Unresectable locally advanced NSCLC
Options and controversy around management options for unresectable stage IIIA and IIIB NSCLC
Several weeks ago I had the opportunity to discuss a series of cases of locally advanced NSCLC with a couple of expert colleagues: Dr. George Blumenschein, medical oncologist in the Division of Thoracic & Head/Neck Oncology at MD Anderson Cancer Center in Houston, TX; and Dr. Walter Curran, radiation oncologist who heads the Division of Radiation Oncology at the Winship Cancer Center at Emory University in Atlanta, GA. Dr. Curran is also the head of the Radiation Therapy Oncology Group, the US-based cooperative oncology group leading important questions about radiation oncology in various cancer types.
The first of the cases we covered is a patient of mine with stage IIIA N2 NSCLC, the most controversial setting in lung cancer management, where many options are all considered as reasonable alternatives throughout the oncology field.
Here’s the audio and video versions of the podcast, along with the transcript and figures.
Here is the second of three cases covering issues in managing elderly and frail patients with lung cancer that I discussed with experts Paul J. Hesketh from Lahey Clinic and Karen Kelly from Kansas University Medical Center. Both major experts in lung cancer, they have a lot of experience and have been leaders in publishing on the understudied population of elderly and poor performance status patients with lung cancer. This particular case covers treatment options for a patient with unresectable stage III non-small cell lung cancer (NSCLC).
Here is the audio and video versions of the podcast, along with the figures and transcript.
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.
Our next podcast slide presentation comes from Dr. Shirish Gadgeel, medical oncologist at Wayne State University in Detroit. He came out to Seattle for a physician education program I run and was kind enough to stay for our NSCLC Patient Education Forum, where he spoke on our Current Standards of Care for Locally Advanced (Stage III) NSCLC.
Here’s his presentation in audio and video formats, along with the transcript and copies of the slides.
Look, before I begin this post let me say that I’m really not trying to be a negative person when it comes to Avastin (bevacizumab; see here and here). It is a great drug in the appropriate setting, and is has been proven to prolong survival in first-line treatment of advanced NSCLC patients when combined with chemotherapy. Given this success, as well as proven success in treating renal cell carcinoma, breast cancer, and colorectal cancer, it is understandable that people would keep testing it in new situations. It’s just that all of the recent publications that try and expand the role of Avastin to new areas seem to have disappointing results. Which brings me to today’s topic.
A new online publication in the Journal of Clinical Oncology by Dr. David Spigel and colleagues from the Sarah Cannon Research Institute in Nashville, TN, describes the experiences from 2 phase II trials in small cell (SCLC) and non-small cell lung cancer (NSCLC) using Avastin in combination with chemotherapy and chest radiation. There had been reports of safety concerns in the past with this combination, specifically with regards to something called tracheoesophageal fistula, but this was my own first look at the data.
A tracheoesophageal fistula is a pathologic connection between the esophagus (food pipe) and trachea (windpipe). It doesn’t take a doctor to imagine why it might be a bad thing to empty everything you eat or drink directly into your lungs, but in case you weren’t sure let me assure you this is what we in the business call “a bad thing”. It is always serious and often fatal, although if caught early can be treated with a stent that covers the opening and prevents passage of material between the two sites.
In 2006-07 there were two phase II trials enrolling patients to investigate the role of adding Avastin to chemotherapy and radiation in limited stage SCLC and in locally advanced (stage III) NSCLC. Concurrent chemoradiation represents the standard treatment for both of these conditions, so the only major change was in adding the Avastin. The SCLC study enrolled 29 patients, but stopped early after an unacceptable level of toxicity. In contrast, the NSCLC study only enrolled 5 patients before having to stop. I think these studies represent a cautionary tale, but are also a positive testament to the safety measures put in place to stop trials if they end up causing too much toxicity. Continue reading
Perhaps the most unexpected clinical trial result in lung cancer over the past 5 years was the finding in the large Southwest Oncology Group (SWOG) 0023 trial that randomized several hundred patients to maintenance therapy with either the oral EGFR inhibitor Iressa (gefitinib) or a placebo after chemo/radiation concurrently and then consolidation taxotere (docetaxel). While just about everyone in the lung cancer community expected to see either a significant benefit or, at worst, no real effect from maintenance Iressa, the actual trial was stopped early and demonstrated a statistically and I would say clinically significant decrease in overall survival with maintenance Iressa. The median overall survival (OS) in the final publication was a full 12 months lower in patients who received Iressa compared with those who received the placebo .
To me, not only did this study demonstrate that giving consolidation EGFR inhibitor therapy was probably a bad idea, at least outside of a clinical trial, it also suggested that we don’t necessarily know as much as we presume we do about how trials will turn out, so it makes sense to do the studies rather than just start a new strategy without the evidence to back it up.
Here is the third portion of a talk I did at the Seattle-based non-profit Cancer Lifeline in May, and this section focuses on our current standards for managing unresectable locally advanced (stage III NSCLC). This covers theissues of sequential vs. concurrent chemo with radiation and the important issue of whether additional consolidation chemo after the radiation is feasible and advisable. It also covers the emerging key trials being done in this treatment setting.
Here is the presentation in video format, the audio version, transcript, and a pdf file of the figures.
In 2008 the SWOG 0023 trial was published, which looked at the question of maintenance Iressa (gefitinib) after definitive chemoradiation in patients with locally advanced (Stage III) NSCLC. The trial randomized patients who had not progressed after completing CRT with concurrent cisplatin and etoposide chemotherapy followed by consolidation Taxotere (docetaxel) to either Iressa or placebo. Patients were then followed until progression or death. In a result which still confounds lung cancer oncologists, it appeared that the arm which received Iressa had a significantly WORSE survival than those who received placebo, with a median survival that was 12 months shorter (23 months in the Iressa arm vs. 35 months with placebo).
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No one has put forth an adequate explanation of why Iressa, a drug used widely now in NSCLC patients for almost a decade, would be harmful (instead of merely ineffective) in these patients. It did not appear that more patients on Iressa died of toxic side effects from the drug, which would have been a convenient explanation. Instead it appeared that the patients receiving Iressa had faster progression of their lung cancer than those on placebo. Some have hypothesized that EGFR inhibition actually stimulates the cancer to progress in this specific population. As a result, this study has been held up as a cautionary tale about how we need to understand that our treatments have the potential to harm patients, not just help or do nothing. I have no bones with this concept in general, but…
“Locally-advanced NSCLC” is a term generally applied to lung cancers with tumors that have either grown into major structures (such as vertebrae or spine bones, the central airways, or involve the main blood vessels supplying the lung or central chest) or those cancers that have spread to lymph nodes in the central chest (the mediastinum). In the case of many of these cancers, removing them with surgery is not possible, but treatment with the combination of chemotherapy and radiation given at the same time may be used with the goal of curing the cancer.
While administering chemotherapy and radiation at the same time (termed “concurrent therapy”) is more effective at killing cancer cells than when the treatments are given separately, this approach also causes increased side effects for the patient. Side effects may include nausea, vomiting, neutropenia (decreased levels of white blood cells which can lead to increased risk of infection) with or without infections, anemia, fatigue, and pain with swallowing (from radiation “sunburn” to the esophagus). In order for a patient to tolerate this rather stout combination, they need to be fairly healthy and active, and to have a strong physical reserve (measured with a term “performance status”).
Most studies of the combination of chemotherapy and radiation, although not excluding older patients, have enrolled younger patients. Typically, the average age of patients enrolled on trials like these is 64 or 65. This allows for decent conclusions to be drawn for patients of this age group and younger, but how do these studies apply to the elderly; patients 75, 80, older?