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School of Medicine
Promise and Progress - CSI Cancer Solving Investigators
CSI Cancer-Solving Investigators, Building the Best GI Cancer Program - Fall 2008-Winter 2009
CSI Cancer Solving Investigators
Date: October 1, 2008
Building the Best GI Cancer Program
Metastatic - it's a word often feared more by patients than cancer itself. It is a word inextricably connected to cancer because it distinguishes a cancer that can be cured from one that cannot.
It means that the cancer has spread, and doctors and patients alike have learned that a cancer that has spread is the most dangerous cancer. It attacks vital tissues and organs,
interferes with normal cell function, and often does not respond to therapy. And, it is a wily opponent. Even to the most skilled surgeon’s eye and pathologist’s microscope, the cancer is undetectable. Researchers have learned, however, that often there are stealth cancer cells that remain,and these micrometastases, as they are called, invisible to the eye and the microscope, travel through the blood stream, lodge in other parts of the body and grow. So while much success has been made treating localized cancers—tumors that have not spread-- advances against metastatic cancers have come much more slowly. Cancers that have spread are still the cancers that kill.
Taking on this uphill battle, however, is a young, darkhaired oncologist who exudes energy. Luis Diaz has a different take on things. He intends to cure metastatic colon cancer. He knows that it won’t be easy, but he already has some promising leads, and more importantly, he is not deterred by naysayers.
“When I walk into patients’ rooms, I don’t think of death,” says Diaz. “I think what am I going to do to cure them? I know it’s difficult, but I’m going to give it a shot,” Quips Diaz, “That’s the kind of defiance you get with youth.”
Whether he is an optimist or realist is up for debate. The truth is that it is probably a little bit of both. Certainly working in his favor is that he is a product of the renowned Ludwig Center for Cancer Genetics and Therapeutics. It is a laboratory started over 20 years ago by Bert Vogelstein, a world-famous cancer researcher widely held as the man who
defined cancer as a genetic disease. Working with other great minds he has brought to his laboratory throughout the years, Vogelstein has mapped the genetic causes of colon cancer, and he has handpicked Diaz to move these laboratory discoveries from mice to humans.
TOUGH CASES REQUIRE INNOVATIVE MEDICINE
Diaz’s focus is on colon cancer patients whose cancer has already spread at the time of diagnosis, patients like Christine Myers and Raymond Nkemanteh.
Myers is a 56-year-old wife and mother of three grown daughters. She waited six months to get approved for an experimental treatment with C. Novyi-NT. At first, it sounds a bit like science fiction because at the center of this treatment developed by Kimmel
Cancer Center researchers is a live, flesh-eating bacteria called Clostridium novyi-NT. However, researchers have taken the teeth out of the bacteria, selecting a strain without a lethal toxin. In animal studies, the reined-in bacteria selectively targeted colon cancer cells and showed no interest in normal cells.
The investigators happened upon the bacteria somewhat serendipitously, borrowing the idea for the therapy from nature itself. When a colon cancer patient became infected,
his doctors noticed the bacteria eating away at the cancer. In a CT scan, they saw that the tumor was disappearing, literally devoured by the bacteria. This was the naturally-occurring variety, however, not the kinder, gentler version the scientists have since engineered. Once doctors began treating the patient with antibiotics to clear up the infection, the bacteria disappeared, and the remaining cancer began to grow. This
patient soon died, but what the physicians learned from him gave rise to the investigative bacterialytic therapy.
The therapy itself is simple to deliver—a single intravenous injection. But because it involves live bacteria, getting to that point is much more complicated. Patients must
be approved by a FDA advisory panel and two internal review boards before they can be treated. In the two years since the clinical trials were approved, Diaz and his research nurse Dana Heslop have only been able to get two patients on the therapy.
Their frustration is palpable as Diaz holds up a DVD of a former patient’s funeral, sent to him by the patient’s family. She died, Heslop says, waiting for the therapy. After, contacting her Congressman, she was approved for compassionate use. However, Heslop says this took six months, lost time that allowed her cancer to grow. Once she finally got approved for therapy, she was too sick to receive it. She died just days after compassionate use approval came through.
