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Introduction
Thank you to member Craig for asking some excellent questions in response to my Highlights of 2011 webinar (http://cancergrace.org/lung/2012/03/30/qa-lc-highlights-weiss/#comment-9498 ). Thank you also to Dr. West, who emailed me to comment more on the idea of radiation for cells with acquired resistance.
We’ve spoken at length about EGFR and related mutations such as EML4/ALK and ROS1 on GRACE. For those who are not familiar with these subjects, I will refer you to my webinar for a summary on the most recent data on EGFR, EML4/ALK and ROS1:
(Parenthetically, we did also cover CT screening and optimal management of elderly patients at http://cancergrace.org/lung/2012/03/22/dr-weisss-highlights-in-lung-cancer-2011-ct-screening-optimal-management-of-elderly-patients-with-advanced-nsclc/ )
In the Q&A for this webinar that covered some of the existing approaches to resistance, Dr. West pushed me and asked if there was one that was particularly promising. Well, I’ve spent a ton of time thinking about this problem and have written a trial to attempt to address it. I couldn’t resist the bait and mentioned my trial. In this post, I’d like to review the rationale for the approach that I described and address Craig (and Dr. West’s) question about how appropriate this approach will be to new mutations, such as EML4/ALK and ROS1.
The Approach:
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The basic idea is to take patient whose cancer has grown on tarceva, do cyberknife to the spots that have grown to eliminate the resistant clones, then continue using tarceva for the rest of the cancer that has shown evidence for ongoing sensitivity to tarceva.
Almost two months ago, I wrote about stage IV NSCLC in the elderly. There, I reviewed existing data and focused on the published results of the French study (IFCT-050, aka Quoix study) that showed that elderly patients, just like younger patients, do better with platinum-doublet regimens in the first line than with one drug. That article focused on the fit elderly, and I promised a follow-up article on the less fit elderly. Well, here we are.
That original article noted that lung cancer is predominantly a disease of the elderly, with median age of presentation 71 years. What is unique about the elderly? Most obviously, they have lived longer. With longer life comes more time for any genetic predispositions to manifest themselves. Further, just like any machine, the body takes on wear and tear with aging. Eighty-five percent of lung cancer patients smoked at some point in their lives. On GRACE, we don’t judge patients for either smoking or not smoking, but we do address the real biologic differences between smokers and non-smokers and how this influences optimal care. Mostly, this has focused on specific mutations that are more or less common based on smoking status. However, in the context of the elderly, another factor comes into play, a smoking-age interaction: more years of life, on average, means more years of smoking and more total cigarettes. Since cigarettes harm the body, older smokers will tend to be less healthy than older nonsmokers.
With more medical problems come more drugs
I met DC in April. He was 62 years old and was principal of a Montessori school. He had smoked a half pack a day for three years in college (which makes him a former/light smoker in my book) and was in fairly good health until the December before when he developed a cough. His cough didn’t get better and thanks to all the talk about lung cancer screening, he requested a chest x-ray. The x-ray revealed a mass, which led to CT scanning. The CT scan shows a large right upper lobe mass, which was hot on PET as were lymph nodes. MRI of his brain revealed metastatic disease and leptomeningeal carcinomatosis. Biopsy was obtained via EBUS, which showed NSCLC, adenocarcinoma subtype.
What is leptomeningeal carcinomatosis? Well, inside the brain, there is a lake called the fourth ventricle; it’s filled with fluid called “CSF” or cerebrospinal fluid. This lake lets out into a river at the base of the brain, which leads down the spinal cord. Leptomeningeal carcinomatosis means that cancer cells have gotten into this fluid-filled space. This state bears a very bad prognosis in lung cancer. Patients typically experience neurologic problems such as visual difficulties or unsteady gait and decline is typically rapid.
(Click on image to enlarge)
When I met DC, he quickly impressed me as a thinker. I remember being impressed that despite being weak from his cancer (PS 2) and having brain mets plus leptomeningeal disease, that he asked sharp, insightful questions. His gait (walking) was a little unsteady, but his speech, strength, coordination, and intelligence showed that his brain was pretty much working. He was accompanied by his wife, who was very supporting at that time and has been a regular ally in DC’s care, keeping me updated about how he’s been doing.
DC had already met a radiation oncologist and there were plans in place to start whole brain radiation. I agreed with this, and also ordered lumbar puncture. My fellow numbed DC’s back, and then inserted a very thin needle into the CSF space to withdraw some fluid. The pathologist then looked at the fluid under the microscope and the presence of cancer cells confirmed leptomeningeal disease. I don’t give chemotherapy at the same time as brain radiation, so I had no conflict between waiting for EGFR test results to come back vs. treating right away with chemo. I ordered EGFR mutation testing and asked DC to come back after completion of his whole brain radiation. His EGFR mutation testing came back positive.
