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The Amazing Case of Rob F: Oligo-Metastatic NSCLC as a Truly Chronic Disease
One of the issues that we’ve commonly discussed and debated here is the question of when a local approach like surgery and/or radaition may be appropriate for I recently saw a patient of mine who I first met more than four years ago. At that time, he was only 37 years old and had just been diagnosed with stage IIIA NSCLC with several N2 nodes involved, after having quit smoking a couple of years earlier. He had actually initiated treatment with another local oncologist, a plan of chest radiation along with concurrent weekly carbo and taxol. He had also met with one of the expert thoracic surgeons I work very closely with, Dr. Eric Vallieres, who felt that he would be a good candidate for surgery after chemo and radiation. In truth, the extent of his disease in his mediastinum (midchest) was enough that I felt that an alternative approach of aggressive chemotherapy and radiation without surgery was a reasonable alternative. But Rob was one of the most informed and proactive patients I’ve encounted in my own practice and came to learn as much about the controversy around how to manage stage IIIA NSCLC as his physicians. Not only did he shape the plan that led him to surgery after “induction” chemo and radiation, he pushed for post-operative prophylactic cranial irradiation (PCI), though that isn’t a standard approach at this time (and I had expressed some misgivings despite the compelling rationale). He had also received a few doses of post-operative chemo with gemcitabine and navelbine, which was as much as even an aggressive-minded man in his late 30s could take after chemo, radiation, and surgery.
Of note, he had received this care through another oncologist, but he transferred his care to me about a year after he had completed these treatment. However, before he came to me, he had undergone a repeat PET/CT that showed an upper abdominal lymph node that lit up on PET, with no other abnormalities. In fact, he had just undergone an exploratory where they found and removed that node, which was recurrent cancer. He came to me for consideration of post-operative therapy, and the entire team had an extensive discussion of the possibilities (this team definitely including the patient, along with surgeon, radiation oncologist, and myself). Though we were without any real precedent and a potential of making him feel worse for no clear benefit, he was young, aggressive, knowledgeable of the balance of potential risks and benefits, and we thought it might still be possible to cure him. He had gone a year and had a single lymph node recurrence, with no evidence of any disease elsewhere. In fact, due to some manipulations that the surgeons had done at the time of his surgery, that lymph node was felt to potentially have drained directly from the surgical bed, so there was a chance that this area of disease hadn’t spread through the bloodstream.
GRACEcast Audio Interview: Dr. Janessa Laskin on Adjuvant Chemotherapy
Interview by medical oncologist Dr. Howard (Jack) West with fellow medical oncologist and lung cancer expert Dr. Janessa Laskin from the British Columbia Cancer Agency in Vancouver, BC, Canada on current standards and controversial topics in post-operative (adjuvant) chemotherapy for early stage, resected NSCLC.
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Differences in Never-Smoker vs. Current/Ex-Smokers Receiving Chemo
A quick point on the importance of biology over treatment. Years ago, I highlighted the results in the TRIBUTE trial of chemo with placebo or combined with erlotinib (tarceva) at the same time (biomarker study abstract here), which showed that patients with EGFR mutations had a much better survival whether they received an EGFR inhibitor or not:
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Here, biology was the prevailing factor. We’ve also recently seen that the patients on the IPASS trial of Asian never-smokers or light former smokers who were then randomized to first line chemo or an EGFR inhibitor had a far better survival if their tumor had an EGFR mutation compared to those who did not (see prior post). Similarly, the IPASS trial also showed that patients with EGFR mutations had nearly double the response rate to chemotherapy that patients without EGFR mutations demonstrated. So maybe the benefit of unique biological factors applies to standard chemotherapy as well as “targeted therapies”. Chemotherapy is also targeted and only benefits a subset of patients: we’re just further behind at understanding the relevant targets and discriminating the beneficiaries from others with standard chemo than with agents like EGFR inhibitors.
The recently published trial of cisplatin/alimta (pemetrexed) vs. cisplatin/gemzar (gemcitabine) (abstract here) showed an interesting result among enrolled never-smokers, who comprised 14-15% of the patients on the 1725 patient trial overall. Although we think of never-smokers as doing especially well with EGFR inhibitors, this trial also showed that never-smokers had a markedly longer median overall survival in both chemotherapy arms compared to current or former smokers (15.9 vs. 10.0 months in the cis/alimta arm; 15.3 vs. 10.3 months for the cis/gem arm).
