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The Argument For A Non-Surgical Standard of Care for Stage IIIA N2 NSCLC
In my last post I covered much of the controversy about whether patients with stage IIIA, N2-node positive NSCLC should be treated with induction therapy (chemotherapy or chemo/radiation) followed by surgery, or an alternative approach of chemo along with radiation delivered at a definitive dose (curative, not just the supplemental, lower doses used in induction therapy). In fact, while there are some flaws in the analysis that suggests that patients who require a lobectomy do better with surgery vs. without it, I really didn’t disagree with Dr. Swisher, the surgeon who provided the pro-surgical view, that a subset of stage IIIA patients are particularly well served by receiving the most aggressive approach, including surgery.
My main counterpoints were these:
1) The patients viewed as most likely to benefit from surgery are currently the ones who respond very well to induction chemoradiation or chemo, specifically the ones who clear their mediastinal lymph nodes. I’ve described this issue in a prior post, and some of the highlight slides/figures are reproduced here:
(click to enlarge; mediastinal clearance after chemo alone was as important as whether the tumor was completely resected in predicting overall survival)
(in another trial of induction chemoradiotherapy, survival was remarkably better for the patients who had mediastinal sterilization before surgery). Continue reading
The Great Debate: Should Surgery be the “Standard of Care” for Stage IIIA NSCLC with Mediastinal Nodes?
It’s over, and I won (did you doubt me?). As I mentioned in a recent prior post, today I spoke at the Eighth International Lung Cancer Congress, where I was assigned the topic of speaking in favor of chemo/radiation as the more appropriate standard of care, with the opposing view, that surgery is the standard, taken by the esteemed Dr. Stephen Swisher, thoracic surgeon (and actually Chair of the Department) at the MD Anderson Cancer Center in Houston.
Now in truth, we didn’t differ very much in our perspectives. One key point we agreed on completely is that the stage of IIIA N2 NSCLC is a very heterogeneous group, ranging from some patients with just microscopic involvement of a single lymph node in the mediastinum (mid-chest, between the lungs) to multiple lymph nodes at multiple areas of the mediastinum that are enlarged and even bulky (more than about 2 or definitely 3 cm). In fact, within that range, outcomes are very different, with the group who have a single area of non-enlarged lymph nodes that have cancer involvement just at the microscopic level having a much better prognosis than those with enlarged nodes or with more than one mediastinal area involved:
(Click to enlarge) Continue reading
Chemotherapy for Mesothelioma
For many years, patients with malignant pleural mesothelioma (MPM) were often not offered treatment. Surgery was offered to rare, selected patients who tended to be much younger and more fit than a typical patient with MPM, but we’ll talk about surgery later. Chemotherapy was only very inconsistently offered to the vast majority of unresectable patients with MPM, because it was not felt to clearly be beneficial. This is pretty similar to the view of advanced NSCLC until the mid- to late-1990s. Fortunately, studies over the past several years have clarified that chemotherapy can improve survival for MPM.
Up until Alimta was approved, the regimen that was most commonly used for MPM was cisplatin and gemcitabine. This combination was reported in a trial of 21 patients with advanced MPM (abstract here) to produce an objective response rate of 48%, median response duration of about 6 months, and a median survival of about 9 month — not amazing, particularly in overall survival, but the best we had. In fact, several later trials suggested lower response rates and not as impressive results overall, but we used it because we wanted to help and patients needed treatment, and there had never been any reasonably large trials undertaken for MPM, so we really didn’t have any good evidence for or against the value of treatment. That changed when a large study evalauted the utility of cisplatin and alimta together.
