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Options and debate about early stage, resectable NSCLC

GRACE Video

The Role of Targeted Therapy Post-Resection

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GCVL_LU-D21_Targeted_Therapy_Post-Resection

 

Dr. Heather Wakelee, Stanford University Medical Center, evaluates the lack of evidence for the use of targeted therapies after surgery, and describes ongoing trials attempting to resolve that issue.

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Since the mid-2000s we’ve known that many patients who have non-small cell lung cancer, particularly the adenocarcinoma type, have particular gene mutations that we can identify and when we find them, treat with specific new drugs. We know this data from patients with metastatic lung cancer — the first to be discovered was EGFR or epidermal growth factor receptor, then ALK or anaplastic lymphoma kinase. Now there’s a very long list of gene mutations that we can identify when we look in patients with advanced stage lung cancer, and when we find them, offer specific targeted therapy that can have a very high likelihood of shrinking the tumor. This has really changed the way we think about and treat advanced stage lung cancer. However we haven’t figured out how to best use those treatments for patients who have earlier stages of lung cancer.

So in the setting of an early stage lung cancer that’s been removed with surgery, patients are theoretically cured at that point. Chemotherapy has been proven to lower the chance of the cancer coming back, but when you find one of these mutations in the tumor, the temptation is to give one of these targeted drugs. That strategy has been looked at in multiple clinical trials and we still don’t have a straightforward answer.

The largest trial to look at this so far was called the RADIANT trial and in that trial, after getting chemotherapy if that was the right thing for them, patients either received the EGFR drug called erlotinib, or a placebo. Now most of those patients in that trial actually did not have a specific mutation in EGFR because the study was designed before we knew about how important those mutations were. In the subset of patients who did have the EGFR mutation, those getting erlotinib seemed to have more time before the cancer came back, but if you looked at their overall survival, it wasn’t any different than the patients who had been on the placebo arm. The theory is that those who were on the placebo arm who had the cancer come back, when it came back they were then able to get erlotinib or a similar drug and have the same benefit. So it’s not clear that starting the erlotinib right at the time of surgery actually helps people live longer, though it might slow down the time to recurrence.

That’s obviously not a complete answer so there are more studies happening now trying to get a better sense of what we should do in that setting. There are a couple of trials in China, actually several trials in China, a study in Japan, and now a big study in the United States, all with the same general idea that a patient who has a tumor resected or removed by surgery, who is shown to have an EGFR mutation in that tumor, is randomized to either get an EGFR drug or to get placebo. Some of the studies have chemotherapy before or after, some compare it to chemotherapy, so there are some differences, but the general idea is whether or not giving the EGFR targeted drug will actually help people be cured or live longer versus waiting, and then for those who do have recurrence, giving it at that time. So those are really important trials that are ongoing and we’ll hope to know the answers in the next few years.

For the patients with the ALK translocation in the United States, the big trial called ALCHEMIST is open not just to EGFR but also to ALK patients. What that trial is about is asking that any patient who has a surgery at a site that’s participating in ALCHEMIST have part of their tissue from the tumor sent in to a central laboratory to be tested for EGFR or ALK. Those patients who have EGFR are then randomized to either get the EGFR drug erlotinib, or to get a placebo pill, and those who have ALK to get the ALK drug crizotinib versus a placebo pill. Over time people will be followed to see — does this change when the cancer comes back, and does it ultimately change overall survival for the patients where the cancer does come back?

So this is a really critical trial and it’s going to help us know what the best way is to use these targeted drugs for patients in this setting. Until we have those trial results back, I do not recommend that patients get the EGFR or ALK targeted drugs after surgery because we just don’t know if that’s going to help them live longer.


GRACE Video

What Is a Standard Adjuvant Chemotherapy Regimen?

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GCVL_LU-D12b_Standard_Adjuvant_Chemotherapy_Regimen

 

Dr. Heather Wakelee, Stanford University Medical Center, lists standard adjuvant chemotherapy regimens, comparing their administration and uses.

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Adjuvant chemotherapy is chemotherapy that’s given after surgery to try to improve the chance of cure, and usually this chemotherapy utilizes a specific drug called cisplatin. Cisplatin is a chemotherapy drug that’s been around for a while but we know is highly effective. Traditionally that drug is given every three weeks, it’s given by vein, and it takes a pretty long amount of time because it’s important that a patient receiving cisplatin gets a lot of fluid, gets a lot of hydration at the same time.