At the time I met DC, I was well aware that Dr. Mark Socinski had treated a similar patient with pulse tarceva and that it had worked-Dr. Socinski’s office was next door to mine and he was mentoring me. I had also read Dr. West’s report (which I blatantly stole the above picture from) of a similar patient right here on cancergrace and had heard scattered stories from other doctors. And so I approached DC with more optimism than I had ever approached a patient with leptomeningeal disease before.
What is “pulse-dose” tarceva? Well, the standard dose of tarceva is 150mg per day. Actually, patients with EGFR mutations can do well on much lower doses, perhaps as low as 50mg per day. At standard doses, the drug doesn’t get into the brain very well, but research has shown that at higher doses, it does get in. So, pulse dose tarceva gives many pills all at once, instead of spread out as a daily dose. Based on the good results of Dr. Socinski’s patient and Dr. West’s patient at 600mg every four days, I chose this regimen.
DC initially tolerated therapy well, although he got briefly admitted to the hospital for fevers of unclear source. We never found infection and they got better with Tylenol. His tumors all showed good response to therapy. By June, his energy had improved sufficiently that I graded his PS at 1. Today, his scans again look good. He reports living an essentially normal life and just had a great time on a vacation to Canada. In summary, he’s been living a high quality life for 7 months (so far!) with stage IV lung cancer including mets to both brain and the leptomeningeal space. Neither he nor I have any plans of that stopping anytime soon!
I’m writing about DC’s case, with his permission, to get the word out about this treatment option that now has many reported cases. Since Dr. Socinski’s case report and Dr. West’s cancergrace.org post, there have been many published case reports and case series of similar patients.
I find one particularly striking. Memorial Sloan Kettering Cancer Center in NY looked back on 9 of their patients, all with EGFR mutation, who all developed leptomeningeal disease while on standard-dosed tarceva or other similar drugs. This group is a bit different from my patient, Dr. Socinski’s and Dr. West’s-these patients had already seen tarceva (or a similar drug) and the cancer managed to spread to the leptomeningeal space despite it. These patients were given a regimen of 1500mg weekly and the results were very good. 6/9 patients had a radiographic partial response in the brain. 1 patient had stable disease, and the other 2 had progressive disease. Of the five patients whose disease in the rest of the body was evaluable, 3/5 had stable disease and 2/5 had progressive disease. The median time to progression in the brain was 2.7 months and median overall survival was 12 months.
There are other reports from all over the world with various pulse-dose regimens for leptomeningeal disease and they all give promise to this therapy. In my opinion, this regimen has become a very strong option for the patient with EGFR mutation and leptomeningeal disease.
DC has been sending me journals of his progress on therapy. I’ve enjoyed them as a window on the life of a patient and they gave me the thought that he might want to comment on this post. I invited him to do so, and here’s what he had to say:
Time to step back from the trees and look at the forest. Cancer is a trip: you develop the habit of watching your body like a hawk, and it is sometimes hard to know what is a regular headache and what is the cancer. Nonetheless, you watch yourself constantly. I’m one of the lucky ones – gradually but pretty inexorably we saw progress: early on certain days after taking Tarceva were characteristically better or worse, but the pattern changed and by this time it is pretty hard to predict. But by now usually 3 days out of 4 are good days – sometimes 4/4. Spiking a fever and going to the ER and hearing the liver enzymes were “elevated” was scary, but the next week it looked like my body was learning to handle that, like everything else. You learn to live each day more-or-less thinking you’ll be able to do what you plan to do (If you don’t overdo it) but never quite sure. But I’ve been able to work almost full time for weeks now, go out to dinner when we planned to – as long as I take it easy in between. Each day is just unpredictable in terms of just how good it will be.
It is also true that by this time I’ve learned more about cancer. Both Dr. Wong and Dr. Weiss have explained things. Kathy has feelings about each doctor’s styles, but I’ve learned from both, and I believe both care about me. I’m probably easier than some to care for because I listen and I’m doing well. But they have explained from the start that they could “treat me, but not cure me.” And as they both have explained, each in their way, the cancer will, eventually, find a way around the Tarceva and gradually return. That is how I see the beginning of the end, even though vague references have been made to “other chemos” we could try. Thankfully, I can enjoy the present – a time when cancer is on the wane – a time when your friends can jauntily email you with boxing metaphors as if I am bloodying my enemy with every Tarceva punch. Perhaps I am.
