The son

One of the second-grade girls got a little frisky with B. yesterday, kissing and hugging him to his professed consternation. 

It brought back memories of the time in kindergarten when Big Tina chased me down like a lion pursuing a sick wildebeest, planting a couple of smackers on my cheeks while I secretly wished that little Tina, the redhead, had done the chasing and the kissing.

We discussed ways to dissuade this behavior. B.'s first instinct was that his fists might be helpful, but I pushed for a softer-line solution. "She's your friend, B.," I said, "and she's hugging you because she likes you. You don't want to hurt or scare one of your friends. It's OK to say that you don't want her to touch you, but if you freak out she'll just want to do it more."

He considered this, and replied. "The school regulations" -- love that word choice, "regulations" -- "say that kissing is never OK, and that hugging is only OK if the person asks first. I didn't ask first!"

Later, at soccer practice, the little girl chanted "B.'s here! B.'s here!" when we showed up and, in fact, snuck in a little kiss in line. B. didn't look too upset.

*

On the way home, we talked about the cancer a little bit.

"Dad, I'm sort of glad that you're sick because we get to spend more time together. I mean, I'm not glad, but..." We went on from there, him breaking my heart with every word. On the one hand, he loves computer games and war books and thinks it might be a good idea to whack a cute little girl for hugging him. On the other, his empathy and sympathy for other people is widening and deepening almost every month. It's such a pleasure to watch his moral acuity grow. 

He then told me that he hoped that I could just stay the same, so that we could stay together with the family. But then he paused, and reconsidered. "But I don't want you to hurt too much." I'm not hurting too much, I told him. I also want me to just stay the same if I can't get better. It occurred to me later that I could have said something about the deforolimus -- that I was, in fact, going to try to start taking a drug that was intended to help me "stay the same." But the placebo muddies those waters, and I'm always cautious -- perhaps overcautious -- about offering false hope. 

I approve this message

Got a call for Dr. S last night -- Ariad's doctors agree, my scans are stable enough to enroll in the deforolimus trial. She also mentioned that she had been e-mailing with my NY doctor, and he was also on-board with the decision to take a shot at the trial. So I'm going to go for it sometime next week after I finish a course of antibiotics I'm taking. 

I'll have much, much, much more about the drug and trial in upcoming weeks. Probably not so much the substance of it, but the psychology. In the meantime, here's an abstract (emphasis added) of an encouraging deforolimus sarcoma trial published in January:

Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies.

Mita MM, Mita AC, Chu QS, Rowinsky EK, Fetterly GJ, Goldston M, Patnaik A, Mathews L, Ricart AD, Mays T, Knowles H, Rivera VM, Kreisberg J, Bedrosian CL, Tolcher AW.
Cancer Therapy and Research Center, Institute for Drug Development, The University of Texas Health Science Center, San Antonio, TX, USA.
PURPOSE: This phase I trial was conducted to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of deforolimus (previously known as AP23573; MK-8669), a nonprodrug rapamycin analog, in patients with advanced solid malignancies. 

PATIENTS AND METHODS: Patients were treated using an accelerated titration design with sequential escalating flat doses of deforolimus administered as a 30-minute intravenous infusion once daily for 5 consecutive days every 2 weeks (QDx5) in a 28-day cycle. Safety, pharmacokinetic, pharmacodynamic, and tumor response assessments were performed. 

RESULTS: Thirty-two patients received at least one dose of deforolimus (3 to 28 mg/d). Three dose-limiting toxicity events of grade 3 mouth sores were reported. The maximum-tolerated dose (MTD) was 18.75 mg/d. Common treatment-related adverse events included reversible mouth sores and rash. Whole-blood clearance increased with dose. Pharmacodynamic analyses demonstrated mammalian target of rapamycin inhibition at all dose levels. Four patients (one each with non-small-cell lung cancer, mixed müllerian tumor [carcinosarcoma], renal cell carcinoma, and Ewing sarcoma) experienced confirmed partial responses, and three additional patients had minor tumor regressions. 

