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The ChEST Trial: Pre-Operative Chemotherapy Looks Great, But That Ship May Have Already Sailed
We’ve covered the potential value of systemic therapy for early stage NSCLC in a wide range of posts and podcasts, and to summarize what we’ve learned in a sentence, it’s basically that chemotherapy can significantly increase progression-free survival (PFS) and overall survival (OS) in patients who have undergone curative surgery for stage I-III NSCLC, but the benefit is far more convincing in patients with a high enough risk to justify the potential adverse effects of chemotherapy. In fact, in patients with node-negative cancers that are smaller than about 4 cm, the evidence isn’t very good that chemotherapy improves outcomes, and there is a strong suggestion from the limited available evidence that it may be net harmful. This makes sense to me: chemotherapy represents a fixed negative effect (both quality of life and risk of adverse effects) whether a patient has a high risk of recurrence or a low risk of recurrence and can reduce the chance of the cancer recurring by a certain proportion. If the risk of recurrence is high (such as in someone with stage II or III resected NSCLC), chemo can reduce that risk quite a bit, so the net effect is very positive: big anticipated benefit exceeds small risk. However, in patients with smaller node-negative cancers, the magnitude of benefit is going to be very low because the risk of recurrence is too low for the chemo to have much absolute effect: small risk exceeds even smaller anticipated benefit.
In recent years, we have generally focused on post-operative, or adjuvant chemotherapy, because the majority of positive trials for early stage patients have used an adjuvant strategy. However, going back in time ten years, both pre-operative (neoadjuvant) and post-operative chemotherapy were investigational approaches, and they each have their advantages and disadvantages. Post-operative chemotherapy has the benefit of being able to make treatment recommendations based on the most accurate staging information (from surgery) and provides the opportunity to do the most pivotal treatment immediately, but many patients are simply not able to consider chemotherapy within the first couple of months after surgery, and/or they need to abort treatment before the intended therapy has been delivered. Pre-operative chemotherapy provides the earliest opportunity to treat potential micrometastic disease, should improve the probability that treatment will be delivered as planned (because few people will decide to abandon surgery), and it gives the chance to get feedback on how effectively the systemic therapy shrunk the cancer. However, it also entails a small but real chance that the person’s cancer will grow and even potentially no longer be able to be resected, and possibly that chemo could increase the risk of surgical and post-surgical complications. Pre-operative therapy may also have an advantage of allowing a patient to receive a less extensive surgery after a good response to initial systemic treatment.
So it’s fair to say that there is a good rationale to test both of these strategies, and studies have been pursued with surgery followed by randomization to chemo or observation, immediate randomization to chemotherapy followed by surgery or immediate surgery alone, and even one trial that randomized patients to pre-operative chemotherapy followed by surgery, surgery followed by chemotherapy, or neither pre-operative nor post-operative therapy and just surgery alone. By 2003 and 2004, several trials of post-operative chemotherapy were reported as positive, and this led to early closure of several of the important pre-operative chemotherapy trials, since the emerging picture was that chemotherapy provided a benefit that made randomization of patients to a surgery alone arm unethical.
It is in this context that we can now review the significance of the newly published Chemotherapy in Early Stages Trial (ChEST), which was conducted at 45 centers in 15 countries in Europe and attempted to assess the benefit of three cycles of cisplatin/gemcitabine before surgery, compared with surgery alone. The trial was designed with an intent to enroll 712 patients with stage IB to stage IIIA NSCLC (stage IIIA only if they had no mediastinal nodal involvement, so T3N1) and was looking to detect a 20% improvement in PFS as the primary endpoint, but from 2000 to 2004 only 270 patients were enrolled (129 randomized to pre-op chemotherapy, and 141 randomized to surgery alone). It closed early in light of the mounting evidence supporting a role for chemotherapy. Continue reading
Chemotherapy Selection for 1st line Non-Small-Cell Lung Cancer (NSCLC) — The Importance of Getting it Right the First Time
Introduction: Why Chemotherapy?
Every cancer therapy has two purposes: to improve duration of life, and to improve quality of life. Every other measure of chemotherapy success, such as response rate or progression-free-survival, is a surrogate to these two true goals. I am using the broken record as my pseudo-apology for repeating this mantra repeatedly on GRACE, to my colleagues, and in my mind every time I make a treatment decision.
