GRACE :: Lung Cancer
Dr West

Death by “Pseudo-progression”: Knowing When to Cut Your Losses with Immunotherapy

Among the many novel concepts in managing immunotherapy is the potential for “pseudo-progression”. This unusual phenomenon is when a patient’s scans of the areas of cancer actually appear worse on early imaging, potentially even with new lesions, after starting immunotherapy, but a patient’s scans later show shrinkage of the cancer.  These patients typically feel well, often with improvement in their cancer-related symptoms (fatigue, appetite, etc.) that don’t seem to be concordant with their worse-appearing scans.

Why might this happen? Some biopsies of lesions that have grown or appeared as new in such patients help explain that the growth is from infiltration of immune cells around tumor cells, preceding the time when those tumor cells are attacked and eradicated by the immune system.  In cases where new nodules appear that then resolve with later scans, it is felt that this situation represents immune cells infiltrating a “micro-nodule” of cancer that wasn’t visible until it was surrounded by immune cells that then enlarged it enough to become newly detectable on scans.

Pseudoprogression West JAMA Oncol 2015

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Dr West

OAK trial with Tecentriq (atezolizumab) is positive: How a “me too” result may change the landscape in advanced NSCLC

With positive trials of two immune checkpoint inhibitors, Opdivo (nivolumab) and Keytruda (pembrolizumab), in second line NSCLC and compared with Taxotere (docetaxel), it should come as a surprise to nobody that another checkpoint inhibitor, Tecentriq (atezolizumab) has also proven superior to Taxotere in the OAK trial of previously treated NSCLC patients, as reported in a press release today.  Perhaps the biggest surprise is that this result actually has the potential to shake up the field even with Tecentriq as a late third entrant into the race.

The trial in question is called OAK, which is a very straightforward head to head phase III trial of Tecentriq, a PD-L1 inhibitor, vs. standard Taxotere in 1225 patients who had received one or two lines of prior chemotherapy and were not restricted by level of PD-L1 expression.

OAK trial image

This trial is very similar to trials with the PD-1 inhibitor Opdivo in patients with previously treated squamous NSCLC (Checkmate 017) and another with Opdivo in previously treated non-squamous NSCLC (Checkmate 057), without restriction by PD-L1 status. Both of those trials demonstrated a significant improvement in overall survival compared with Taxotere, leading to the approval of Opdivo in previously treated patients with advanced NSCLC, regardless of PD-L1 status.  In addition, the Keynote-010 trial of the PD-L1 inhibitor Keytruda vs. Taxotere also demonstrated a very similar survival benefit but was restricted to patients with PD-L1 expression.  At this time, the approval of Keytruda is only specifically for patients who test positive for PD-L1 with a threshold level of >50% expression, based on an earlier trial with Keytruda that demonstrated clearly greatest benefit in the much smaller minority of patients with high level PD-L1 expression using a 50% cutoff (about 28% of patients).

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Denise Brock

Lung Cancer Video Library – Basics of Small Cell Lung Cancer

 
GRACE Cancer Video Library - Lung

 

 

Dr. Rachel Sanborn, Providence Thoracic Oncology Program, discusses the topic of lung cancer and that there is an entire spectrum of different kinds of cancers that have started inside the lungs.  Small cell lung cancers behave very differently than non-small cell lung cancer.  

 

 

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Basics of Small Cell Lung Cancer

Rachel Sanborn, MD, Medical Oncologist and Co-Director

Providence Thoracic Oncology Program

TRANSCRIPT

When we think about a lung cancer that is being diagnosed for a person, many people think of lung cancer as one single entity. However, what we know is that lung cancer is an entire spectrum of different kinds of cancers that have just started inside the lungs. At the very first blush when we think about breaking those different lung cancers apart in order to understand how that cancer may need to best be treated and what the behavior of that cancer is, the first broad breakdown that we look at is a category we call small cell lung cancer and then other lung cancers are in a broad category we generally term non-small cell lung cancer. The reason that there is that first separation is that small cell lung cancers behave in a very different fashion than a non-small cell lung cancer.

When a small cell lung cancer forms, these are very rapidly dividing, rapidly moving cancers that tend to spread very quickly in the body. A very classic story that people tell when they are diagnosed with a small cell lung cancer is that they were feeling fine and that they suddenly became very ill. This is not a cancer that sneaks up on a person over the course of a year, or they’ve had a gradual decline or a gradual symptom onset over that time. This is something that hits people harder and faster than that.

When a small cell lung cancer is diagnosed, because of how rapidly it moves in the body, for the vast majority of people starting with trying to remove the cancer by surgery is not going to be helpful, because that only would attempt to tackle something locally, but the problem is more systemic. So when we think about small cell lung cancer there is urgency to start a treatment because of how quickly people get sick and how rapidly it spreads in the body. When we think about that what that means is starting urgently with chemotherapy, which as a systemic treatment that is traveling through the bloodstream helps to treat the cancer wherever it may be located in the body.

