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Ras Mutations and EGFR Resistance
Most of the focus on predicting response to EGFR inhibitors has been on identifing molecular markers that are associated with major response to this kind of treatment. But we know that there is a group of patients who get no benefit from these expensive drugs, and in these patients, EGFR inhibitors would just lead to side effects and keep them from a potentially more effective therapy for them. As you can see, the overall survival and progression-free survival curves from the BR.21 trial (abstract here) show that there are a group of patients clustered on the right side of the curve who do no better than the placebo group. In addition to detecting which patients are going to be the greatest beneficiaries, we need to identify which patients will get no benefit at all from EGFR tyrosine inhibitors like Tarceva.
Ras (rhymes with mass) is a gene and protein product that are involved in molecular signalling and very important in many cancers. There are several related genes in the family, and most of the focus is on k-ras. Mutations are seen in a significant minority of lung cancers and are far more likely to be seen in smokers than in non-smokers (abstract here). As you can see from the tables below, ras mutations are consistently more common in smokers than in non-smokers in multiple case series, and they are essentially mutually exclusive with EGFR mutations that have been associated with a high response rate to EGFR tyrosine kinase inhibitors like Iressa and Tarceva.
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Continue reading
Surgery vs. Non-Surgical Treatment of Stage IIIA N2 NSCLC: The Debate Continues
There is still plenty of active debate about whether patients with stage III NSCLC who have mediastinal lymph nodes, the ones in the middle of the chest between the lungs but on the same side as the main tumor, should receive surgery in some circumstances or not. There was a trial done in the US that I described in a previous post, essentially demonstrating a better progression-free survival for patients who received “induction” chemo and concurrent radiation followed by surgery and then more chemo compared with chemo and higher dose radiation, but no surgery; however, overall survival was not significantly better for the arm that had surgery because much of the benefit against the cancer was nullified by the risk of dying from treatment, which was notably higher on the surgical arm, particularly if patients required a pneumonectomy, the removal of a whole lung. In the wake of these trial results, some experts feel that without a significant benefit shown for surgery, patients with stage IIIA N2-node positive NSCLC should not have surgery and should instead receive chemo/radiation, others still favor surgery if patients are up for it, and some people still consider it so complex that they individualize recommendations for each patient based on their health, the bulk of the mediastinal disease), the number of nodal areas involved, and the extent of surgery that would be required. I would say that stage IIIA NSCLC remains the most controversial setting in lung cancer management, even with the results of this trial, which produced results as clear as mud and hasn’t yet been published with full data.
Another trial looking at the same popualtion was very recently published by van Meerbeeck and colleagues (abstract here) from the European Organisation for Research and Treatment of Cancer (EORTC) – Lung Cancer Group, a cooperative group in Europe similar to SWOG, ECOG, and CALGB in the US. In this trial, 579 patients with stage IIIA N2 NSCLC started with induction chemotherapy for three cycles, then had a CT scan to assess their response to induction chemotherapy. If they didn’t progress, patients were randomized to receive subsequent definitive radiation or surgery. The trial design is shown here:
(click to enlarge) Continue reading
Video-Assisted Thoracic Surgery (VATS) for Early Lung Cancers
Historically, surgery for lung cancer has been through an open thoracotomy (thorax = chest; otomy = cutting/slicing), which involves a long incision around the side of the chest, removal of ribs, and spreading of the remaining ribs to get a good view of the area of the operation. Even with the most skilled surgeons, it’s a procedure that is rigorous for a patient to get through and has a recovery period typically of weeks. Just as many other surgeries can now be done with video assistance through thin tubes with cameras to help a surgeon see what his happening in the chest through several small incisions, a growing number of thoracic surgeons are becoming trained to do video-assisted thoracoscopic surgery, or VATS. This is generally done through a small incision and a couple of small holes or “ports”, just a centimeter or so, through which narrow tubes containing tools and amazingly small, very high quality cameras can be placed:
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Among the advantages of VATS vs. an open surgery are the ability to do a surgery as good as a more extensive one (the proponents believe), the ability to convert to an open procedure if there is a need, the ability to still resect lymph nodes, the opportunity to a good cancer surgery with less trauma, pain, and recovery time, and a potential to be better able to give post-operative chemotherapy more easily. One of the problems with the idea of post-operative chemotherapy is that it’s very hard for patients to get through it (only about 2/3 of the motivated patients on clinical trials of adjuvant chemo get through a significant amount of it), partly because they are dealing with the recovery from a major surgery, so a less extensive surgery could make it easier to complete further treatments.
