He was referring to the recent Radiation Therapy Oncology Group's trial of memantine (a drug for dementia) given during whole brain radiation: RTOG0614. So, to answer, I polled a couple of my friends who do nothing but neuro-oncology and reread the results of the trial (not out in published form yet, just as an abstract (paper #1 on this page) and the full talk from ASTRO).
As a quick summary: Whole brain radiation therapy (WBRT) is a treatment given to patients who have metastatic cancer in their brains. There are a number of situations in which WBRT is given and it improves survival and significantly improves the life of patients. On the downside, it has been shown to cause cognitive decline with as many as 60% of patients exhibiting measurable decline at 4 months after WBRT. So, to combat this, a trial of memantine during and immediately after WBRT, an NMDA-receptor blocker used to treat Alzheimer's dementia was proposed and carried out.
In this trial, about 500 patients were enrolled, stratified by their RTOG brain metastasis RPA class (they only enrolled class 1 and 2 patients) and given either 20mg of memantine or placebo daily for 24 weeks. A lot of their patients weren't able to be properly analyzed because of issues with survival (sadly, to be expected in this population), but those who were evaluable (~150) took a battery of 6 different cognitive tests. The primary endpoint was performance on a specific test at the 24 week point, the e Hopkins Verbal Learning Test-Revised Delayed Recall (HVLT-R DR) and there was NOT a significant difference in the results of this (but it 'teetered on the edge of significance', with a p-value of 0.059). Now, don't get me started on p-values. Oops, too late.
The all holy p<0.05 is an arbitrary cutoff level by which we determine 'significance'. I say again, arbitrary. What it has become, I fear, is a gold-standard for a 'positive study'. So in the case of this one, which technically did not meet its primary end point, many people are not swayed, because p wasn't less than or equal to 0.05. the secondary endpoint, cognitive decline (a measure using several other of the tests) was met with p=0.01 and, crucially, there were no difference in side effects or survival. My *suspicion* is that the primary endpoint will be met if they can accrue (and analyze) another 50 patients, and this debate will end. However, until then, the jury is out.
Personally though, even though it failed to meet its primary end point, I will be recommending memantine to patients in a favorable RPA class getting WBRT, or at the very least having this discussion with my patient.
As an aside, the two Neuro specialists I polled had opposite answers, so it is fair to say that this remains in the undetermined category. But, the drug has been shown to be safe, and now *likely* efficacious. In a situation where we don't have other options, I'm sold.
Earlier this week in our morning didactics session we had an interesting discussion about advanced stage non-small cell lung cancer (NSCLC). Now, there is certainly a LOT to discuss about advanced stage NSCLC, and there is a lot of uncertainty in how to treat it with the multitude of new targetted agents coming on the market for mutations like ALK, KRAS, N-RAS, BRAF, EGFR, etc... and the trials that have been run are often difficult to interpret because of changes in standard of care, stage migration due to novel imaging modalities (PET) and other things.
To add to all the uncertainty in treatment, the staging guidelines (AJCC in this case) can change. When I started my residency in 2009, we were on the 6th edition, and now it's the 7th. While the changes are usually small, they matter, because the trials that are now having results reported were often stratified using earlier editions of the staging guidelines, once again clouding the picture for patients needing treatment decisions today.
One thing that hasn't changed, and never will (?) however, is the location of nodal stations. Right? Maybe not! As a refresher, we care about a number of nodal stations when staging lung cancer. Here is the picture we all know and love (also available from the AJCC in poster form here):
Please direct your attention to the lymph node station labelled #7 - this is the sub-carinal station, and one that is often involved, and often biopsied because of the relative ease of access (bronchoscopically). Notice it is, by definition N2. However, it is also considered mediastinal.
Now, this is all well and good, until you have a patient present, as we did at our cancer center several weeks ago with a Left sided T2 NSCLC with station 7 involved TO THE RIGHT OF MIDLINE. We went through the imaging carefully, it was NOT station 8R, it was station 7, creeping down and crossing midline to the RIGHT.
So, now the patient has, by one definition, T2N2 disease (there were no other contralateral nodes or other nodes to make him N3) by virtue of his involvement of station 7. HOWEVER, he could also have T2N3 disease by virtue of having contralateral mediastinal involvement! This is not a trivial difference as it is the difference between IIIA and IIIB, resectable and unresectable.
What to do? Well, he had poor performance status, so surgery was out either way, so we opted or combined, definitive chemo-radiation. However, this uncertainly raise the possibility of a need for more detail in the staging system. Sort of in jest, we proposed a change for the 8th edition - maybe we should have a station 7.5R/L dichotomy for significant involvement, or possibly a 7C/R/L trichotomy?