The next question that we need to look at is understanding head to toe where that small cell lung cancer is located in the body, and as we think about these lung cancers in general we consider whether that cancer may be still limited inside the lung area where it started or whether the cancer may have become more extensive, where it has spread in other locations in the body. In general, if a person has a cancer that is limited in the chest where it started, then we may be able to think about treating that cancer with the attempt to try to cure it, using the combination of chemotherapy in addition to radiation right to where the cancer is located. If the cancer is extensive in the body, then what we know is that although the cancer is very treatable the cancer at that time is not going to be curable.  So we generally start with chemotherapy. In both situations, because of the high risk of the cancer spreading to the brain – small cell lung cancer spreads to the brain very quickly – then after the after the chemo and radiation therapy, or after chemotherapy alone, one considers preventive, low dose radiation to the brain.

The reason that we talk about the urgency with starting treatment is because if left untreated, small cell lung cancer can take a person’s life generally within weeks of the time that they are diagnosed. However, if it is diagnosed and treatment is started quickly, for those patients who have limited stage disease, then a small number of people can have their cancer cured, meaning going on to live the rest of their life without that cancer coming back. Even if the cancer is not able to be cured, the treatment in either setting can significantly help to prolong life and to help with quality of life.  

 


Denise Brock

Lung Cancer Video Library – Adjuvant Chemotherapy for Elderly and Frail Patients Part 2

 
GRACE Cancer Video Library - Lung

 

 

 

Dr. Rachel Sanborn, Providence Thoracic Oncology Program, discusses using adjuvant chemotherapy for elderly and frail patients.  What was seen in particular in the trial performed by NCI Canada, using cisplatin with navelbine chemotherapy, was that people who were considered elderly were able to achieve just as much benefit from chemotherapy in terms of survival as younger people did.

 

 

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Adjuvant Chemotherapy for Elderly and Frail Patients

(Part 2)

Rachel Sanborn, MD, Medical Oncologist and Co-Director,

Providence Thoracic Oncology Program

TRANSCRIPT

When we look at the actual data is for the people who are older getting chemotherapy, in the adjuvant clinical trials, those trials that evaluated whether adding chemotherapy after surgery would provide a benefit, they looked at how patients did according to age. What was seen in particular in the trial performed by NCI Canada, using cisplatin with navelbine chemotherapy, was that people who were considered elderly were able to achieve just as much benefit from chemotherapy in terms of survival as people who were younger did. People who were older did require more dose reductions of chemotherapy in order to minimize toxicity. In general, that would be lowering the dose of the chemo based on kidney function or based on other side effects. However, even with that little less chemotherapy that those people got, they were able to achieve the same survival benefit. So what’s shown as more important in thinking about age is considering how healthy a person is overall.

We have to be careful about what is defined as “elderly” in clinical trials, because in most studies, and even in this study that I’m talking about, people were defined as elderly when they were age 65 or greater. I hardly consider a person at the age of 65 to be elderly. When we look at the average age of diagnosis of lung cancer in the United States, that average age is 72. So is the evidence different in much older populations? That part is difficult to understand at this time because not as many people were enrolled in studies. However, even in those elderly populations there were older patients evaluated in that group as well.

When I am talking to a person about chemotherapy, age doesn’t factor in as much as we look at a person’s overall health. We have to look at how much they’re able to be up and active through the day. In all of these trials that showed a benefit with chemotherapy a person needed to be up and active through the majority of their day, able to carry out all of their own daily needs and to be able to do different activities without severe physical limitations. For a person who is up and active and moving, we then also look at their overall health status in terms of risks, including kidney function and heart function and lung function. Also it’s important to consider any type of cognitive deficits as well as those physical deficits and in addition the support that a person may have at home. But for a person who is older who is otherwise healthy, who still has many years of expected life outside of the possibility of the lung cancer coming back, adding chemotherapy after surgery is still an important thing to discuss, although it is important for us to monitor those people closely for toxicities and have a low threshold for decreasing the dose as needed in order to help keep a person safe.

On a separate side of consideration, is thinking about a person who has a lung cancer removed with surgery who may not have that same recovery, who may not have the same level of what’s called functional status after their lung cancer has been removed. In the clinical trials again, a person is required, to be eligible, to be able to be up and moving and active through the majority of their day without any significant physical limitations. What happens when a person has been less active at baseline? What happens when a person may be still having a difficult time to recover after surgery, where they’re active for less than half of their day, when they don’t have the ability to be up and moving around? They still have a risk of a cancer coming back. At the same time, we have to be very careful in those situations because chemotherapy when given has significant risk as well. The risks of the complications increase the less active that a person is, particularly risks of getting infections, like pneumonias, bladder infections, things that can be life-threatening when a person has more physical limitations than in a person who is able to be up and active without restriction in their day. It’s important to think about the fact that although we’re trying to cure a patient, we also don’t want to kill them with that cure.

