GRACE :: Lung Cancer




Maintenance Therapy for Advanced NSCLC




Dr. Jack West, Swedish Cancer Institute, defines maintenance therapy in advanced NSCLC and discusses maintenance treatment strategies.

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For patients with advanced non-small cell lung cancer, our typical approach, if we have someone who does not have a driver mutation that we typically treat with a pill-based targeted therapy, is to give chemotherapy. That chemotherapy is typically given in a cycle of three weeks or sometimes a four week period of time where the blood counts go down and then recover. That treatment is typically given once every three weeks, sometimes once or twice on a weekly basis in that three week interval, but we typically give that therapy for about four to six cycles of therapy — that’s about three to five months of treatment. By that time, by four to six cycles in, the two drug combination that includes a drug called platinum is usually creating some cumulative side effects: fatigue, low blood counts, and other complicating issues that make it increasingly challenging to administer more of the same potentially intensive therapy, and by four to six cycles you really tend to reach a point of diminishing returns.

At that point we often favor a maintenance therapy approach. That is, dropping the carboplatin or stopping all of the agents that have been given previously and either continuing one or more of the agents from the first line setting, or using what’s called switch maintenance to give a completely different treatment. These maintenance therapies are designed to do what their name suggests — to maintain a response after we’ve seen the most shrinkage that we’re likely to get from the more intensive first line therapy.

When we do a continuous maintenance approach, it’s typically taking a drug like cisplatin or carboplatin in combination with one or two partner drugs, usually a second chemotherapy agent and sometimes Avastin which blocks a tumor’s blood supply, and then after four to six cycles we drop the platinum and we will typically continue a drug like Alimta if that’s been given in the first line setting, and if a drug like Avastin has also been given we might continue that and give Alimta and Avastin together until the cancer progresses.

If a combination like carboplatin and Taxol were given with Avastin, the maintenance therapy is often just the Avastin because Taxol tends to have some cumulative neuropathy issues — numbness and tingling that can lead to a real limitation in how much of that therapy you can give. We might also consider a switch maintenance approach — instead of continuing some of the agents, come in with Alimta as a single agent if a patient has non-squamous histology. Another agent that is approved as a switch maintenance therapy is Tarceva (erlotinib) — this doesn’t tend to be as favored as a switch maintenance because the efficacy of Tarceva in patients who don’t have an EGFR mutation tends to be on the lower side.

What do these maintenance therapies have in common? Well they’re all agents that can be given on a longitudinal basis without a lot of cumulative side effects and they tend to be the agents that have good activity in patients who have already been on prior therapy. So any of these is a reasonable choice, the most common being a continuation maintenance of dropping the platinum and continuing one or two partner drugs that were given with it, or sometimes switching to an agent like Alimta (pemetrexed) or Tarceva (erlotinib). It’s also reasonable to not pursue maintenance therapy if a patient has cumulative side effects and really needs a break from therapy. That is certainly something to discuss with the patient; it’s not as if maintenance therapy is a mandate for all patients, but it is something that is a strong consideration if a patient is motivated and can continue to tolerate ongoing therapy after four to six cycles.


What Is a Standard Adjuvant Chemotherapy Regimen?

GRACE Cancer Video Library - Lung



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.


Dr. Sarah Goldberg: The Potential Value of a Treatment Break as an Alternative to Maintenance Therapy in Advanced NSCLC


Dr. Sarah Goldberg notes that while maintenance therapy after first line treatment of advanced NSCLC is always worthy of a discussion, many patients need and benefit from a break from treatment to recover before pursuing additional therapy.

Dr West

Low Testosterone with XALKORI (Crizotinib): A Newly Identified Side Effect


It started with a patient reporting an unexpected side effect. A 35 year old ALK-positive man with lung cancer who was on XALKORI (crizotinib) noted that he had markedly diminished libido lower energy that had been worsening while on treatment, despite the fact that his cancer appeared to be responding well  His doctor checked his testosterone (T) level and noted it was well below the normal range, then referred him to the endocrinology clinic for consideration of testosterone replacement therapy, which he decided to do, and which helped with his symptoms.  Because this occurred at the University of Colorado, where they have more experience with patients on XALKORI than almost any other institution, they checked testosterone levels of as many men as they could find on XALKORI and compared the results to a comparable group of men with lung cancer who were not on XALKORI.

Low T levels lead to fatigue and depression, hot flashes and night sweats, potentially insomnia, as well as diminished sexual interest and function.  Low testosterone (sometimes called hypogonadism) is relatively common in cancer patients overall, though it historically hasn’t been well studied.  It’s generally unclear whether low T is caused by the underlying disease, the treatment, other medical issues, or some combination of these factors.

The initial observation from the patient at the University of Colorado led to the report that was just published online in the journal Cancer, showing that 100% of their male patients on XALKORI had a T level below normal (range 241-850 ng/dL there, though this varies a bit from lab to lab), compared with just 6 of 19 matched control patients with a similar distribution of age and other factors, median T levels 131 vs. 311 ng/dL.  Also very interestingly, a few patients who stopped and started XALKORI due to other side effects and had their T levels checked at a few time points along the way, showing a remarkably good correlation between T levels falling quickly when on XALKORI, rising within days on a break from it, then dropping again when the drug is restarted:

The authors developed a new policy of checking testosterone routinely in their male patients and referring those with low testosterone to their colleagues for consideration of T replacement therapy that could potentially help reverse both sexual side effects and the fatigue and depression. However, since T can also potentially lead to worse problems with urinary function in men with an enlarged prostate and may accelerate prostate cancer in a man who has that, the overall conclusion is that the decision to start T replacement is an individualized one that depends on the degree of symptoms that a patient has and the anticipated risks and benefits of the treatment.

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