A reasonable man

L. and I left the cold state for a couple of days to check in with Dr. Bow Tie (who, on this occasion, lived up to his nickname, wearing a tie that apparently required an MD-Ph.d. to divine how it related to his slacks and shoes). 

The goal was to get a plan in advance of the CT I will have next week, and we got one -- several, actually, depending on how things turn out with the scan. The hope is to continue on with Temodar, but I'm not sure if that's going to be possible. Although being relatively non-symptomatic makes it difficult for me to tell if my chemo is working or not, I tend to believe that the tumors have advanced a bit over the last couple months and we'll need to start something new. I hope I'm wrong.

Fun details of the NY Trip are TK, but here's a few paraphrased comments from the discussion that might interest people who know me or other epithelioid sarcoma patients:

• I "look good" -- I have "low tumor volume." I'm a "great candidate" for a clinical trial because I'm doing relatively well at the moment.
• Why did he try gem/tax again when my cancer began spreading this winter? Because you "go where the money is"; the tumor had shown some sensitivity to that drug combination before and enough time had elapsed to make it reasonable to think it might work again.
• What about temodar? How likely is a good or stable disease response from that? Temodar is a "reasonable choice." So why did he strongly prefer gem/tax after the tumors got into the nodes behind my belly, while my local oncologist advocated for temodar? Because we didn't know what would work best. There's no formula.
• How are you feeling about deforolimus? The mTor inhibitors have a huge amount of promise (some background here), but they aren't quite ready for prime time (though they may be soon). It may turn out that deforolimus needs a little help -- that it will work better in combination with some other drug.
• What about using rapamycin, the transplant drug, off-label as a substitute for deforolimus which is now pretty much only available in Ariad's SUCCEED trial (which is placebo-controlled)? He's done it, and he's even seen an epithelioid sarcoma have a mixed response to it, but it's a down-the-road option for me. Rapamycin doesn't have terrible side effects, so you don't have to worry as much about being too late with it. Incidentally, Dr. BT has also heard about ES responding to deforolimus.
• The caveat he pointed out is while it is reasonable to pore over study tables to look for epithelioid sarcoma responses, it's not a dependable enterprise because you usually don't know if ES has any particular sensitivity to the drug, or if the drug just happens to have positive effects for X% of soft-tissue sarcoma patients and the ES response was just the luck of the draw.
• I may be a good candidate for a trial of a new tyrosine kinase inhibitor -- a member of the "nib" family of drugs being actively developed by several pharma companies. Imatinib, dasatinib, sorafenib... etc.
• How about sorafenib, anyway? Could be a "reasonable choice."
• Other options? Maybe high-dose single-agent ifosfamide since I haven't had any ifos before.

None of this is, of course, is medical advice for anyone -- not even me. The doctors will consult after my scans and then we'll lock down a plan. 

It's great to have so many "reasonable" options; of course, the catch is that there is no compelling third-line drug for metastatic ES that would make more options "unreasonable." 

The clear options come earlier: some sort of doxrubicin-based chemo as the first line, gemzar and taxotere as the second line. Finding the best third- or fourth line defense is much murkier: I will keep you all posted about what we end up trying...

Expiration dates

Leroy Sievers of NPR's My Cancer blog is usually worth reading (and listening to, when he's feeling up to going on air). He has a horrific colon cancer that has metastasized in all sorts of vicious ways requiring all sorts of hellish interventions -- and yet, there he is working professionally and savoring life when possible personally.

I found some "difficult hope" in this recent entry he wrote after Ted Kennedy's sad diagnosis:

When a limit has been put on your life, when all of a sudden life seems more urgent, you want to know.

"How long?"

When I asked that the first time, the answer was about three months. Here I am, almost 30 months later. What's the lesson here?

I guess it's, what's most important is the living, not the preparing to die.

This can't be said enough, I guess. Sievers' prognosis (30 months and counting from three) also reminds me that prognosis is not destiny -- it's often not even tied to reality.

He posts, but doesn't understand

I won't pretend that I have any idea of what this recent abstract from the International Journal of Surgical Pathology that I harvested from PubMed means, but I am interested to see more variation in the way the disease looks to pathologists than I previously thought existed.