Sorry for the long radio silence - I re-entered my residency after a 3 year hiatus to pursue full time research and things have been busier than anticipated. While I am on a light rotation (sarcoma), which requires only 50% of my time actually in clinic, I had forgotten what being a #resident is like, and more importantly, what having a pager is like!!!
My personal research efforts have slowed somewhat - with my efforts now divided between the clinic, being a dad and thesis writing. I've changed my focus to writing up what I have currently, rather than chasing after new results, so I haven't much to report. A student I'm working with, however, +Daniel Nichol , recently finished up a paper that he and I have been working on for some time. He is going to write a full blog post about the work, but this will take some time. In the mean time, I thought I'd at least let the community know we've finally submitted our paper to the +bioRxiv Preprints site, as well as a journal (contemporaneously), which you can find here:
In this paper, my first personal foray in theoretical #evolution we build on theory from some exciting theoretical and experimental papers from Steven Weinreich (Weinreich et al. Science) and +Jeff Gore (Tan et al. PRL) to explore the concept of 'steering' evolution as a method of preventing the emergence of resistant strains of bacteria (or cancer!).
I look forward to putting Dan's proper post up, but until then, enjoy the #preprint - we welcome comments!
This is the story of a Cancer Connection I never hoped to make and also the one that has brought me the most joy.
About a month before my family and I left for Oxford, my dear friend and neighbour Ray came over and asked if I'd look at this side, where a orange sized mass was growing. I took a feel and suggested he get the thing cut out by a cancer surgeon. Like any good neighbour, he asked if I'd do it... which I declined (I only do RADIO surgery). Being a self-employed artist, Ray didn't have any insurance, so he ended up convincing a friend to resect it in return for a painting.
So, you know I'm a cancer doc... so you can probably guess how this story plays out. But before I tell you (or let Ray tell you), I want to share a bit about Ray (you can also learn more about him on his website: http://raypaulart.com). Ray's paintings have always struck me, and my scientist and physician friends in similar ways. There is just something alive about them. Something cellular. Something moving.
This makes sense as Ray studied biology as an undergrad, but it is also something that is always moving in his mind: at the heart of this artist is a scientist. Here is the one that first grabbed my eye when we first met (and that I immediately bought for my house): Lionfish. (Sorry for the terrible image quality, the rest will be better).
Ray and his partner Missie have also always been a touchstone for me during my training - reconnecting me to art and beauty when my world became overrun with data and facts and death, and for that I can never repay them or thank them enough.
Anyways, I'll let Ray's words tell the rest of the story: here is his manifesto about his treatment, and the subsequent healing that he has found through this new project, My Sarcoma.
**
My name is Ray Paul. I am a 50 year old artist, musician, frustrated biologist and myxofibrosarcoma patient at Moffitt Cancer Center in Tampa, FL. I received a BS in Biology from Florida State University in 1986, and a MFA in Painting from the University of Cincinnati in 1991. As of my latest scans in February 2013, I am free of detectable cancer. My next round of scans are scheduled for June 2013.
My journey begins in the spring of 2011, when I noticed a rapidly enlarging lump protruding from my left flank. Unfortunately, I fell into the category of the uninsured who wait and hope for their medical issues to resolve magically. Finally, as the mass grew to the size of an Idaho baking potato, I felt compelled to go into the local Emergency Walk-In Clinic. I was told it was likely a lipoma and I needed to find someone to remove it. After weeks of worry and several inquiries, I approached a surgeon friend who agreed, with some trepidation, to perform a tabletop resection, using local anesthesia. It soon became clear that the mass was more than a lipoma.
I was sewn up and a sample was sent to his pathologist who forwarded it to the pathology team at Moffitt Cancer Center. Soon thereafter, I received "The Call." Shock and confusion rushed in, but curiously, was followed by a sense of calm resolve and numb determination. Fear was thankfully suppressed. By pure, sublime serendipity, my next door neighbor, and friend, happened to be a resident in the Radiation Department at Moffitt. Through him, I have enjoyed a deep well of knowledge, compassion, honesty and inspiration. For that I am eternally grateful.