Chemotherapy is the most important treatment for achieving these two goals in stage IV disease. Stage IV means that the cancer has spread and is no longer curable. Incurable is not the same as untreatable. Cure means eliminating every last cancer cell. Treatment means providing real benefit, in the form of achieving these two goals.
Cancer cells are microscopic. The tip of a pen is the size of more than ten billion cells. So, if a single cell has spread to a site, say, the liver, you won’t be able to see that cell on a CT or even the most sophisticated PET/CT. So, once you see the cancer having spread to distant sites, it becomes systemic-in more sites than you can see; we call this “metastatic” or stage IV disease. To achieve our two key goals, you need to knock down the cancer everywhere-the places that you can see and those you can’t. Chemo gets almost everywhere in the body and is therefore the best and most important way to do this for most patients with metastatic disease.
Dr. Alan Sandler Provides General Intro to Treatment of Advanced Non-Small Cell Lung Cancer
Dr. Alan Sandler is an international leader in the lung cancer world, also identified as among the most down to earth and funniest people in the field (and though that might not sound like much, he travels with an audio clip of a rim shot to play after his jokes). His talks are light-hearted, but he’s so highly regarded because he has also been deeply involved in several of the pivotal research activities that have helped shape our current treatments. He led the original study that led to the approval of gemcitabine in lung cancer, and more recently he led the ECOG 4599 trial that was published in the New England Journal of Medicine and established the benefit of Avastin with carbo/taxol for advanced lung cancer.
Dr. Sandler recently moved from Vanderbilt to my corner of the world (more or less), where he leads the Division of Hematology and Oncology at Oregon Health & Science University in Portland. He was kind enough to participate in our NSCLC Patient Education Forum, where he provided a general introduction to the biggest questions of managing advanced NSCLC: does treatment really help, and how much? He also provided an overall review of the landscape in how we approach first line therapy for metastatic NSCLC, from someone who has been a big part of developing those standards.
Here is the audio and video versions of his presentation, along with the accompanying figures and transcript.
sandler intro to first line treatment of advanced nsclc audio podcast
sandler-intro-to-first-line-treatment-of-advanced-nsclc-figures
sandler-first-line-treatment-of-advanced-nsclc-transcript
I’m trying to leverage my proximity to Dr. Sandler, as well as my longtime friendship with him, to get him to involved with more of our GRACE activities. Fortunately, he’s been very gracious and generous with his time, so get more of his perspective , and maybe even some good jokes, from him in the future as well.
Podcast: Play in new window | Download (36.2MB) | Embed
Does it Matter Which Chemo Agent You Get with Your Platinum? Maybe it does…
For years it has been generally accepted that the choices for the second drug in a platinum doublet for treating metastatic non-small cell lung cancer (NSCLC) were pretty much interchangeable. The question of whether cisplatin is better than carboplatin is a separate question, one which GRACE’s own Dr. Sanborn recently reviewed quite nicely. For the second drug, as long as the choice was a “newer generation” drug, oncologists would mix and match cisplatin or carboplatin with Taxol (paclitaxel), Taxotere (docetaxel), Gemzar (gemcitabine), or Navelbine (vinorelbine) based mostly upon which drug they liked the best or had the most experience with.
This perception that the specific second drug was irrelevant was not just pulled out of a hat; there has been reason to think they are all equally good. The most often quoted study to make this point has to be the ECOG 1594 trial (Comparison of Four Chemotherapy Regimens for Advanced Non–small-cell lung cancer), which randomized NSCLC patients to one of 4 arms: cisplatin/Taxol, carboplatin/Taxol, cisplatin/Gemzar, and cisplatin/Taxotere. The survival curves were essentially identical (see below), as were the response rates of the tumors.
Are we are Making Progress in Treating Non-small Cell Lung Cancer? You Bet!
We all know now that lung cancer, and in particular NSCLC, sits atop the list of cancer killers in the United States and western world. We also have been having extensive discussions on this site about all these great new treatment modalities: better staging (i.e. PET), better surgeries (i.e. VATS), radiosurgery (i.e. gamma knife), better radiation (i.e. IMRT), and better chemotherapy or targeted agents. But have all of these advancements done anything other than raise the cost of healthcare so much that Medicare is in danger of going broke paying for $100,000 Avastin-containing regimens?
