|
|
|
Small Cell Lung Cancer 101: An Introduction
After several weeks of posts on other aspects of lung cancer, I am long overdue to write on small cell lung cancer (SCLC). Although it is good to see the number of SCLC cases decreasing over time, and becoming a smaller and smaller percentage of lung cancer cases overall (only about 13% in the US and steadily falling), this has translated into fewer clinical trials and less of a focus on SCLC in the lung cancer community. However, there are some promising developments that may lead to some long overdue progress in the field.
First, this post will start with some general concepts and an introduction to SCLC, and this will be followed in the next few weeks by posts describing current and emerging ideas for the basic stages of small cell lung cancer, and also a discussion of prophylactic cranial irradiation for small cell, where it has been most extensively studied. Continue reading
Never-Smokers, Part II: Different Responses to Treatment
I reviewed some of the differences in the biology and clinical behavior of never-smoker lung cancers vs. the much more common lung cancer seen in current or former smokers. The main reason it is worth discussing is that there appear to be important differences in how never-smokers with NSCLC respond to some treatments, particularly EGFR tyrosine inhibitors like Tarceva, or Iressa previously. Among the first reports of this came from Memorial Sloan Kettering Cancer Center in NYC, which reviewed their experience with single-agent iressa several years ago and found that never-smokers were much more likely to demonstrate a significant response to iressa than current or former smokers (36% vs. 8% response rate, shrinking the cancer by 50% or more of the total measured volume). Along with bronchioloalveolar carcinoma histology, smoking status was among the most important variables in predicting response to iressa (abstract here).
As we learned about EGFR receptor mutations, first described in 2004 and associated with a high likelihood of response to EGFR inhibitors, we got some explanation for why never-smokers seemed to do well. In fact, the initial report by Dr. Lynch in the New England Journal of Medicine described 9 patients with excellent responses to gefitinib, of whom 6 were never-smokers. A study of tumor tissue out of Memorial Sloan Kettering showed that 7 of 15 lung tumors from never-smokers carried an EGFR mutation, compared with only 4 of 81 from smokers. Another study of patients who had surgery for early stage lung cancer in Japan showed that among 154 resected tumors (36% were from never-smokers, really highlighting how common never-smoker lung cancer is in Japan!). Since then, multiple trials have shown that never-smokers are significantly more likely to have EGFR mutations than smokers, and are also significantly less likely to have mutations in the gene k-ras (rhymes with mass) that in study after study are associated with no benefit from EGFR inhibitors. There are many controversial issues in lung cancer, but this is not one of them. From all over the world, the studies all show the same thing. Continue reading
Do Never Smokers with Lung Cancer Have a Different Disease?
Just a few years ago, the only distinction in the field of lung cancer that meant anything was small cell vs. non-small cell. The different types of non-small cell, like adenocarcinoma vs. squamous cell vs. large cell, were of little interest and didn’t change management (only a very recent development). And although we often asked about smoking history, the answer never changed our treatment plan. Only in the last few years have we come to recognize that we will do better as “splitters” than as “lumpers”, by tailoring our treatment recommendations to the clinical and molecular feature of one particular patient and tumor at a time, rather than using a one size fits all approach.
First, some definitions. Although there is a little variation, most of the lung cancer research community has come around to a definition of a “never-smoker” as less than 100 cigarettes in a lifetime. A “former smoker” is more than that and has quit smoking for at least a year. A “current smoker” is anyone else, so less than a year after quitting, a patient is still considered a current smoker. Continue reading
Avastin Studies Beyond its Current FDA Approval
As mentioned in prior posts, the anti-angiogenic monoclonal antibody Avastin (bevacizumab) is now approved in first-line treatment of advanced NSCLC in combination with carboplatin/paclitaxel chemotherapy. Among the very interesting questions is whether Avastin should be added with other active drugs for NSCLC. Most of us in the field strongly suspect that the survival benefit from Avastin will also be the case with other types of therapy, but we’re only starting to get the evidence to address this. Continue reading
Are EGFR Inhibitors Only Useful in Certain Patient Groups?
Since the earliest clinical trials of EGFR inhibitors in NSCLC, certain clinically defined patient subsets became identified as more likely to show a benefit than others. Such studies suggested that women, patients with adenocarcinomas rather than squamous cell carcinomas, Asian patients, and never-smokers compared with current or former smokers were the patients who would do well with EGFR tyrosine kinase inhibitors like gefitinib (Iressa) or erlotinib (Tarceva). Since that time, we have been debating whether these targeted therapies should be used primarily or exclusively in selected populations or whether they should be used in general lung cancer populations. The correlation of rash with better outcomes is another interesting issue that is a big enough topic I’ll discuss it separately in the near future. Since it’s not something you know about before you start treatment, unlike patient sex race or subtype of lung cancer, it’s a different issue.
Erlotinib (Tarceva) in Previously Treated NSCLC
In a recent post, I described the approval of taxotere as a second-line chemotherapy with a modest but survival benefit for patients previously treated with one line of chemo, usually a platinum-based doublet. Two years ago, erlotinib/tarceva, an inhibitor of a target on many NSCLC tumors called the epidermal growth factor receptor, was approved by the FDA as an additional treatment option for previously treated patients with advanced NSCLC, based on a large randomized clinical trial led by the National Cancer Institute of Canada that was published in the New England Journal of Medicine (BR.21 abstract here), demonstrating the importance of the results.
