Chemosurgery goes directly to tumor
New option helps ocular oncology.
The Philadelphia Inquirer
PHILADELPHIA — Emily Sanzone watched her son in his bouncy seat. As Tyler looked toward the ceiling light, there it was again, a whiteness in his right pupil, like a cataract. He looked down, and it disappeared.
It's probably nothing, Emily and her husband, Mike, agreed. The Old Bridge, N.J., couple marveled that their thriving 4-month-old was already wearing clothes for a 9-month-old. Even so, when Emily took Tyler for a routine pediatrician visit, she mentioned the whiteness.
That casual observation would transform her infant into a cancer patient, research subject, and pint-size pioneer in ocular oncology.
Tyler's right eye appeared white because light was reflecting off a tumor. It was growing in his retina, the sensitive membrane at the back of the eye that converts light rays into signals the brain interprets as images.
In early March, he became one of about 300 children diagnosed annually in the United States with a malignancy called retinoblastoma, or RB.
The tumor, tests showed, was the size of a grape, nearly filling Tyler's eyeball. It had forced the retina to peel away from its nourishing support tissue, leaving the eye blind. Untreated, such tumors typically invade the optic nerve and then, with ferocious lethality, the brain.
Fortunately, Tyler's cancer was still confined to the globe, and his left eye was fine. Removing the diseased eye would give him a 98 percent chance of survival, explained ocular oncologist Carol L. Shields, a renowned retinoblastoma expert at Wills Eye Institute and Thomas Jefferson University.
Not many years ago, the discussion would have ended there. Standard therapies — eye radiation or whole-body intravenous chemotherapy — could not save such a "hopeless eye."
But in March, Shields laid out a novel option: squirting chemotherapy directly into the eye through the tiny ophthalmic artery, the only vessel that feeds into the organ. It might save the eyeball so Tyler wouldn't need a prosthesis. It might even restore some vision.
Shields stressed that there were risks. Maneuvering a catheter through the baby's vessels could cause a stroke, hemorrhage, loss of a limb, even death. The chemo might scar the artery, foiling repeated catheterizations. And if three infusions, one a month, didn't kill the cancer, it would all be for nothing.
Tyler's eye would then have to be enucleated. Removed.
In poor countries with little health care, retinoblastoma is usually diagnosed too late. Death rates are 75 percent in some parts of Africa.
In developed countries, early detection is the norm. Because RB is so curable if the cancer is inside the eyeball, survival rates are more than 95 percent. Tyler's white eye, called leukocoria, was the classic warning sign. Parents may first notice it in a flash photograph because the healthy eye appears red — the spooky but normal effect of the flash's reflecting off blood vessels.
With survival almost certain, treatment has evolved to try to salvage eyes and, if possible, vision. This is vital for children with tumors in both eyes. They have the heritable form of RB, so the mutation is in every bodily cell, not just cells in one eye.
At Wills, which treats about half the nation's cases and many from overseas, most eyes wind up being saved, yet deaths due to metastatic RB have been vanishingly rare in recent decades, Shields said.
Still, history has shown that today's RB advance may be tomorrow's anguish.
Eye radiation was long the mainstay of therapy — until it became clear in the 1990s that it could cause secondary cancers in the head and neck.
The next big step was IV chemotherapy. It cured many children but had moderate effectiveness within the eyeball and often had to be followed by laser, heat, or freezing treatments. What's more, pumping toxic chemicals into babies — two-thirds of RB cases are diagnosed by age 2 — left some with hearing loss and a few with leukemia, a deadly blood cancer.
What doctors needed was a way to deliver the power of chemo with the precision of surgery.
— — —
Sitting in the conference room after Shields presented their options, Mike and Emily Sanzone grappled with the implications. Tyler, meanwhile, was so exhausted from being poked and prodded that he had fallen asleep in the arms of Emily's mother, Diana Gabardi of Pottsville.
Married just two years, the Sanzones felt torn.
Mike, 48, an apartment-complex manager with mechanical prowess, was pragmatic and, by nature, a bit pessimistic.
