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Stage III/Locally Advanced NSCLC

Management for locally advanced 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

Is There a Role for PCI in Locally Advanced NSCLC?

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GCVL_LU-E10d_Role_PCI_Locally_Advanced_NSCLC

 

Dr. Nasser Hanna, Indiana University Health, addresses the issue of prophylactic cranial irradiation (PCI) in locally advanced NSCLC.

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Unfortunately many people with stage III disease are not cured of their cancer. We’re doing better, but we’re not doing good enough for most people and for those people who are not being cured, oftentimes the cancer will recur in what we call “distant sites.” That may be bones, it may be the liver, it may be the adrenal glands, these two small glands that sit above the kidneys, and sometimes it can be the brain.

When cancer progresses and shows up in the liver or shows up in the adrenal gland, it can certainly be disconcerting, sometimes it can cause symptoms and people don’t feel well, but oftentimes it’s something we just see radiographically. That’s oftentimes not true when cancer recurs in the brain. When it recurs in the brain, oftentimes it’s very unpleasant for somebody. They may have headaches, they may have double vision, they may have unsteadiness or nausea, they may pass out, they may even have seizure activity. So the idea of trying to prevent cancer from spreading to the brain is of paramount importance.

Now in another type of lung cancer, small cell lung cancer, we have utilized a strategy of prophylactically radiating the brain because we know that so many patients with small cell lung cancer eventually develop cancer in the brain. Prophylactically radiating the brain before any signs of cancer have appeared there may do one of two things. Number one is there actually may be microscopic disease in the brain that we really can’t detect on imaging studies for which you’re radiating when you’re doing the so-called prophylactic brain radiation. Secondly, some people believe that when you radiate the brain, it forms sort of an inhospitable environment for cancer to subsequently implant and seed. Either way, we’ve demonstrated that in patients with small cell lung cancer, you can reduce the incidence of brain metastases and in some cases actually help people live longer if you prophylactically radiate the brain.

Now the incidence of brain metastases in those with stage III non-small cell lung cancer is not as high as those with small cell lung cancer. Having said that, about 30-35% of those with stage III disease do eventually develop brain metastases. So the question has come up: should we or could we prophylactically radiate the brain and achieve fewer brain recurrences and perhaps maybe even help people live longer or cure more disease? Well the answer to this question is really unknown — there was one attempt at a carefully conducted clinical trial to test this idea, and unfortunately it was very difficult to accrue to this clinical trial, and it ended up only accruing about a third of the patients that it was meant to accrue.

We got some limited information from this clinical trial and what we learned is yes, we can reduce the incidence of cancer appearing in the brain by prophylactically radiating it. We really weren’t able to demonstrate in this small group of patients an ability to cure more people or help more people live longer, and certainly prophylactically radiating the brain does come with some side effects such as hair loss, fatigue, sometimes headaches, and sometimes nausea.

As of today, it is not standard to prophylactically radiate the brain in patients with non-small cell lung cancer and I’m not sure we’re ever going to get the completion of a clinical trial that will adequately address that, so I suspect for now and probably forever that will not be a standard approach for patients with stage III disease.


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