Potentially Life-Threatening Hypersensitivity Reaction with Erbitux: A Region-Specific Side Effect
Erbitux (cetuximab) is a monoclonal antibody to EGFR, and it’s actually made from a protein that is part mouse and part human (called a chimeric protein, named for the mythologic creature chimera that was composed of multiple parts from different animals). It’s uncommon but not rare for patients to have an allergic reaction to this protein, and in most large national and international studies show rates of hypersensitivity reactions (HSRs) in the 1-3% range. In severe cases, these reactions can be very serious, causing low blood pressure, fainting, wheezing, and shortness of breath; they can even be fatal. While that is a small but real risk, wht is fascinating and especially scary is that there is an area in the southwest US — including Tennessee, the Carolinas, northern Georgia, and perhaps other areas — in which about 20-25% of patients develop these reactions.
Oncologists in these areas had noted over the past few years that they seemed to have a higher than expected rate of these complications, but the problem was highlighted in real terms in a 2007 article in the Journal of Clinical Oncology (abstract here) that retrospectively reviewed the experience of 88 patients on clinical trials and 55 patients off of clinical trials who received erbitux at one of three institutions in the region: Sarah Cannon Cancer Center and Vanderbilt-Ingram Cancer Center in Nashville, TN, and the University of North Carolina at Chapel Hill. They found a 22% rate of moderate to severe HSRs, ten times what we see in the rest of the country or world. These reactions occurred at the time of the first infusion but rarely afterward if someone did well the first time. They were more commonly seen in patients with a history of allergies, and it was interesting to see that reactions were more commonly seen in patients with NSCLC than other tumor types. The association of this type of reaction with lung cancer more than colon cancer is puzzling and suggests that there may be some correlation with a tobacco-related antigen, but we still need to learn more about this.
Can Development of a Rash on Erbitux Predict Who Will Benefit?
The improvement in median survival of 1.2 months with the monoclonal antibody to EGFR erbitux (cetuximab) in the FLEX trial that I’ve previously described was statistically significant, but there’s plenty of room to debate whether it’s really clinically significant (see prior post). What If we could add some way to refine our predictions of who will benefit from the addition of erbitux?
At the Chicago Lung Cancer meeting in November 2008, Dr. Ulrich Gatzemeier presented results of a planned subset analysis of the FLEX trial, in which the results compared the outcomes of patients randomized to receive cetuximab by whether they developed an acne-like rash within three weeks of starting this treatment. This was based on a growing and rather consistent experience that patients who receive EGFR inhibitors, whether oral tyrosine kinase inhibitors or IV antibodies, generally show a a strong trend or significantly better survival than patients who develop no rash (see prior post). The investigators found that there was a very significant difference in efficacy with cetuximab among the patients who developed a rash (of any severity) after two weeks (56%) compared with those who didn’t (44%). The difference in median survival was a near doubling: 15.0 months for the patients with any rash, compared with 8.8 months for those who didn’t:
First Line Chemotherapy for Advanced NSCLC: An Introduction
This pilot video slide presentation covers the development of our current standards for first line chemotherapy to treat advanced non-small cell lung cancer.
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These series will be called GRACEcasts (love it?), and we’re in the process of developing a bunch of audio interviews with experts for an audio channel, and multiple video presentations, which are going to be about 10 minutes each, just little chapters at one time.
And you don’t need to worry about getting all of the information in one viewing, because we’ll plan to upload a copy of the slides and a transcript of the narration that you can download and review anytime.
Adv NSCLC First Line Chemo Slide Set
Adv NSCLC First Line Chemo Transcript
Podcast: Play in new window | Download (31.0MB) | Embed
Tales from the Clinic: Mucinous BAC
In my last post I outlined the typical clinical scenario for pneumonic bronchioloalveolar carcinoma (BAC), which is typically the mucinous subtype of this unusual disease. In fact, we are still actively learning a great deal about BAC, enough for the lung cancer experts to begin to develop a more sophisticated view that the mucinous and non-mucinous subtypes have different behaviors and respond differently to treatments. Here is a case that illustrates a situation that I would consider to be typical for the mucinous, pneumonic form of BAC.
Ella A. was 74 year-old woman with a very long smoking history of about 50 years, who quit last month in the face of worsening pulmonary and other symptoms. Specifically, she experienced an initial dry cough that became productive of sputum over a six-month period, during which time she also developed increasing shortness of breath and a 20-pound weight loss for a woman who was pretty slender beforehand. This led her to her primary care physician, which showed extensive “consolidation”, shadows in both lungs and particularly extensive on the left. These findings were confirmed on a CT.
