Here’s a webinar case discussion I did with Drs. Julie Brahmer from Johns Hopkins in Baltimore, and Greg Riely from Memorial Sloan Kettering Cancer Center in New York. They’re great thoracic oncologists as wellas friends, and they were kind enough to join me for discussion of several complex cases that don’t have clear answers and illustrate the reality that even when we know the evidence, there’s plenty of room for judgment.
Our first case is about a 63 year-old woman who has a poorly differentiated NSCLC that is just outside of the range we’d feel feasible for radiating, and it brings up issues related to trying to integrate chemo and possible radiation, the debatable role of agents like Avastin (bevacizumab) and Alimta (pemetrexed) for cancers that are hard to classify, and then how we approach managing patients who have responded well — observation or maintenance?
Here is the audio and video versions of the podcast, along with the associated transcript and figures.
Dr. Quynh Le, radiation oncologist and Professor at Stanford University, was kind enough to participate in our NSCLC Patient Education Forum. She spoke on the topic of emerging treatment options using radiation for early stage NSCLC. The new work she’s describing on stereotactic body radiation therapy (SBRT) is looking promising enough that it’s being considered increasingly as a very strong choice for people with localized lung cancer but who aren’t good candidates for surgery or are disinclined to pursue it. In fact, much of the debate in the lung cancer community is about whether SBRT appears compelling enough to be considered as a viable alternative to surgery even in patients who are fine candidates for resection.
The podcast and additional materials from her presentation are here:
Some passages of the program may be a little difficult to follow, so please use the transcript if you need to clarify parts. You can also ask questions here, for clarification or follow-up. I hope you find it helpful.
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).
In my earliest introductory post about SCLC, I described the typical staging breakdown used clinically, which is essentially divided into limited disease SCLC (LD-SCLC), which is typically treated with chemo and chest radiation together, with curative intent, and extensive disease SCLC (ED-SCLC), which is typically treated with chemo alone and is not considered conventionally curable. But one of the murky areas in SCLC staging is the situation of what is limited disease except for a pleural effusion on the same side as the main tumor (called an “ipsilateral” pleural effusion) . In some trials and at some centers, this situation is considered ED-SCLC, while at others, it’s considered LD-SCLC. On the diagram below, an ipsilateral pleural effusion is designated as a controversial staging question:
A recently published report from Japan (abstract here) describes the experience of 63 patients with LD-SCLC and an ipsilateral pleural effusion. This retrospective review of patients over several years who were all treated at the same center compared the outcomes of patients who initially received chemotherapy and then received chest radiation if their effusion had resolved to the experience of patients who didn’t receive radiation after their effusion resolved. They also compared the results for these groups to outcomes in the patients whose effusions didn’t resolve after chemo.
One of the core ideas in the management of stage III, or locally advanced, NSCLC is that unresectable disease that is being treated with curative intent is most effectively treated with a combination of concurrent systemic (“whole body”) therapy and chest radiation to all of the visible cancer. The systemic therapy, which has been conventional chemotherapy, is given to both make the radiation work better and to treat potential micrometastatic disease, cancer cells in the bloodstream that can’t be reached by radiation but could potentially be killed off by a treatment that goes throughout the bloodstream.
The challenge, though, is that concurrent chemo and radiation is hard on people, with a rate of treatment-related deaths of about 5-7% of people even on clinical trials (which often select for a fitter population than are seen in the “real world” of many ineligible patients). So we reach a point where the aggressiveness of the treatment can be associated with problems that are as threatening or worse than the underlying disease. And this is a particular problem for older and/or frailer patients, which happens to cover a significant proportion of people with lung cancer.
Part of the promise of targeted therapies all along has been that they could potentially substitute for standard chemotherapy as a systemic therapy that is perhaps as effective as chemo but with fewer side effects. Most of our work with these agents has been to just add them to our current standards, but it still makes sense to consider using them as a substitute in patients for whom conventional chemo is really at the upper limits of what is tolerable. And it’s clear that doing chemo concurrent with radiation is overall more effective than doing them sequentially, but perhaps we could get the tolerability of a sequential approach with the efficacy of concurrent therapy by doing a program of targeted therapy (and no chemo) concurrent with chest radiation.
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:
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