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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.
What I Really Do: Frail and/or Elderly Patients with Advanced NSCLC
I doubt there is a group of lung cancer patients more common but less well studied than the substantial subset of frail and/or very elderly patients with advanced NSCLC. While “elderly” patients, usually defined as age 70, have been evaluated as a subset of the population in larger studies and even been the subject of specific studies just for the elderly, most of this work has shown that fit elderly patients do as well as younger patients getting the same aggressive treatment. What we have relatively little information about is how frailer patients, regardless of age but certainly more likely to be in their mid-70s or older, should be treated.
The available evidence shows that either a carboplatin doublet (I don’t advocate for cisplatin here) or single-agent chemo are feasible and associated with our best results. Among doublets, carbo/taxol (paclitaxel) looks favorable, and I’ve also felt very comfortable with carbo/gemcitabine, a combination that is usually associated with very little in the way of perceived side effects other than fatigue, and most of the adverse side effects are so called “paper toxicity” of low blood counts that the doctor needs to tell a patient about, not the other way around. However, older patients tend to have more of a problem with maintaining adequate blood counts without needing treatment delays, injections of white blood cell stimulators like neulasta (pegfilgrastim) or neupogen (filgrastim), or transfusions of red blood cells). Still, with minimal hair loss and nausea, and no requirement for steroids (which can be a problem in patients with diabetes because it increases blood sugar levels), carbo/gem is an option I’ve commonly turned to. And now with more extensive study, carbo/alimta (pemetrexed) is emerging as a convenient, quite well-tolerated doublet, but one I’d only consider for patients with non-squamous cancers, since converging evidence strongly indicates that alimta is simply not effective against squamous NSCLC (see prior post). I haven’t yet had occasion to use a carbo/alimta doublet in a marginal performance status patient, but if alimta is approved with a platinum as a first line agent by the FDA soon, it will become a leading consideration for my non-squamous patients.
The decision about whether to recommend a single agent or a doublet is really a hard one, for which I use a combination of a read on the general health of a patient and also their concern about side effects. Since either approach is completely reasonable, I lean more toward a single drug if a patient is kind of wobbly, expresses concern about whether treatment for advanced NSCLC is “worth” the side effects, etc. – and despite the findings that fit elderly can do well with treatments commonly used in 60 year-olds, I’m still more likely to recommend a single agent approach for a patient of about 78 or older. But it’s always got to be individualized. I’m actually giving a 76 year-old man cisplatin/navelbine as adjuvant therapy (a setting in which I am particularly wary about causing excess harm) because he appears to be healthier than many 62 year olds, and it’s a curative therapy setting where cisplatin may make a difference. If he were receiving treatment for metastatic disease, I wouldn’t even hesitate to give him a doublet, even projecting his age forward by a few years. But I’ve also recently struggled with the “carbo doublet vs. single agent” question in an aggressively minded, pretty well-appearing 79 year old man, then elected to give single agent therapy and was very glad I did when he had a remarkably hard time, and I turned him from a fit 79 into a frail 79 in a hurry (thankfully, just temporarily).
Japanese Study Demonstrates Elderly Patients Benefit from Post-Operative Chemo
In Japan, a different chemotherapy approach than cisplatin doublet chemo has been used in the post-operative setting. In contrast to the North American and European approach of 3-4 cycles of platinum-based chemo, in Japan they have studied an oral chemotherapy called UFT, a combination of uracil and tegafur. This combination is in the same family as an old chemo drug called 5-FU that is still used in various settings today, although not commonly in lung cancer. Nevertheless, this oral chemotherapy, which isn’t and probably won’t become available in the US and several other parts of the world, has been studied in a Japanese population and actually shown to improve survival in patients with stage I NSCLC. And this year we saw an analysis of the benefit of chemotherapy on the basis of patient age in this trial (abstract here).