In some situations, when a person may have a higher risk tumor, but their functional status, that ability to be active through the day, may be more marginal, we may consider an adaption of the chemotherapy. Instead of using cisplatin-based chemotherapy, for example, one may consider carboplatin-based chemotherapy. But those situations need to be very carefully evaluated, with lots of discussions with the oncologist and the patient, working through what the risks may be, both with the lung cancer itself as well as from the chemotherapy and its possible toxicities.

 


Denise Brock

Lung Cancer Video Library – Adjuvant Chemotherapy for Early Stage NSCLC Patients Part 1

 
GRACE Cancer Video Library - Lung

 

 

Dr. Rachel Sanborn, Providence Thoracic Oncology Program, discusses the reasons behind using adjuvant chemotherapy for early stage NSCLC  patients.  Clinical studies have shown that adding chemotherapy after surgery for lung cancer can indeed improve survival. 

 

 

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Adjuvant Chemotherapy for Early Stage NSCLC Patients

(Part 1)

Rachel Sanborn, MD, Medical Oncologist and Co-Director,

Providence Thoracic Oncology Program

TRANSCRIPT

Although the most important part of a curative approach for lung cancer, if at all possible, is having a lung cancer removed with surgery, even in the best of situations, a patient still has a risk of the cancer coming back. The reason is that even despite the best technology that we have, microscopic cancer seeds may have spread in the body and have not been detectable at the time of surgery which, if left there untreated will grow and show up later. When that happens, although a cancer may be treatable at that time, the lung cancer in general would no longer be curable. So that’s why we consider adding chemotherapy immediately after surgery, if a person has an early stage lung cancer removed, trying to kill off those microscopic tumor deposits and trying to improve the chance of cure at that time.

There have been multiple clinical studies that have shown that adding chemotherapy after surgery for lung cancer can indeed improve survival, although the majority of this evidence is for people who have had larger tumors, tumors with more lymph node involvement. The dilemma comes more when we think about what do we do to try to help a person with an earlier stage cancer, a smaller tumor that does not have the lymph nodes involved. That’s where the data gets a little more difficult to interpret.

There have been previous studies that looked at different types of chemotherapy, one of those, a CALGB trial, looked at carboplatin with taxol and included people who had stage I lung cancers. That trial eventually was negative, which means that no benefit was seen. However, when they looked back over time at the people that received chemotherapy in that study, what was shown was that, for people who had lung cancers that were at least four centimeters in size or greater, those people may have had a benefit from chemotherapy.

There was a different study run by the NCI Canada that looked at cisplatin with a different chemotherapy called navelbine that evaluated this chemo after surgery. What was shown in that study was that people did indeed have a benefit, but when that trial looked back over time, the benefit was in people who had lymph node involvement, and those people who did not, those people with stage I lung cancers, did not get a benefit from chemotherapy. So we have conflicting data.

There was a very large meta-analysis done, called the LACE meta-analysis, that evaluated more than 4500 people in different clinical trials getting adjuvant chemotherapy. In that study, what they saw was that for people with the smallest lung cancers, those with stage Ia lung cancer, meaning three centimeters or smaller in size at the time, there was actually a trend toward harm getting chemotherapy, whereas people with slightly bigger stage I lung cancers, stage Ib, may have had a benefit but it was not significant. So in that group of people, the question was still open. It did confirm that for people with lymph node involvement of their cancers, there was indeed a benefit with chemotherapy. Again, we’re stuck in a gray zone with slightly larger tumors, but there is concern that for those people with the smallest lung cancers, the risk of the chemotherapy itself becomes higher than the benefit a person could get. That’s the reason why the next versions of adjuvant clinical trials only allowed for people who had lung cancers at least four centimeters in size.

In general, when I think about adding adjuvant chemotherapy for an early stage lung cancer, then I would consider that for a person who has a lung cancer four centimeters or greater but not smaller than that. In general, the considerations to discuss, or the considerations to evaluate, would be to make sure that a person has recovered very well after the surgery, that they have a good overall health status, that they’re able to be up and active through their day. What we want to do is make sure that the risks of toxicity are as low as they possibly can be, but we also have a long and very frank discussion about the fact that chemotherapy can be considered in those situations, but there is not the same proof of survival benefit as there is in larger tumors, that there’s not the same proof of survival benefit as there is in cancers that have lymph node involvement. So it’s important to have a very informed discussion with the patients who are considering adjuvant chemotherapy in that setting.

 


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