for this post are stolen appropriated from Dr. David Gandara, one of the true leaders in the field of lung cancer, who heads the Lung Cancer Program at the University of California at Davis, as well as the Lung Cancer Committee for the Southwest Oncology Group (SWOG).  He is also the new President Elect of the International Association for the Study of Lung Cancer.  He and his collaborators have been adding to our understanding of this field as it relates to lung cancer.

   Whether we’re talking about conventional chemotherapy, EGFR inhibitors, or just narcotics, it’s clear that there are major differences in how different patients respond.   Although we’re on the cusp of tailoring treatments based on type of NSCLC (squamous vs. adeno, or BAC, for instance), and smoking status, and perhaps even racial background, our general practice has historically been to use a one size fits all approach:

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In fact, though, we know that some patients have a very nice response to chemo, or a targeted therapy like tarceva, while others have a minimal response or actually progress on treatment.  We also know that some people tolerate chemo very well, while others terrible side effect problems.  We could really improve the field if we could identify, using molecular profits, the best vs. the worst responders and the patients who were destined to develop terrible treatment side effects before we actually give the therapy:

By doing that, we could separate out those patients who would have a poor response or bad toxicity and give them a different treatment instead:

    At the present time, we routinely use squamous vs. adenocarcinoma histology, as well as smoking status, for clinical decision-making, but these are clinical and not molecular profiles.  We have several examples of molecular profiles that are very promising and are beginning to be employed but are not yet considered standard approaches for routine management.  Examples include ERCC1 for assessing resistance to cisplatin (post here), gene signatures to predict which patients are responsive to various chemo agents (post here), EGFR FISH in predicting improved outcomes on cetuximab (post here), or resistance to EGFR inhibitors as predicted by ras mutations (post here).  

    Another potential implication of this work is that there may be important differences in how various treatments work in different populations.  EGFR inhibitors may be considerably more effective in studies from Japan than ones from the US or Europe.  Chemo may work differently in some populations than in others.  But as more and more trials are done in Asia, Europe, and elsewhere around the world, the study of pharmacogenomics reminds us that it is important to consider whether we can generalize conclusions across continents and different races.  We’ll turn to such questions next.

   Member Wendy asked me about a drug called picoplatin that I had heard of but really didn’t have much familiarity with.  This gave me an occasion to flesh out some background on this agent, which is being developed as a potential therapy for patients previously treated for lung cancer.  Developed by Poniard Pharmaceuticals in South San Francisco, picoplatin is a variant platinum drug, which cause cell death by binding to DNA and interfering with its ability to make copies and divide, which in turn leads to programmed cell death (a self-destruct program), also known as apoptosis.  It was designed to have a slightly different shape from cisplatin or carboplatin that would make it overcome resistance to these other platinum drugs, and early studies suggest that it has some activity in platinum-pretreated patients, and also a lower risk for kidney damage and neuropathy that can accompany platinum use, particularly cisplatin. 

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   People who have been following my comments know that I am often questioning the wisdom of surgery in patients who don’t fit the usual criteria for resection, which is most commonly pursued in stage I and II NSCLC and is often considered an option for some patients with stage IIIA NSCLC.  To provide a very quick review of NSCLC staging, it’s a combination of three factors:

1) Tumor (T) stage — from 1 to 4, going from smallest and easiest to remove to hardest or largest to remove

2) Node (N) stage — from 0 to 3, going from none to further distances from the main tumor

3) Metastasis (M) stage — just a 0 or 1, to reflect whether there has been distant spread outside of the tumor’s lobe of origin

Here is the more detailed staging system, for T stage on one figure, and then for N and M stage in the other. 

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At the bottom of the second figure are the “Stage Groupings” that define our current (although increasingly refined over time) staging system.  You can see that stage, which correlates with prognosis overall, is a product of a combination of how advanced the tumor itself is and measures of likelihood of distant spread, which is nodal stage (correlates with increasing risk of micrometastatic disease and distant spread) and M stage (M1 defining metastatic spread).

   A key point is that there are related but distinct risks from a lung cancer.  While we are generally most worried about distant spread of SCLC, which is why surgery has no established place in SCLC management, NSCLC can have very differing degrees of local or distant risk.  We need to weigh these, potentially also along with the third variable of risk in the brain, as we develop treatment plans:

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    Many of us who work in the field of lung cancer, whether as doctor, patient, friend, or family member, bemoan that lung cancer is too often viewed as a black sheep among cancers – little attention and too few resources.  But one of the key ways in which lung cancer has lagged behind has been in terms of clinical trials participation, and this is something that we can control, and our underperformance (on both the physician and patient side) has hurt the field. 
 
   The field of oncology is used to seeing trials with thousands of patients with breast cancer and colon cancer, to name two other common cancers, and the pace of clinical research in those fields has led to major momentum and rapid advances.  The field of lung cancer has certainly had advances too, but the question is how far we’re falling behind our potential, with 200,000 new cases in the US alone, and with pharmaceutical companies recognizing the size of that market and falling over each other to get their new drugs used in lung cancer.  Despite these factors, the pace of progress in the field is maddeningly slow, in large part because of the slow pace of clinical trial completion that drives our development of new diagnostic and prognostic tools, and of course also new treatments.

    Lung cancer patients make up a far smaller percentage of the clinical trial populations in the US (9% of male patients on cancer trials are on a lung cancer study, and 4.6% of women) than they do overall US cancer patients (14% and 12.6% of cancers in men and women, respectively) (abstract here).  Even more acute is the under-representation of older and sicker patients, as well as minorities.  In many countries, minority patients do poorly compared with Caucasians.  As we learn more about relevant differences among different racial/ethnic groups based on genetic differences in how cancer behaves or treatments work in patient subsets, it becomes increasingly clear that we need to include diverse populations in our lung cancer trials.

   There’s no doubt that there are multiple causes for low trial participation.  Historically, there have been times when there were not interesting clinical trials.  Now there is a broad range of interesting trials, but certainly access is a problem.  Others have done work suggesting that lung cancer patients may feel more hopelessness about changing their plight than people with other cancers (abstract here).  People may see the offer of a clinical trial as a “last resort” and be less inclined to pursue clinical research because of that.  And even among highly proactive and educated participants on OncTalk, 73% of the 107 respondents here who participated on a recent online poll said they would not participate in a placebo-controlled trial that included standard of care treatment (with placebo) on the control arm.  I realize that people would prefer the new agent, but we can only determine the value of a new treatment if we compare it properly to a standard treatment arm. 
 
     I’m certainly interested in people feeling the “guinea pig syndrome” in trying new treatments, but I think that while some people fear the new, for many people the objection to a trial is in not getting the new approach.   Regardless, at the present time some of our problems controlled by investigators/physicians who write protocols that are too restrictive and “cherry picking”, or they don’t prioritize trial options when speaking with patients.   Other obstacles are controlled by patients reluctant to try anything “investigational”, or else unwilling to accept being randomized to a treatment and not receiving the non-standard treatment they have decided is critically important.
 
    But we all need to do better if we’re going to move the field forward and improve our survival results in the next five years compared to the last five years.  Clinical trials, including randomized ones and even placebo-controlled ones, are an important driver of the evolution of our understanding of cancer and its best treatment.