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Video Podcast Presentation on Locally Advanced NSCLC
Ask and ye shall receive! The leading requiest for a video podcast presentation was for a summary of the subject of locally advanced, unresectable stage III NSCLC. Here you go:
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Sorry it’s a little rushed, but it’s a struggle to do a topic justice with a 10 minute limit (the most YouTube accepts). In the future, we’ll try to divide bigger topics into two podcasts if it’s going to require cramming into a 10 minute interval. It may help for you to have the images and transcript available, so here they are:
Locally Advanced NSCLC vodcast images
Searching for Low-Hanging Fruit: Identifying Critical Targets in Lung Cancer
One of the most pressing issues in lung cancer research is in identifying patients who could benefit from a particular drug, both to increase their chances of having a good outcome and to spare everyone else from an ineffective drug with unnecessary toxicity. There have been some exciting advances in this field, but before I elaborate I want to give some (simplified) background on how drugs are traditionally developed. Classically, potential cancer drugs are tested on cancer cell lines in a Petri dish, and if the drug appears to kill the cells, it is then tested in animals. If the animals don’t die the drug may eventually be tested on small numbers of humans with advanced cancer as part of a phase I trial. The drugs are normally given to patients with no regard as to how likely the drug is to work on that type of cancer, and the results are generally predictable. If the patients are able to tolerate the drug, and some of them have shrinkage of their tumors, the drug can then be tested on larger groups of patients with the same kind of cancer as the patients from the phase I trial who seemed to benefit.
However, if none of the patients in the phase I trial respond the drug is usually abandoned. Rarely, a drug will jump through all these hoops and lead to an approved chemotherapy drug, usually over a period of a decade or more. However, even “effective” drugs typically work only in a minority of patients. Drug companies are typically more interested in developing drugs that work on ever larger numbers of patients rather than on identifying why the minority of patients who responded did so.
When the effectiveness of this process plateaued with the current stable of chemotherapy drugs, companies began to focus more on “targeted drugs” like Gleevec, Herceptin, and Tarceva. These drugs were designed to affect only a single (or small number of) proteins such as the platelet-derived growth factor receptor (PDGFR), Her2, or the epidermal growth factor receptor (EGFR). The best example of this is Gleevec, which turns off the single protein that drives chronic myelogenous leukemia (CML) cells (bcr-abl), and has revolutionized the treatment of CML. In lung cancer, the best examples are the EGFR inhibitors Tarceva and Iressa, which can cause dramatic tumor responses and prolong survival in about 10% of Western NSCLC patients. It has been shown that the tumors in these patients are “addicted” to signaling through mutated EGFR, and shutting off this signal kills the cells. In the other 90%, however, there is either no benefit at all from Tarceva or some stabilization of disease, probably because EGFR is important to these tumors but not to the same extent as in the EGFR mutants.
Iressa for Elderly and/or Poor Performance Status Patients with an EGFR Mutation
Several years ago, we learned that EGFR tyrosine kinase inhibitors (TKIs) were not a very helpful strategy for an unselected population of frail patients in the US, clearly inferior to standard chemotherapy (see prior posts here and here). This work was in patients who hadn’t been tested for molecular markers like EGFR mutations, and our interpretation of the previous US-based trial left us with the conclusion that an EGFR TKI like tarceva (erlotinib) or iressa (gefitinib) was an inferior chemotherapy alternative and apparently ineffective treatment for the majority of patients with a marginal performance status, but it could still be an effective option for patients selected to be especially likely to benefit from this class of agents, like patients with an EGFR mutation.
