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Imaging and Response Measurement

Lung Cancer Imaging, Debate and New Issues

High vs. Standard Dose Chest Radiation in Stage III Lung Cancer

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Dr. Jeffrey Bradley, Radiation Oncologist at Washington University in St. Louis, provides trial evidence showing that patients may not benefit from high dose chest radiation therapy vs. standard dose therapy.

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This is a topic I’ve been a little passionate about over the past ten years or so. We published a paper in Lancet Oncology this past February, it was RTOG 0617, and it was a comparison of high dose radiation therapy, 74 Gy, versus standard dose radiation, 60 Gy, in patients with stage III non-small cell lung cancer. They were unresectable, they received either the high dose or standard dose of radiation, and they were further randomized to receive cetuximab or not; cetuximab is an EGFR antibody.

The trial was published — it didn’t show an advantage to high dose radiation therapy, in fact, it shows a disadvantage to high dose radiation therapy. The median survival of the patients that were treated with 60 Gy without cetuximab was 28 months, compared to 20 months for patients receiving high dose radiation therapy. It turns out, even though we used the most sophisticated treatment techniques at the time, perhaps normal tissue doses were the cause of the high dose arm failing to achieve a better outcome, and a poor outcome in fact. We look at this as the heart dose — it turned out to be very important. We didn’t place heart dose constraints because, at the time, no one was placing heart dose constraints, and now we find out that’s very important. So, our subsequent trials have included heart dose constraints going forward, within, at least, the Energy Oncology Cooperative Group.

Likewise, there was no advantage to cetuximab in this patient population. These patients were unselected for EGFR status, and there’s an indication from the paper that if you look for EGFR status, people who had a high H-score may have benefitted from that drug. Nevertheless, there was no distinct survival advantage to receive cetuximab.

So the standard of care nowadays is 60 Gy with concurrent chemotherapy  — in that trial we used weekly paclitaxel and carboplatinum. We also used two cycles of consolidative chemotherapy in that study.


Second Line Chemotherapy Options for SCLC

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Dr. Cathy Pietanza from Memorial Sloan Kettering Cancer Center discusses standard chemotherapy options for treatment of both sensitive and refractory small cell lung cancer (SCLC).

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The type of treatment that one receives in second line does depend on whether the disease is refractory to initial chemotherapy, or sensitive to initial chemotherapy. Once again, to define each of those: patients with refractory disease are those whose relapse or progression has occurred while they’re getting first line chemotherapy, or within 60 days of completing their last cycle — some studies have used up to 90 days; for patients with sensitive disease, as the term implies, they have had a good response to initial chemotherapy, have maintained that response for 60 to 90 days, post-completion of their last cycle. The terms refractory and sensitive will help us determine, again, what types of treatment to give, and how effective that treatment will be for them.

In general, patients with refractory disease are less likely to benefit from other treatments, but we will try, and patients who have sensitive disease usually can benefit from additional chemotherapy. It also tells us that one is more aggressive than the other. For patients with sensitive relapse, the time frame is very important — if patients recur after six months of receiving their last cycle of etoposide and platinum, they can then receive more etoposide and platinum; if not, the other options include topotecan, and CAV. Now, there was one phase three study, that compared topotecan and CAV, and found that they were about equal, and Topotecan actually had a better side effect profile, and so it was FDA approved, and it’s actually the only agent that’s FDA approved in the second line setting for small cell lung cancer. Additional studies then showed that both patients with sensitive, and refractory small cell lung cancer can benefit from topotecan, and therefore, even patients with refractory disease can get this agent. We also like to use CAV because it is an effective chemotherapy regimen — CAV is cyclophosphamide, doxorubicin and vincristine, and in patients, especially if we feel that they need a quick response, this generally elicits that.

The other option for patients with refractory disease is to receive best supportive care. Now, in either of these types of relapse, another very, very important option is a clinical trial, and the last two to three years has seen a flurry in clinical trials in small cell lung cancer, which is extremely exciting and was very much needed, and hopefully we will come across new agents for this disease. It is imperative that if patients are in good shape after their disease recurs, that they seek a clinical trial — it may benefit them, and it will hopefully benefit our knowledge of the disease and the treatment of future patients with the disease.


What is the Optimal Duration of Immunotherapy?

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UCLA Med Center’s Dr. Eddie Garon discusses the open question of the optimal duration of ongoing treatment with immunotherapy for lung cancer.