CONCLUSION: The MTD of this phase I trial using an accelerated titration design was determined to be 18.75 mg/d. Deforolimus was well tolerated and showed encouraging antitumor activity across a broad range of malignancies when administered intravenously on the QDx5 schedule. On the basis of these overall results, a dose of 12.5 mg/d is being evaluated in phase II trials.

Patient power

I've been thinking a lot about clinical trials lately, as you'd imagine, and one of the things I've been wondering what percentage of drugs at a given stage of trial eventually make it to market. 

I tend to think about it in sports terms -- that for every 20,000 high school basketball players, maybe 10 will play in division 1, and for every 100 D1 players, maybe five or ten make the league. But this is obviously vague, plus it leads to inappropriate analogies: Is this upcoming cancer drug a seven-foot-gazelle, or a 5' 11" point guard who shoots too much? So I was interested to see this passage in a Forbes article about the perils and possibilities of patient-directed medical research:

The patient groups are filling a void in drug research created by the industry's legitimate fear of failure. Biotech executives dread what they call "the valley of death," the period of time between a drug's conception in a lab and its first clinical trial. For every 10,000 would-be medicines chemists create, only one makes it to market. But if a drug has already been through enough tests in cell cultures and lab animals to justify starting clinical trials, the odds of success have risen to one in nine. Put the substance through early clinical trials with a few dozen patients, and the odds jump to one in six. At some point a drug for even the most uncommon disease becomes every bit as appealing to drug companies as an untested potential heart treatment or impotence pill.

I'm not sure I completely believe this -- one in nine drugs in phase-1 trials eventually make it to market? -- but it's encouraging. The rest of the article is interesting as well, and even features a quote from sarcoma celebrity and all-around oncological badass Dr. George Demetri. It's clear that there are highly-motivated and talented individuals (many with business expertise) who can make good things happen faster than they would otherwise, especially for rare conditions that may not have the "market share" to immediately attract pharma dollars. But the emotions involved are intense. Forbes describes prostate-cancer advocates running amok against doctors skeptical about the evidence backing an investigational drug. I get both the advocacy side -- just try to keep me away from something that may work -- and also why some kinds of advocacy absolutely are not helpful to researchers trying to practice good science and good medicine and minimize unintended consequences.

Sarcoma, incidentally, has at least one collaborative group pushing to link researchers at different institutions and secure funding for trials. Though the Sarcoma Alliance for Research through Collaboration was founded by academic researchers, there's at least one seat for a patient-advocacy organization on its board, and they sponsor an array of collaborations, studies and trials.

Banned

The Berkeley Bowl is the greatest supermarket on earth. It's where I learned that cheddar doesn't have to be bright orange and that you could purchase random spiny little chunks of fish to make a delicious broth, steps in a 20-year-plus journey of becoming ever-more engaged by food and cooking. But it's a weird place, as the Los Angeles Times explains:

The produce emporium -- one of the nation's most renowned retailers of exotic fruits and vegetables -- creates its own bad behavior. Kamikaze shoppers crash down crowded aisles without eye contact or apology for fender-benders. So many customers weren't waiting to pay before digging in that management imposed the ultimate deterrent: Those caught sampling without buying will be banned for life -- no reprieves, no excuses. (Not even "I forgot to take my medication.")

Raphael Breines, who was ejected last year for eating on the premises, said he couldn't decide between two types of apricots, so he sampled both. Security stopped him in the parking lot.

"They treated me like a thief," said the 37-year-old park planner, who was photographed and required to sign a no-trespass agreement. "Technically I was stealing, but I wasn't trying to hide anything. I was just deciding which type of apricot to buy."

Breines, a longtime customer, sent an apology letter, asking to be reinstated. His request was denied.

The really great part of this -- and why I go off-topic to link to the piece -- is the fate of John Glionna, the reporter. He has been, you guessed it, banned from the Berkeley Bowl for life.

'Heal me, my darling'

Just because: Ben Harper, covering "Sexual Healing." (Also solo.)