This was the subject of pure speculation until now. A manuscrupt by Inoue and colleagues (abstract here) has just been published that describes the experience of treating patients with an EGFR mutation and who are either elderly or have a poor performance status or both with an EGFR TKI (iressa at the standard 250 mg/day) as first line therapy. Specifically, they enrolled 30 patients who either had a poor performance status (3 or 4 on a scale of 0 to 5 where 0 is asymptomatic and 5 is dead: details here), or were 70 or older with a marginal performance status (2 -4) or 80 or older with any symptoms (1-4). It’s worth noting that there are relatively few studies that include patients with a performance status of 2, and almost none that have included patients with a performance status of 3, who spend more than half of their day in bed and can’t take care of many of their activities of daily living. Continue reading
Serum Test Being Launched to Test for Likelihood of Benefit from Oral EGFR Inhibitors
About 18 months ago, I wrote a post about a new technique being developed that looks at the pattern of proteins in the blood of a patient in order to determine whether a patient is likely to do well or poorly after receiving an EGFR tyrosine kinase inhibitor like tarceva (erlotinib) or iressa (gefitinib) for advanced NSCLC. This work was the product of collaborative work among folks at Vanderbilt University, the University of Colorado, and a Colorado based company called Biodesix.
At the time that I wrote the original post, there was a general plan to bring this test to commercial use. Earlier today, I met with some of the folks at the company, who told me that this plan is now moving forward, with a plan to launch the test, now known as Veristrat, in early March. While they didn’t have additional published or formally presented information to highlight, they told me that they have continued to do studies of the serum from patients from all over the world that has validated what their test is trying to do. Here’s the idea:
Trimodality Therapy (Chemotherapy, Surgery, and Radiation) for Malignant Mesothelioma: Can Some Patients actually be Cured?
Malignant mesothelioma is a relatively rare but particularly deadly malignancy that arises from the lining of the pleural (chest) cavity or peritoneal (abdominal) cavity. About 70% of cases of mesothelioma are directly related to asbestos exposure, usually with about 30 or 40 years between exposure and diagnosis. While there are only about 2200 cases per year in the USA, this number is expected to increase over the next decade, as workers exposed to asbestos earlier in their lives eventually begin to manifest symptoms of the malignancy. After 2015 or so, this may begin to decline due to laws regulating exposure to asbestos in recent decades, but these laws don’t exist in the developing world, so mesothelioma is likely to be a worldwide problem for the foreseeable future.
The usual patient with mesothelioma presents with chest pain and/or shortness of breath, with x-rays showing thickening of the pleural lining with as associated pleural effusion. Many times the fluid around the lung contains no cancer cells, so a biopsy of the pleura is necessary to make the diagnosis. It usually occurs only on one side; distant spread is unusual. So if it is technically “localized”, why is it so hard to cure? The main problem with mesothelioma is that most patients present with advanced disease that has no chance of curative treatment with surgery. In fact, mesothelioma is a malignancy that classically is not thought to be really “curable” at all. Surgery is usually used for palliation, to drain the fluid and peel the malignant rind away from the lung so that the patient can breathe easier and with less pain. Of course there are case reports or case series of patients with limited disease who can be aggressively treated with surgery and have lived >5 years (most oncologists’ definition of cure), but the reality is that these patients are few and far between. To date, studies of patients treated with surgery have shown about the same average overall survival as patients treated palliatively with chemotherapy alone (about 9-12 months).
The Carboplatin/Irinotecan Combination for SCLC: A Phase II Study
Several years ago, I participated in a clinical trial with a combination of carboplatin and irinotecan for treatment of extensive SCLC, just now being published (abstract here). As a bit of background about the potential utility of irinotecan, the well established cornerstone of treatment of extensive SCLC for about two decades has been a platinum agent (cisplatin or carboplatin) with etoposide, but an important trial in Japan suggested that a cisplatin/irinotecan regimen may be superior to cisplatin/etoposide (abstract here). Subsequent work done in the US did not support that conclusion, and one leading consideration is that there are meaningful differences in the activity and side effect profiles of different chemotherapy drugs in different racial populations, due to factors like the enzymes that alter metabolism of these agents. Nevertheless, irinotecan and its cousin topotecan are still high on the list of drugs most active in SCLC.