These patients have cancers that do not respond to currently available therapies.
“Surgery cannot cure them. Radiation cannot cure them. Chemotherapy cannot cure them,” says Diaz. “This may. The FDA considers it high risk because it uses live bacteria,
but metastatic colon cancer is high risk also. Left alone, it will definitely kill.”
Patients like Myers believe the risks involved when receiving C. Novyi.NT therapy are more acceptable than the risk of not getting it. “Am I nervous, yes. But I gave this a lot of
thought, and I discussed it with my family. I’m going into this with my eyes wide open, and I wanted this therapy. There is nothing else for me.”
Since the trial is currently in the safety or phase I stage where investigators must prove that patients can tolerate the therapy without suffering harmful side effects, they are
required to give patients antibiotics if they develop a fever. As the therapy involves a bacterial infection, reactions such as a fever are anticipated, but the FDA wants to be sure the team can control the bacteria before they will allow treatment without antibiotics or scaled-back use of antibiotics. Diaz, says this will probably mean that it will not significantly benefit patients treated in these early, safety trials because once you
get rid of the of the bacteria with antibiotics, you get rid of the cancer-fighting part of the treatment.
Myers has developed a fever, and now her biggest concern is that the antibiotics she receives will completely get rid of the bacteria that are eating away at her colon cancer. Diaz and Heslop have the same concern.
Diaz also worries that, in current times, there is a tendency to completely err toward safety at the cost of clinical progress.
“There is always a trade off between safety and therapeutic benefit,” he says. “If bone marrow transplantation and heart transplants were just being developed today, we wouldn’t have them. They would never make it through the regulatory agencies.”
Diaz says the current regulatory climate prevents some patients from getting the best care, and he worries that this mindset could have far-reaching effects.
“It is tough to do risky science today, and it is affecting junior faculty and the next generation of researchers and clinicians that will lead us. Pharmaceutical companies see this, and are moving toward ‘gentle’ therapeutics. We have to get brave, because if we don’t, the cost will be in human lives.”
Patients are exasperated and so is Heslop who speaks almost daily with patients waiting to hear whether they have been accepted for treatment. She is a small-framed, calm, and
soft-spoken woman, but she fights like a giant for her patients.
It is not completely clear what is most dangerous to patients, the cancer or the regulatory measures put in place to protect patients.
“The regulatory process, in theory, is good,” says Heslop, “but it has gone too far.” She says it is no longer helpful, and patients like Myers argue that it is actually harmful. As they
wait to receive approval for treatment, their cancer continues to progress.
“On one hand, we have been asked to speed the pace of transferring research results to the bedside, but on the other hand, the pace of clinical trials has been slowed to a crawl
because of regulatory processes,” says Diaz.
Now, in an effort to move things forward, investigators have developed a different kind of animal model to help prove their case to the FDA. They are working with veterinarians,
treating canine sarcoma with C. Novyi-NT and hoping that if they can show they can safely treat dogs, the FDA will give them more leeway in humans.
A BOUTIQUE OF A CLINIC
In the meantime, Diaz is attacking the cancer on other fronts. “We are working more closely with surgeons and radiation oncologists,” Diaz says, “and as a result, cures are coming more and more. In my mind, metastatic colon cancer no longer means death. We can control it.”
His bright outlook on what has been viewed for years as a hopeless cause does not end there. Even the way he describes his colon cancer clinic is uplifting.
“I envision a boutique of sorts,” he says. When patients come to the clinic, while they are waiting to see the doctor, they will meet with a nutritionist, pain specialist, a palliative
care specialist, and other members of the supportive care team.
“All of this will take place before the patient even sets foot in my door,” says Diaz. “More than an hour may pass between when the patient arrives and sits down with the doctor. I want to use this time to allow the patient to take advantage of all of the supportive services we have,” he says. Diaz doesn’t want his patients sitting in the waiting room worrying about the cancer. Rather, he wants them meeting with caregivers that can make their treatment experiences better.