On the downside, there is the belief among some that VATS is inferior to an open surgery, that you can’t see as much, and it’s certainly true that you can’t feel as much. Sometimes, with small tumors, a surgeon needs to get in with his or her hands to feel for a small nodule, which can’t be done through tools that go through small holes in the chest. It’s also generally not feasible for larger tumors — it has been suggested that 5 cm may be a cut-off. It is also argued that it is not as feasible to perform a thorough lymph node dissection, so this could potentially compromise the outcomes of surgery. And there are certainly only a subset of thoracic surgeons who are well trained to do it, so it’s not available everywhere. Continue reading
Large Cell Neuroendocrine Carcinomas as a Unique NSCLC Population
In most of the history of lung cancer management, we have been “lumpers” rather than “splitters”, tossing together many different kinds of lung cancer together and presuming that they all respond similarly and should be treated similarly. After decades of primarily focusing just on whether a lung cancer was SCLC or NSCLC, with drugs like avastin, it’s more important now to recognize squamous cell carcinoma, while there’s also been a focus on using EGFR inhibitors for adenocarcinomas (although there is actually good evidence that patients with squamous cancers receive a very similar survival benefit despite a lower response rate). Beyond that, there are also a few “special” subset populations defined by lung cancer histology (microscopic appearance), such as bronchioloalveolar carcinoma, or BAC, which is a very well-differentiated end of the adenocarcinoma spectrum that can have a slower and more favorable prognosis than many other kinds of lung cancer and are often treated a little differently. On the other end of curve is an unusual NSCLC subtype called large cell neuroendocrine carcinoma (LCNEC), which many experts are inclined to treat as a distinct subset because it is generally recognized as having a poorer prognosis than other NSCLC tumors.
Neuroendocrine tumors come from cells that are part of the tissues that develop into neurons and hormone-releasing glands, and these cells are not only in specialized organ tissues like the adrenal glands or the pancreas, but also scattered in other tissues of the body, including the lungs. These cells make proteins that act as hormones, and these types of neuroendocrine tumors can be identified under a microscope by the pathologist performing special stains that demonstrate secretory granules typical of endocrine cells. The specifics aren’t important, but rather just to know that neuroendocrine tumors are a distinct class, and in lung tumors there is a complete spectrum of neuroendocrine tumors that range from very favorable to much less favorable. Much of the most pivotal work in defining these types of tumors has been done by expert pathologist Dr. Bill Travis, now at Memorial Sloan Kettering Cancer Center in New York City. Continue reading
Does Tumor Grade Matter in NSCLC?
Historically, the main task of pathologists in lung cancer has been to divide them into small cell lung cancer and non-small cell lung cancer. Beyond that, there is now more of an emphasis than there used to be on trying to clarify whether a NSCLC tumor is a squamous cell carcinoma, adenocarcinoma, large cell, or another subtype, partly because we now have drugs approved just for certain subtypes (avastin for non-squamous tumors only) and others that are commonly observed to have a higher response rate in some histologies (lung cancer categories based on microscopic appearance) than others (sucha s EGFR inhibitors consistently showing a high response rate in adenocarcinomas/bronchioloalveolar carcinomas compared with other subtypes). Several members have asked questions similar to the one reported in a recent paper from the Mayo Clinic (abstract here): is the grade of the tumor, ranging from well differentiated to moderately differentiated to poorly differentiated and even undifferentiated, associated with a better or worse prognosis for a person?
What do we mean by differentiation? The degree of differentiation of a tumor is how much it looks like normal, non-mutant lung cells. Well differentiated lung cancers are pretty close to normal appearing, while poorly and undifferentiated lung cancers look completely wild, not like the cell they originated from. It’s important to note that pathologists can readily and reproducibly say a well differentiated cancer is an adenocarcinoma, for instance, but a poorly differentiated tumor may be said to resemble an adenocarcinoma by one pathologist, while another pathologist may think that the same tumor is a poorly differentiated squamous cell carcinoma (and even give different results when the same pathologist reads a tumor at two different times). So there is a good concordance (agreement) of pathology findings only for the better differentiated tumors. In addition, there are not clear standards of what constitutes moderate differentiation and what consistutes poor differentiation, so this will differ somewhat from one pathologist to another. Continue reading
Options for Managing Recurrent Pleural Effusions
Between 7 and 15% of patients with lung cancer develop a malignant pleural effusion (MPE), a fluid collection outside of the lung in the chest cavity. Very often, if it develops, it recurs frequently. This is typically associated with shortness of breath, also know as dyspnea, so we want to try to manage these recurrent pleural effusions to minimize pulmonary symptoms (although some lung cancer patients have several reasons for shortness of breath and cough and still have symptoms even with effective management of an effusion. We’ll review several ways to manage this problem. Continue reading
Introduction to Pleural Effusions
Pleural effusions related to lung cancer are quite common, so it’s time that I discussed this issue. First, a pleural effusion is fluid outside of the lung, and it tends to follow gravity and pool at the bottom (base) of the lung, primarily along the back. Here’s how it appears on a chest x-ray, filling up the bottom of the left side of the chest. The right side, in contrast, is mostly black, which is the way lungs should appear on a chest-x-ray (but not in real life, we hope).
