Penn surgeon makes headway against a rare lung cancer

During a grueling operation early last year, when the intractable five-pound tumor seemed to mock his skills, thoracic surgeon Joseph S. Friedberg felt buoyed by what he and his scrub-suited crew had already achieved.

The University of Pennsylvania team battles pleural mesothelioma, a rare, ferocious, incurable type of lung cancer.

Typically, patients die within a year of diagnosis. Yet more than two years after treatment at Penn, 27 out of 38 patients - 71 percent - were still alive, including four who had marked five years. These were advanced-stage cases, ostensibly hopeless, and they were defying the odds.

Friedberg, who was about to submit a study on those results for publication, knew there would be skepticism. The number of patients was small. And the treatment was almost as formidable as the disease. He spent up to 14 hours stripping out the cancer while preserving the patient's lung; then residual malignant cells were zapped with laser light therapy.

He was disappointed, but not surprised, when the Annals of Thoracic Surgery demurred at publishing the study. "The reviewers said the follow-up time was too short and we were overestimating" the projected survival time, he recalled.

The only way to address that concern was to let more time elapse.

Last month, with a fuller picture, the journal published the results, which are impressive.

This story is about those results, and how the 25 members of Penn's pleural and mesothelioma program are making remarkable progress against a dreadful disease.

It's also about the heartbreaking inadequacy of that progress.

"I don't particularly consider it a victory," said Friedberg, co-director of the program. " 'Good' for me would be 10 years. Every time these patients' cancer recurs, it kills me."

Pleural mesothelioma is caused by exposure to asbestos, a once-ubiquitous building material. Decades after exposure, renegade cells arise in the mesothelium, a cellophane-thin membrane that lines the chest cavity, lungs, heart, and diaphragm.

By the time the classic symptom of breathlessness shows up, the cancer usually has a stranglehold, invading all surfaces and organs in the cavity.

Conventional treatments - chemotherapy, radiation, and surgery - have dismal outcomes. In the pivotal study of the only chemotherapy specifically approved for mesothelioma, 60 percent of patients did not respond. For the rest, it extended median survival just 13 weeks, to 12.1 months.

Mesothelioma has become a big specialty for liability lawyers, but with 3,000 new cases a year in the United States, it is hardly a hot research field.

Nonetheless, for more than two decades, Penn scientists have been doggedly pursuing innovations. They are combining conventional treatments with gene therapy, T-cell therapy, and the laser technology, called photodynamic therapy.

Patients come thousands of miles to Penn after exploring their options - or lack thereof.

William J. McQueen, 63, an ear-nose-and-throat doctor from San Antonio, Texas, is one of them. Because his cancer encased one lung - the typical pattern - and because he was in good overall health, specialists at several top hospitals recommended an "extrapleural pneumonectomy."

The harrowing surgery involves removing the lung, the lining of the chest, the heart's sac, and the diaphragm muscle, which controls breathing, then reconstructing certain tissues with high-tech fabric.

Up to 10 percent of pneumonectomy patients die of complications. The rest die of the cancer, which invariably comes roaring back, typically within months.

McQueen asked about preserving his lung but was told that would depend on the extent of his cancer - something that would be assessed on the operating table.

"I got the impression they would not take the time to strip the tumor out," he said. "They'd go in and take the lung out. That's what most surgeons do."

That's what Friedberg used to do.

Theoretically, taking the lung left minimal cancer for conventional therapies to mop up, thus lowering the chance of relapse. In reality, he could see it didn't work. It was like uprooting a garden to get rid of weeds, only to have the weeds grow back worse than ever.

In the late 1990s, Friedberg teamed with Penn radiation oncologist Stephen Hahn, an expert in photodynamic therapy, to try it for mesothelioma.

It requires injecting the patient with a drug, a photosensitizer, that makes cancer cells ultra-sensitive to visible light. When the drug is exposed to red light, it sets off a chemical reaction that destroys the cells, damages blood vessels that feed the tumor, and activates the immune system.

The cell-killing effect only works near the surface, because red light penetrates only half an inch or less.

Regulators have approved photodynamic therapy for several cancers, but evidence that it works for mesothelioma is mixed. In the most rigorous study, published in 1997, it did not improve survival or time to recurrence.

But surgeons in that study were allowed to leave a thin layer of tumor - too much, Friedberg speculated, for the laser light to reliably penetrate.

Still, he knew that even if he cut out every speck of detectable tumor, preserving the lung would leave behind more microscopic disease than removing the organ would. So beginning in 2004, the team performed a modified pneumonectomy - removing the lung but preserving the heart sac and the diaphragm - followed by the light therapy.