NOT END-OF-LIFE, BUT QUALITY-OF-LIFE CARE
Often, the services he describes occur quietly behind the scenes, but at other times, they become the front line of therapy. Such was the case with Ray Nkemanteh. The 49-year-old was first diagnosed and treated for colon cancer in 2004 at a community hospital near his home. After a number of surgeries and failed therapies, he was discharged by his doctor in August 2007 and told there was nothing more they could do “They were sending him home to die,” said his wife Thecla.
But she wasn’t having it, and the next morning she drove him to the emergency room at The Johns Hopkins Hospital.
He was near death, suffering from many complications, including sepsis and severe dehydration. He was admitted to the Kimmel Cancer Center, but doctors could not treat his cancer because he was so sick.
Nkemanteh was not ready to give up. He had four daughters at home and a mother in Cameroon who was not even aware he was ill. Diaz came to see him the next day. He saw a spark, and issued a challenge. He told Nkemanteh, “If you can walk into my office, I’ll treat you.”
To get him to that point, staff at the Harry J. Duffey Family Pain and Palliative Care Program joined forces with the medical team. While the term palliative care has become
associated with end-of-life care, nurse coordinator Lynn Billing says it is really about helping patients feel better— physically, spiritually, and emotionally and to live well with
their cancer. This is how they intended to help Nkemanteh.
“Ray had a lot of problems causing many symptoms—an intestinal blockage, sepsis, nausea and vomiting, severe pain, and intractable hiccups,” says Billing. He wanted to get
chemotherapy, but he could not be treated unless these symptoms could be managed.
And, manage them they did. The team, including nurses, physicians, nutritionists, a pharmacist, a social worker, and a chaplain attacked what seemed like insurmountable obstacles to take this patient from the brink of death to the clinic for therapy. It took nearly a month and treatment with three to four different antibiotics, several procedures and medication to manage the intestinal blockage, acupressure for his persistent hiccups, and a pain management plan, but Nkemanteh walked into Diaz’s clinic on day 28 and began treatment for his colon cancer.
The team’s social worker Donald List spent hours with Nkemanteh and his wife discussing their concerns, fears, and goals. During this, time, List and the medical team were able to get his mother from Cameroon to be with her son.
With his mother and daughters with them, Father Paul Sparklin blessed Raymond and Thecla as they renewed their wedding vows.
“Sometimes we can’t change the outcome,” says palliative care nurse Colleen Apostol. “This time we could.” Their goal was to meet his goal, and that was to get well enough to
The team struggles with the misperceptions about palliative care. Many patients have misguided ideas about pain and palliative care, misconstruing their involvement to mean the doctors have given up, and they’re going to die. In fact, Billing says, it isn’t palliative care that takes away hope, but rather the debilitating symptoms that patients endure.
“Palliative care is not about how you die. It’s about how you live,” she says. Diaz believes so strongly in the new medical subspecialty, only recognized in 2006, that he has incorporated it into his clinic. Not every patient will need the amount of care that
Nkemanteh required, but he wants all patients to be able to take advantage of the services they offer.
Diaz is now treating Nkemanteh with an aggressive weekly chemotherapy regimen, instead of the standard two-week cycles. His cancer is not cured, and he may never be cured.
He understands that, but for now, his cancer is under control, an almost unbelievable change from where he was a year ago.
“I appreciate that Dr. Diaz and his team was willing to try. Not everything has worked, but they have always been willing to try. I am so grateful to be alive, and I know I am alive today because of them. I think every hospital should follow this example. They are my heroes,” says Nkemanteh. “We thought he was going to die, and here he is,” adds Thecla. “Our community, our friends, our family cannot believe it.