To digress slightly, I myself am an example of unusual ES pathology: My official diagnosis is that I have the more aggressive proximal subtype of epithelioid sarcoma, but the review pathologist looked at the tissue and pronounced that it was of the distal subtype. All eventually concurred that the sample that went to Harvard for review was anomalous and the diagnosis remained proximal, but clearly there were at least some distal tumor cells in my tumor, perhaps explaining why the course of my disease has been a little slower than it could have been, given its problematic location and metastasis.

The takeaway here is to get your pathology reviewed by a good sarcoma pathologist -- Sharon Weiss at Emory (thank you commenter), Christopher Fletcher at Dana Farber, the armed services institute, someone at a big referral center, etc. And if you've got views on what significance (if any) this abstract has, feel free to enlighten me in the comments.

Anyway, the abstract ("myxoid," by the way, refers to a semi-transparent, glutinous, mucous-like material):

Myxoid Epithelioid Sarcoma: Clinicopathologic Analysis of 2 Cases.

Fadare O.

In the nearly 4 decades since its original delineation as a distinct clinicopathologic entity, several morphologic variations of epithelioid sarcoma have been described. Proximal, angiomatoid, and fibroma-like variants have been reported, as have cases displaying significant hyalinization, calcification, and/or ossification. Furthermore, it has long been recognized that epithelioid sarcoma may display focal myxoid change. Herein, the authors describe 2 examples of epithelioid sarcoma that displayed diffuse myxoid change. Both cases were otherwise typical, both morphologically and immunophenotypically, of epithelioid sarcoma. The tumors in both cases were localized, and the patients were treated with wide local excision followed by adjuvant radiotherapy. The patients are free of disease recurrence after 25 and 37 months of follow-up. Differential considerations that may arise because of the composite of morphologic and immunophenotypic findings noted in these cases are discussed, especially if encountered in a small biopsy. These cases further expand the morphologic spectrum of epithelioid sarcoma.

A four-time cancer patient's notes

Carter aide Hamilton Jordan beat cancer three times over 24 years, finally succumbing recently to mesothelioma. In a memoir, he published his "top 10 tips for cancer patients," which the New York Times Well blog helpfully summarized, along with some more information about Jordan. I found these tips particularly resonant with my ES experience (follow the link for all of them):

No. 2: Seek and know the truth about your illness, and prognosis.

If you don’t have the facts, and don’t know the truth, you won’t make good decisions. It takes courage to ask questions about statistics and your prognosis.

No. 3: Get a second opinion.

We wouldn’t buy the first computer or cellphone we looked at. Shop around when your life is at stake….I got second opinions on all of my cancers.

No. 4: Determine upfront how broad or narrow your physicians’ experience is.

If you have something that your doctor says, “I’ve never seen this before,” get another doctor. You want your doctor to be very familiar with your disease.

No. 5: If you have a poor prognosis, or a rare form of cancer, try to get to a center of excellence.

If your doctor doesn’t believe he or she can cure you, you won’t believe you’ll be cured.

No. 6: Do not allow your caregivers to project their values, goals and expectations onto you.

In my book I tell the story of a 68-year-old man who was diagnosed with PCa (prostate cancer). And this man is in very good health other than the PCa. His 35-year-old doctor reasoned that since his life expectancy was only five or six years, that he recommended that the man do nothing for his PCa and told him it would take the PCa four or five years to kill him. This man wanted to live to be 80 or 85. He didn’t accept that. He had his prostate removed, and many years later he’s in good health, and probably will live to be 80 or 85. Don’t let your doctor project his or her expectations in life out on you.

Metastasis mysteries (and innovation)

I have, oh I don't know, an interest in metastasis, so this passage from a recent New Yorker article by Malcolm Gladwell caught my eye. The piece argues that big ideas aren't as rare as we think, and spends a lot of time on a venture Nathan Myhrvold, a former executive at Microsoft, and a group of multidisciplinary experts, have formed to generate patentable ideas.

