Saving Orion

Unlike humans, whose hair falls out during chemotherapy, dogs don’t lose their fur. I didn’t learn that when I was training to be an oncologist.

I know it now because my dog has cancer.

My 9-year-old golden retriever Orion, who is undergoing a pioneering cancer treatment at Oregon State University’s College of Veterinary Medicine, still wears his luxuriant fur coat of amber flecked with gray. His oncologist, Dr. Stuart Helfand, is designing a treatment unique to Orion’s particular cancer by growing the dog’s own cells in a laboratory and using them to test the effectiveness of various therapies. Orion may be the first canine with cancer ever to receive this type of “personalized medicine.”

“Mayo Clinic for Dogs”

Before he got sick, Orion often jogged with me. Several days after one of our regular runs, I found him collapsed on the living-room floor. We rushed him to our hometown vet, Dr. Robert Franklin. After hearing a muffled thumping through his stethoscope and then taking an ultrasound of Orion’s heart, Dr. Franklin told us that Orion had cardiac tamponade, a life-threatening accumulation of fluid inside the sac that encloses the heart. When fluid accumulates, the sac acts like a balloon. The pressure builds up, compressing the heart. Eventually, it can no longer pump blood, as in Orion’s case.

Dr. Franklin placed a needle into Orion’s chest and drained a liter of fluid, a risky but life-saving procedure. Orion’s heart resumed beating vigorously, and within minutes he was back on all fours, heading straight for the door.

Orion, it turned out, has hemangiosarcoma, a devastating cancer that arises from the lining of blood vessels. Because of their vascular location, the tumor cells are perfectly poised to spread easily and extensively throughout the body. Capricious tumor cells are swept into the bloodstream and carried to distant locations, in Orion’s case forming a large tumor inside his heart. His prognosis was particularly poor because of the size and location of the tumor, which would continue leaking fluid around his heart.

Knowing the cherished place Orion holds in our family, Dr. Franklin advised us to take him to OSU. In less than an hour, we had an appointment for the next day. Even with my connections as a physician, I would be hard-pressed to arrange appointments for an internist, cardiologist, oncologist, and surgeon along with a few diagnostic procedures, all in the space of a single afternoon on less than 24 hours’ notice.

My husband and I, along with our two children and our 12-year-old golden, Woof, accompanied Orion to the Lois Bates Acheson Veterinary Teaching Hospital. What we found was an unparalleled, state-of-the-art facility equipped with high-tech instruments and staffed by an impressive, multidisciplinary team of board-certified specialists. “OSU is like the Mayo Clinic for dogs,” I’ve been telling my friends ever since.

After examining Orion, OSU surgeon Dr. Milan Milovancev said, “I might be able to remove the tumor from his heart.” He described a high-risk procedure for a patient of any species. It would not cure Orion, but it would solve his most urgent problem. He might not survive the surgery, but without it, he would not survive at all. This was our reasoning as we made our heart-wrenching decision and departure from the hospital, leaving Orion behind looking at us with confused but trusting eyes.

Pate and Biscuits

The following morning, Dr. Milovancev skillfully and successfully removed the tumor from Orion’s heart. With a boost from a blood transfusion, Orion sailed through this remarkable surgery. Recognizing the importance of family, his doctors invited us to visit the next day. With unpleasant mental images of the intensive care units (ICUs) I’m all too familiar with, I was surprised when my daughter and I were ushered out to a lush lawn beside the hospital. A frail and surgically shaved Orion appeared, flanked by two of his doctors. He walked tentatively but with a definite tail wag when he saw us.

The four of us lounged in the grass, hand-feeding Orion doggy pate served up on his favorite biscuit as exotic aromas from the nearby large-animal facility wafted by. Dr. Krystal Claybrook, the oncology intern, described Orion as periodically restless and anxious in his ICU cage. “He calms down after I climb in with him and pet him for a while,” she added, as if this were a routine physician practice. Perhaps it is in this place where everyone emanates kindness. She reminds me of the power of personal touch, and I am grateful for her willingness to provide it to Orion. (It served, too, as a refresher course on bedside manner.)

“You can pick him up in the morning,” the student announced as we prepared to leave. I stared at her in disbelief. Could Orion really be discharged 48 hours after major heart surgery? “He’ll do better at home,” the student explained. And he did. Within a week, he was already eying the squirrels.

Smart Drugs

Despite the successful surgery, Orion’s squirrel-chasing days are limited. Hemangiosarcoma is a virtual death sentence for dogs, and Orion’s cancer has already spread. Surgery followed by chemotherapy can prolong life, but only by months. It is typically treated with doxorubicin, an old chemotherapy drug with no new tricks.

Enter Stuart Helfand, professor of veterinary oncology at OSU, who has devoted most of his professional life to fighting canine hemangiosarcoma. This man brings so much energy to the battle, you get the feeling he just might eventually win. Dr. Helfand has identified an Achilles heel of these cancer cells and is looking for a lethal therapeutic arrow.