Then came a patient in her 80s. Taking her lung would be too risky, agreed the physicians - Friedberg, Hahn, Daniel Sterman, Keith Cengel, and Steven Albelda.

To their shock, she was back on the golf course not many months after Friedberg preserved her lung. So he preserved the next patient's lung. And the next. With perseverance and ingenuity, he found he could save the lung no matter the extent of the tumor.

By 2008, it was clear the lung-sparing strategy was superior. The 14 patients whose lungs were removed had a median survival of only 8.4 months. But most of the 14 who kept their lungs were alive after more than two years - at least twice as long as other studies had reported for such advanced disease.

Though those with two lungs were physically better able to cope with a relapse, Friedberg believed the light therapy was playing a big role, somehow priming the immune system to keep resurgent cancer under control. "The cancer comes back more like a house cat than a tiger," he said.

To try to prove it, the team decided to treat 24 more patients - 38 in all.

On April 19, 2011, Bill McQueen was rolled into the operating suite, a three-ring medical circus of physicians, nurses, anesthetists, laser physicists, and technicians.

Some of the photosensitizer, given intravenously two days in advance, had migrated into his healthy cells, as expected. To protect them from burning, the team covered the operating room lamps with protective filters, sewed blue surgical towels to the edges of his skin incision, and clipped the oxygen monitor to a different finger every 15 minutes. Even the tiny red light in that device could activate the sensitizer and burn his nail bed.

Friedberg spent 111/2 hours cutting out the cancer. Though it had not penetrated into the airways of the lung - it typically does not - it formed a thick, reddish rind around the organ, and mottled the chest cavity with nodules and plaques.

The volume of McQueen's cancer, about a pint, was comparatively small. Some patients have a quart or two.

But Friedberg also had to remove a rib, two nerves, parts of the diaphragm and heart sac, and lymph nodes.

The thing that best prepared him for the arduous marathons, said the lanky 53-year-old, was being on the crew team at Penn.

"You just keep going no matter how much it hurts or how tired you are. You just have to make the commitment that you're not going to fail [patients] that way."

After the cancer was out, Friedberg sewed seven light detectors in strategic locations in McQueen's chest cavity. These were connected to a computerized "dosimetry" system, enabling real-time calculations of the laser light dosage. Too little and the chemical reaction would not kill the cancer. Too much and a vital organ could be perforated, causing a fatal hemorrhage.

Next, radiation oncologist Keith Cengel took over, looking a bit sinister in black goggles and protective garb.

He poured a warmed liquid containing fat particles into McQueen's chest while moving a fiber-optic laser around the cavity. The fat particles reflected the light, dispersing it into the recesses of the chest - and creating an eerie red glow that made McQueen's torso seem like a magic cauldron.

Despite the care and precision, McQueen had complications. Lymphatic fluid leaked from a thoracic duct, requiring eight more hours of surgery the next day. A small stroke temporarily impaired his vision.

"But I came through it," he said.

Indeed, within four weeks, he was playing the tourist, wandering Reading Terminal Market with his wife, Karen.

In the harsh calculus of cancer, "median survival" - the point at which half the patients are still alive - is a crucial number.

The median survival for the 38 patients Friedberg's team treated from 2004 through 2010 was 31.7 months - more than 21/2 years - even though the cancer came back in a median time of 9.6 months.

That's a windfall of birthdays, holidays, time with loved ones.

The researchers still can't say for sure why the treatment combination failed to delay the return of cancer, yet made it "less imminently lethal."

Friedman points to the well-documented immune effects of photodynamic therapy. Debris from dead cancer cells signals the immune system to send scavenger cells to clean up the mess.

He believes that may act like a vaccine, preparing the immune system to strike when cancer reappears, thus curbing the explosive growth usually seen when mesothelial cancer recurs. The cancer, he says, becomes "more indolent."

Photodynamic therapy pioneer Harvey Pass is not convinced. The New York University thoracic oncologist led several mesothelioma studies that found light therapy didn't help.

"There may be an immune effect, but I don't know about a more indolent form," Pass said. "But I think Joe has the right idea. I think we ought to be saving lungs on these people. The patients are in better shape, and they can get more therapy" to fight relapses.

McQueen is now waging that fight with chemotherapy and, in a few months, radiation. He needs narcotics to manage his pain.

But he recently went hunting with his daughter, and he and his wife will soon fly cross-country for a wedding. "I'm going to do the best I can for as long as I can," he said.

That could be the Penn team's mantra. Researchers are now working to parse the immune effects at a molecular level, to find better photosensitizers, and to develop minimally invasive ways to deliver the laser light energy.

"I'd be happy to turn this into a chronic disease, like diabetes," Friedberg said. "My goal for my career is to make it truly better for these patients. That's what I want to do with the rest of my life."