And to make your day: Stevie Wonder doing "Superstition" live on Sesame Street in 1973. (The little kid dancing at the top of the stairs is my hero.)

And hey, to make my day: My little tune-fest this morning (which I've spared you most of), made me think of my rinse-cycled iPod so, with some trepidation, I plugged it in.

It worked!

It will be interesting to see if it holds up -- often, exposure to water leads to corrosion that destroys electronics over time -- but things are looking good for the moment. I didn't do anything much for it except leave alone for a few days and run it briefly through the dryer.

Update: Unsurprisingly but disappointingly, it didn't hold up.

Next time, bring up the weather

Doctors fall short in comforting cancer patients:

Researchers taped 20 exchanges between cancer patients and their oncologists and surgeons at a VA hospital. They found that the docs did provide a bit of empathy, but ignored most instances where patients expressed worry about treatment, sickness and death.

Because, you know, why would a patient want reassurance about treatment, sickness or death?

¡Viva México!

Here's a happy thing from my life: Tuesday was Mexican Independence Day, when our neighbors to the south threw off the shackles of the Latin American rogue state Spain (or so John McCain would call it -- sorry, sorry, couldn't resist). Señor E., L. and myself celebrated with chiles en nogada; poblanos stuffed with picadillo, then topped with a creamy walnut sauce studded with bits of pomegranate. The pepper, sauce and pomegranate deliciously form the red, green and white of the Mexican flag. Although I was feeling quite sick for most that day, I Tylenoled up and felt well enough to gorge myself on the chiles, saffron rice and brownies topped with cajeta, an ultra-rich goat's milk caramel.

Embracing uncertainty

I had a scan yesterday, and the news was good -- mostly. (It would be really nice to have unambiguously positive results from a study, but it's just not in the cards.) My lymph nodes are all the same size, there are no new mets, my disease is technically stable. The pictures and a whole lot of my blood is now being shipped to Ariad, where they will review the information and determine if I am eligible to participate in the deforolimus study. If I get the OK, I'll probably start on the drug or placebo in late September or early October, just after my birthday.

So why don't I feel exultant? Well, I've been wiped out with another mysterious fever for the last couple of days, and in the interlude yesterday between the scan and the doctor's visit, I managed to put my iPod through the wash. (It looks great, but no longer works.) Also, the collapsed lung that had completely healed last month is back in a big way, and it may require intervention at some point. Fortunately, my nightmarish pleurodesis is still somewhat in effect, adhering the lung to the pleura at a couple points, so hopefully the lung won't completely fall down and require immediate action. The scan also revealed several small, hollow cysts on the surface of the lung, which my doctor and the pulmonologist she consulted believe are the source of my collapsed lungs. What's the source of the cysts? We don't know, but some sort of respiratory infection is a possibility. The tiny nodule they found in my last study, incidentally, occupies a piece of real estate that once contained one of these cysts, so they are now more confident that the nodule is not a malignancy. 

As I'm reading this, it's sounding pretty good, so let me try to explain why I'm so anxious. Part of the anxiety is just a learned response; I've gotten a lot of bad news over the last two years. Part of it is the fear of any cancer patient that something is lurking invisibly deep within the body, biding its time, lurking and waiting to rear up and do harm. Part of it is that I know of several epithelioid sarcoma patients who are dealing with pneumothoraces, some with visible lung mets, some without. (Have you had your lungs collapse four or five times in six months? No? Then you can see why I'm not convinced this has nothing to do with the cancer.) 

It comes down to the uncertainty, I guess. One of my mantras throughout this illness has been that we need to learn how to embrace uncertainty, or at least live with it, because the only certainties we're going to get are going to be bad. That's true, but it's a hard way to live. I'm trying, though.