The original trial enrolled just under 1000 patients with stage I adenocarcinomas (a remarkably common presentation in Japan, where they really do see a fundamentally different lung cancer biology than we see in North America and Europe, at least). This focus on patients with adeno NSCLC is based on earlier work that indicated this drug worked preferentially in adenocarcinoma tumors, and randomized patients with stage I tumors to observation or up to two years of daily oral chemotherapy after surgery (abstract here). As shown in the curves below, there was a modest but significant survival benefit, and nearly all of that benefit was seen in patients with larger, higher risk T2 cancers, rather than the smaller T1 cancers with the lowest risk for recurrence and death:
Interestingly, this is really the most conclusive survival benefit we’ve ever seen for stage I NSCLC, and in the curve for the overall trial population (left curve), the separation of the curves that signifies a survival benefit from treatment doesn’t occur until four years out. Unfortunately, this is with a drug not available in the US and was a benefit seen only in patients with stage IB adeno NSCLC: we haven’t been able to do another study with UFT to confirm this, but it’s currently a standard treatment in Japan.
Erbitux with Radiation in More Marginal Patients with Locally Advanced NSCLC
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.
Tarceva (Erlotinib) in the Elderly
One of the initial appeals of targeted therapies like tarceva (erlotinib) was that they may have fewer side effects and emerge as an alternative to standard chemo for some people. And one of the most appealing areas for offering a good alternative to standard chemo has been in the setting of older patients, who may be more wary of side effects and/or have additional medical problems than younger patients.
A theme that has emerged very consistently in studies of elderly patients in lung cancer, and largely in oncology in general, is that fit older patients without many medical problems are very likely to do every bit as well as younger patients. Although studies of older patients with lung cancer have largely paired the elderly and “poor risk”/frailer patients (performance status of 2, corresponding to being symptomatic, a little limited in activities, but spending more than half of the day in bed or a chair) in pooled trials. More recently, though, we’ve come to recognize that these are overlapping but definititely distinct groups. We also learned in a prior post that unselected patients (not singled out by things like having never smoked, or having an EGFR mutation, for instance), with a marginal performance status who receive tarceva instead of standard chemo clearly do less well than patients who get standard chemo. But how well do older patients do with tarceva, independent of performance status? This is an important question now that more than half of all newly diagnosed lung cancer patients are over 70. A couple of trials help shape our thinking here.
Second Line Treatment in Elderly Patients
Completing the analysis of the randomized trial that compared alimta (pemetrexed) and taxotere (docetaxel) in second line treatment of NSCLC (abstract here), which showed nearly identical response rates and survival but a more favorable side effect profile with alimta, another retrospective review of results looked at differences between the arms in older vs. younger patients (abstract here).
Typically, the trial enrolled only a minority of patients 70 and older, who accounted for only 86 of the 571 patients on the study (15%), despite the fact that the median age for patients newly diagnosed with lung cancer in the US is now just over 70. Besides age, they didn’t differ significantly in performance status, NSCLC subtype, or other variables from the younger patients. There were also no clear differences between the older patients who were randomized to taxotere vs. alimta.
The trial as a whole showed no differences in efficacy between the two drugs, and that was true for the 85% of patients who were under 70. But in the patients 70 and older, there was a better progression-free survival (PFS) and overall survival (OS) in recipients of alimta:
(Click on images to enlarge)
By the numbers, median PFS in patients 70 and older was 2.9 months with taxotere and 4.6 months with alimta; for OS, the numbers were 7.7 and 9.5 months, respectively. One year survival numbers weren’t different, 23.1% vs. 20.4%. Continue reading
Tarceva vs. Standard Chemo Compared for Marginal Performance Status Patients, by Dr Laskin
One of the issues we struggle the most with, as oncologists, patients, and families, is how to choose a therapy that won’t make someone feel worse. There are so many things to factor into these decisions: what is the baseline function of the person, what comorbidities (other chronic illnesses) might interact or interfere, what side effects are acceptable or worth the risk, to what degree is the cancer interfering with their functioning and can this be reversed with chemo, and of course what does any individual patient want and expect from chemo? Not to mention the choices between a few different agents or combinations of agents!
The issue of “performance status” (PS) is fundamentally important in lung cancer, especially in non-small cell lung cancer (NSCLC). There are different scales we use to measure this, which have been posted and discussed previously. Most publications use the Eastern Cooperative Oncology Group (ECOG) scale – partly because it’s rated 0 – 4 which is easy to remember. Zero is normal, and 4 is very debilitated, essentially bed-bound. Perhaps it is somewhat surprising that despite all of the fancy molecular markers and blood tests we have, a person’s functional impairment of PS is one of the most important predictors of how “bad” a cancer is. The other two factors are stage (how much cancer is there?) and degree of weight loss. It is well described, and there are other posts on the site elaborating on this, that if someone is very sick either from the cancer or from other concurrent illnesses, standard chemotherapy will only make things worse. But there’s an “in between” group, with a performance status of 2, who may not be as well served by the more aggressive standard approaches but still may benefit from cancer treatment.