In a typical day, a patient would come in, get a lot of IV hydration, get some anti-nausea medications, and then get the chemotherapy drug only over about an hour — they will often get a second drug and we’ll talk about what those are in a second — finish up the day with hydration with the cisplatin, then normally would get about four days of oral anti-nausea medications just to help control nausea. That regimen is usually pretty effective. Some patients have to come in for additional fluid hydration the second or third day, then get two and a half to three weeks off and then come back to get the next cycle of chemotherapy with cisplatin and the other drug. That’s repeated for a total of four cycles of chemotherapy — so that’s traditional adjuvant chemotherapy.

The cisplatin is not the whole story though, it’s usually given with a second drug and there are multiple different drugs that have been studied to be given in that way. The one with the most data is a drug called vinorelbine. That drug is given weekly, so the first week you get the cisplatin and the vinorelbine, the second week you would just get the vinorelbine, and the third week depending on how it’s being given you either would or would not get it.

Another drug that’s frequently used is called docetaxel and that’s given just once every three weeks with the cisplatin. For patients who have the adenocarcinoma type of non-small cell lung cancer, or anything that’s not a squamous cell type, they’re eligible to get a drug called pemetrexed. We don’t have a lot of data yet for patients after surgery getting the cisplatin and pemetrexed but it’s very commonly used in the United States because we know that regimen tends to be well tolerated and we know it’s very active for patients who have more advanced types of lung cancer. That’s used quite a bit, and occasionally there will be a drug called gemcitabine used in combination with the cisplatin.

So those are the four most common, there are some others — cisplatin and etoposide is another regimen that’s been used as well. We don’t yet have any data comparing those regimens to each other in this type of a setting for patients who have already had their tumor removed — in that time you don’t have a way to measure whether the chemotherapy is actually helping or not so you don’t have a good way to compare against each other. We know from metastatic lung cancer that those drugs all tend to be fairly equivalent, those combinations, and that’s why they’re all used. It gets to be a discussion about the different toxicities, the different side effects, the different schedules, and then some specifics about the tumor, especially whether it was adeno or non-adeno, and making those decisions with the physician.

We do know from clinical trials that have been conducted that if you look at a group of patients who have had their tumors removed with surgery and half get chemotherapy and half did not, in these trials, the group getting chemotherapy, on average, did have a higher chance of cure. Now that chance of cure improvement unfortunately was not huge, it was somewhere in the order of five to ten percent depending on the trial, and so the decision about getting adjuvant chemotherapy is a complicated one and one that involves a discussion with your physician and care team, trying to make that decision about whether the potential benefits of chemotherapy make sense, versus the potential downsides. It ends up being about a three month regimen of chemotherapy. Again, you’re coming in only maybe four times to get those chemotherapy drugs, but during that time, in those three months, you’re going to not be 100% as far as energy level. We are very good at controlling nausea now, but the fatigue can be a particular issue for patients and sometimes in that time where you’re recovering from surgery, it’s difficult to get through, but it has been shown to show a survival benefit.

We do recommend that if chemotherapy is going to be given after surgery, that it starts somewhere in the four to, at most, twelve week period after surgery, so if it’s taking longer to recover, we don’t recommend starting after that time period.


GRACE Video

Why Give Adjuvant Chemotherapy, and to Which Patients?

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GCVL_LU-D12_Why_Adjuvant_Chemotherapy_Which_Patients

 

Dr. Heather Wakelee, Stanford University Medical Center, discusses the purpose of adjuvant chemotherapy, and which patients benefit most from it.

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Adjuvant chemotherapy is chemotherapy given after surgery for early stage non-small cell lung cancer. What is early stage non-small cell lung cancer? That’s lung cancer that has either not spread at all, or spread just to lymph nodes in the lung which would be called stage II, or to lymph nodes in the central part of the chest or mediastinum called stage III.