Everyone is amazed.” To Diaz, this is nothing more than what should be expected at a place like Johns Hopkins. He understands firsthand what it is like to be the patient, and he has used this experience to build his clinic. When he was a resident, Diaz stuck his hand with a syringe. The syringe was filled with blood from a patient with treatment-resistant HIV. He was treated with four different kinds of drugs and every three
months had an HIV test.
“It was the worst experience of my life,” he recalls. “I was constantly looking in my mouth for signs of thrush. With every ache or pain, I was certain that I had HIV.” He did not,
and now more than 10 years has passed, but Diaz remembers what it felt like to be the waiting, wondering patient and believes it has made him a better doctor. “How I felt when I was waiting for my HIV test results is just how my patients are feeling when they are waiting for their CT results and living in fear of those dreaded words ‘your cancer is back or your tumor has grown’.”
A CONCERTED EFFORT
Once patients’ symptoms are managed, Diaz’s plan is to attack these cancers with an intelligent but aggressive approach, integrating surgeons and radiation oncologists and using genetic findings to create better therapies. “We are talking about life and death here. There is basic science information that could make a real difference, and the medical community is ignoring it,” he says.
One example of this is genetic testing for Kras mutations. Diaz says it is widely known that mutations of the Kras gene can predict if patients will respond to drugs known as EGFR
inhibitors. A test for the mutation is already available. Insurance companies even pay for the test, but doctors aren’t using it. “It is as important as a CT scan in the treatment of
colon cancer, but right now, patients are not getting the test,” Diaz says.
Another test checks for an enzyme that causes a terrible reaction to 5FU, a mainstay drug for colon cancer. Patients who have the enzyme, Diaz says, would definitely end up in
the hospital if they got the drug and could potentially even die. Testing for this, they can know in advance which patients would suffer a reaction. Diaz wants genetic analysis for
“This is where Johns Hopkins needs to be, and this is where we are going,” he says. He believes that the secret to why patients’ cancers don’t respond or stop responding to
treatment is revealed in alterations in their tumor’s gene code.
These gene codes are as unique as a fingerprint. While there are several gene mutations that occur widely across all colon cancers, there are far more mutations that occur less often overall but are instrumental in controlling how a tumor behaves. “We used to think there were three or four key mutations in colon cancer, but now we know there are maybe 20key mutations,” says gastroenterologist Francis Giardiello.
“Now that we know the genes, we can figure out the pathways they work through and use them as targets for treatment.”
Historically, cancer treatment has focused on drugs that kill rapidly-reproducing cells—cancerous ones and normal ones. Now Diaz and team are looking at new drugs like
Avastin and Erbitux that appear to work through molecular pathways and shut the tumor down by putting the brakes on the genetic mistakes that cause it and drive it without harming normal cells.
Just as all other body parts and functions have a multiplicity of actions and reactions, so too does colon cancer, Giardiello says therapies that hit just one molecular pathway
or cell activity won’t work because the body has many systems in place that protect key functions and, like other normal cellular mechanisms, cancer has hijacked these protective
properties to act as barriers to therapy.
“There are multiple pathways involved in colon cancer, so we have to target them all and that means using multiple drugs,” says Giardiello.
“Up until 2000, we used one or two drugs to treat colon cancer, with 5FU being the main one. It wasn’t that great, but nobody had a better drug,” says Giardiello. “It is a targeted
drug, so if we use it in combination with other drugs, it could hit more pathways and be more effective.”
Along, these lines, Diaz and leading colon cancer surgeon Michael Choti have developed a blood test that detects genetic mutations found in colon cancer. When cancers
grow, they shed their DNA into the bloodstream. While not all colon cancers can be cured with surgery, it is often the first course of treatment. With their test, which measures levels of known cancer-causing mutations in the blood, Choti and Diaz can tell within 24 hours after surgery if any microscopic cancer was left behind.
“Basically, we count the mutations in the bloodstream,” says Choti. “The more you see, the more likely the cancer is to come back.” It is the cancer doctors can’t see that kills, so
uncovering these hidden cells is key to curing the cancer.