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As you might suspect, this led to a referral to a pulmonologist for a brochoscopic biopsy. The pulmonolgist needed to start her on oxygen before he could do a thorough bronchoscopy. The biopsy revealed well differentiated BAC, but the pathologist (an expert in lung pathology) didn’t have enough material to specify whether it was mucinous or non-mucinous.
Frankly, at the time when I first met her, in December of 2006, there were only the early inklings that this could be relevant. We don’t have much more information since then, except for the anecdotal experiences of myself and a few others who treatment many patients with BAC, which have corroborated the early impression that the well described effectiveness of oral EGFR inhibitors like iressa (gefitinib) and tarceva (erlotinib) in BAC appeared to be limited to the non-mucinous subtype.
Tales from the Clinic: Anne S and her Indolent Metastatic NSCLC
Let’s return to what happened with Anne S., who I introduced in the last post. The highlights are that I met this woman in September of 2005, when she was 79, slowing down from many medical issues unrelated to cancer, wary about chemo, and with a cancer that was metastatic but that had progressed only minimally in the months between the initial detection of her cancer and when I first saw her. We agreed that attentive follow-up made sense.
And so, I saw her regularly, and her scans showed very minimal progression 6 and 12 weeks after her initial visit with me. She also felt pretty much the same, bothered primarily by her arthritis, fatigue (which preceded her cancer), and other issues…but no appreciable decline. In fact, she didn’t really show very convicing progression until late May of 2006, when one liver lesion grew pretty notably, and a new one emerged. We again discussed the risks and benefits of treatment, and she decided to start single-agent gemcitabine (navelbine is a well-studied option in the elderly, and it’s a fine choice I’ve also given frequently in similar situations, but it does have the inconvenience of generally needing to have a port-a-cath placed, because it can cause a chemical burn if it leaks out from the IV catheter into the surrounding tissues).
Clinical Cases: 79 Year-Old Woman with an Indolent Metastatic NSCLC, Part 1
In addition to the presentations about the evidence, I thought it might be helpful to highlight some of my own clinic cases that can illustrate how I use the principles in practice. These cases should highlight that many if not most people don’t exactly follow the “classic” example, and that if we were to open the case files from most oncologists, we’d find that it’s very common (and appropriate) to bend the guidelines, to individualize based on the particular issues of a specific person. And I think it may also be helpful to see the range of what’s possible. I’ll plan to cover not only the patients who do far better than average, but also will discuss some other cases that have illustrated the harder aspects of lung cancer. There’s a great spectrum in how people do, and we’ll provide a glimpse of that spectrum.
I’ll start with Anne S., a truly delightful woman who came to me in September of 2005 with metastatic NSCLC and still seeing me today, and feeling as well as she did then (so you know that this is a relatively happy case). I’d like to say that this is because of her brilliant oncologist, but I think her case largely illustrates how indolent metastatic lung cancer can be, particuarly in some elderly patients. If there is an element that I think I was able to manage well, it’s that we haven’t over-treated her along the way, with a cost to her quality of life.
mTOR Inhibitors for Small Cell Lung Cancer
We’ve covered the modest activity of a few mTOR inhibitors in NSCLC (see prior post), so now we’ll turn to SCLC. Everolimus, an oral mTOR inhibitor, has been studied at 10 mg by mouth daily in patients with relapsed SCLC and had received 1 or 2 prior regimens and no brain metastases (abstract here). The investigators did a preliminary analysis of 19 patients, among whom there were no responses, and only 3 achieved stable disease. Though tolerated well enough, there wasn’t enough of a signal to move forward with it. The IV mTOR inhibitor temsirolimus (Torisel) has also been studied in a more favorable prognosis scenario of maintenance therapy after a good response to first line chemo for extensive stage SCLC (abstract here). A total of 85 patients were treated with either of two doses, 25 mg IV weekly, or ten times that amount, 250 mg IV weekly. The median survival of 8 months was reasonable, but it was notably better at the higher dose (6.6 months vs. 9.5 months). The problem was that these patients also tend to do well, and the patients receiving temsirolimus didn’t do better than the investigators would have expected otherwise. Because of this, there was little enthusiasm for continuing with it as a single agent in SCLC, but there was more interest in adding it to chemo for SCLC.
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