David Foster Wallace

I found out that David Foster Wallace killed himself last night, and the news made me sick. My relatively brief and shallow acquaintance with his writing changed permanently how I see John McCain, right-wing talk radio, the nervous system of a lobster, professional tennis, television commercials, cruise ships, irony, grammar and literary fads. (I wonder what the hell might happen if I ever read his fiction seriously.) Years ago, driving the car, I chanced upon an interview that Wallace did with Michael Silverblatt, and I had to pull over. His erudition, passion and richly timbered voice captivated me. Here's a little bit of Wallace from another interview:

I had a teacher I liked who used to say good fiction’s job was to comfort the disturbed and disturb the comfortable. I guess a big part of serious fiction’s purpose is to give the reader, who like all of us is sort of marooned in her own skull, to give her imaginative access to other selves. Since an ineluctable part of being a human self is suffering, part of what we humans come to art for is an experience of suffering, necessarily a vicarious experience, more like a sort of “generalization” of suffering. Does this make sense? We all suffer alone in the real world; true empathy’s impossible. But if a piece of fiction can allow us imaginatively to identify with a character’s pain, we might then also more easily conceive of others identifying with our own. This is nourishing, redemptive; we become less alone inside. It might just be that simple.

I was also moved by his commencement address at Kenyon College (I'm a fan of the genre), some of which I'll quote below:

And I submit that this is what the real, no bullshit value of your liberal arts education is supposed to be about: how to keep from going through your comfortable, prosperous, respectable adult life dead, unconscious, a slave to your head and to your natural default setting of being uniquely, completely, imperially alone day in and day out. ...

If I weren't so tired and depressed by the whole thing, I'd go on and on. Maybe I will later. In the meantime, you can find links to some of Wallace's journalism here. 

'Survivors' by Errol Morris

Worth watching:

Donne and death

A nurse unexpectedly loses a patient:

What can one do? Go home, love your children, try not to bicker, eat well, walk in the rain, feel the sun on your face and laugh loud and often, as much as possible, and especially at yourself. Because the only antidote to death is not poetry, or drama, or miracle drugs, or a roomful of technical expertise and good intentions. The antidote to death is life.

Shaggy dog story

The dog cancer took from me is shaggy, lovable and weighs 130 pounds. L. will kill me for saying it, but she was a lousy dog by any conventional definition -- but lousy in grand and amusing ways, the kind of bad dog that someone might write a best-selling memoir about.

Her behavior was bad, but her heart was good. She would follow us around the house, lying down with a sigh and a thud when we settled. Her head was heavy and noble, and she would lay it on my feet when I sat on the couch. When she desired petting, she would sidle up in front of someone and present her mighty expanse for a rub, leaning into her human by ever greater degrees, until they staggered back or braced themselves against something solid enough to take the weight, something like an anvil. She was a fierce, if overzealous, protector of her home and family; woe to the UPS man approaching the door or the house cantering down the road. Abby was always ready defend our home against shipments of Amazon books or potentially rabid equines.

Her appetite was ravenous, even if dog food was often too pedestrian for her tastes. Her great size and athletic ability meant that nothing on the counters was safe from her predation; she mastered the trick of setting her feet, rising slowly and silently like some great crane or drawbridge, and snatching a peanut butter jar, baguette or small child from the countertop. With her prize tucked within her capacious jaws, she would drop to the floor with a snap, then stealthily but quickly run to her dog bed, or “office” as I called it, which would at times be littered with plastic wrap, ceramic bowls, even the occasional pilfered chef’s knife. To this day, almost two years since she’s been gone, I still find myself setting my cooking mise en place on top of the refrigerator -- but not on the edge, because Abby could occasionally manage to snare things from the fridgetop. This was a big dog.

It was the refrigerator, ultimately, that proved her undoing in our home. Before I was diagnosed with epithelioid sarcoma, I spent about seven months undergoing a succession of exploratory surgeries and the like while my tumors grew ever-more symptomatic. By the time I was diagnosed with the cancer and began chemotherapy, I had already been staggered by the illness for some time. With my health troubles, and with two kids four and under in the house, Abby wasn’t getting walked and her behavior began to decline precipitously. She finally learned how to open the refrigerator -- a jab of her long nose into the seals. We made a few feeble attempts to stack furniture in front of the door (she moved it out of the way easily), but it was clear that we needed to focus on our kids and my treatment, not on cleaning up the carnage that results when a dog learns to open the door to culinary paradise at will. In one of the most loving things anyone has done for us, a friend drove her nearly 300 miles to a Newfoundland rescue group, which exercised and rehabilitated her and found her a great adoptive home.