Often the process involves convening a group of extremely smart people, seeding the discussion, and letting things roll. Here's a riff I found particularly interesting:

“Lowell came in looking like the Cheshire Cat,” Myhrvold recalled. “He said, ‘I have a question for everyone. You have a tumor, and the tumor becomes metastatic, and it sheds metastatic cancer cells. How long do those circulate in the bloodstream before they land?’ And we all said, ‘We don’t know. Ten times?’ ‘No,’ he said. ‘As many as a million times.’ Isn’t that amazing? If you had no time, you’d be screwed. But it turns out that these cells are in your blood for as long as a year before they land somewhere. What that says is that you’ve got a chance to intercept them.”

How did Wood come to this conclusion? He had run across a stray fact in a recent issue of The New England Journal of Medicine. “It was an article that talked about, at one point, the number of cancer cells per millilitre of blood,” he said. “And I looked at that figure and said, ‘Something’s wrong here. That can’t possibly be true.’ The number was incredibly high. Too high. It has to be one cell in a hundred litres, not what they were saying—one cell in a millilitre. Yet they spoke of it so confidently. I clicked through to the references. It was a commonplace. There really were that many cancer cells.”

Wood did some arithmetic. He knew that human beings have only about five litres of blood. He knew that the heart pumps close to a hundred millilitres of blood per beat, which means that all of our blood circulates through our bloodstream in a matter of minutes. The New England Journal article was about metastatic breast cancer, and it seemed to Wood that when women die of metastatic breast cancer they don’t die with thousands of tumors. The vast majority of circulating cancer cells don’t do anything.

“It turns out that some small per cent of tumor cells are actually the deadly ones,” he went on. “Tumor stem cells are what really initiate metastases. And isn’t it astonishing that they have to turn over at least ten thousand times before they can find a happy home? You naïvely think it’s once or twice or three times. Maybe five times at most. It isn’t. In other words, metastatic cancer—the brand of cancer that kills us—is an amazingly hard thing to initiate. Which strongly suggests that if you tip things just a little bit you essentially turn off the process."

The panel started riffing around the idea of a mechanical blood filter that would remove cancer cells -- and found another company was already working on a similar idea... Wouldn't that be nice?

By the way, check out Natalie Angier's interesting piece on mets if you haven't already.

(I Can Get Some) Satisfice-ion

My friend LH was getting ready for a big trip with the family and, three days out, she was feeling overwhelmed about the massive amount of work it would take to get from point a to point DC. “I have this vision of all these things I need to do," she said, "but of course I’ll eventually give it up and start satisficing.”

You say that like it’s a bad thing, I said, surprised.

**

Sometimes I feel like what remains of my undergraduate degree is an unwavering, insane loyalty to an often-mediocre football team; some great friends; and a pillowcase full of disconnected intellectual trivia (“these fragments I have shored against my ruins” -- see what I mean?). But one idea I take out my bag, often, is Herb Simon’s concept of satisficing. Simon coined the term as a combination of satisfy and suffice -- to satisfice, then, is to quickly make a decision that meets your bottom-line criteria rather than agonizing over making the perfect decision.

Here’s some thoughts on the matter from the author of a blog (and book) called The Happiness Project :

Satisficers (yes, satisfice is a word, I checked) are those who make a decision or take action once their criteria are met. That doesn’t mean they’ll settle for mediocrity; their criteria can be very high; but as soon as they find the car, the hotel, or the pasta sauce that has the qualities they want, they’re satisfied.

Maximizers want to make the optimal decision. So even if they see a bicycle or a photographer that would seem to meet their requirements, they can’t make a decision until after they’ve examined every option, so they know they’re making the best possible choice.

Most people are a mix of both approaches. For example, one friend was a satisficer about renting an apartment, but a maximizer about buying an apartment...
In a fascinating book, The Paradox of Choice, Barry Schwartz argues that satisficers tend to be happier than maximizers. Maximizers must spend a lot more time and energy to reach a decision, and they’re often anxious about whether they are, in fact, making the best choice. (emphasis added)

**

In the context of cancer treatment, I think striving for maximization makes sense. Lots of studies indicate that better (eg, more experienced) surgeons get better margins. One recent non-sarcoma example that leaps to mind is a Sloan-Kettering doctor’s paper that found the long-term outcome of prostate surgery was strongly influenced by the surgeon's experience. Choosing third- or fourth-line chemotherapy for metastatic epithelioid sarcoma is by necessity an exercise in satisficing -- perfect information just isn’t out there -- but I do believe in consulting with at least a couple of experts to make the best possible decision, even if they disagree for largely “arbitrary” reasons, as one physician told me.