There are worse ways to be very sick. I can have a great time and I’m surrounded by friends and family. I am more glad I’ve been the teacher and parent I’ve been because my children, my wife, relatives, family friends, former students, current colleagues and students – I feel the love and am happy to feel it. A good guy doesn’t always finish first, but always finish surrounded by friends. I can reflect on my life and be really really proud. I have no regrets. I can reflect on all this and yet know I’ve got lots of time left to enjoy what comes next. The decision to retire next year is immensely “freeing”, and I thank Kathy for suggesting it. (written June 9, 2011)
Since writing those words in June, the family and I have taken our usual two plus weeks in our cabin in the woods of Maine, and we both have returned to full time administrative jobs at our respective schools. Since medications are down to practically nothing, Tarceva every 4th day and some other vitamins and minerals I’ve picked up over the years (to satisfy my desire to improve my health without substantially changing my lifestyle), the days go by without much thought about cancer. Except the week I go for scans and consultation with the good Dr. Weiss. Then I’m hungry for the data. Can’t help it – I can watch the ups and downs of the stock market and not lose any sleep if my portfolio loses 2% in a day (over time it’s held its own) – but I want to see shrinkage in a tumor because the day cancer starts “progressing” (an odd term for getting worse again) feels like the beginning of the end, and I haven’t had to go there yet because it’s been shrinking. I’ll adjust – I’m an optimist and a happy person (it will be harder on Kathy). But like everything else about having cancer, it’s a series of ups and downs that you just have to live with. It is what it is.
Thank you fortmyr for bringing our attention to the recent publication of exciting data on talactoferrin. We’ve talked about talactoferrin before on GRACE. This is an exciting new drug that both Dr. West and I feel has a lot of promise.
When you eat food, you ingest a lot of bacteria with your food and so it’s not surprising that there are a lot of immune cells in the gut. Appropriately this system is called GALT, or gut-associated lymphoid tissue. In the simplest terms, talactoferrin is a chemical that activates GALT in the hopes that this will activate the immune system to better fight the cancer. The drug is not absorbed and does not travel in the bloodstream the way that chemotherapy and even most targeted agents do. Rather, we believe that it activates GALT, and then the body’s own immune cells go off to better fight the cancer. Dr. West has described the proposed mechanism of action in much greater detail, and I refer the curious to his post. Talactoferrin is found in several body fluids. Poetically, its concentration is highest in breast milk, where it is believed to support development of the infant’s immune system, thus the term, “mother’s milk.” Cycles are fourteen days in length. For twelve weeks, the patient takes this pill twice per day, and then there are two weeks off before starting the next cycle.
Two major studies started the clinical work on talactoferrin. One randomized patients to who were previously treated with chemo to talactoferrin or placebo. Dr. West has reported on these results in 2008. All patients were previously treated with at least one and up to two lines of chemotherapy. In other words, these were 2nd line or 3rd line patients. In the US, I would not have opened this study for my patients because of the randomization to placebo. Since alimta, docetaxel and erlotinib all have proven efficacy in the second line, I would have felt ethically uncomfortable. As a rule, I believe that investigators should only open trials that they believe are very promising compared to the standard of care and that they would feel comfortable putting themself or a loved-one on if they had cancer. In fairness, the trial was conducted in India. The little that I know about lung cancer care in India is only from GRACE members’ postings. If 2nd line chemotherapy is not universally available in India, making placebo equivalent to the standard of care, then this trial would seem more acceptable to me. Regardless, the comparison to placebo does provide quality information about the efficacy of talactoferrin.
This was a randomized phase II study. This means that like any phase II study the goal was not to definitively prove the efficacy of talactoferrin, but rather to see if the agent was worthy of further evaluation in a larger phase III study. This design has gained favor because without a control arm, single-arm studies can be made to look very promising just by using strict inclusion criteria. This problem has resulted in too many patients being enrolled on phase III studies that were ultimately proven not to help. Just to be clear what I’m talking about, I’ll make up an example. If I designed an uncontrolled (single-arm) phase II study of dark chocolate for 2nd line treatment of lung cancer and wanted to artificially make it positive, I could require all patients to have PS0, ideal renal function, absolutely normal bone marrow function, minimal burdens of cancer and to have had dramatic response to their first line of chemotherapy. Even if dark chocolate did nothing to stop cancer growth, these patients would live longer than historic controls, leading to a “positive” study. We would then proceed to phase III study, where dark chocolate would get trounced by a standard second line agent, because it is not actually active and patients on both arms would have the same requirements to enter the study. Of course, the major confounder here would be the massive improvement in quality of life that comes with dark chocolate.
Introduction
When I wrote my first review article on the treatment of the elderly, I entitled it, “NSCLC in the elderly—the legacy of therapeutic neglect.” Dr. Corey Langer and I chose the title to directly criticize the major mistake that we perceive in the treatment of the fit elderly—a therapeutic nihilism that leads oncologists to not give sufficiently aggressive treatment to the fit elderly. Lung cancer is a terrible cancer and failure to suppress it with sufficiently active therapy leads to great suffering. This is as true in the older patient as in the younger patient. However, there is great misunderstanding about the efficacy of therapy in the fit elderly patient, the subject of this post. I will seek to summarize coverage of this topic on GRACE previously, highlighting the now published French data on 1st line treatment of the elderly. You may have noted the repeated use of the word, “fit.” Not all elderly patients are as fit as younger patients—aging brings with it more medical problems and more pills; not all elderly patients are as fit as younger patients with lung cancer. I will address this topic in a follow up post dedicated to this important topic.