“It is these cells that get into the lungs, liver, and brain and clog normal functions in normal tissue,” says Diaz. He likens it to the viral load in HIV. “We’ve learned that if you
keep the virus in check, it doesn’t kill. We can apply this same approach to cancer.”
Choti says the same test can be used to tell if drug or radiation therapy is working. Typically, physicians rely on imaging, such as CT scans, to see if the tumor is getting smaller.
Choti says, since the scans are not done frequently, as much as two months of therapy could go on before the doctors realize that it’s not working.
“With this blood test, we could potentially know after one week, maybe after one dose, whether therapy is working,” he says.
CURING BY CONTROLLING
Colon cancer is unique among cancers in that patients get what Choti calls controlled metastases. “We can cut out or destroy spots on the liver with such techniques as liver resection and ablation and cure many patients,” he says. This approach is now becoming standard care, and Choti says it’s being expanded to other GI cancers.
“We have more and more data to support surgical therapy for metastases to the liver and the lung,” says Choti. It significantly improves survival.”
A new colon cancer vaccine, monoclonal antibody therapy, radio-immunotherapy, imaging-guided and robot-assisted surgery, and molecular-targeted therapies are all new
approaches to treating advanced colon cancer.
One of the more interesting efforts is being led by Choti and a young surgeon Timothy Pawlik. It is directed at cancers of the liver—ones that originate there and ones that
begin in the colon or other organs and spread to the liver.
The liver is a vital organ that humans cannot live without. Liver transplantation is an option for some patients with primary liver cancer, but not for patients with colon cancer that
has spread to the liver. These patients are often told there is no surgical therapy for them. Not at Johns Hopkins, however, where Choti and Pawlik are doing what others said could not be done. As a result, they are attracting patients from around
One good thing about the liver is that it can regenerate itself. If there are a limited number of tumors in the liver, surgeons can take them out, and the organ rather quickly repairs
itself. “We are helping patients who have tumors that require removing 70 to 80 percent of the liver, a surgery the liver could not recover from without some help,” says Pawlik
Using CTs of the liver tumors and working with radiologists Pawlik determines how much of the liver will have to be removed to get all of the cancer. If it is too much, he turns to
interventional radiologists for a technique called portal vein embolization that actually grows the liver.
The liver has two halves, and each has a portal vein that carries blood and the critical growth factors that give the liver its unique rejuvenation abilities. The interventional radiologist uses embolization to clot and cut off the blood supply to the tumor-filled side of the liver, redirecting the blood supply to the normal side, causing it to grow. It must grow to where it repre-sents 20 percent to 30 percent of the total liver before Pawlik can operate and remove the tumors, which can require him to take out as much as 80 percent of the original liver.
In some instances the same approach is used to treat patients with breast and melanoma skin cancers that have spread to the liver. Among his success stories is an 80-year old
North Carolina man who traveled to Johns Hopkins after being told his metastatic melanoma skin cancer was untreatable.
Pawlik removed the cancer that had spread to the man’s liver, and two years later, the patient remains disease free.
“We are one of the few Centers in the country doing this, so I am seeing more and more patients who have been told they are unresectable because of the type of cancer they have or because of the technical aspects of the surgery,” says Pawlik.
For patients considered by most to be inoperable because they have tumors throughout the entire liver, Pawlik takes a two-step approach. First, he removes all of the cancer from one side of the liver. He waits for the patient to recover and the liver to re-grow, and then he operates again to remove the cancer remaining in the other half of the liver. This procedure has cured some patients who had been told they had no options.
The introduction of new anticancer drugs and surgical approaches over the last 10 to 15 years is beginning to make a real difference in patient outcomes. “Survival rates for
patients with metastatic disease to the liver have doubled,” says Pawlik.
To help patients with primary liver cancers who are not candidates for transplantation and whose cancers are too advanced to be surgically removed, Pawlik has teamed with
radiologist Jeff Geschwind on a new clinical option. It is called TACE for trans arterial chemo embolization. Clinicians insert a catheter through the groin into the femoral
artery and into the blood vessel feeding the tumor so that they can deliver chemotherapy directly into the tumor. Then they clot off, or embolize, the vascular escape route making sure the anticancer drugs stay in the tumor.