I was admitted as a patient to Moffitt Cancer Center in August of 2011. I began neoadjuvant radiation therapy in September 2011. Whilst undergoing treatment, I enthusiastically and gratefully took part in a clinical trial: "A Phase II Study Evaluating Neoadjuvant Administration of High Dose Radiation Therapy and Intratumoral Dendritic Cells in Patients with High-Risk Soft Tissue Sarcomas." I am also a part of a research study: "Total Cancer Care Protocol: A Partnership with High Risk and/or Diagnosed Cancer Patients for Life." In October 2011, I underwent a radical resection of the 12 x 12 cm ulcerated high-grade left flank myxofibrosarcoma, along with a right-sided DIEP flap closure of acquired 20 x 17 cm soft tissue defect. In April 2012, I had liposuction and debulking surgery of the flap area (30 x 10 cm). In July 2012 I was diagnosed with a left lung mass. I underwent a lung subsegmentectomy to remove a 0.8 x 0.6 x 0.6 cm metastatic myxofibrosarcoma. During a followup visit, a large mass was detected in my right posterior thigh. In August 2012 I started chemotherapy with pazopanib. In October 2012 I underwent a radical resection of a 13.5 x 10 x 3.5 cm metastatic myxofibrosarcoma. In November 2012 I began adjuvant radiation therapy.
During this life-consuming ordeal I have managed to keep a calm and positive attitude, never becoming too emotionally low or too ecstatically high. I have remained otherwise healthy and have maintained my body weight. I have placed my complete faith and trust in my team at Moffitt, and in my physical and spiritual ability to heal. I am surrounded and supported by friends, family and my steadfast partner, Missie. I made the decision to go public with my battle, posting my progress on Facebook. The outpouring of love and support has been overwhelming and has provided me with a warm blanket of peace and strength. Between surgeries and treatments, I have enjoyed long walks with my beloved Boston Terrier, Blue. He went blind concurrently with my cancer diagnosis. Watching him bravely attack life has been an inspiration and has helped prevent me from descending into self-pity. Music has remained vitally important, and I have managed to write and record. In fact, this whole experience has been strangely life-affirming and fascinating. Never have I dreaded going into Moffitt. The strength and determination of my fellow patients has been humbling and has greatly increased my sense of compassion. It is a great honor to have had the opportunity to interact with my medical team, all members of a profession I so deeply admire. I am proud to have contributed, in my own small way, to the field of medicine and cancer research. I have been inspired to create a painting for the Radiation Department, which hangs in the waiting room
My SAE Fraternity brothers, both past and present, at FSU have joined the cause, and are currently involved in fundraising for the Sarcoma Department. A "SAE Slams Sarcoma" sand volleyball tournament benefitting the Moffitt Cancer Center is planned for April 14 in Tallahassee.
I am currently embarking on a collaborative endeavor entitled "The My Sarcoma Project." I plan on combining painting, photographic images of my tumor cells, printmaking, video and music to create an exhibit that illuminates my experiences as an artist and cancer patient. My pathologist at Moffitt, Dr. Marilyn M. Bui, has graciously provided me with the images. She has stepped out of the shadows of the lab and made me realize that pathologists are an integral part of the team and are vital to patient care. We are also collaborating on a book proposal. She is helping me begin my journey from cancer patient back to artist. All my experiences as a biology student, artist and cancer patient seem to be coalescing in this project. Hazy memories of undergraduate experiments involving plasmid mobilization and bacterial resistance, forms and shapes that have evolved in my paintings over the past 10 years, and the inspiration I have gleaned from my time at Moffitt have all come into focus and have given my work direction and resolution. This revelation has led me to a deep understanding and appreciation of my work. I envision my art to be a prescient, visual manifestation of the battle raging within, and a powerful testament to the beauty of Hope.
Ray Paul
**
As a teaser, here is a prototypical 'My Sarcoma' piece. You can see his signature style of abstract forms detailed into cellular figures, and beneath, an H&E pathology image of his own tumor.
I can't be prouder to be part of Ray's healing journey, but I can also take no credit at all. I delivered no radiation, removed no tissue, prescribed no medications. I have been just a friend and guide.
I'll be sure to tweet about My Sarcoma as Ray continues his project, but you could also follow him on Twitter at @raypaul4 for details and music.
One of the benefits to being in my group at Moffitt Cancer Center is that we have three really smart, world renowned thought leaders: +Alexander Anderson, Robert Gatenby and +Robert Gillies. These three gentlemen are so busy, in fact, that they can't even go to all the amazing events that they are invited to. Sometimes, when this happens, they are able to suggest a replacement. I was lucky enough to be in the right place at the right time when Bob Gillies (Bob G_i) was unable to go to Lugano, Switzerland, to attend the World Oncology Forum, and further, lucky enough to be accepted as his replacement. This is an event that would not have qualified to attend for another 20 years, assuming that I did well for those coming 20 years. It was hosted by the European School of Oncology (ESO), an organization less well known in America than it should be, but quite influential in Europe and the rest of the world.
The mission of ESO is to contribute to the reduction of death from cancer due to late diagnosis or inadequate treatment, with a focus on education. On the occasion of their 30th anniversary, they held a conference, the World Oncology Forum, to bring 100 cancer experts and cancer specific journalists (including Clifton Leaf, Science editor at the NYT whose face is just above) together to answer one question: Are we winning the war on cancer?