Now I find myself increasingly longing for another dog, and resenting the uncertainty that shrouds my present and future. I could walk and groom a dog now -- but what about six months from now? (Hell, two months from now?) What if I get sicker? I can’t summon any logic to support the proposition that getting a dog now makes sense. But I want one anyway.

Cocktail hour

Greg's comment below reminded me of this Wall Street Journal article from last year. It emphasizes childhood tumors, but also features some adult cancer patients who are pursuing a "cocktail" approach to chemotherapy.

Neil Hutchison, 45, isn't a doctor. A defense-contractor recruiter, he's part of a growing underground pushing the edge of medicine to find combinations of anticancer agents to save themselves or loved ones. Many of the medicines Sam takes haven't been tested in clinical trials for his disease. Some are meant for other illnesses; others are still in animal testing for safety and efficacy. But the fact is that Sam, who suffers a rare and often-deadly cancer of the nerves, is otherwise almost certain to die. Hence Mr. Hutchinson's decision, as he puts it, to play "lab rat" with his son.

...

But Mr. Hutchison is pursuing what many researchers believe is the most promising approach for curing or curbing cancer, which killed about 565,000 people in the U.S. last year. Because cancer seems to eventually overcome most individual therapies, researchers for a decade have advocated using combinations of new, targeted therapies on the theory that the best hope lies in cutting off all known avenues for the cancer to grow.

Trials of such methods have been slow to gain traction. "Everyone knows the future of cancer treatment lies in cancer cocktails," says David Kessler, dean of the school of medicine at the University of California, San Francisco. Dr. Kessler says the Food and Drug Administration needs to undertake an effort similar to one it did when he was commissioner in the 1990s, when it amended the drug-approval process to speed approval of AIDS-drug combinations. "What's missing today is leadership."

You gotta fight

Sick Guy, Sr. passed on this Steve Lopez column about the importance of second opinions. 

Lopez's sister's oncologist recommended whole-brain radiation after ovarian cancer metastasized, a treatment that has immediate and often severe side-effects. But after the writer described the case to first one, then several, experts no one thought whole-brain radiation was indicated. Lopez's sister got a workup and formal second opinion at a top facility, which recommended more targeted "gamma knife" radiation. Whole-brain radiation was barely considered. Whether out of misplaced personal pride, the limitations of your health plan, or the limitations of in-network facilities (which in this case did not include a gamma knife facility), docs don't always make the right call.

Of course, this story suffers from the Teddy Kennedy problem -- how am I going to get several experts on the phone if I'm not a senator or Pulitzer Prize-winner? You probably aren't. But supportive communities like the Sarcoma Alliance bulletin board offer access to quite a bit of knowledge, and most insurance companies and doctors will support at least one formal second opinion.

Rethinking the war on cancer

One of the many disconcerting things about getting cancer -- or having a friend or loved one get it -- is the sudden undermining of your sense of progress. (Literally: I tend to think of "progress" as a good thing, and during one of my early doctor's visit I was pleased when the fellow said something about progress after a CT scan. She meant, of course, that my disease was advancing.) For all the new understanding of the genome, the new smart drugs, the new collaborative research centers and the advances in basic biology made every day, the outlook for many people with metastatic cancer isn't appreciably better than it was 30 years ago. 

In an excellent, if depressing article, Newsweek tries to offer a bracing corrective to the usual puff coverage of new advances, drugs and, er, progress. The idea isn't so much to knock down hope as it it is to suggest that we need a change in how cancer research is approached and funded. The article is here.