In this month’s Journal of Thoracic Oncology, a group of cancer epidemiologists published a study looking at the survival of almost 11,000 patients with lung cancer over the 20 year period from 1985 to 2004, looking at the contributions of surgery, radiation, and chemotherapy and how the survival changed over that period. All of the patients were treated in Manitoba, Canada, so they can be considered to have received standard treatment for the time period and I think these patients can be compared to lung cancer patients anywhere in the developed world.
The first thing that jumped out from this study was that the rate of patients receiving surgery fell over time. Most people don’t realize that CT scans were not widely available in the early to mid-1980s, so many patients with metastatic (incurable) disease were going to the operating room when their chest x-rays incorrectly suggested they had curable disease. It makes perfect sense that fewer patients are having inappropriate surgery these days, now that staging is better in the CT and more recently the PET era.
The next interesting thing from this study, and the main point of this post, was that the authors found that overall survival in all NSCLC patients began to improve starting in 1997, and has been increasing by about 2 weeks every year between 1997 and 2004. Added together, this is about 3.5 months in improved survival over this period.
Not only did survival improve overall, it improved for early-stage patients receiving primary surgery, for locally advanced (stage III) patients getting chemotherapy and radiation, and for incurable patients treated with chemotherapy alone. The improvement in surgery is almost certainly because the staging has improved dramatically, so that only true early stage patients are getting surgery these days. Put another way, when large numbers of more advanced patients receive surgery but are not cured (because surgery does not cure stage 3 and 4 NSCLC by itself), the overall group looks like it has poor survival. So by only doing the surgery in the right patients, the overall group ends up having better survival.
The improvement in locally advanced and metastatic NSCLC survival also makes sense. Again, I doubt most people realize this today, but until 1995 there was no real evidence that chemotherapy helped anyone live longer with NSCLC. In 1995, a large meta-analysis of prior trials showed that platinum-based chemotherapy regimens did have an impact in lung cancer survival, and modern chemo began to be used much more often.
So many of you may be thinking that 3.5 months doesn’t seem like a big deal, but I would argue that it is a big deal. Keeping in mind that the average survival for patients with advanced lung cancer in 1997 was about 9 months, this represents a 39% improvement in survival in only 7 years!
I think one of the most encouraging things about this study is that this improvement in survival took place before the treatments that I mentioned above: before extensive use of IMRT or radiosurgery, before the common usage of targeted agents like Avastin or Tarceva, even before the common use of adjuvant chemotherapy after surgery, which began in 2004 and clearly is improving survival in early stage patients. I think there is a good chance that our most recent advances may actually be advancing the survival of patients at an even faster rate than described in this study.
I know that everyone secretly hopes for a dramatic cure of lung cancer. When new studies come out that show a 5 week or 2 month improvement in survival, there can be a collective yawn from the world at large. But I would argue that this is how it really works in the world of oncology, in incremental little advancements that build up over time. Colon cancer used to have an average survival very similar to lung cancer, but over 10-12 years the survival has more than doubled with the addition of several incremental advancements, each only adding 2-4 months but together helping move average survival from 10 months in the 1990s to >24 months today. It is my hope that NSCLC is well on its way!
More…
Video Presentation on Second Line Chemo for Advanced NSCLC
One of the core issues in managing advanced NSCLC is second line chemotherapy, which was established as improving survival several years ago. This video presentation provides a brief summary of the work that led to the common use of chemotherapy in previously treated patients. Most typically, this is taxotere (docetaxel) or alimta (pemetrexed), and this presentation describes why we focus most commonly on these chemo agents.
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Doc, Am I Too Old for Chemo?
The average age at which lung cancer is diagnosed in the US is 71. Would it be fair to say that at least half of those who are diagnosed with lung cancer are elderly? How do we define “old”? How does age impact the effect of chemotherapy?
Two decades ago, analysis of “older patients” who received chemotherapy for advanced lung cancer revealed that chemotherapy improved survival in the elderly to the same extent as in patients who were younger. The down side was that older patients experienced more side effects from chemotherapy. It is easy to see how this result could lead to mixed feelings: live longer, but with side effects. In the 1990’s clinical trials directed towards the elderly began. The pivotal trial was called ELVIS (Elderly Lung cancer Vinorelbine Italian Study). This study compared the effect of chemotherapy (vinorelbine) against no chemotherapy in lung cancer patients ≥70 years of age. This direct comparison clearly demonstrated that chemotherapy not only improved survival but most importantly, quality of life.