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However, pleural effusions can also be loculated, which means that they don’t follow gravity but rather are contained in pockets that are formed from scar tissue, inflammation, etc. Here’s a CT image showing a loculated effusion on the left side, not freely flowing in the chest to follow gravity:
CALGB 9734 and the Limitations of Small Clinical Trials
I recently wrote a post about combining chemo and radiation after surgery for unsuspected stage IIIA N2 node-positive NSCLC (if discovered prior to surgery, it is more common to administer chemo and/or radiation before surgery). In the comments that followed it, Carlos brought to my attention a study that I neglected to mention a recently published trial. This is the prematurely closed CALGB 9734 trial, (abstract here), which intended to enroll 480 patients with “occult” N2 nodal involvement, but it was closed due to poor accrual, with a mere 44 patients over two years, and two of them were actually ineligible. The trial was designed to test the value of adding radiation after chemotherapy for this setting, and all patients started with four cycles of carboplatin and paclitaxel given every three weeks for cycles. Following that, patients were randomized to be observed or receive daily radiation up to 50 Gray over five weeks, with 74% of those assigned to RT completing it (11% progressed before starting RT, and 15% refused it). The trial design is shown here:
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The results of this very small trial supported the potential value of radiation added to chemo, since the median failure-free survival (progression or death) was 16.8 months for the chemo alone arm and almost exactly twice that, at 33.7 months, for the chemo followed by radiation arm. Despite the large difference in those numbers, the difference was not statistically significant. Despite that, there were no differences in one year overall survival, which were 72% and 74% for chemo and chemo followed by RT, respectively. The authors couldn’t draw any real conclusions from the study. Continue reading
Timing Post-Operative Chemo and Radiation
Adjuvant chemo has become increasingly established as having a survival advantage, at least for the general population of stage II and IIIA patients, and potentially for some with earlier stage disease (see adjuvant chemo post). However, post-operative radiation therapy, or PORT, does not have an established role. While historically there has not a clear advantage from PORT for patients with N1 nodal disease, for those with N2 nodes there has been a consistent improvement at least in local control and now emerging evidence of an survival benefit from PORT (see PORT post).
So for patients who undergo resection and had N2 nodes, there may be a benefit from both chemotherapy and radiation. One way to treat patients with N2 disease, if we know from a mediastinoscopy or another method that someone has N2 nodes involved prior to surgery, induction chemotherapy, or chemotherapy and radiation, are commonly used. In those cases, sometimes additional chemo is recommended after surgery, but not typically more radiation if it was given before surgery.
But there are also plenty of patients who either had unsuspected N2 disease until after surgery, or who undergo upfront surgery despite pre-operative staging showing N2 disease. Such patients were included on many of the trials testing the value of adjuvant chemo.
The problem of administering chemo and radiation after surgery is that it’s hard enough to take chemo after surgery, and adding another modality can escalate the challenge significantly. In the many clinical trials with cisplatin-based chemo after surgery, only approximately 70% of patients are able to get though the majority of planned chemo (carboplatin-based chemo is more feasible, with 85% of patients on the CALGB 9633 trial (initial positive 2004 abstract here, updated and now negative 2006 abstract here).
So when adding radiation to chemo, we need to balance the effectiveness with the safety and feasibility of what is now a tri-modality approach (surgery + chemo + radiation). In the ANITA trial that allowed radiation while testing the value of adjuvant chemo (abstract here), the patients who received both chemo and radiation did not receive them concurrently, but rather received chemo followed by radiation. Our experience with patients receiving chemo and radiation together for unresectable NSCLC has consistently demonstrated that concurrent chemoradiation is associated with a much higher likelihood of serious esophagitis, inflammation of the esophagus, that can limit the ability to eat and drink and make it very hard to continue treatment to completion. Continue reading
Post-Operative Radiation Therapy: Helpful or Harmful?
I’ve discussed the trials that have led to a general recommendation in favor of chemotherapy after surgery for patients who have stage II and IIIA NSCLC, with some ongoing questions about the value in stage IB NSCLC. I haven’t touched the issue of post-operative radiation therapy, but the question comes up from members who ask about the evidence for or against radiation, and how it might be given.
Adjuvant, or post-operative radiation therapy (PORT), has been a reasonable option for lung cancer patients for decades, but the concept took a big hit from the “PORT meta-analysis” published in the British Medical Journal in 1998 (abstract here). This meta-analysis aggregated the results from 9 different studies of surgery alone or surgery followed by radiation, for a total of over 2100 patients. Overall, the results demonstrated a significant detriment in survival from PORT, primarily from more cardiac and lung problems (2-year survival 55% vs. 48%) — the curve on the bottom is radiation, with a worse survival:
(click to enlarge) Continue reading
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