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Results with Chemotherapy in Different Racial Populations
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:
(Click on image to enlarge)
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. Continue reading
Racial Differences in Response to EGFR Inhibitors
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.
(Click on image to enlarge)
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. Continue reading
Intro to Pharmacogenomics: Trying to Understand Differences in Treatment Outcomes
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:
(Click on image to enlarge)
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.
Picoplatin for SCLC: A New Platinum for Salvage Therapy?
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.
(Click on image to enlarge) Continue reading
Surgery for T4 Tumors: The Importance of Local vs. Distant Failure Risk
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.
(Click on image to enlarge)
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:
Overcoming Obstacles in Lung Cancer Trial Participation
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.
Cancer Care in the Canadian System, by Dr. Laskin
Is the grass greener?
I have noticed that a number of the participants on this site are Canadians, which is only one reason I always keep my extra Canadian “u”s in my posts. There have been a few issues that have come up that might be different on the other side of the border, but for the most part, cancer is cancer and the questions are universal. However, a recent question on second line therapy prompted Dr West to wonder what happens in our more regulated health care system so I thought I’d provide a bit of a commentary. If you read my bio you will already know that I did all of my medical training in Canada but I did have the pleasure of spending a year in Nashville, Tennessee at the Vanderbilt-Ingram Cancer Center and University Medical Center. I spent this year in a lung cancer research fellowship that included at least 2 days a week in the clinics. So, although limited, I do feel that I have some sense of the similarities and differences in cancer care, at least in an academic setting.
Rather than get trapped in a debate about which country has a better system let’s just agree that there are good things and bad things about each one. Both could use some improving, neither is perfect, and both will need to evolve over time.
Access is usually the issue in Canada. We often seem to be “behind” the United States in terms of access to new drugs. Although we pay close attention to the rulings of the FDA, our own Health Canada carefully considers the evidence, data, and trials available for each new chemotherapy. And, even if a drug is approved for use in a given disease state, each province will have to decide if the drug will be paid for or not. If it is available then it is provided free, to everyone. If it is not covered by the province but it is approved by Health Canada, then patients can usually get access to it by paying for it themselves or sometimes through any additional health care insurance programs an individual patient might have. Additional health insurance is certainly not the norm, but it is relatively common. For example, pemetrexed (Alimta) is approved for use in the second line setting for advanced NSCLC, but most provinces do not pay for it (except in mesothelioma). It is paid for/covered in British Columbia, which is why I use it more than docetaxel (Taxotere) (mainly because of the hair loss issue), but I had no problem using the equally effective docetaxel before and I do not think that the other provinces are providing inferior treatment because they do not have it available.
There is a similar issue with erlotinib (Tarceva), which is covered by almost every province (and being reviewed by the territories) for use in second line if someone cannot take a taxane and for third-line treatment for any NSCLC. This approval is based on the trial (BR21) that demonstrated benefit in this particular group of people. It is not approved in first-line because the results for the studies that are testing that haven’t been released yet. I agree, it is tempting to give it a try first-line – why not? If it works later why shouldn’t it work first, right? Well, I’m not so sure, and I think looking before you leap might be wise sometimes.
For example, erlotinib works by itself, we saw that from the phase II studies in the 1990s. Chemotherapy agents seem to work best when we combine them together – carbo/taxol or gem/cis so it must be that all 3 together would work even better. Right? Except when this concept was tested on over 4000 people there was no benefit to adding in the erlotinib (or gefitinib). Good thing we tested it rather than just adding it in automatically.
That’s not to say I haven’t used erlotinib first line. In fact I have a clinical trial open right now that is testing this exactly, with a solid rationale and a thorough ethics review. Beyond trials, I must admit it makes me nervous, though in individual cases I think it is worth considering.
Yes, I admit that it is sometimes incredibly frustrating that I cannot have access to every new drug that comes up in any creative combination for as long as I want to use it for. But this is supposed to be an evidence-based practice; the people I’m treating deserve a rationale for what I prescribe. And I believe that as responsible physicians we do need to put some thought into the cost of what we’re recommending. There is not an endless health care budget, in Canada but also in the USA. Even at a patient level, is it worth spending the last few months of your life struggling to go to work so you won’t lose the insurance that pays for your $200,000 of chemotherapy that maybe only adds 2 weeks to your survival?
Someone will ask about Canadian waitlists – yes, this can be a problem. Sometimes it takes 2 weeks to get a CT scan or 2 weeks to book an appointment for palliative chemotherapy. That waiting can be very anxiety-provoking for patients and families. From a biological point of view, it’s hard to know how much difference a week or two makes. When it does make a difference, in a curative situation or in a medical emergency, there is no waiting.
So of course there are differences. Having worked in both countries, I see that there are a lot of misconceptions about the other’s systems and there is a huge amount of variability for individual situations. Hopefully we can learn from each other.