The clinical trial in which I participated combined irinotecan with carboplatin, the alternative to cisplatin that is often substituted because of generally comparable activity and a more favorable side effect profile. In this trial, both agents were given IV on a single day every three weeks. There were two different groups of patients enrolled, with 40 patients in each: one had received no prior treatment for extensive SCLC, and the other had previously received first line chemotherapy (with cisplatin or carboplatin and etoposide) and had now relapsed. For the group that had received prior chemo, a lower dose of irinotecan was given (150 mg/square meter vs. 200 mg/square meter every three weeks). Patients received up to six cycles of this combination.
The Shifting Ground in Advanced NSCLC: A Quick Survey of the Experts
Although there has always been lattitude for individualizing treatment, I think developments in the last few years have added so many options that pretty much any standards we had from a few years ago have eroded. Particularly in a world in which the eligibility for avastin (bevacizumab) has is debatable (with growing experience of little risk when treating patients with brain mets, on coumadin, etc.), some less impressive results on the AVAiL trial with cis/gem +/- avastin, marginally positive results with erbitux (cetuximab), and a complete free-for-all in the transition from first line to second line (timing? maintenance?).
I thought it would be interesting to take the pulse on where the experts were, since my sense is that there’s a lot of variability in how people are interpreting the data now. I sent an e-mail to about 30 expert colleagues from around the country and different institutions, with a simple thumbnail sketch of a fairly typical patient and asked specific questions of what treatment they would recommend as first line therapy, when they would stop it, and whether they would continue a maintenance therapy or switch to a new treatment, and if a new treatment, when. I also asked whether they would send any molecular markers. Here’s the thumbnail sketch of the patient:
A never-smoking Caucasian 62 year-old woman has a cough, sees her MD, found after full workup to have a lung adenocarcinoma metastatic to lungs, liver, adrenals on PET/CT. Brain MRI shows multiple sub-centimeter asymptomatic brain mets without edema. She is referred to you for systemic therapy after seeing a rad onc, getting whole brain irradiation. Her PS remains good, kidney function fine, insurance would cover anything (this is something that can limit our treatment decisions). Summary: A healthy, motivated Caucasian woman with advanced adenocarcinoma of the lung, recently treated asymptomatic brain mets. And though I asked whether people would want to send for molecular markers, I limited responses to clinical variables, for the sake of argument I asked them to presume that there adequate tissue for this, and/or the patient refused another biopsy.
Playing “Whack a Mole”: Exploring the Molecular Heterogeneity of Lung Cancer
Mrs. M was a 46 year-old woman who, despite having never smoked, was diagnosed with metastatic adenocarcinoma of the lung. She had a nice initial response to chemotherapy, and when she eventually progressed, she was treated with Iressa (an EGFR inhibitor similar to Tarceva which is no longer available in the US). To both her and her doctor’s delight, she had near resolution of her lung mass and most of her liver lesions after 2 months on Iressa. Unfortunately, after remaining stable for 10 months, her restaging CT scan showed one lesion in the liver was growing. Despite holding the course for another 2 months, it became evident that Mrs. M was progressing in the liver, even though her lung mass remained as stable as ever it had over the preceding year.
If you’ve ever wondered why a patient with lung cancer can have a beautiful response in one area while growing in another, or why new metastases can develop while everywhere else the disease remains stable, you aren’t alone. The truth is that cancer heterogeneity (different cancer cells or tumors in one patient behaving differently from one another) has been observed for a long time. Studies of induction chemotherapy in lung cancer (chemotherapy given in early stage disease prior to surgery) performed in the 1990’s routinely reported response rates in excess of 60%, while we know that the same chemotherapy in metastatic disease has a response rate of only 25-30%. Clearly there is something fundamentally different in the metastatic cancer than in the early stage cancers. So what gives? This concept gets to the center of the question of why cancer can initially respond to chemotherapy but eventually becomes resistant.
Hypertrophic Pulmonary Osteoarthropathy (HPOA): An Unusual But Distinctive Complication of Lung Cancer
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!).
The Subtleties of Progressive Disease: Why Some Oncologists Continue EGFR Inhibitors (or Other Agents) after Progression
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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