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Lung Cancer and the Enzyme Connection
Erlotinib (Tarceva) was approved for treatment of progressive non-small cell lung cancer (NSCLC) after the BR21 study that showed that tarceva not only improved survival but also improved lung cancer symptoms and quality of life. This study and others have also taught us that the benefit of tarceva is much better in those who had never smoked and less effective in current smokers. It is important to note, however, that even those who currently smoke obtain a benefit from treatment with tarceva, albeit smaller.
In the wake of the BR.21 trial, it became known that certain EGFR mutations in the tumor are associated with a dramatic benefit with tarceva, as well as the other EGFR tyrosine kinase inhibitor (TKI) gefitinib (Iressa).We also began to realize that these EGFR mutations were found most commonly in never smokers and rarely in current smokers.
There it was: the reason why tarceva worked better in never smokers. But in fact that was not the whole story. Tarceva, like many other drugs, is broken down in the body by an enzyme group called CYP 1A1/1A2. Enzymes are proteins that help to break down and digest our food, but enzymes can break down and digest many other things as well. The products in inhaled tobacco smoke stimulate this enzyme CYP, which then further breaks down tarceva in the body before it has a chance to work.
Video Presentation on Second Line Chemo for Advanced NSCLC
One of the core issues in managing advanced NSCLC is second line chemotherapy, which was established as improving survival several years ago. This video presentation provides a brief summary of the work that led to the common use of chemotherapy in previously treated patients. Most typically, this is taxotere (docetaxel) or alimta (pemetrexed), and this presentation describes why we focus most commonly on these chemo agents.
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Exercise as Therapy for Advanced Lung Cancer?
One of the most common questions I am asked by newly diagnosed lung cancer patients is “What can I, personally, do to help fight my cancer?” The two most common topics are diet and exercise. While the influence of diet on cancer outcomes is a good topic for discussion, today I wanted to focus on the question of exercise in cancer patients, and whether exercise may help people with lung cancer either live longer or at least have a better quality of life.
We have known for some time that there is a strong association between general fitness and cancer. In particular, obesity has been associated with increased risk of developing cancer of the colon, breast (in postmenopausal women), uterus, kidney, esophagus, stomach, pancreas, prostate, gallbladder, and liver. In fact, some estimates have indicated that between 14-20% of all cancer deaths can be related to obesity. In patients who already have cancer, recent studies have shown increased risk of recurrence in both colon and prostate cancer in obese patients, and weight gain is associated with increased recurrence in women with breast cancer. This may be related to increased hormone levels and levels of IGF-1 in obese patients, which can promote tumor growth. Of note, there has never been a direct association of obesity with lung cancer, probably because other risk factors are dwarfed by tobacco smoke. But obesity is an indirect measure of fitness, so what about exercise directly?
PSA Screening and Cancer Screening in General: Questioning a Sacred Cow
Lung cancer screening is one of my least favorite topics to discuss because it’s probably one of the biggest areas where there is a gulf between the medical establishment’s party line and the expectations of many patients and advocates. I tackled a discussion of screening a few years ago that included the anticipated benefits as well as the challenges with LC screening (nowadays really focusing on low dose, spiral CT). That was probably about the most frustrating topic I’ve pursued, initially heralded after my post on the arguments in favor of screening, but feeling like I was being vilified as a kitten torturer in the responses I received after my post about the thorny issues with it.
There is no doubt that LC screening is an important issue, and it has become one of the most central causes for many non-profits in the LC world. I think that it’s an easily identifiable, understandable issue that provides a tangible thing to do that can give people a sense of control in an otherwise largely uncontrollable situation.
Doc, Am I Too Old for Chemo?
The average age at which lung cancer is diagnosed in the US is 71. Would it be fair to say that at least half of those who are diagnosed with lung cancer are elderly? How do we define “old”? How does age impact the effect of chemotherapy?
Two decades ago, analysis of “older patients” who received chemotherapy for advanced lung cancer revealed that chemotherapy improved survival in the elderly to the same extent as in patients who were younger. The down side was that older patients experienced more side effects from chemotherapy. It is easy to see how this result could lead to mixed feelings: live longer, but with side effects. In the 1990’s clinical trials directed towards the elderly began. The pivotal trial was called ELVIS (Elderly Lung cancer Vinorelbine Italian Study). This study compared the effect of chemotherapy (vinorelbine) against no chemotherapy in lung cancer patients ≥70 years of age. This direct comparison clearly demonstrated that chemotherapy not only improved survival but most importantly, quality of life.
How was this possible? We all recognize that controlling the cancer will control cancer related symptoms. The challenge with treatment is balancing the side effects of chemotherapy against the benefit gained by controlling lung cancer symptoms. However, vinorelbine (Navelbine) is a well tolerated chemotherapy that made it possible to improve quality of life. Subsequently, more trials in more modern times with more modern chemotherapy have repeatedly shown us that chemotherapy is feasible and worthwhile in the elderly.
Polling Lung Cancer Experts: Metastatic NSCLC, Squamous Subtype
Several weeks ago, I described the results of a survey I sent out to several colleagues who are lung cancer experts around the country, asking how they would manage a case of a newly diagnosed Caucasian never-smoking patient with advanced NSCLC, adenocarcinoma, and asymptomatic subcentimeter brain metastases, treated with whole brain RT before starting systemic therapy.
I then asked these same experts the question but now with the patient being an ex-smoker with a squamous NSCLC tumor. The basic sketch is that it’s a 61 year old Caucausion woman with a very good performance status, no limitation on health or motivation for treatment, and a metastatic NSCLC, squamous subtype . As in the prior case, she had treated asymptomatic brain metastases and was presenting for consideration of first line treatment. What would various experts recommend as a plan for the next few months?