Good morning, GRACErs.
Plenary
The first talk was by Dr. Hisao Asamura of Tokyo, Japan who discussed a surgeon’s view on adjuvant chemotherapy.He started with a 2010 meta-analysis, which included some older regimens yet still showed a 4% increase in survival at 5 years. Another analysis restricted to more modern regimens showed 9% benefit and some oncologists claim even higher numbers with yet more modern regimens.
Last night I had the good fortune to attend the fun young lung dinner. I had a lot of fun seeing old friends, and greatly enjoyed making a few new ones:
Plenary Session: Lung Cancer in Never Smokers
The day started if with Dr. Thun from the American Cancer Society. He reviewed environmental factors contributing to Lung Cancer in never smokers. He started by reminding us that although only 10% of lung cancer deaths in men and 15-20% of lung cancer deaths in women are due to nonsmoking cancer, the burden of suffering caused by non-smoking lung cancer is actually rather high. If non-smoking lung cancer were treated as its own disease, separate from smoking-driven lung cancer, it would rank eighth among the most common fatal cancers in America! He reviewed environmental factors known to cause lung cancer: secondhand smoke, radon, asbestos, certain metals, some organic chemicals, radiation, air pollution, tubercoulosis, and other chronic inflammatory conditions. Others exposures likely also play a role, but have yet to be proven: human papilloma virus and chronic inhalation of cooking fumes and incense. Indoor air pollution from cooking, coal burning, and smoking men may explain the extraordinarily high rate of nonsmoking lung cancer among women in some areas of Northern China.
Dr. Pierre Massion of Vanderbilt took the stage second to talk about the molecular pathogenesis of never smokers. He reminded us of the different histologic tendencies of never smokers—less SqCC, more adenocarcinoma including the multiple subtypes once called BAC. He reviewed genes associated with susceptibility including cyp1a1, gstm1, xrcc1, gpc5, and fam38b. He pointed out the role of genetic differences in key molecules in inflammatory pathways: IL-1b, IL6, and IL1RN. Finally, insults from the environment may be expressed differently based on variations in genetic susceptibility.
Dr. Massion then used the figure, reproduced below, from Pao et al, Lancet Oncology 2011 to remind us how far we have come in understanding the molecular drivers in nonsmoking cancer:
Studies have shown particular genomic signatures in never smokers. But not only is the DNA changed, but DNA modifiers (epigenetics) are also changed and we have defined specific genes whose expression is modified.
Ah, I must be in Europe. After seeing a few old friends last night, including our very own Jack West and a few hours of sleep, I got some much-needed sleep. On the way to the tram, my roommate, Tom Stinchcombe, and I stopped by a coffee shop for a cup, only to learn that they didn’t serve coffee—it’s the other kind of coffee shop! Welcome, lung-cancer docs, to Amsterdam!
The Lung Cancer Epidemic
The conference room is now full with thoracic oncologists from all over the world waiting for the first session to start. Appropriately, it started with Dr. Jan Willem Coebergh speaking about the epidemic in the Netherlands. Apparently, the Dutch considered lung cancer to be endemic since 1949, and had a case-control study to demonstrate the causative effects of cigarettes in 1957. To this day, the Netherlands is a major cigarette exporter to the rest of Europe. Statistics on incidence in the Netherlands look remarkably like the stats I know better from the US—male lung cancer is declining, while female lung cancer is increasing. Small cell and squamous cell carcinoma are declining, while other histologies are roughly stable; this likely reflects the effects of filters.
Next up was Dr. Richard Peto discussing patterns of mortality across the world. He started by noting that prolonged smoking is the greatest risk factor. With great dry British humor, he encouraged us that if we want to kill ourselves, we should start before 20, and keep going, because quitting smoking works. He showed a graph of lung cancer incidence by time of quitting–stopping smoking at age 30 was closer to being a never smoker than it was to stopping at age 50 or never stopping (reproduced below from Petro, BMJ, 2000). It’s never too late to quit, and the earlier the better!
What is FGF?
FGF is a type of receptor tyrosine kinase. What, you might ask, is a receptor tyrosine kinase? Well, since you were so kind as to ask, and since I’m a bit of a nerd at heart, I’ll tell you. Receptor tyrosine kinases are a part of the machinery of a cell; they have a role in signaling to the rest of the cell what it should do.
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