At ASCO 2007, Nick Vogelzang and colleagues presented a plenary session abstract on mesothelioma (here) that was subsequently published as a full publication in 2003 (abstract here). The first major MPM trial ever, it enrolled 456 patients from 114 sites in 19 different countries. It had a straightforward design, randomizing patients to the likely minimally active cisplatin alone in one arm, and cisplatin/alimta in the other arm:
(Click to enlarge)
It was a plenary session presentation because the combination of cisplatin and alimta led to a significantly higher response rate (41% vs. 17%, p < 0.001), but also a significantly higher median survival by 3 months (12.1 vs 9.3 months, p < 0.02), as well as a nearly two month difference in median time to progression (5.7 vs. 3.9 mo, p < 0.001). The differences are shown here, with pretty striking differences (gaps) on the survival curves:
Introduction to Malignant Pleural Mesothelioma
We haven’t covered this on OncTalk yet, but it’s a real shortcoming that I haven’t discussed malignant pleural mesothelioma (MPM). Although it’s not exactly lung cancer, it’s another chest cancer that is often managed by thoracic oncology specialists like myself, and the only reason I haven’t introduced it until now is that it’s such an unusual cancer, accounting for just 2000-3000 cases each year in the US. But it’s infrequency means that it doesn’t get studied or discussed, so the people with MPM have far less information and support available for them (the one clear exception, aside from lawyers who are avidly interested in working with MPM patients, is MARF, the Mesothelioma Applied Research Foundation, which is a phenomenal central resource for the small but mightly mesothelioma community). By contrast, lung cancer is unfortunately a very common cancer, but at least being common means that your get a reasonable amount of attention and research dedicated to the problem.
MPM is a cancer of the pleural lining around the lung, not the cells of the lung itself. Normally a thin onion-skin-like layer, this layer thickens to something more like an orange rind but often thicker and tougher often adhering to nearby structures like the chest wall, heart, and major blood vessels. It looks like this on CT, with the thick MPM tumor on the left side of the chest, which is the right side of the CT images here:
(Click to enlarge) Continue reading
Surgery or No Surgery: What Would You Choose?
I’m heading off today to Hawaii (Maui), which I must hasten to add is for a conference, the Eighth International Lung Cancer Congress, not just a vacation, although working in Hawaii often seems better than time off at home. The meeting not only includes a lot of good lectures and debates, but it gives us the opportunity to actually discuss the importance and implications of the trials that were just presented a few weeks before at ASCO. Some of the important clinical trials and collaborations are developed during free hours at this meeting.
In addition to participating in a panel discussion on optimal management of never-smokers with lung cancer, I’ll be arguing in a debate on how to manage stage IIIA NSCLC. The specific topic is whether this stage of cancer should be treated with surgery (generally combined with chemo and sometimes also radiation) or whether chemo and radiation together without surgery should be more commonly recommended. Some of my posts that discuss the controversy about this issue are here and here. My debate will be with a surgeon from the MD Anderson Cancer Center, so it should be a challenge, but it’s all pretty light-hearted. We couldn’t have a debate if there was a clear right answer.
In lung cancer, as in many other types of cancer, people generally receive surgery if it’s possible to resect the tumor, and other treatments are considered alternatives. Part of this is historical: before there was chemotherapy or radiation, surgery was the only way to manage cancer. In addition, surgeons are often the first specialists to meet a cancer patient, since they often perform the biopsies that establish a tissue diagnosis. And, in truth, surgery often is a very effective treatment, particularly for earlier stage cancers.
So I have a question for members here: would most people definitely prefer surgery if it’s possible (“get it out!”), and consider non-surgical treatments to be a less desirable alternative, or would people be very happy to pursue a non-invasive approach if it produces comparable results? I’m making this the new polling topic for the next several days. When options produce similar outcomes, patient preferences should be a key component of what strategy to follow. So offer your comments here, and I hope you’ll vote in the poll on the right column.
Individualizing Chemotherapy Regimens for NSCLC
One of the central ideas in management of advanced NSCLC is that many two-drug chemo combinations have been compared and show essentially superimposable results, as I described in a prior post.
(click to enlarge)
Perhaps we’re underachieving by using a “one size fits all” approach, getting everyone to a middle ground that falls short of what we might do if we could pick the right drugs for each patient.