Living with cancer is different. Where I really try to satisfice, to suffice, to satisfy, is in how I allocate my time. I rarely have the energy to, say, maximize the tasks accomplished on an outing, or play every game my children desire during a particular afternoon, but I try to make the most satisfactory choices I can, and get on with life instead of feeling bad about the things I might do, I used to do, I dream of doing.

This purple stuff is trying to kill me

A few of my pathology slides somehow ended up on the internet, so I thought I'd put one here for the record. This is the yucky stuff -- big, bad, rhabdoid-like epithelioid sarcoma cells. I had hoped, before looking through the various images, that there would be some kind of terrible beauty in one of them. Nope. They are all banal. Like this one -- it could be a close-up of some hipster's recycled glass countertop or unfortunate Marmoleum choice. 

In praise of difficult hope

Hope may have feathers, it may float like Ivory soap, but its key characteristic for me is this: You have to put some weight behind it. That rock isn't going to push itself up the hill by itself. Hope is an idea put into action, a melding of thought and deed that results in something powerful -- the idea gains conviction from the action, and the action gathers reach and scope from the idea.

This is part of why Barack Obama's voice is so powerful. He taps into our sense that we need hope -- and action. I don't expect Obama to magically transform Washington (much less the United States, or our beautiful, miserable world) through the beauty of his face, story and words. But I do expect him to get some crucial work done because when he talks about hope in one breath, he usually talks about action in the next. He'll conjure up images of mutual respect, increased civility, finding common ground -- and then he puts some weight on it, by talking about how he'll build a working legislative majority.

I digress. What I really want to do here, because I haven't sorted out what I think about hope, is defer to Dr. Jerry Groopman, whose book The Anatomy of Hope: How People Pervail in the Face of Illness, has a lot to offer to people working to stay hopeful in the face of calamitous illness:

Hope is one of our central emotions, but we are often at a loss when asked to define it. Many of us confuse hope with optimism, a prevailing attitude that "things turn out for the best." But hope differs from optimism. Hope does not arise from being told to "think positively," or from hearing an overly rosy forecast. Hope, unlike optimism, is rooted in unalloyed reality. Although there is no uniform definition of hope, I found one that seemed to capture what my patients had taught me. Hope is the elevating feeling we experience when we see -- in the mind's eye -- a path to a better future. Hope acknowledges the significant obstacles and deep pitfalls along that path. True hope has no room for delusion.

Here's some of Groopman's sense of how action feeds hope:

Hope can arrive only when you recognize that there are real options and that you have genuine choices. Hope can flourish only when you believe that what you do can make a difference, that your actions can bring a future different from the present. To have hope, then, is to acquire a belief in your ability to have some control over your circumstances.

A little more on the use of hope:

Each disease is uncertain in its outcome, and within that uncertainty, we find real hope, because a tumor has not always [SG note: Uh, Mr. Harvard, ever?] read the textbook, and a treatment can have an unexpectedly dramatic impact. This is the great paradox of true hope: Because nothing is absolutely determined, there is not only reason to fear but also reason to hope.  And so we must find ways to bridle fear and give greater rein to hope.

Will this hope charge up the immune system? Mute pain signals? Power some of us through to survival? I'm not so sure, and Groopman's chapter on the biology of hope isn't terribly convincing. But I know that it makes life richer -- and maybe, just maybe, lays the foundation for the kind of miracle that some of us need (and a few of us get).

Live Strong, Live Weak, Just Live

I visited the doctor last week, and the check-in area was laden with free stuff from the Lance Armstrong Foundation: bracelets, brochures, postcards. I do love free stuff.

As I wondered just how many yellow bracelets I could in good conscience take, my eyes drifted to the foundation’s “manifesto.” (The word “manifesto” makes me want to reach for a rock, but that’s another issue.) I read:

We believe in life.
 Your life. 
We believe in living every minute of it with every ounce of your being.
 And that you must not let cancer take control of it. 
We believe in energy: channeled and fierce. 
We believe in focus: getting smart and living strong.
Unity is strength. Knowledge is power. Attitude is everything. 
This is the Lance Armstrong Foundation.