I was lucky enough to be the pinch hitter for Bob Gillies, and represent Moffitt as one of only 4 partipants from the USA. Most of the people with whom I was speaking were knights of the realm (one even had his own paradox!), cancer center directors and even ministers of health for entire countries. I was, in a word, outclassed. That being said, my patron, Bob G_i, made sure I felt emboldened to speak out for our agenda - the use of rigorous theory and evolutionary thinking in cancer research. And, as luck had it, I ended up at the table next to Marge Foti, the head of the AACR (who, it turns out, is a super nice lady), so I got to talk a bunch (when she finished saying what she wanted, I just grabbed the microphone and kept going!).
I think my role there was really to be an uninhibited, undogmatized voice unafraid to say 'We don't know'. Because of my role as a student, and not as someone that entire nations look up to, I am able to say that without breaking trust... and in cancer, this is a very important thing to say. We really, honestly, don't. know. &*!@. Cancer is a disease that keeps outpacing us and our results aren't much better than they were 50 years ago. We have learned a LOT, but it is not obvious how what we've learned is useful. Where we have done well is in patient care and in maximizing the effectiveness of the therapies that we do have, but we have a long way to go before we can hope to end this disease (if we can at all...)
My major contention (and one that I managed to get squeeeeezed into the consensus statement) is that there is a MASSIVE theory gap in cancer research. I would argue that we still don't have a deep understanding of the data generated 30 years ago! Do we REALLY know the meaning of aneuploidy in cancer (feel free to weight in +Arturo Araujo)? What about chromosomal aberrations? How can we possibly hope to make sense of (and utilize) the information coming out of The Cancer Genome Atlas, if we don't understand the first principles?
I honestly fear sometimes that we've been blinded by the promise of easy answers in the genome, and because of this, we have abandoned almost all other forms of research in cancer. If you don't have genetic analysis of some sort in your project, good luck getting it funded. But what if the answerisn't in the genome? Well, that is a topic for a future post... back to the WOF.
So - what was the answer we came up with? It was: No. We aren't winning the war on cancer.
We published a call to arms in a number of newspapers throughout the world on World cancer day, February 4th. (International Herald Tribune, Le Monde, La Repubblica, El País, and Neue Zürcher Zeitung) that looked like this:
and a piece in the Lancet (which I don't have access to, ARGH why isn't THE LANCET #openaccess??). And finally, a piece in Cancer World magazine, the ESO's own journal, in which I they put this paragraph, largely about our contention (yes, it was me who wasn't convinced), right after Professor Hanahan's hopeful talk that suggests that all we need to do is target the hallmarks of cancer, and we'll be OK.
Not everyone at the Forum was convinced. Doesn’t hitting targets harder (with all that implies for accompanying toxicity), and hitting multiple targets, sound a bit like a return to the chemotherapy carpet bombing approach? Given the way tumour cells mutate, shouldn’t we expect that if we target and shut down one mutation the cancer will simply find other mutations to exploit to keep going? Before investing billions on drugs targeted at one mutation after another, shouldn’t we start by trying to understand basic principles of cell behaviour, so we can anticipate the cancer cells’ evasive strategies, and devise rational counterstrategies, based on rigorous mathematical models, to cut off their options?
So I managed to at least get the words 'mathematical modeling' and 'rigorous theory' into the minds of the world's cancer leaders...
I also came away with a deeper understanding about the worldwide cancer situation: that really, my theories on metastasis, cancer stem cells, or the evolution of resistance to targeted therapy, while exciting to me, mean very little to the tens of thousands of people without access to a properly trained surgeon, ANY radiation therapy or even pain medication. Humbling. But, we do what we can.
Thanks to Anna Wagstaff for listening to me when she had MANY more influential people eager to get their two cents in. Also, thanks for featuring me in their magazine, where I think I managed to piss of a few old teachers and maybe even some prospective bosses with my final answer in their 'My World' feature.
It was an amazing meeting run by passionate people. If you ever have a chance to interact with the ESO, take the opportunity. The USA could do with an organization like it.
Just a quick post to let you know about a review I published with two collaborators today in Surgical Neurology International. The heavy lifting for this was done by +Emory McTyre, a very bright and motivated medical student who has recently matched into radiation oncology at Wake Forest. This is a comprehensive review of the use of whole brain radiotherapy in the treatment of brain metastases. It is written for a clinical audience, but since it is #openaccess anyone can read it and use the information therein. The corresponding author is a friend and radiation oncologist at Moffitt Cancer Center, Prakash Chinnaiyan.
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