The great hope of the next generation of “targeted” therapy is that oncologists will be able to more accurately predict who will benefit from which drug and that the newer drugs will be less toxic and thus perhaps even better for people who are too sick to tolerate our current forms of chemotherapy. Continue reading
How Should We Treat Frail Patients with Locally Advanced NSCLC?
Despite the fact that a very significant proportion of the “real world” patients have considerable medical problems such as markedly decreased lung function (pretty common with many years of smoking), weight loss (5 or 10% of body weight is usually considered a problem), or otherwise are not able to be very active. The vast majority of clinical trials for potentially curative, combined modality (chemo and radiation) approaches of chemotherapy and radiation have often been restricted to patients with a good performance status (PS), which means that patients are either unrestricted in their activities or are symptomatic but able to perform light work activities. Chemoradiation approaches, and especially those that include concurrent chemotherapy and thoracic radiation therapy (RT), are generally accompanied by considerable acute side effects and a treatment related death rate in the 5-6% range even in quite fit patients. With such challenges even for the healthier patients, this precluded those with marginal PS at baseline from participating in more rigorous multimodality strategies. So how should we manage patients with a PS of 2, corresponding to an ability to care for themselves but unable to work? The short answer is, we don’t have enough information to say, but there are a few studies that have addressed this very under-studied population.
One early study that demonstrated the feasibility of an attenuated concurrent chemoradiation approach in marginal patients not able to safely receive standard platinum-based chemotherapy and radiation was SWOG 9429 (abstract here). This multicenter, single arm study (everyone received the same treatment) accrued 60 “poor risk” patients, defined as having a PS of 2 with low blood protein levels or >10% weight loss, insufficient lung function reserves for more aggressive combined therapy (measured by the amount of air someone can blow out of their lungs in one second, called the FEV-1, for forced expiratory volume), or medical problems that made it infeasible to give standard cisplatin (including hearing loss, kidney problems, congestive heart failure, or peripheral neuropathy). The treatment approach included a relatively low dose of carboplatin IV on days 1 and 3, along with etoposide the first four days of a 28-day cycle. Chemo was given for a total of two cycles concurrent with daily chest radiation to 61 Gray (Gy) — a full dose. This trial demonstrated feasibility of this approach, with moderate acute toxicity and no treatment-related deaths, as well as encouraging efficacy: the median overall survival of 13 months, and the two-year survival was 21%; these numbers are in the ballpark of results from trials with more vigorous patients. Probably significantly, the majority of enrolled patients had a good PS and compromised pulmonary function, with only 18% of enrolled patients having a PS of 2. Continue reading
Comparison of Iressa to Single Agent Chemo in First Line treatment for Elderly Advanced NSCLC Patients: The INVITE Trial
In addition to a direct comparison of iressa to chemo in the second line setting for advanced NSCLC (see recent post on INTEREST trial), as conducted with the INTEREST trial I described in a recent post, a very similar comparison of Iressa to chemo was also performed in another setting where single-agent chemo is also the treatment of choice. Specifically, the INVITE trial evaluated iressa vs. navelbine as a single agent in previously untreated advanced NSCLC (abstract here).
(Click to enlarge)
As discussed in one of my early posts, there is room to debate whether single agent approaches or older patients should receive single-agent chemo or standard platinum-based doublets (particularly carboplatin-based instead of the more challenging cisplatin doublets). Among the most commonly used single chemo agents in the elderly population is navelbine (also known as vinorelbine), based on it being proven to improve survival compared with supportive care alone in the memorably named ELVIS trial (Elderly Lung Cancer Vinorelbine Italian Study – paper here). We’ve seen the results of a trial in which tarceva was compared to the chemo doublet of carbo/taxol in patients with a marginal performance status (not the same population as elderly), and as I described in a prior post, the recipients of chemo fared better than those who received tarceva. So did the INVITE trial show similar results for gefitinib in the elderly compared to a single chemo agent? Continue reading
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