We kick in the moment you’re diagnosed. 
We help you accept the tears. Acknowledge the rage.
 We believe in your right to live without pain. 
We believe in information. Not pity.
 And in straight, open talk about cancer. 
With husbands, wives and partners. With kids, friends and neighbors. And the people you live with, work with, cry and laugh with.
 This is no time to pull punches.
 You’re in the fight of your life. ....

There is much to admire here -- and even more to admire in the foundation’s work.

But I found myself repulsed and saddened by the manifesto’s rhetoric. Some of it was the jabby marketing talk. The short sentences. The powerful verbs.

But what really got me is the pernicious limitations of “strength” as a model for living with and through cancer. Surviving this disease is not just a fight, and strength is not the only necessary commodity. As George Demetri, the Harvard sarcoma genius, pointed out somewhere: Lance Armstrong is a remarkable man, but he had perhaps the most chemosensitive type of tumor in existence. This is not to minimize what he went through, and what he accomplished afterward, it’s just to highlight his limitations as a model for the rest of us. And to be fair, Armstrong himself is quite well aware of this.

I want to live strong -- and, in fact, I wear the bracelet to remind myself that I am strong and that others are in solidarity with me, sharing their strength -- but I know that strength isn’t everything. Which is why Bill Stuntz’s thoughts on “living weakly” with stage-4 colon cancer touched me deeply when I read them yesterday. (Another thing that touched me that day of thinking of bracelets, and manifestos, and cyclists: My friend BY sent me a picture after completing his first 100-mile bike ride. He was wearing a bracelet for me. More bacon for you, my friend.)

When you’re not manifesto-ing or writing marketing copy, strength is a slippery concept. Sometimes it means embracing weakness. Here’s Stuntz (and do read the whole thing):

Reduced life expectancy aside, the chief consequence of stage 4 cancers—even more, the chief consequence of their treatment—is weakness, not strength. Cancer and chemotherapy, taken together, are exhausting. Walking up a flight of stairs feels to me like running a couple of miles would feel to a typical out-of-shape 50-year-old, which is what I would be if I were healthy. All mental exercises are several times harder than they used to be...

In short, I can’t live strong, because there isn’t much strength left in me. But I can live weak.

What does that mean?

.... An interesting thing happens when you put aside all the yardsticks and just do what’s possible. Motivation changes. Work is no longer about achievement and reward. It’s more about love and beauty. There is something very powerful—C.S. Lewis might have called it deep magic—about working for love of the work itself: labor becomes less labored, more gift than obligation. I don’t know how much longer I’ll be able to put words on a computer screen—but the ability to do it now, even if only sometimes, is more precious than I can describe. I don’t know whether that makes the work better, but I’m pretty sure it makes me better.

Likewise, there is something inexpressibly lovely—notice that word’s first syllable—about ordinary tasks done for love of the tasks, and done while in the grip of a disease that seems determined to make those tasks impossible. It’s the beauty of a runner’s last marathon, the beauty of an aging athlete’s final game, the game he pours his soul into, as the best artists do in their best work. It may not be lovely to anyone else, and that’s OK by me: cancer is an ugly disease, in every possible way. No wonder people recoil from it. But in the midst of all its life-sapping, soul-destroying ugliness, something amazing can happen: the most ordinary things, the most mundane tasks, take on value and beauty beyond anything I could have imagined. Whether or not anyone else sees it, I see it. And that’s enough.

“Live strong” sounds to me like denial: I’m not strong, and pretending I am can’t change that fact. But I can live weak: do what I can, however small and ordinary, day by day. Some of the living—I wish it were more, but at the same time, I thank God for the “some”—is surprisingly good.

Yes.

