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Dr. Jack West is a medical oncologist and thoracic oncology specialist, and Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center in Duarte, CA.

What I Really Do: First Line Advanced NSCLC, Avastin Eligible Patients
Fri, 08/22/2008 - 19:14
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

As I described in a recent post introducing the concept of the series, “What I really do”, I wanted to provide a summary of how interpret the evidence I show here, how I really approach real life patients. Some of this will illustrate that the experts don’t agree 100%, and that we all add some interpretation and style to how we manage patients. What I describe isn’t meant to be a dogmatic declaration of what everyone should do, but just the way I apply the evidence from trials of somewhat selected patients in the real world. At the same time, I typically modify plans based on things like a patient’s other medical problems, their aggressiveness vs. aversion to side effects, travel distance to get to me, and other factors. I don’t have any setting where 90% of patients get the same treatment, because I think many patients need a more individualized approach.

That said, let’s start on how I think about a patient presenting with new advanced NSCLC, which is the stage at which about half of the patients with NSCLC are diagnosed, and a higher proportion of my lung cancer patients (because many of the patients with early stage NSCLC, especially stage I, may not need or be feasible candidates for chemo).

Performance status is the first indicator. There’s certainly some correlation with age, but most experts agree that the overall activity level of the patient counts far more than chronologic age. A 77 year old man who walks his dogs 2 miles per days is a much stronger candidate for aggressive treatment than a 57 year old with severe emphysema who rarely leaves the house because she becomes short of breath making the bed or walking around. Treating poorer risk patients is a separate issue, so we’ll concentrate on healthier patients who are able to manage their own activities of daily living (ADLs) without assistance and get out and about.

Within the healthier population with advanced NSCLC, the question I ask is whether they are a candidate for avastin (bevacizumab), which has been shown to improve survival for a limited subset of patients who don’t have brain metastases, squamous NSCLC, active heart disease, require full dose blood thinners, or have a history of coughing up blood (prior post here). Since that initial approval of avastin for lung cancer, increasing evidence has emerged suggesting that it’s probably pretty safe to give avastin to patients with treated brain metastases (prior post here), and also for patients on blood thinners (prior post here), but right now the FDA approval doesn’t include these groups, and serious or even fatal bleeding episodes can occur even in well-selected patients receiving the treatment, Avastin added to carbo/taxol, just as it was given in the large trial that led to its approval. If a bleeding complication occurs in someone treated as Avastin was approved, it’s a terrible thing, but it’s known to happen. But if, God forbid, a patient on blood thinners bleeds, or someone with a treated brain metastasis has a hemorrhage in their brain, there’s no way to prove it didn’t happen because you treated someone outside of the FDA guidelines. And some people feel that even if you have a careful discussion with a patient with brain metastases or on blood thinners, and even if you document the risks well, a family member can still come back months after a patient’s unfortunate death and sue their doctor. I happen to be one of those people, so I use avastin by the book. And for the sake of completeness, I wouldn’t consider trying it in someone who has coughed up any significant amount of blood (more than slight flecks or streaking), nor someone with squamous NSCLC, since both groups continue to look like they have an unacceptable risk of bleeding complications.

So if patients are eligible and are inclined to pursue it, I recommend carbo/taxol /avastin for up to six cycles, then maintenance avastin. I don’t have a real problem with other platinum-based doublets combined with avastin, but no other regimen has shown a survival benefit, and cisplatin/gemctibine has failed to show a survival benefit in the AVAiL trial (prior post here). This trial also showed that a lower dose looked comparable to the higher dose (but neither was better than placebo). Putting it all together, I think it’s reasonable to give a lower dose, but I still favor the higher dose that was used in the ECOG trial, the only one that showed a survival benefit, particularly since the side effect profile wasn't appreciably better with the lower dose.

Another point is that the failure of the AVAiL trial to show a survival benefit suggests to me that avastin’s benefit isn’t astounding: I would have hoped to see it significantly improve overall survival with the cisplatin/gemcitabine regimen if it were that remarkable (most oncologists have considered the regimen attached to avastin to be pretty much interchangeable, since we presumed that the effect of avastin would be the same for all of these doublets). One large trial was positive, and another was negative, and I'm not sure that we'd consider it a standard of care if the negative trial had been reported first. But as it was, US-based oncologists were already conditioned to accept avastin as part of our initial plan, and the AVAiL trial leaves enough unanswered questions that I don't think it was enough to reverse our practice of giving it. But it didn't increase my confidence about how much the avastin was adding. So I don’t think it’s a crucial mandate that every eligible patient receive avastin. And it's something I think about in a patient who is perhaps borderline for eligibility, maybe because of treated stable brain mets or anticoagulation or has had some mild hemoptysis (coughing up blood). While there is growing experience suggesting that we can be more comfortable giving avastin to patients who may have previously been excluded or are just questionable for it, is it clearly beneficial enough to accept the risk if it didn't show a benefit in both of the large trials that studied it?

The other issue is that an analysis of patient age on the ECOG trial showed that elderly patients (defined as 70 and older) didn’t receive the same degree of survival benefit and experienced a significantly higher rate of many side effects compared with younger patients (prior post here). The trial wasn’t designed to test this, and this remains a debatable point, but I definitely discuss this issue with older patients, and although I wouldn’t hesitate to recommend the triplet to a fit 72 year old, I’d think hard about how to guide a 78 year old.

That's more than enough for now. I would estimate that only about 40% of my patients are eligible for avastin, so another post will cover how I approach healthier patients who aren't candidates for avastin for one reason or another.

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