Among the studies at ASCO 2007 that generated considerable interest was the Molecular Analysis Directed Individualized Therapy in Advanced Lung Cancer (MADeIT) study by George Simon, Gerald Bepler and colleagues from Moffitt Cancer Center in Tampa, FL (abstract here). This study tested the feasibility of individualizing doublet chemotherapy as first-line treatment for patients with advanced NSCLC. They did this by using a rather labor-intensive method of studying tumor cells with laser-capture microdissection (using a laser to remove areas of cancer from slides of biopsy tissue). Tumor cells are then tested for their level of expression (using a rather complex technique known as real-time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) — don’t worry, it’s not important to the story) of a couple of proteins that appear to play a key role in predicting the degree of sensitivity vs. resistance to certain chemotherapy drugs. One of these, excision repair cross complementing-1 (ERCC-1), helps repair DNA damage such as that induced by drugs like cisplatin. So if the ERCC-1 level is high, it suggests that these cells will be resistant to platinum drugs (cisplatin, carboplatin being the common ones used in lung cancer); if low ERCC-1, the cancer cells should be more sensitive to these drugs. Another protein, ribonucleotide reductase subunit-M1 (RRM-1), is very important in the metabolism of nucleotides, the building blocks of DNA. If levels of RRM-1 are high, some studies show that those tumor cells will be resistant to gemcitabine (and sensitive if the levels are low). Continue reading
Prophylactic Cranial Irradiation (PCI) for ED-SCLC
As I described in prior post, prophylactic cranial irradiation (PCI) is established as a treatment approach for patients with LD-SCLC who have had a complete or “good partial” response to chemo and radiation. Some physicians also recommend PCI for patients with ED-SCLC who have experienced a very good response, since about 10% of the patients on the PCI trials that led to our current recommendations had ED-SCLC. But a trial presented by the European Organization for the Research and Treatment of Cancer (EORTC) at the plenary session of ASCO (abstract here) demonstrated a survival benefit from PCI for a much broader range of ED-SCLC patients that is likely to change our practice patterns. Continue reading
Genetics, Family History, and Lung Cancer
Many members have asked questions about increased risk of lung cancer among family members of people who have developed lung cancer. Overall, I have not highlighted this, partly because we don’t tend to highlight genetics as a major contributor of lung cancer risk. But the fact is that 10-15% of people who develop lung cancer never smoked, and the vast majority of smokers never develop lung cancer. And we see that the never-smoker population with lung cancer is disproportionately female (as covered in a prior post), and that multiple surgical series of show much higher proportions of never-smokers with lung cancer in studies from China (57% never-smokers in article here), and Japan (48% never-smokers in article here). Genetics must be an important modifier, since some people chain smoke for decades without developing lung cancer, while others can develop lung cancer with no obvious risk factors. Continue reading
Serum Tumor Markers in Lung Cancer Management
I’ve been meaning to write on tumor markers detectable in the blood for the management of lung cancer. These are proteins that are produced by some tumors, and the idea is that the levels of the tumor markers in the blood can potentially be used to monitor the status of the disease. For prostate-specific antigen in prostate cancer, carcinoembryonic antigen in colon cancer, CA19-9 in pancreatic cancer, and several others in breast or ovarian cancer, these markers have been well studied and are commonly used. The more commonly used tumor markers in lung cancer are CEA, and sometimes CA-125, as well as occasionally some others.
The problem is that there’s so little written and even carefully researched on these issues in lung cancer. In one very good clinical textbook on lung cancer, tumor markers are mentioned on just a couple of the >450 pages. The National Comprehensive Cancer Network (NCCN) guidelines for NSCLC and SCLC do not have any mention of tumor markers, and they really have no standard role in management or treatment, which is why the use of them is so variable in the real world. Many experts do not consider there to be any real role for tumor markers in lung cancer. There are some very highly regarded cancer centers that as a policy never check or use tumor markers in managing lung cancer. Continue reading
MAGE-A3 as a Vaccine Target in NSCLC
One of the more intriguing presentations at ASCO this year was the one in which a novel vaccine against a protein called MAGE-A3 was tested in patients who underwent surgery and then received the vaccine post-operatively. What is MAGE-A3? It’s a nearly tumor-specific antigen, which means that it’s a protein seen almost exclusively on cancer cells, including lung cancer, head & neck, bladder, and melanomas. The only normal non-cancer tumor tissue it’s seen on in the testicles, but there have been no problems with auto-immune or other complications against testicular tissue, as these cells don’t have the capacity to generate an immune response.
The limited available evidence suggests that expression of MAGE-A3 is associated with a worse prognosis, and along with that is the finding that it’s more commonly seen in higher cancer stages. It’s seen in only about 16% of stage IA NSCLC tumors, about 35% of stage II and IIIA resected NSCLC tumors, and about 50% of more advanced NSCLC cancers. Continue reading
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