A corrective:

She has seen real progress in her 19 years in practice, but the upbeat focus on cancer survivors, cancer breakthroughs and miracle drugs bothers her. "The metaphor of fighting cancer implies the possibility of winning," she said after seeing the last of that day's patients one afternoon. "But some people are just not going to be cured. We've made tremendous strides against some cancers, but on others we're stuck, and even our successes buy some people only a little more time before they die of cancer anyway." She pauses, musing on how the uplifting stories and statistics—death rates from female breast cancer have fallen steadily since 1990; fecal occult blood testing and colonoscopy have helped avert some 80,000 deaths from colorectal cancer since 1990—can send the wrong message.

And some precedent for possible new approaches...

At the same time that molecular biologists were taking the glamorous, "look for the cool molecular pathway," cojones-fueled approach to seeking a cure, pediatric oncologists took a different path. Pediatric cancer had long been a death sentence: in Farber's day, children with leukemia rarely survived more than three months. (President Bush's sister Robin died of the disease in 1953; she was 3.) Fast-forward to 2008: 80 percent of children with cancer survive well into adulthood.

To achieve that success, pediatric oncologists collaborated to such a degree that at times 80 percent of the children with a particular cancer were enrolled in a clinical trial testing a new therapy. In adults, it has long been less than 1 percent. The researchers focused hardly at all on discovering new molecular pathways and new drugs. Instead, they threw everything into the existing medicine chest at the problem, tinkering with drug doses and combinations and sequencing and timing. "We were learning how to better use the drugs we had," says pediatric oncologist Lisa Diller of Dana-Farber Cancer Institute and Children's Hospital Boston. By 1994, combinations of four drugs kept 75 percent of childhood leukemia patients—and 95 percent of those enrolled in a study—cancer-free. Childhood brain cancer has been harder to tame, but while 10 percent of kids survived it in the 1970s, today 45 percent do—a greater improvement than in most adult cancers. (To be sure, some scientists who work on adult cancers are sick of hearing about the noble cooperation of their pediatric colleagues. Childhood cancers, especially leukemias, are simpler cancers, they say, often characterized by a single mutation, and that's why the cure rate has soared. Neutral observers say it's a little of both: pediatric-cancer scientists really did approach the problem in a novel, practical way, but their enemy is less wily than most adult cancers.)

ES Facebook group launched

I mention this mainly for completeness, since I'm not myself a Facebook member, but someone has launched a "causes" page for epitheloid sarcoma on the social-networking site. The gateway is here. It seems like a worthy venture, but one line from the page gave me pause. Caroline, the page owner, writes, "It is proven that it does not respond to chemotherapy." 

This is verifiably false; this paper doesn't quite get to core of the issue, since it's in vitro, but it shows that ES cells are killed by paclitaxel, aka Taxol (the standard second-line treatment for ES, and many other sarcomas, is now a combination of gemcitabine and docetaxel, another taxane). It is true that ES is highly chemo resistant, and it may be true that chemotherapy does not have a proven overall survival benefit for ES. The jury is still out, unfortunately. But based on my response to chemo and the anecdotal accounts of others, I'm convinced that at the very least chemo can increase progression free survival. I'm puzzled as to why more than a few people dealing with ES want to say that chemo is useless. The situation is bad enough -- let's not make it any worse with overly sweeping statements about the disease's drug resistance.

Studying loss

An arresting (but difficult to read) article from the Los Angeles Times about a college course in which students visit autopsy rooms, hospices and convicted murders to learn about death and loss. College students study death to learn the meaning of life:

For the last decade, Bowe has led her classes of 30 students into the refrigerated tombs of bodies stacked bunk-bed-style in the morgue and into hospice bedrooms, glowing from television screens, occupied by the sickly and soon-to-die. She guides them through the barbed-wire fences of Northern New Jersey State Penitentiary, past the outdoor recreation kennels where gang members sweat and swear, to a law library where they sit down with murderers.

Her students are from suburban small towns and inner cities. They enroll in Bowe's class because they are curious about her unusual field trips. But something more powerful also draws them here: a need to know how we die, and why. What happens to our bodies, and is there such a thing as the soul?