“This is such an exciting time in GI cancer,” says Diaz.“There are strategies available now that did not exist even a year ago.”
BUILDING A MODEL CLINIC
As co-directors of the gastrointestinal program, Scott Kern and Elizabeth Jaffee have one main requirement: that is that the clinical programs are as strong as the basic science
research programs. With the depth of the colon cancer and pancreatic cancer laboratory discoveries, this is a tall order but one that both clinics are well on the way to achieving.
On the pancreas side, the clinical push is being driven in large part by the success of a pancreatic cancer vaccine.
The vaccine, spearheaded in the clinic by cancer immunology experts Jaffee and Dan Laheru, turns on the immune system, and leads immune cells, typically blind to cancer, to attack the cancer cells in the pancreas and throughout the body. With pancreatic cancer being one of the deadliest cancers and few treatments making any real difference
in long-term survival, the vaccine discoveries resulted in a barrage of patient inquiries and appointments. Clinic coordinator Barbara Biedrzycki receives more than 60 calls each month and even more e-mails from patients wanting the pancreatic cancer vaccine. When Jaffee and Laheru’s work makes news, the calls increase.
Jaffee and Laheru had to come up with a way to triage patients, getting those who were candidates for the vaccine into trials as quickly as possible, but just as important, getting
the right care for patients who were not candidates.
Joe Herman, a young radiation oncologist envisioned a new type of clinic, in which patients would come to the Kimmel Cancer Center, and after a single day’s visit, receive an integrated plan of treatment. This required getting all of the experts—surgeons, pathologists, gastroenterologists, radiologists, oncologists, radiation oncologists, and more—in one room together one day a week to review patient records and determine the right course of treatment for each.
“I thought this is a great idea and told him to go for it, but we wondered whether he could really pull it off,” says leading pancreatic cancer surgeon Richard Schulick.
It seemed like an impossible feat because the clinic Herman was envisioning involved a team of experts considered the best in their fields. Finding a day that all of them could meet seemed unlikely. Herman succeeded, however, making possible a pancreatic cancer clinic encompassing all specialties and one that could become a model for essentially
every cancer program.
In the early days of cancer care, and even the not too distant past, cancer therapy involved a singular approach. If a tumor could be surgically removed, the patient would be
treated first by a surgeon and then handed off to medical and radiation oncologists for chemotherapy and radiation therapy.
The radiologist would image the tumor and send a report to the oncologist. Each would do his and her part well, but there was no formal concerted effort.The pancreatic cancer clinic is blazing new trails. Cancer clinicians and researchers are learning that cancer therapy transcends the boundaries of medical disciplines and so it is imperative to have all of the key players involved in the plan and execution of therapy from the onset. The idea for the multi-disciplinary clinic is born.
“The department lines have really been blurred here,” says Jaffee. The Kimmel Cancer Center is so invested in a multidisciplinary attack on cancer that it pays the rent of Schulick,a surgeon, Ralph Hruban, a pathologist, and other nononcologists whose laboratories and offices are located in the Center’s cancer research buildings.
“It works because everyone is an equal member, and the proximity makes for easier and greater communication,” says Jaffee.
Every Tuesday at 12:30, the team meets. Sometimes there are heated debates about the course of action, but by the time they all leave the room, they have agreed on a treatment plan.
Patients can be confident that all of the experts played a role in the decision. Also having a seat at the table are research nurses, genetic counselors, social workers, nutritionists, the
pain management team, and others.
“They are getting a first, second, and third opinion all at the same time,” says Schulick. By the time a physician meets with the patient, a CT scan has been done, a fellow or resident
has done a physical examination, and a full history has been taken. In a single day, patients receive a comprehensive evaluation, involving all the resources available for the education,
diagnosis, treatment and research of pancreatic cancer.