"To me, it was weighing the benefits and risks," he recalled. "Dr. Shields didn't feel enucleation was not the route to go. She said he'd probably be blind in that eye, although he might get back some peripheral vision or shapes. But he could suffer a stroke! And they might have to take the eye out anyway."
Emily, 29, a pharmaceutical sales representative, was the medically savvy one. Tyler's eye was Grade E — the most advanced stage confined to the globe — yet they had a chance to save it. As for life-threatening complications, the 28 children treated by then at Wills had not had any.
"This was cutting-edge medicine," Emily said. "What if ... 10 years later, we find out all these eyes have been saved with this treatment? How could we tell Tyler we didn't at least try?"
Enucleation was an irrevocable choice. It would render Tyler's world two-dimensional. It would mean a lifetime of caring for an artificial eye.
His unusually young age at diagnosis also suggested he had a heritable mutation, putting his healthy eye at risk. But getting genetic test results would take months.
Finally, Emily turned to Shields with the clincher.
"What would you do if it were your son?" Emily asked.
Shields, a mother of seven, said, "I would try the chemo."
— — —
Shields and her equally eminent husband, Jerry A. Shields — also an eye-cancer specialist at Wills and Jefferson — have urged that chemosurgery be studied "slowly and meticulously."
"It might be a long journey" before its true value is known, they wrote last year.
That journey began 15 years ago in Japan, where enucleation may be refused because of social, cultural, and religious factors.
"In much of Asia, when parents are given a choice of removing the cancerous eye or dying with two eyes, they choose two eyes," said David Abramson, chief of ophthalmic oncology at Memorial Sloan-Kettering Cancer Center in New York.
The Japanese method exposes part of the brain as well as the diseased eye to chemo.
Five years ago, Abramson's team pioneered the ultra-selective approach, which he dubbed "chemosurgery."
"It has completely transformed the way we manage the disease," he said. It not only salvages eyes, "but 15 to 30 percent get some sight back because the retina reattaches and regains function."
Chemosurgery is so trailblazing that it's not yet clear which drugs — or which patients — are too risky.
For example, Abramson has used it in many children with RB in both eyes.
Shields disapproves. Treating both eyes subjects the tots to twice as many invasive catheterizations. And because their defect is in every cell, they are predisposed to RB recurrence and to other cancers. Whole-body chemotherapy reduces those risks.
Then again, Shields has pushed the envelope in a way Abramson has not. He recalled treating only two Grade E eyes, while Shields' tally before Tyler was eight.
Four of those eight were saved and got back some vision.
One of the successes is Jeri and Bill Milleman's son Logan, treated two years ago.
"Dr. Shields said there was at best a 50 percent chance that it would work," his mother recalled. "She said if it were her child, she would just enucleate."
The Millemans, who had come from Kechi, Kan., wanted to try one round of chemosurgery before giving up on Logan's eye.
Now 4, he strengthens that eye by wearing a patch on the healthy one for a few hours a day — his "pirate time."
"He went from being blind in that eye to playing baseball and taking bike rides with the patch on," his father said.
— — —
On March 9 at 8 a.m., Tyler lay on the operating room table, dwarfed by machines and eight bustling professionals.
The procedure sounded simple: Jefferson neurosurgeon Pascal Jabbour would worm a tube through Tyler's circulatory system, guided by X-rays on a video monitor.
But the anatomical scale was daunting. A baby's ophthalmic artery is a few hundredths of an inch in diameter — half as big as the average pinhead — and is accessed at a hairpin turn in the internal carotid artery. Until the 1990s, suitable catheters didn't exist.
Although Tyler was big for his four months — 19 pounds and 25 inches — he was one of the smallest, youngest children treated so far.
Marc B. Goldberg, a Jefferson anesthesiologist, gave Tyler a paralyzing drug and taped his head in place.
"Even 1 millimeter of movement will distort" the X-ray images, Goldberg said.
The tracheal tube in Tyler's three-inch windpipe was equally unforgiving; a fraction of an inch of slippage could deprive him of oxygen.
"Fifteen seconds without oxygen, a baby turns blue," Goldberg said.