Department of More Yes: Here's L., hoisted up from the comments to guest addendum blog:

I love this entry and Bill Stuntz's thoughts. I have long had ambivalent feelings about the "live strong" bracelet, which I wear in hope for you but mostly because of the intense and beautiful solidarity with which they were given to us by T., friend and colleague who passed them out at work for us to wear with knowledge that everyone there was behind us. And truly, what gives them meaning is to sit in a meeting and look around the room and catch a glimpse under a sleeve or right there on a bare wrist -- so many yellow bracelets. They are crazy sunshine (OK, winner's yellow jersey) yellow that doesn't match a thing anyone would wear, and yet there they are, a silent message of hope and caring. But everytime I think of the literal message that I'm wearing I feel my failure. It's a great idea, a Tour de France-winner kind of ideal that I wish I had some kind of kinship with, but maybe "live weak" is as fairly applied to the sufferers and the caregivers as long as we make the effort to see beauty and joy at least sometimes. I've asked myself, if you die, what will I do with this bracelet? Never take it off in remembrance, of both you and a life ethic I'd like to embrace? Have a symbolic and satisfying moment with scissors? Or tuck it in a drawer to come across along with all of the other things that will break my heart? I can't answer that yet. But to the people who wear these ugly rubber bracelets, no longer cool, every day because they love you -- us -- it does not escape my notice. The friends who stay through the long, bloody, tedious battle, this to me is grace and god.

Clearly L. deserves her own blog, but I'm happy to have her with me, here and everywhere.

ASCO, but will you receive?

Online abstracts are now available for the sarcoma presentations scheduled for the American Society of Clinical Oncologists meetings later this month. I spent a few minutes going through them and didn't notice any obviously relevant epithelioid sarcoma stuff buried in the abstracts, but I'm not qualified to make that judgement and it's better to wait until after the meetings to see what gets covered in the medical trade press anyway.

Ariad posted some phase I results for deforolimus that look encouraging for soft-tissue sarcoma generally:

Abstract No:
3509
Citation:
J Clin Oncol 26: 2008 (May 20 suppl; abstr 3509)
Author(s):
M. M. Mita, C. D. Britten, E. Poplin, W. D. Tap, A. Carmona, L. Yonemoto, D. S. Wages, C. L. Bedrosian, E. H. Rubin, A. W. Tolcher
Abstract:
Background: Deforolimus is a non-pro-drug rapamycin analog which specifically and potently inhibits mTOR. In Trial 202 intravenous deforolimus demonstrated notable anti-tumor activity in bone and soft tissue sarcomas. (JCO 2006; 24, 18S: 9505). Oral deforolimus allows greater treatment flexibility and offers potential to treat patients in a maintenance setting. We report preliminary results on oral deforolimus in a comprehensive dose finding study in patients (pts) with refractory malignancies. Methods: The trial was an open label single arm study with dose escalation and a standard 3+3 design. Patients had advanced/metastatic solid tumors refractory to therapy. 7 regimens, all over a 28 day cycle were investigated. Definitions of dose limiting toxicity (DLT; Gr 4 or Gr 3>3 days) were based on CTC criteria. Anti-tumor activity was evaluated by modified RECIST criteria. Patients achieving stable disease (SD) or better lasting for at least 4 cycles of 28 days were classified as achieving clinical benefit response (CBR). Results: 147 pts (85 sarcoma) received deforolimus. Median age was 56 (range 23-84 years); 65 (44%) pts were male. Pts had a median of 2 cytotoxic therapies at entry (range 0-7); 113 (77%) of this population had documented progressing disease at enrollment. The median ECOG score was 1 (range 0-2). The DLT for all regimens was aphthous-ulcer like mouth sores which were reversible by dose reduction or symptomatic therapy. 36 pts achieved CBRs (23 sarcomas). MTD was increased with the addition of a weekly dose holiday interval. CBRs were seen in all regimens and several types of sarcomas and a variety of carcinomas. 24 pts received 40 mg QDx5/wk and in this group 3 of 13 (23%) sarcomas had CBR; 2 (liposarcoma, dendritic cell sarcoma) (15.4%) achieved PR. Pharmacodynamic analysis showed potent inhibition of mTOR. 7 patients remain on therapy after 6-24 cycles. Conclusions: Oral deforolimus has a safety and anti-tumor activity profile consistent with the intravenous form. 40 mg QDx5 each week is an active, well tolerated regimen and has been selected for further evaluation in SUCCEED, a global phase 3 trial of patients with metastatic soft-tissue and bone sarcoma in the maintenance setting.