Normal healthy cells contain intricate networks of tightly regulated pathways that carry the messages which control how fast cells grow and divide. The signaling pathways inside a single cell are more complex than a modern computer microprocessor integrated circuit. Tyrosine kinases are the gatekeepers that regulate the flow of signals and trigger activation of the cell. In cancer cells, this circuitry is “turned on” permanently, resulting in uncontrolled tumor growth and spreading.

Tyrosine kinase inhibitors, or “TKIs,” are a new class of “smart drugs” targeted at the cancer-causing defect. Like modern military weapons, they are designed with precision guidance. Because they are aimed directly at the deranged circuits, they kill cancer cells while sparing their healthy counterparts. In contrast to conventional chemotherapy, which kills all dividing cells indiscriminately, TKIs are selectively lethal with less collateral damage. The difference between drugs like doxorubicin and TKIs is like the difference between a carpet-bombing and a satellite guided missile that uses stealth to take out a target with surgical precision.

Bench to Bedside

Dr. Brian Druker, now director of the Knight Cancer Center at Oregon Health & Science University, developed the first TKI, imatinib (Gleevec). By targeting the defective tyrosine kinase driving the uncontrolled proliferation of leukemic cells, imatinib has revolutionized the treatment of chronic myelogenous leukemia (CML)

Fast-forward 10 years through the development of new and more potent TKIs. Dr. Helfand’s lab has shown that these drugs are active against canine hemangiosarcoma cells, which are also driven by malfunctioning tyrosine kinase-controlled circuitry. Several of these drugs are now available for veterinary use. Unfortunately, the most promising TKI, dasatinib, is not.

“I feel a moral obligation to try to do a better job for each new hemangiosarcoma patient I see,” Dr. Helfand says. As a test of his conviction, he proposes treating Orion with dasatinib, showering me with research data identifying this as the most effective TKI. The evidence is compelling, and he makes a strong case for translational research, the fashionable term used when research results are fast-tracked from the bench to the beside for use in patients. Dr. Helfand took a generous chunk of Orion’s tumor at the time of surgery and cultivated his tumor cells (now named “OR-HSA”) in his lab for further investigation. “Orion’s cells are now growing with unbounded fury,” he announces, information I digest with mixed emotions as I envision similar reckless behavior inside Orion’s body.

Over the next week, he tests Orion’s tumor cells against four different TKI’s and confirms they are exquisitely sensitive to dasatinib. Researchers call this individualized selection of therapy “personalized medicine,” and Orion may be the first canine patient to receive it. This novel strategy not only targets a drug selectively to the specific cancer-causing defect, but also delivers the right therapy to the right patient most likely to benefit.

However, there are a few practical considerations: Dasatinib has never been used as a treatment for dogs. Since it is approved for people, I could prescribe it, to the tune of about $6,000 for a one-month supply — a prohibitive cost for most families without pet insurance. There is also no published information defining a safe and effective canine dose. In Orion’s case, translational research and personalized medicine carry substantial risks.

Ironically, I was an oncology fellow working in Dr. Druker’s lab when imatinib was initially tested on animal and human tumor cells. It was exhilarating to watch this drug make the giant leap from the lab to the first clinical trial in patients with CML. I now find myself on the cutting edge of veterinary oncology asking Dr. Druker’s advice on a source and dose of an imatinib offspring. We call this a “curbside,” a term that probably has different connotations for Orion. It’s “doctor speak” for an informal consultation or picking of a colleague’s brain, in this case an internationally recognized expert who is willing to advise me about my dog.

Pills in Meatballs

Time is of the essence. Appeals to the manufacturer for “compassionate use” (free drugs) are fraught with bureaucratic delays, especially a request for a dog. Fortunately, Dr. Druker has other inspired ideas and over the next several days, his sympathetic colleagues uncover several sources of the drug. A few hours after Orion’s story is posted on a CML patient discussion website, a woman in Minnesota offers to donate a stash of unneeded drugs in her closet. She finds time to package them up between trips to another state where she is also in a clinical trial of a new TKI.  The next day a veterinarian in Florida offers to send her partner’s leftover drugs. A self-described stargazer who “just loves that big bright guy and his dog in the sky,” she finds cosmic satisfaction in donating drugs to his astronomical namesake. Meanwhile, my OHSU colleagues also find some local dasatinib leftovers to tide us over. A pharmacist friend cuts the pills into guesstimated doggy-size doses and hand-delivers them to an unsuspecting Orion. Within three days, I have drugs in hand and an ample supply on the way.

“I’m amazed how things are coming together for Orion,” remarks Dr. Helfand when I tell him about the bounty. Scrounging up free drugs was a coup, but giving them to Orion is another story.   “I have no idea what dose to give a canine patient,” he admits. Research dogs are often used to determine the doses that cause toxicity during drug development. Obtaining this information from the pharmaceutical company, however, is harder than procuring national security secrets from the CIA. As a clinical investigator, Dr. Druker has privileged access but discovers that dog data are disappointingly sparse.