At 8:45 a.m., Jabbour entered the O.R. He used ultrasound and a keen tool — his index finger — to find the entry point, the femoral artery near Tyler's groin. In adults, it's a half-inch-wide highway to the heart; Tyler's was angel-hair-spaghetti narrow.
Jabbour made an incision and inserted a short hollow sheath, creating a gateway for the first tube, the guide catheter, and its curve-tipped guide wire.
His wrist deftly snaked the tube to the aorta, then through the maze of chest and neck vessels.
In the homestretch near Tyler's eye, Jabbour felt resistance. X-rays showed an odd loop in the carotid. Forcing the guide could puncture it.
Instead, he threaded the microcatheter — the hose for the chemo — up through the guide catheter and then beyond. The tiny tube was floppy and, without the stiffer guide, tough to maneuver.
Finally, Jabbour nosed the microtube tip into the ophthalmic artery and began pulsing the chemo, three-hundredths of an ounce per minute, in synchrony with the contractions of Tyler's heart.
Suddenly, the baby's blood-oxygen level plunged. Overhead monitors tracked the spiral: 98 percent, 85, 73, 71. A bronchospasm was shutting the tiny airways in his lungs.
Goldberg dashed to help nurse anesthetist Joe Thomann take Tyler off the ventilator and administer oxygen. They stabilized him, reinserted the tracheal tube, and sprayed in a drug to soothe his airways.
Crisis averted, chemo resumed. Thirty minutes later, at 11 a.m., it was done.
Jabbour carefully withdrew the tubes, then pressed a gauze pad on Tyler's femoral incision for 45 minutes while a clot formed. It was a mundane task, but he refused to delegate it, knowing a baby's half-liter of blood — one-tenth the adult volume — could be lost in just two of the minutes he was dedicating.
"I'm very protective of my babies," he said.
— — —
At the follow-up exam on March 29, Mike, Emily, and her mother were all smiles. Ultrasound showed Tyler's tumor had shrunk by half.
"Great news," Shields said.
Tyler smiled, too. He had been miserable after chemosurgery — his eyelids swelled, and he wailed in pain despite Tylenol — but by the third day he was his sunny self, laughing as Emily bounced him to "I'm a Little Teapot."
"We're going to swaddle him now," Shields said, snugly wrapping him in a blanket.
Tyler kept smiling — until he felt the metal speculum clamp his eye open.
"This is scary for him, but it doesn't hurt," Shields reassured over his screams.
As she looked into his right eye with an ophthalmoscope, her evaluation, recorded by a nurse, sounded positive: Excellent movement. No swelling. No sign of "ectropion" — the eyelid turning out.
Even a disturbing observation — "a little blood in the vitreous" — sounded innocuous. Blood may have oozed from eye capillaries, or from the shriveling tumor.
But it was not innocuous.
For all the technology at Shields' disposal, her most reliable instruments were her own trained eyes. Because of the blood, she couldn't clearly see the tumor, or tell whether it had sloughed clumps of cells into the vitreous, the clear gel that fills the eyeball.
Removing the bloody gel with microsurgery would risk spreading the cancer. Better to proceed with chemosurgery and hope the blood went away naturally over three to five months.
"We see bleeding in about 10 percent of 1/8chemosurgery3/8 patients," Shields said. "In half of them, it resolves."
The rest, she said, have to be enucleated, just to be safe.
— — —
Three months later, on June 1, the three chemosurgeries were done, but the uncertainty continued.
Shields told the Sanzones that, based on ultrasound, the tumor was "a dead scar." However, Tyler had fresh bleeding in the vitreous.
Four months of close follow-up would tell if he could safely keep his right eye.
Still, Shields said, "there is much to be thankful for."
Tyler was now 7 months old, sprouting adorable curls. The only outward sign of his ordeal, a slight eyelid droop, would likely go away. He could perceive light with the eye, although the retina had not reattached. And his left eye remained fine, suggesting his mutation was a fluke, not heritable.
Shields foresaw "a wonderful, full life" for him.
So did his parents.
"We are humbled and have a deep sense of gratitude as Ty has turned a corner in this journey," Emily emailed relatives, friends, and doctors that night. "He has taught us at a young age to realize that each day is a gift and to live life to the fullest."
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