How was this possible? We all recognize that controlling the cancer will control cancer related symptoms. The challenge with treatment is balancing the side effects of chemotherapy against the benefit gained by controlling lung cancer symptoms. However, vinorelbine (Navelbine) is a well tolerated chemotherapy that made it possible to improve quality of life. Subsequently, more trials in more modern times with more modern chemotherapy have repeatedly shown us that chemotherapy is feasible and worthwhile in the elderly.
Polling Lung Cancer Experts: Metastatic NSCLC, Squamous Subtype
Several weeks ago, I described the results of a survey I sent out to several colleagues who are lung cancer experts around the country, asking how they would manage a case of a newly diagnosed Caucasian never-smoking patient with advanced NSCLC, adenocarcinoma, and asymptomatic subcentimeter brain metastases, treated with whole brain RT before starting systemic therapy.
I then asked these same experts the question but now with the patient being an ex-smoker with a squamous NSCLC tumor. The basic sketch is that it’s a 61 year old Caucausion woman with a very good performance status, no limitation on health or motivation for treatment, and a metastatic NSCLC, squamous subtype . As in the prior case, she had treated asymptomatic brain metastases and was presenting for consideration of first line treatment. What would various experts recommend as a plan for the next few months?
One major difference was that, unlike the never-smoker with an adenocarcinoma, very few experts now favored sending tissue for an EGFR mutation. The vast majority had favored checking this in a never-smoker, who might be considered for up-front EGFR inhibitor therapy, but when the case was an ex-smoker with a squamous tumor, only 6 of 20 were interested in any molecular testing: 3 for KRAS mutation, 1 for EGFR IHC before considering erbitux (cetuximab), and two who still wanted to check for an EGFR mutation. Most were inclined to make a treatment recommendation without any molecular testing.
How Much Does Treatment Sequence Matter in Lung Cancer?
One of the general rules in oncologist is that we typically use our most effective treatments first, and often early, though there are certainly exceptions. Women with metastatic breast cancer may have a higher response rate by receiving combination chemotherapy than single agent chemo, but when a gentle single drug chemotherapy or hormone therapy option will do very well and provide fewer side effects, that’s usually the approach we recommend until bigger guns are needed. Similarly, patients with slow-growing cancers like chronic lymphocytic leukemia (CLL) often do well for many years and sometimes forever without needing treatment, so we often hold on initiating any treatment unless there’s a good reason to (and I think the same argument can be made for some lung cancers, most commonly indolent bronchoioloalveolar carcinoma, or BAC). So we don’t want to treat patients with less therapy than they need, but we’d also prefer not to treat them with more.
When you have multiple potential treatments to pursue, one question that becomes relevant is whether the sequnce matters. If you have choices A, B, and C, does it matter if you give AB followed by C, or C followed by AB or even A followed by B and then C? First, we need to take a step back and recognize that this is a good dilemma to have, because 10 years ago we didn’t have multiple effective treatments to try to position. For advanced NSCLC, the value of giving chemo for metastatic disease was debated until about 10-12 years ago, when the survival benefit of platinum-based doublet chemo regimens became a clear standard. In 2000 or so, second line taxotere emerged as a second line treatment option that improved survival and was approved by the FDA in that setting. A few years later, additional treatment options for previously treated patients with advanced NSCLC were approved, ushering in agents like alimta and EGFR inhibitors (initially iressa and then tarceva, with iressa removed from the US marketplace. These all became viable options, and over the last few years all of these agents have also been studied as first line treatments. Taxotere and alimta are now both FDA approved as first line combination therapy with platinum, and the EGFR inhibitors have also been studied as first line treatment and have appeared particularly attractive in certain subsets of patients, such as those with an EGFR mutation or patients with advanced BAC.
Video Podcast Presentation on Locally Advanced NSCLC
Ask and ye shall receive! The leading requiest for a video podcast presentation was for a summary of the subject of locally advanced, unresectable stage III NSCLC. Here you go:
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Sorry it’s a little rushed, but it’s a struggle to do a topic justice with a 10 minute limit (the most YouTube accepts). In the future, we’ll try to divide bigger topics into two podcasts if it’s going to require cramming into a 10 minute interval. It may help for you to have the images and transcript available, so here they are:
Locally Advanced NSCLC vodcast images
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