With patients traveling from all over the country and the world, the team not only wants to ensure the best and mostadvanced care but efficient care as well. The ultimate goal of the clinic is to seamlessly incorporate all elements of pancreatic cancer care, from detection
through therapy. The National Familial Pancreas Tumor Registry is based at Johns Hopkins. The first of its kind, it was started in 1994, and today more than 3,000 families are registered. With the help of these families, Kern, Hruban, Michael Goggins, and others have been uncovering the molecular genetic causes of pancreatic cancer while registry director Allison Klein has developed a novel computer software tool that helps identify people at risk of developing the disease.
Patients also are helping investigators get to the root causes of this disease through a rapid autopsy program. In this selfless endeavor, those who lose their fight against the disease are allowing investigators to study their tumors, cells, and genes to help save the lives of others. More than 80 rapid autopsie shave already been done, allowing investigators to look for genetic differences in pancreatic cancer. The program helped investigator Christine Iacobuzio-Donohue and team link a gene discovered by Kern to pancreatic cancer metastasis.
Investigator Jim Eshleman has engineered a mouse that grows pancreatic cancer providing some of the groundwork for a massive exploration of the pancreatic cancer genome.
Hruban, Kern, and Eshleman are working with Vogelstein on the Goldman Pancreas Cancer Genome Initiative. It is the largest cancer gene project ever undertaken, involving the sequencing of all 24,000 known genes in a series of 24 pancreatic cancers followed by validating the findings in an additional 96 cancers.
Marcia Canto runs an endoscopy center that helps people with a family history of pancreatic cancer learn if they have treatable precancerous lesions before they develop into cancer.
Sometimes Schulick can remove the precancerous lesions and save the pancreas, but other times patients are faced with a gut-wrenching decision to have their pancreas taken out before it can turn on them. Those who opt for the prophylactic removal of the organ face diabetes and lifetime dependence on insulin, but even that seems like a victory when faced with the alternative: an almost certain battle against lethal pancreatic cancer.
After all, this is better than having no chance to fend off the cancer. That is the position most patients are in when they come to clinic. Having already learned they have pancreatic cancer, they come to the Kimmel Cancer Center clinic to get the best treatment available. Here they will learn if their cancer can be treated with an intensive but potentially curable surgery known as the whipple procedure, or if their cancer cannot be treated with surgery, maybe a combination of chemotherapy and radiation therapy can at least buy them some time. What most want to hear—the reason they came to the Kimmel Cancer Center—is that they are a candidate for the pancreatic cancer vaccine.
About 20 percent of patients will go directly to the OR and be cured after surgery. “Most will need novel therapies”, says Schulick. Other centers are doing the same thing they were doing 20 years ago. Here, we’ve shifted the paradigm.”
They’ve done that by altering the ordered regimen of surgery followed by chemotherapy and radiation therapy. In the newest vaccine study, patients are given the vaccine two weeks before surgery. Jaffee says it gets the immune system juiced up. Even at Johns Hopkins, where surgeons have dropped the surgical death rate to 1 percent to 2 percent, the whipple is still one of the most complicated and difficult procedures to perform. As a result, patients require two months to recuperate, but this lag time without additional therapy gives any remaining microscopic cancer cells time to travel, spreading the cancer.
Laheru say pancreatic cancer is notorious for being in areas outside of the pancreas, and giving the vaccine before surgery may allow them to get ahead of the disease and attack these microscopic renegades before they can take hold.
With promising results from early vaccine studies, including a modest but real improvement in survival time, the investigators continue to tweak the vaccine. One approach they are trying is a chemotherapy-vaccine combo. They alter the tumor’s environment by treating patients with the drug cyclophosphamide before giving them the vaccine. It seems to make the tumor more responsive to the vaccine. Doing this before surgery not only gives them an advance attack on the lethal tumor but also allows them to see what impact the treatment has had when they do operate. The team also has found
that giving radiation therapy sequentially to vaccination, also improves vaccine effectiveness.