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The duration of therapy that’s appropriate for immunotherapy is very hard to know. There are not good studies, to date — there are some theoretical reasons that you could go either way, that being, you could say that you’re going to need to treat these patients forever, versus that you would need to treat patients for a period of time. Different clinical trials have had different durations of therapy — there are some trials that have treated until the time of progression, there are some trials that have treated patients for one year, some trials that have treated patients for two years. We certainly know that there are some people who, for a variety of reasons, need to come off drug for a period of time, who will continue to do well after going off drug for even long periods of time; whether that means that these patients can stop the drug, we don’t know. Also, many of the toxicities tend to be seen early, but there are patients that can have toxicities that are seen late, so it’s not that there is no harm in continuing to treat a patient who is doing well — there may be harm, they may derive no additional benefit but some risk of additional toxicity.

The answer is: we don’t know yet. There are studies that are under way that are trying to evaluate this question, but in reality, those studies are very, very hard to conduct, they take a long time to get results, and you have to enroll a huge number of people upfront, knowing that only a percentage of those patients are going to still be on drug a year later, and it does end up being a very difficult question to answer. I think, in many respects, these questions are going to be answered in our clinics. There will also probably be payers that have some input into this. In my clinic, I tend to have a lot of people who, you know, sort of — that’s where we reached out for clinical trials of immune checkpoint inhibitors, and those people are terrified of stopping their drug; they understand that it may be the wrong thing to continue it after years, but they still want to continue it. On the other hand, patients who are seen in a practice that is not the same as mine, where they’re maybe not quite as motivated, they’re not the people who have flown in for a checkpoint inhibitor every few weeks, that group of people may get sick of coming in for the drug, and they may choose to stop it, and that may be where our data comes from — although, as I say, there are studies that are ongoing, the CheckMate 153 study looking at Opdivo will look to address that question, but again, studies like that take a long time to answer their question, if they can answer it at all.


The Blood/Brain Barrier for ALK Patients

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The brain is a common site of disease in patients with ALK+ lung cancer. In this video, Dr. Horn illustrates the line-up of ALK+ treatments and how they work breaking through the blood/brain barrier.

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Time to Response to Immunotherapy and the Concept of Pseudoprogression

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Dr. Eddie Garon reviews the pattern of response to immunotherapy in lung cancer, along with the concept of “pseudoprogression”.

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So, we have seen, certainly, some variability in the time to response; we have seen some people who will even have palpable lesions that will shrink, you know, within days — although that is rare. In general, what we find is that, generally, somewhere around 6 to 8 weeks is when we see patients who are having response to drug. It tends to be quite rapid — when you look at the clinical data, you can see that probably most of the patients who have what we call a clinical response to these drugs, that response occurs probably at the first imaging analysis, usually somewhere about two months after starting. Although there has always been this sense that it will take a long period of time for someone to respond to an immune therapy, and that is true, for instance, compared to a standard chemotherapy, where the effects are often seen within a couple of weeks, here it tends to be delayed from that, but it doesn’t tend to be delayed for months and months.

One other important issue to address is this issue of pseudoprogression, and this is something that people in the immunotherapy field have talked about for a long time, that if you have an effective immunotherapy, that you may have immune cells that infiltrate into the tumor and, as a result, rather than getting smaller, that the tumor would actually get larger. That could certainly happen over a short period of time, but what I would say, to date, is it’s not something we’ve seen a lot in lung cancer. Our colleagues in melanoma certainly report this as being a significant issue — patients who will have initial growth of their tumor on imaging, and then, afterwards, will have shrinking. We certainly do have several intriguing anecdotes, sort of individual patients that people will describe who have had, sort of, increases in their tumor volume, but then get better, but I would say that it is actually quite uncommon in lung cancer.

What we do see with some frequency is someone who will develop a new lesion. So, for instance, maybe they’ll have three areas that you’re following, all of them will get a little bit better, but then you will find one area that is a new area, that’s, you know, a centimeter and a half, that shows up on scans. By our typical way of evaluating radiographs, we would consider that to be progression. In my clinic, and as part of clinical trials, we’ve incorporated sort of different evaluations, that have, in some cases, allowed patents in that setting to continue on therapy. And, what I would say is, in somebody who is feeling good, who has an ambiguous response, one like what I mentioned, where several areas got better, but one area is new, or one area grew while other areas got better, but is clinically doing well — it may be worth continuing that patient on drug. But, when I see patients in second opinion and things like that, I will say that I much more frequently tell them that it is time to stop the immune checkpoint inhibitor, than to continue and hope for pseudoprogression. That, I would say, is very rare to see; we treated 98 patients at UCLA on the KEYNOTE-001 study, and I can’t think of a single patient that had, what we would call, sort of a flare response, where everything on the scan got worse, and then subsequently got better. So, I can’t give you an exact percentage, but what I would say is that it is rare. The thing that’s going to be more important is trying to interpret some of these ambiguous radiographic responses, which can be seen, but if everything is getting worse on the scan, what I’ve told people is, almost certainly, it means that the drug is not working.


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