Zactima (Vandetanib) in SCLC: An Argument Against Maintenance Therapy
There’s been several discussions about the potential value of maintenance therapy after the initial chemotherapy for SCLC; I’ve discussed this subject in a prior post, in which I focused on chemo (prior post here) — while the results haven’t been strong enough to lead to a change in standard practice, at least one trial showed a strong trend in the right direction. On the other hand, other studies, such as one recent large one with thalidomide (described in a prior post), looked quite unfavorable for maintenance therapy, at least with this agent. I’ve described the drug zactima (vandentanib, or ZD6474, which inhibits both angiogenesis and EGFR) in yet another post, and it has continued through several large trials, which could potentially lead to its approval in lung cancer if one or more of these is positive. But we’ve already seen the results of one trial of zactima as a maintenance therapy in SCLC. It’s fair to say that this trial won’t lead to it’s FDA approval.
This particular study came out of Canada and was known as the BR.20 trial (the lung trials conducted by the NCI-Canada are numbered BR.__, where BR stands for bronchus). Presented by Arnold and colleagues at ASCO 2007 (abstract here), the study enrolled 107 patients with SCLC, including both limited (about 43%) and extensive disease (57%) who had achieved a complete or partial response to chemo for at least 4 cycles; patients also received chest and/or brain radiation if it was clinically appropriate. Patients were randomized to receive either zactima at 300 mg by mouth daily (a dose that likely inhibits both angiogenesis and the EGFR axis effectively) or a placebo pill as a maintenance therapy after completing chemo (+/- radiation). The focus of the trial was disease-free survival, looking for a delay or prevention of recurrence after treatment.
While zactima was generally well tolerated, there were some side effects that were signficantly increased in the recipients of zactima compared with a placebo, including EKG changes (15% vs. 0%), high blood pressure (21% vs 9%), diarrhea (79% vs. 40%), rash (71% vs. 49%), and abnormal liver tests (46% vs. 15%). Frankly, I’m surprised to see placebo associated with diarrhea in 40% and rash in half of the patients. In both groups, about 55% of patients reported nausea, and about 80% reported fatigue, underscoring the importance of a placebo (because many of us would be concerned about a drug that produces such significant diarrhea, rash, nausea, and fatigue, but perhaps less so if that’s almost entirely just the background of the disease), and the problems caused by advanced lung cancer.
Whether you consider the side effects problematic or not, many people would find it worthwhile if the drug is effective. Unfortunately, there was no benefit to zactima as a maintenance treatment, with an equal progression-free survival, and a nearly significantly worse overall survival for the active drug compared with a placebo:
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Although there aren’t many positive things to say here, one interesting thing is that zactima may have been more effective in women, when they picked apart the data (they gave no details). With a small study, this kind of subgroup analysis is very limited, but it’s interesting that the same subgroup trend has also been seen in advanced NSCLC (although we haven’t covered this issue, which is still pretty preliminary, but provocative).
Zactima has looked better in other settings, and maintenance therapy has been more encouraging when chemo was used, so I wouldn’t want to throw out the baby with the bathwater. But this trial at least pretty convincingly tells us that this is the wrong drug, wrong disease, and wrong time. We’re still looking for just the right combination as a maintenance therapy in SCLC.
Is Surgery Ever an Option for Small Cell Lung Cancer? – by Dr. Laskin
Dr. Laskin has appreciated the warm welcome. Not only have you not scared her off, she’s written her first post for us.
By the way, it’s misleading to have my name and picture and “about the author” next to these posts by our new faculty — the software upgrade will fix this. Here’s her picture, so you can associate a name with a face (I had threatened to use a Wonder Woman picture if she didn’t supply one).
Dr. Laskin And without further adieu, her post:
Small cell lung cancer (SCLC) is a distinct sub-set of lung cancers representing about 15% of the entire group. We tend to think of it as a completely different cancer, and so we call all of the other lung cancers collectively “non-small cell lung cancer” (NSCLC); terms you are all familiar with from this website. Dr. West has previously posted an introduction to SCLC (post here) as well as the standard approach to both limited (post here) and extensive stage disease (post here) so I will try not to repeat too many of these points. Recently a question came up about the utility of surgery in the treatment of SCLC, and this is what this posting will address. When and how is surgery a part of the care for people with SCLC?
Since SCLC is generally considered a more systemic (whole body) disease with a high rate of chemo and radiation response, surgery is not usually the first treatment approach when the diagnosis is already known. So, the bottom line is that there is little or no consensus on the role of surgery for SCLC either as a first-line treatment or after chemo and/or radiation. But let’s explore some of the data.
The most common surgical intervention is when surgery is the first-line of treatment of a lung nodule when the diagnosis (pathology) is not known pre-operatively or when a small biopsy looks like NSCLC but at surgery is found to be SCLC. Post-operative (adjuvant) chemo and often local radiation therapy is important to consider to minimize the risk of recurrence; the majority of oncologists would consider at least adjuvant chemo if not chemo-radiation to be the standard of care. Continue reading
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