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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.
First Video Presentation Available for Download
While we work on making audio and video presentations available as podcasts and on youtube, I wanted to make the initial video presentation available for people who want to see the format and have an internet connection fast enough to download a LARGE file (>80 MB) in a timely way. If you’re interested, click here to download the file, using a workaround application. The link expires midday on 12/30, so I may just update and replace the link until we can get the video uploaded another way.
I know a few of the slide transitions are too abrupt (in fact, there’s brief overlap at one point — I’ll fix that). These should be a small tweak to fix, but I wanted to give people an idea of the format.
Merry Christmas! It may not have been what you asked Santa for, but I knew you didn’t already have this. And it’s just a glimpse of what we plan to do more of. Continue reading
Investigational Agent Update: mTOR Inhibitor Therapy for NSCLC
In a recent post I described a class of novel targeted treatments being studied in lung cancer as well as other treatment settings. These drugs inhibit mTOR, or the mammalian target of rapamycin, an immunosuppressant used to prevent rejection of organ transplants, but other drugs that inhibit this intracellular protein also have some anticancer effects. One called Torisel (temsirolimus) is a weekly IV therapy approved for kidney cancer and studied in othre settings, while another called Certican (everolimus) is a daily pill that is approved in Europe but not yet in the US, also being studied in several types of cancer. So today we’ll cover a little work done with mTOR inhibitors in NSCLC, and then we’ll turn to SCLC studies.
What I Really Do: Potentially Resectable Stage IIIA NSCLC
I’ve covered stage IIIA NSCLC in several prior posts, mentioning that it’s a clinical setting that is among the most controversial, but I don’t think I’ve really described my real world approach. To review, the controversy is that for stage IIIA NSCLC with mediastinal lymph node involvement on the same side as the tumor (N2 nodes), some people would recommend surgery as a main treatment strategy, and others would recommend chemo and radiation without surgery. The trials that have directly compared a surgical to a non-surgical approach have shown no significant survival benefit for either approach. However, one key study demonstrated that patients who underwent surgery had a lower risk of a recurrence of lung cancer, but this was largely offset by a higher risk of treatment complications and even death related to the more aggressive treatment of chemo and radiation followed by surgery (see prior post).
There is also the question for people who are planned to undergo surgery of whether they should start with surgery or receive “induction”/neo-adjuvant therapy beforehand. And if they receive induction therapy, should it be with chemo alone or chemo and radiation together? The typical standard is that for patients who have mediastinal node involvement identified before planned surgery, we usually give chemo with or without radiation as well before surgery. You could make the argument that it’s just as good to give it afterward, but stage III NSCLC is a setting in which the risk of recurrence with surgery alone is very high, and I’d feel far more optimistic about getting in chemo +/- radiation as well as surgery by starting with induction therapy and following with surgery, rather than starting with surgery and hoping to get additional therapy post-operatively. Too many patients can’t or won’t take more treatment after a big lung surgery to really expect that you can deliver it in the adjuvant (post-operative) setting.
SWOG Trial Combines Carbo Taxol Avastin Erbitux
When I first described the developing work with the EGFR monoclonal antibody erbitux (cetuximab) two years ago (see prior post), I described a trial that was just getting started called SWOG 0536. This was a trial testing the safety and feasiblity of a new combination that was moving beyond the triplet therapy of two chemo drugs plus the angiogenesis inhibitor avastin (bevacizumab) to add weekly erbitux to all of these; following 6 cycles of this combination, patients would continue on maintenance avastin (every 3 weeks) and erbitux (weekly). We got the early results from this trial very recently, and they were encouraging enough to move forward with a larger phase III trial that SWOG is about to initiate.
The SWOG 0536 trial was presented by my friend Ed Kim at the recent lung cancer meeting in Chicago (abstracts are all here, but no links to individual abstracts). The trial enrolled 99 eligible and analyzable patients with previously untreated advanced NSCLC, and as is the case with most trials with avastin, patients were excluded if they had a squamous tumor, brain metastases, history of coughing up blood, or required blood thinners. They had a median age of 64, were almost perfectly evenly split between men and women, and 22% of the patients had never smoked. The primary objective of the study was to assess the safety of this regimen, and 2 patients (2%) died from bleeding complications, which is definitely unfortunate but about what was seen in the larger ECOG trial of carbo/taxol/avastin (abstract here). Other common side effects that were moderate to severe included acne (18%), fatigue (19%), neutropenic (very low white blood cell count) fevers (6%), neuropathy (12%), and blood clots (10%). Others following the trial had jokingly said that the treatment limiting side effect of this combination would be cost, since we’re talking now about something in the range of $20,000/month. So perhaps they were only half joking.