(Click to enlarge picture)
Treatment after Initial Chemo in Advanced NSCLC: Second Line and Beyond
Although we are all frustrated by the relatively slow pace of progress in lung cancer, there are times when we can look back and feel that we have made a real impact. Six years ago there were no treatments that were FDA approved and appeared to benefit patients who had previously been treated with first-line chemo for NSCLC. Now there are several. Continue reading
Clinical Trial Focus: RADIANT Trial in Adjuvant NSCLC
As described in a prior post, chemotherapy after surgery is often recommended after surgery, at least for a subset of patients with stage IB to IIIA (without mediastinal lymph node involvement) NSCLC, based on a potential to increase cure long-term survival compared to surgery alone. At this point, two forms of targeted therapy (erlotinib, or Tarceva, as a single agent in second- and third-line advanced NSCLC, and bevacizumab, or Avastin, combined with carboplatin and paclitaxel for first-line treatment of advanced NSCLC) have been approved by the FDA for advanced NSCLC because they have demonstrated an improvement in survival. At this point, however, we don’t know whether adding targeted therapies as a strategy in earlier stage NSCLC can increase cure rates. But one key trial that is evaluating this possibility is the RADIANT trial.
RADIANT Trial; click to enlarge.
RADIANT is an acronym for Randomized, Double-Blind Trial in Adjuvant NSCLC with Tarceva. This will be an international trial designed to enroll 945 patients who have undergone surgery, with no residual cancer left behind, for stage IB, II, or stage IIIA NSCLC. Patients may have received up to four cycles of chemotherapy after surgery, but patients who received no chemo are still eligible. Patients are then randomized to receive either tarceva or a placebo, with two-thirds of patients receiving the active drug and one-third receiving placebo. Because it is a double-blinded study, neither patients nor their treating doctor know who is getting tarceva or a placebo. This is appropriate because we don’t know whether Tarceva is going to be better, the same, or actually worse, with side effects of treatment but no added benefit.
Importantly, although Tarceva is approved by the FDA for all patients with previously treated advanced NSCLC, regardless of whether their tumor has high levels of EGFR, the target of Tarceva, or amplification of the EGFR gene in tumor cells. We still debate whether Tarceva works best, or perhaps only works at all, in patients with EGFR protein expression as detected by a test called immunohistochemistry (or IHC) or amplification (excess copies) of the EGFR gene by a test called fluorescence in situ hybridization (or FISH). Many trials that are investigating the future role for Tarceva are using more selected populations based on clinical characteristics such as never-smoking or BAC, or molecular characteristics such as EGFR overexpression by IHC, gene amplification by FISH, or presence of an EGFR mutation detected by gene sequencing. Perhaps the benefits of Tarceva can be found to be more pronounced and more consistent if we can identify and treat those patients most likely to do well with it, rather than use a “targeted therapy” unselectively.
Further information about eligibility details and participating centers can be found here.
Can We Define “Best Treatment” for Stage IIIA NSCLC?
Stage IIIA NSCLC, particularly with N2 lymph node involvement, is probably the NSCLC treatment setting that is most controversial. While it is the latest stage that we routinely consider surgery for, it is actively debated whether patients with stage IIIA NSCLC should have surgery or be treated with a combination of chemo and radiation without surgery.
For the patients who undergo surgery, most patients receive preoperative therapy before resection. This standard was established from a series of small randomized trials published more than a decade ago that demonstrated striking improvements in survival in the group of patients that received chemotherapy prior to surgery. Despite the clear conclusion that pre-op chemo improves survival, these trials were all very small (primarily because they were stopped early when the huge benefit of pre-operative treatment became apparent), the patients one the surgery arm of one key trial did much worse than expected, and there were problems with some prognostic factors not being well balanced between the two groups in one trial. Regardless, the benefits in the patients who received chemo before surgery were so great that this became a preferred approach, but there is no standard approach that has emerged as a best choice. Continue reading
Current State of the Art for Unresectable Locally Advanced NSCLC
Locally advanced, or stage III, NSCLC, can potentially include patients for whom surgery is an option, but for many patients with stage IIIA and a majority of those with stage IIIB NSCLC, a non-surgical approach is the best treatment recommendation. It’s important to keep in mind that the goal of treatment for patients with locally advanced NSCLC but who don’t have a malignant pleural effusion (fluid inside the chest but outside of the lung, with cancer cells in it) can potentially be cured. The risk of doing poorly are from both local growth and distant micrometastatic spread (living cancer cells traveling elsewhere in the body through the bloodstream).
The old standard in the 1980s was radiation alone. An important clinical trial the “Dillman Trial” then compared the old standard of just radiation alone to chemo with a two drug combination of “cisplatin-based” chemo for two cycles followed by the same radiation plan. The cure rate was significantly better, although unfortunately we were still curing these patients far too rarely. However, it changed the standard of care from radiation alone to a combination of chemo and radiation together. Continue reading
| Follow us on... |    |
||
Copyright ©2012 GRACE |
|||