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Never-Smokers Needed for Study of Molecular Risk Factors for Lung Cancer
Actually, it’s some background information and your blood that’s needed.
Memorial Sloan-Kettering is running an important trial that is trying to determine some of the molecular factors that lead some never-smokers to develop lung cancer while other never-smokers don’t. The trial is just a one-time collection of information in a questionnaire, I believe about medical history and environmental exposures, and submission of two vials of blood. There is no cost to participants, with all packaging and mail expenses pre-paid, and the registration and additional information is online here.
Early Report: SATURN Trial of Maintenance Tarceva Positive for Improvement in Progression-Free Survival
Well, it happened again that the first word came from the financial community (report here), as we learned today that a large trial testing the value of maintenance tarceva (erlotinib), the oral EGFR inhibitor, provides a significant improvement in progression-free survival (PFS). In the following slide, I show the design for two similar trials that test the value of tarceva after four cycles of first line treatment of advanced NSCLC.
The first, called the ATLAS trial, is for avastin-eligible patients who would typically receive avastin alone as maintenance therapy after initial chemo/avastin. It randomizes patients to maintenance avastin/tarceva vs. avastin alone. We don’t have results from that trial yet. The results we have are from the SATURN trial, which asks a similar question but without the avastin: is there a significant delay in progression if patients who haven’t progressed after four cycles of platinum-based standard chemotherapy (and no avastin) receive tarceva as a maintenance therapy, compared with an oral placebo?
What I Really Do: Treating Beyond the Evidence
Most of what I write about here highlights the evidence supporting treatments, and that’s certainly how we strive to practice oncology. But the reality is that patients and doctors often find themselves in the middle of settings where we don’t have any answers and need to rely on judgment, or we think we can potentially do better by defying conventional wisdom. Doctors lie all along the spectrum of being “data-driven” on one end and being a “cowboy” on the other end. The general perception is that many academics are more evidence-based, but I’m not sure that’s true: experts defy the guidelines all the time and say that the key is knowing when to follow and when to deviate from them.
One of the typical places in which we find ourselves at odds with a lack of evidence is in treating patients beyond about third line treatment. We have trials that show the evidence of a limited number of our treatments for NSCLC out to third line, and second line for SCLC. Most patients run out of energy and/or interest in treatment by about that time, but some patients have slow-growing and/or particularly responsive cancers and come back after multiple lines of treatment feeling well enough to come back to the clinic and ask, “what next?” Many people participating here are beyond the point where we have evidence that further treatment is beneficial. How do we manage these situations?
Incidental N2 Nodal Disease and the Heterogeneity of Stage IIIA N2 NSCLC
Probably the most contentious areas of lung cancer management is stage IIIA NSCLC, with N2 nodal involvement, the nodes outside of the lungs, toward the middle of the chest but on the same side as the main tumor. One of the key issues is that the staging is the same whether there’s a single microscopically involved lymph node or multiple enlarged lymph nodes in a few areas of the mediastinum (mid-chest, between the lungs). But the outcomes of these groups of patients is very different, so it may be worth thinking about them a little differently. As shown here, from a retrospective review of just over 700 patients in France who had N2 mediastinal nodes involved (abstract here), outcomes were much better for the subset who had a single lymph node area involved (called a nodal station), and no clinically enlarged nodes (meaning that on a CT scan they didn’t appear abnormally big, defined as more than a centimeter):
(Click to enlarge)
The curves show that the patients with a single (L1 for one level instead of L2 for more than one, in the legend above) non-enlarged (m for microscopic instead of c for clinically involved) nodal area involved have a long-term survival in the range of 35%, while the outcome for patients with visibly enlarged mediastinal nodes and/or more than one level/station involved isn’t as favorable, although there are still long-term survivors. But this retrospective series is limited because it pools together people who had differing rigors of staging, some receiving chemo after and some not, and otherwise just a very heterogeneous population. That’s somewhat helpful for teasing apart signals within that broad range, but it helps to look at patients treated somewhat uniformly.
Management Options for SVC Syndrome
As I introduced in my last post, the superior vena cava SVC syndrome occurs in about 2-4% of lung cancer cases, and lung cancer is the leading reason for it. One of the most important factors in managing it is to determine, usually with CT imaging, the cause of the SVC syndrome — generally whether it’s caused from tumor or a blood clot, such as around a catheter.
To recap, the appearance of a CT scan may look like this, with the large vein known as the SVC compressed between the tumor (in the lung, which is black) and the mass of lymph nodes toward the middle of the chest:
(Click to enlarge)
If this is an initial presentation and there is no diagnosis yet, it’s important to get tissue as one of the first steps. The symptoms usually develop over weeks, and studies have actually shown that it’s rare for there to be significant consequences in taking the time to complete the workup and figure out the cause, rather than just frantically start treating without knowing what you’re treating. The treatment of choice depends in part on whether this is SCLC, NSCLC, lymphoma, or something else. And just jumping in with something like radiation can make it hard to determine the actual diagnosis later.
Introduction to Superior Vena Cava (SVC) Syndrome
Superior vena cava (SVC) syndrome is an infrequent but not rare complication of lung cancer, occurring in 2-4% of cases, most typically an early symptom that leads to the diagnosis. The SVC is the main vein that drains blood back into the heart from the upper body, and it runs in the middle of the chest on the right side, where it is vulnerable to being compressed by a nearby lung cancer or enlarged lymph nodes, such as from lung cancer or lymphoma. Less commonly, SVC syndrome can be caused by a clot within the blood vessel, and it’s also possible to have a combination of external compression and blood clot (clots are more likely to develop where blood flow is compromised). This leads to blockage of the blood flow from the upper body and engorged blood vessels and often swelling of the face, neck, and sometimes upper extremities, as shown in this figure (from this summary article):
The leading symptoms of SVC syndrome are facial edema, distended veins in the neck and sometimes chest, arm edema, shortness of breath, cough, facial plethora/fullness, and less commonly wheezing, lightheadedness, headaches, and even confusion.
Trial of Ongoing Chemo vs. Switch to Iressa for Japanese Patients with Advanced NSCLC
An interesting trial presented at ASCO 2008 came out of Japan, asking the question of whether there is an advantage to continuing first line platinum-based doublet chemo for up to six cycles or whether it might be better to give just three cycles and then switch from chemo right to the EGFR inhibitor iressa in Japanese patients with advanced NSCLC (abstract here). I haven’t mentioned it before because the trial, although interesting and with some provocative findings, didn’t clearly provide conclusions that would lead to obvious management changes.
For trial 0203, the West Japan Thoracic Oncology Group (WJTOG) enrolled 600 patients with previously untreated advanced NSCLC, with asymptomatic brain metastases permitted. Unlike North American NSCLC patients, among whom 10-15% are never-smokers, 31% of the patients in this Japanese trial were never-smokers; about 78% had adenocarcinomas (a higher proportion than in North America or Europe). They were randomized to receive chemo for six cycles vs. three followed by Iressa. The chemo could be carbo/taxol or cisplatin with gemcitabine, taxotere, navelbine, or irinotecan, all comparable in activity.
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