One major difference was that, unlike the never-smoker with an adenocarcinoma, very few experts now favored sending tissue for an EGFR mutation. The vast majority had favored checking this in a never-smoker, who might be considered for up-front EGFR inhibitor therapy, but when the case was an ex-smoker with a squamous tumor, only 6 of 20 were interested in any molecular testing: 3 for KRAS mutation, 1 for EGFR IHC before considering erbitux (cetuximab), and two who still wanted to check for an EGFR mutation. Most were inclined to make a treatment recommendation without any molecular testing.
EGFR Mutations Demystified
It has become a common topic of conversation on this site (and in the lung cancer community at large) to discuss mutations in the epidermal growth factor receptor (EGFR). However, since we frequently throw out the terms “deletion 19 mutation”, “L858R”, and “T790M”, I thought would be worthwhile to explain a little bit about the different EGFR mutations and what we know about their clinical significance.
The history and significance of EGFR mutations has been covered quite well in previous posts here, but I’ll provide my own quick synopsis, from the perspective of someone working in Boston during the time this work was being done. In the early 2000s the EGFR tyrosine kinase inhibitors (TKIs) Iressa (gefitinib) and Tarceva (erlotinib) were tested in large numbers of patients with non-small cell lung cancer. It was known the EGFR was an important target in lung cancer, since most NSCLC tumors express it and high levels of expression were associated with a worse prognosis, and the results of numerous trials testing these drugs in unselected patients were modestly positive. In a phase III trial, Iressa did not improve overall survival compared to placebo treatment in previously treated NSCLC patients (leading to the death of this drug in the USA), but the similar BR.21 trial (testing Tarceva rather than Iressa) did show a modest (~2 month) improvement in overall survival in previously treated NSCLC patients. This led to the approval of Tarceva in all NSCLC patients who had failed one or two prior chemotherapy regimens.
However, what was immediately evident from these and earlier trials, was that about 10% of Western patients treated with either of these drugs had dramatic and sometimes long-lasting responses. When they looked at who these people were, they found that most were women, all had adenocarcinoma (or BAC, a type of adenocarcinoma), many were Asian ethnicity, and most had either never smoked or smoked very little compared to average NSCLC patients. In 2004, investigators at the Dana Farber Cancer Institute and at Massachusetts General Hospital in Boston, and also at Memorial Sloan Kettering Cancer Center in NYC, simultaneously published results showing that most of these “dramatic responders” had specific mutations in the tyrosine kinase (TK) domain of the EGFR gene. The EGFR protein sits in the cell membrane and straddles the inside and outside of the cell.
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Interview with Dr. Toni Wozniak, Covering SCLC Basics
I recently had the opportunity to sit down with Dr. Toni Wozniak, Moedical Oncologist and lung cancer expert at the Barbara A. Karmanos Cancer Center at Wayne State University in Detroit, MI. We covered several topics, including SCLC, the subject of this podcast. It is an audio interview but includes a few figures that are synchronized with the audio on the video version, or you can download the pdf of the figures and just follow along with the audio.
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As with some prior podcasts, it’s primarily audio, but with some synchronized figures that pop up on the video version, or you can download a pdf file with the images to go with the audio. There’s also a transcript available to download.
Second Line Chemotherapy for Advanced NSCLC: One Drug vs. Two
One of the key points that has been established in first line treatment of advanced NSCLC is that two drug chemotherapy is superior to one drug chemo. Several trials from a decade ago showed that a two drug “platinum doublet” led to a longer overall survival than either a platinum alone (typically cisplatin at the time that these trials were performed) or another agent, such as paclitaxel alone. Starting in 2000, second line chemotherapy has also been shown to improve survival, originally with taxotere (docetaxel), later with alimta (pemetrexed) also being shown to produce essentially the same survival.
Since second line single agent chemo was tested and approved by the FDA, the next question was whether more is better. Would two drug chemo lead to better survival in the second line setting? Though there have been several trials that have tested this, none has been large enough to say anything definitive. But when multiple similarly designed trials are too small to say anything definitive, it can be helpful to pool the data from these trials to see if there is a clear signal as an aggregate experience.
VeriStrat Test for EGFR Test: Initial Impressions after Sending a Few
A few weeks ago I described a blood test for predicting survival after getting an oral epidermal growth factor receptor (EGFR) inhibitor that is just becoming commercially available. This is called the Veristrat test and from company called Biodesix. As I noted previously, this technique looks at the protein patterns in a patient’s serum and reportedly can reliably predict whether a patient is likely to have a prolonged survival after receiving an EGFR inhibitor. The company gave me the opportunity to send off a few of these tests at no charge, and after a few weeks of trying it in a handful of patients, I’m finding that it seems to do what it says it does, for better or for worse.
What they specifically say is that, by separating serum samples into the two thirds that will have a “good” survival and the one third that will have a “poor” survival after getting an EGFR inhibitor, clinicians can use this test to determine which patients shouldn’t get an oral EGFR inhibitor like tarceva (erlotinib) or iressa (gefitinib) for advanced NSCLC. The test may well be great for this, but I haven’t had the opportunity to send this test off in the last few weeks for this purpose.
Instead, what I was hoping we might use this test for is to get a faster answer about whether a patient will do well with an EGFR inhibitor. Even though I and many other lung cancer experts are increasingly becoming converts to the idea that EGFR mutations are quite relevant and override clinical predictors of benefit with EGFR tyrosine kinase inhibitors (TKIs), these mutations aren’t always very accessible. Only a minority have enough tumor tissue from their original biopsy to send off for mutation testing, and the test itself takes 3-4 weeks, which is long enough that many patients will not be inclined to sit around and wait for a month before starting treatment.
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