When a patient is thought to have stage I or II lung cancer, for most people the best treatment is to go to surgery, and with surgery we’re able to cure more than half of patients. However there is still a high chance of the cancer coming back so chemotherapy is given to reduce the chance of the cancer coming back. With stage III lung cancer it’s a bit more complex, and normally if we know it’s stage III beforehand, other treatments are given instead of just going straight to surgery, but sometimes we can’t see the cancer on the imaging studies like PET scans and CT scans and you only find out about it after surgery.

So we end up with patients with stage I, II, and III who have gone to surgery, have recovered from surgery, and now have to face the question of, “what can I do to reduce the chance of the cancer coming back?” It’s in that setting that we offer adjuvant chemotherapy. We know from randomized clinical trials where half the patients got chemotherapy and half didn’t, that we can improve the cure rates by giving chemotherapy.

The benefit is different for the different stages — we know it definitely helps for stage III, we know it definitely helps for stage II where there are lymph nodes in the lung — in stage I it’s a bit more controversial. For patients with stage I lung cancer that’s small, less than 4cm, we don’t think the chemotherapy actually improves the cure rates, and so it’s not usually recommended. For patients with tumors over 4cm, it becomes a discussion between the patient and their providers trying to make that decision because the data is just not as strong. When we look at subset analyses from clinical trials, there was a survival benefit seen in the subset with the larger tumors, but again it was a subset, it wasn’t the primary endpoint of the trial, and so you have to take that cautiously because you don’t know it’s the definite truth.

So it’s always an important discussion to go through that with the patient and with the providers as well.


GRACE Video

Video-Assisted Thorascopic Surgery vs. Open Thoracotomy

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GCVL_LU-D07_Video-Assisted_Thorascopic_Surgery_Open_Thoracotomy

 

Dr. David Harpole, Duke University Medical Center, compares traditional open thoracotomy with video-assisted thorascopic surgery, highlighting the advantages of the newer approach.

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Historically, lung cancer has been treated with a large incision between the ribs, and in the early-mid ‘90s we began to investigate uses of the laparoscope, which was used to do gallbladders and so forth, in the chest. So we began using the devices to do more limited resections with this and ultimately we were able to have instrumentation which has allowed us to do more anatomic resections, in other words a lobectomy and segments and so forth, with the video instruments — so-called video thoracoscopy.

Probably at this point two-thirds to three-quarters of my patients undergo a video-assisted approach and in the most recent Society of Thoracic Surgeons Database, which enters all of the information on lung cancer surgery for 500 centers in the U.S., it’s around two-thirds of all of the resections are done this way now. We’ve watched that evolve from centers such as my own where we were islands that did this 12 to 15 years ago, now to the majority of centers have surgeons that are facile with the scope.

The advantage to the patients is obvious. If you don’t have an incision on your side, you have two or three small holes of about three-quarters to half an inch, your recovery time is faster, less drainage from the tubes, home faster. I have people playing golf and tennis in two weeks, certainly everyone is driving in two weeks. What we found in a lot of the investigations we’ve done, not only that, if a patient has a larger tumor that requires adjuvant chemotherapy which is chemotherapy after surgery, sometimes there is a delay in the recovery of the patient because of the large incision, so that it delays their chemotherapy, and we’ve found with the video-assisted approach there is no delay and so patients are able to get their therapies on time and are able to tolerate them better because they haven’t had such a large insult.

Now not all cancers are able to be resected with a video-assisted approach, but I will say that in 2015 the vast majority are. We can do pneumonectomies or take out the whole lung with a scope, we can do surgery after chemotherapy and radiation — I just did one of those last week with a large tumor but we were able to do it with a scope. You can take out two lobes with a scope and you can do chest wall resections with a scope, so that’s much less invasive.

So we’ve really reserved now, the large incisions for really large operations that require you frankly from a safety standpoint to have your hands in there. Our instrumentation is so good with the video-assisted technique that we’re able to do it on lots of people.

The next question people ask is, “what’s the difference between using the video thoracoscopy and the robot?” The robot has come along over the last five to six years as another potential instrumentation in a minimally invasive fashion you can use for patients. The robot does require several small holes but they’re all holes about 1/4 centimeter each and the robot allows the surgeon at the console to really see things well. The video system that I use magnifies things about 3 times, and I’m at the table with my hands using instruments through small holes. With the robot it magnifies things 6 to 10 times and you have a virtual reality headset that you wear that really shows you things in 3 dimensions. What’s nice about the robot hand, whereas my sticks, I can only do this, the robot has a little wrist on it so it’ll move in all directions inside the chest and some surgeons like that for its mobility.