Chantix for Smoking Cessation: Concerns and Current Recommendations
Medications to help people quit smoking are typically recommended as an early intervention, and over the past several years these have included nicotine replacement such as a patch or gum, or sustained release buproprion (zyban), and now chantix, with evidence supporting it as a leading effective option, as described in my prior post. The FDA has also approved these options for smoking cessation. Specifically, chantix is approved for people who have not received prior treatment to help them quit smoking, or in those who have tried another method unsuccessfully. Still, this is a treatment that is indicated for patients who possess the motivation. There are people who can quit smoking without the assistance of medication, and medication without an underlying commitment to smoking cessation is not likely to be successful.
The most advocated way to pursue smoking cessation successfully is to set a quit date that is a week after starting chantix. During that first week, the dose of chantix is gradually increased from 0.5 mg by mouth once daily for the first 3 days, then twice daily for the next 4 days, and then the full dose of 1 mg by mouth twice daily after the first week, which should coincide with the target quit date. The gradual dose escalation can help reduce nausea, which is typically mild to moderate but can occur in 30-50% of people and tends to be worse when starting right at the full dose. In addition, nausea can be reduced by taking chantix with food. Still, some patients may continue to have nausea, and in such cases it may be best to drop the dose down to 1 mg daily and then consider trying to get back up to 1 mg twice daily later.
Introduction to Chantix (Varenicline) for Smoking Cessation
Although we’ve established that 60% or more of the new cases of lung cancer in the US each year are now in never-smokers or former smokers, active smoking is still a big problem. Ongoing smoking can worsen survival in patients receiving active treatment for lung cancer, and the risk of developing lung cancer in people who don’t have it already can be decreased significantly by quitting smoking as early as possible (see prior post).
There are several approaches to consider, and several of these are highlighted in a prior post. But one that has emerged as among the more effective is chantix (varenicline), which is a drug that was developed by modifying the structure of a naturally occurring plant derivative called cytisine. The modified version gets into the brain much better than cytisine itself. Once in the central nervous system, chantix works by attaching to and partially stimulating the nicotine receptor (actually the nicotinic subtype of the acetylcholine receptor) in the reward centers of the brain (the same ones that mediate the pleasurable feeling of eating when hungry, drinking when thirsty, sex (gasp!), as well as reward of drugs like cocaine), but in partially activating the receptor, it blocks the receptor from being stimulated by nicotine, which provides the full reward effect.
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I don’t need to tell smokers that nicotine is truly addictive and leads to unpleasant withdrawal symptoms when those receptors are unoccupied for too long – this is exactly why it’s so hard to quit smoking. So chantix blocks the withdrawal symptoms by providing just enough stimulation of the nicotine receptor, at the same time blocking the more powerful reward effects of tobacco-delivered nicotine itself.
Should Iressa Come Back in the US? The Argument that Convinced Me
One of my good friends in the lung cancer community, Dr. Ed Kim from MD Anderson, was in town tonight and gave a talk that I attended. He’s one of the emerging real leaders in the field, and last week had published in Lancet one of the largest trials in advanced lung cancer, the INTEREST trial (see prior post describing it, and the link to the summary of the published article). The trial compared the EGFR inhibitor iressa (gefitinib) to standard chemo taxotere (docetaxel) and reported that the two approaches produced identical survival results.
(click to enlarge)
This is interesting (excuse the pun) in its own right, because some oncologists hold on to a belief that chemo is the treatment that really works and that EGFR inhibitors are a late consolation prize to offer. Even a less effective EGFR inhibitor like iressa (compared with tarceva (erlotinib)) was absolutely comparable, truly equivalent to a chemo approach that was less well tolerated. But we’ll cover the full results of the INTEREST trial in more detail separately.
Dr. Kim mentioned in passing that he wanted to see iressa return to the US market. Continue reading
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