Dr. Helfand opts for the low-dose conservative approach, “because we need to crawl before we can run.” In the end, giving him dasatinib is a leap of faith for all of us. Orion makes canine medical history as he unceremoniously wolfs down half of a donated pill in a Purina One meatball.

Determining an effective but tolerable dose remains a challenge. Doses and side effects are usually established by a series of clinical trials over several years, an investigational luxury not afforded many dogs. Despite his impressive research track record, Dr. Helfand will tell you his job “is always about quality of life,” and he means it. We exchange a flurry of emails and phone calls while we try a variety of remedies for the drug’s assault on Orion’s gut. He is on call for Orion 24/7, ready to discuss everything from the quality of his poop to the quantity of his pep. True to his word, he remains as committed to maintaining the quality of Orion’s life as he is to prolonging it. En route from Corvallis to the airport, Dr. Helfand cheerfully makes a detour from I-5 to hand off a bag of a new medicine to add to his anti-nausea arsenal. A compassionate doggy drug deal goes down in a Starbucks parking lot.

Chemo Cocktail

Orion also receives doxorubicin, a drug that is delivered directly into a vein. Dasatinib may weaken his tumor cells, making them more vulnerable to the next doxorubicin carpet bombing. Dr. Helfand’s work suggests this combination chemotherapy cocktail might achieve an overall greater tumor cell kill.

So once every three weeks Orion returns to the teaching hospital for an intravenous blast of old-fashioned chemotherapy. He snoozes during the drive, but wakes up when we exit from I-5, probably already smelling the alcohol-and-disinfectant odor of the hospital. He knows exactly where we’re going, yet trots willingly from the car toward the hospital. “Orion’s here!” calls out the receptionist before we’re even through the front door. In my hospital, hollering a cancer patient’s name in the front lobby would violate a multitude of HIPPA (Health Information & Privacy Protection Act) regulations. Here, it’s just plain friendly, and Orion’s tail wags with the rhythm of a metronome when he hears his name.

Now a seasoned patient, he’s a willing examinee for a team of students and vets at various levels, tolerating indignities as egregious as a rectal thermometer. He enjoys being hoisted up on the slippery stainless-steel examining table for an ultrasound about as much as I enjoy root canals. But he knows that no one can resist a golden and everyone treats him kindly. Goldens, if nothing else, are opportunists, and he enjoys the extra attention even more than the cookies.

So much to do, so little time. Even on chemo day, Orion is still the dog who thinks cats were created for the single purpose of high-speed chases. He races off in hot pursuit of the neighbor’s cat and returns looking triumphant, having re-established his rank and authority in the neighborhood.  This is “quality of life,” Orion style.

Medical Crosstalk

Dasatinib is not a magic bullet, but pioneering its use in a dog with hemangiosarcoma is a step forward in controlling this lethal cancer. Orion’s personal battle has sparked an innovative collaboration among researchers in veterinary and human medicine. A flask of his frozen tumor cells was shipped to the Druker lab early on in his course. Dr. Jeffrey Tyner, an investigator there, tested Orion’s cells against a large panel of TKIs still in early phases of research and development. Although these drugs are not realistic treatment options for Orion, they might be for a dog or person down the road.

Orion’s case illustrates the crosstalk between veterinary and human medicine and the physician-scientists who deliver it. He is the hub of a collaboration united around a crucial common goal: to win the battle against cancer by translating laboratory research into patient care. His crusade is also an unprecedented example of the blending of scientific investigation with unselfish acts of compassion from unexpected sources. The dedication of his oncologist and devoted long-time vet, ongoing support from his enlarging constellation of friends, and the love of his family articulate around him in a rich flow of energy as he takes tough medicine.

Of course, Orion is unaware of this behemoth effort on his behalf and his legacy already in place. His cells may be immortalized, even if he cannot be, perhaps providing the material for groundbreaking discoveries in cancer research. Trotting through the neighborhood still sporting his surgical buzz cut, he is a magnet for curious dog lovers. Orion has taught the neighborhood children that cancer is not contagious — and that you can fight it, live with it and joyfully chase tennis balls during the battle. He has taught my children how to give unconditional love as well as how to receive it, and reminded our family to adhere to Horace’s adage carpe diem.

We don’t know how long Orion will be with us, but he is now, and that is a gift beyond measure. So far, it has been an amazing run with an extraordinary dog.

Jody Kujovich is a hematologist/oncologist at Oregon Health & Science University. Her writing ranges from scholarly articles on her area of specialization, hemostasis (blood clotting), to lunchbox poetry for her children.

Update: On July 4, Orion died after his condition worsened over the weekend. “Even though you know this will come, it is still a shock to go through it. He was such a fighter,” Ken Strothcamp and Judy Kujovich said in an email to Terra.