In my center we have two surgeons that use the robot, there are three of us that use the video-assisted technique. We have the same results and I think the two methods are equivalent and I think that they are allowing us to do more things in smaller areas in patients, because frankly our goal is to remove a cancer and not hurt the patient. “First do no harm” is what we’re all taught and these minimally invasive techniques have allowed us to do that. The other nice thing about it is that we have videos that the patients can watch and see the surgeries, see the incisions and see what’s going to happen to them, and I think they’re more informed when they make the decision of whether or not they would like to have a video-assisted approach for their operation.


GRACE Video

Targeted Therapies in a Post-Operative/Adjuvant Setting

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GCVL_LU-D21_Targeted_Therapies_Post-Operative_Adjuvant_Setting

 

Dr. Nathan Pennell, Cleveland Clinic, reviews the available trial evidence for the use of targeted therapies in the post-operative/adjuvant setting.

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I’d like to talk to you now about adjuvant treatment with molecularly targeted therapies for non-small call lung cancer. We know that early stage patients, so patients with stage I, II, or III non-small cell lung cancer — many patients are cured with surgery, but unfortunately, many patients go on to recur with metastatic disease. The reason this happens is that some of the cancer cells have escaped from the tumor before surgery and spread elsewhere in the body. This is called microscopic metastatic disease, and for this reason, we offer patients at high risk of occurrence adjuvant therapy. Adjuvant just means that we give four cycles of chemotherapy after surgery, and we know that this provides a modest, but significant improvement in cure rates after surgery alone.

Well, what about for patients who have molecularly defined subgroups of cancer, like EGFR mutation-positive cancer, or ALK-positive cancer? We know that, in the advanced setting, targeted therapies like Tarceva or Gilotrif for EGFR-positive cancer, or crizotinib or Xalkori for ALK-positive lung cancer, are better than chemotherapy in terms of inducing tumor responses, delaying the progression of cancer, and potentially even improving overall survival.

Since they work in the advanced setting, wouldn’t it make sense that they might work better in the adjuvant setting as well? Well, it’s not quite that simple. For one thing, we don’t have any evidence for any type of molecular subgroup, other than EGFR mutation-positive patients, but even in that setting, we really don’t have good evidence that adjuvant therapy improves cure rates after surgery alone. We have a little bit of evidence, so we know that the doctors at Memorial Sloan Kettering Cancer Institute in New York have treated several hundred patients with adjuvant Tarceva after surgery and they’ve reported that the patients have probably a lower than expected recurrence rate compared to what we might expect for that risk of patients, and they’ve suggested that maybe even they’re improving cure rates with adjuvant Tarceva.

Unfortunately, you can’t draw conclusions from a retrospective series and not a prospective trial. There have been at least two prospective trials that have been done, including one phase II trial that treated patients with two years of adjuvant Tarceva after surgery and then a subgroup of patients from a phase III trial called the RADIANT trial — so these were not EGFR mutation-positive patients in the overall trial, but there were 160 mutation-positive patients on the trial who were treated with two years of Tarceva, or two years of a placebo. All of these put together have suggested that adjuvant Tarceva does potentially delay the recurrence of cancers, but once the adjuvant treatment stopped, many patients went on to recur at a later time. None of the trials have suggested that patients lived longer or were cured at a higher rate than patients who were treated with standard treatment, including adjuvant chemotherapy.

What we really need is a randomized prospective phase III trial. Luckily, there is one that’s open and enrolling called the ALCHEMIST trial. Patients with stage IB, II, or III non-small cell lung cancer are tested for EGFR mutations or ALK gene fusions, and if those are found, they’re randomly assigned to two years of Tarceva for EGFR, or Xalkori for ALK-positive lung cancer patients, or two years of a placebo. Hopefully, at the end of this trial we’ll know whether patients are cured at a higher rate when treated with these adjuvant target therapies, versus just delaying the recurrence of the cancer.

For now, in 2015, I would not routinely recommend adjuvant therapy with a targeted drug like Tarceva or Xalkori outside of a clinical trial, but would strongly encourage patients to enroll in the ALCHEMIST trial.


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