“Our philosophy is to attack the disease on all fronts,” says Jaffee. “We want to get the
disease so we are controlling it, not it controlling us.”
More recently, Jaffee and Laheru have begun working with new faculty recruit Dung Le in an approach that combines targeted therapy with vaccine therapy. The protein mesothelin is believed to play a role in causing pancreatic cancers to grow and spread. Hruban’s studies found high levels of the protein on the surface of tumor cells in many patients. The team hopes that shutting down mesothelin will slow the growth of the tumor and give the vaccine more traction.
It is a delicate dance to turn on the immune system and turn off cells standing in the way. The team must activate the immune to system to recognize pancreatic cancer cells, but at
the same time they must suppress cells hijacked by the tumorto protect it from the immune system. Without attacking the cancers many mechanisms, the investigators know that the
vaccine will never be fully effective against the disease.
Yet another attempt to strengthen the vaccine includesanother live bacterium listeria.
“It’s pretty wimpy,” says Schulick. “If you eat bleu cheese dressing, you have been exposed.” In fact, listeria is almost everywhere and resides throughout the GI tract. For most people, it is harmless, and the version the pancreatic cancer team is using is even more so because they have genetically engineered it to remove the nasty genes.
So far, they have treated nine patients with no adverse effects. In two patients whose cancer had not responded to any other therapies, biomarkers indicative of the pancreatic
cancer have declined. And, Jaffee notes, these patients did not even receive the maximum dose of the vaccine.
The team is now looking at whether the vaccine can prevent cancer in high risk patients and if it may help colon cancer patients with liver metastases.
“You almost have to be willing to stake a career on your research,” says Jaffee referring to the vaccine studies she began in 1991. And, that is exactly what she did. To make vaccine therapy a reality, Jaffee became an expert in vaccine manufacturing, opening a GMP facility (good manufacturing processes) at the Kimmel Cancer Center to make the vaccine and learning the huge compendium of FDA regulations.
“We’re in this for the long haul,” says Jaffee. “If it doesn’t work the first time, we don’t give up. And, of course, we can’t overemphasize the importance of our generous donors. It is their support that makes it possible to do this work and to keep trying these
SOMETIMES IT IS ALL ABOUT THE MONEY
While the Kimmel Cancer Center has led the way in successful attacks against the lethal cancer, Jaffee says there is still a lot of ground to cover, and it all comes down to funding.
Pancreatic cancer is one of the most underfunded cancers, according to experts. Because it is relatively rare, it does not attract the attention from the public or the research world that other cancers like prostate, breast, and colon cancers do.
What’s more, pancreatic cancer patients don’t usually survive their disease, so there aren’t enough of them to form activist groups or speak out and demand the attention that’s needed.
“We are so far behind in understanding the biology of this cancer compared to breast or prostate cancer,” Jaffee says.
At the Kimmel Cancer Center, however, we are catching up with the help of philanthropic support. Peter Kovler, Chairman of the Board of the Blum KovlerFoundation, had for some time supported Kern’s research. His mother and grandfather died of pancreatic cancer years ago, so he had a personal interest. After reading an article about the disease in the New York Times, he was struck by how little money was available for pancreatic cancer research.
After meeting with Kern and other leading researchers, he waseven more inspired to take action.“Their expertise was quite impressive,” says Kovler. “Theywere very persuasive about the need and timing for funding,and I believe what Johns Hopkins offers is as good as it getsanywhere in the world.” His goal was to ensure continuity of funding, so his family’s foundation donated $2.5 million to establish the Everett and Marjorie Kovler Professorship in Pancreas Cancer Research. Kern, who is funded through the professorship, says it is the only fully-funded chairfor pancreatic cancer research, a commentary to the money issues facing this cancer.
“It seems to me that the philanthropic community has an obligation to help when there is a good chance for progress,” Kovler says. He calls it venture philanthropy. “Here is an
opportunity for philanthropists to step up and take a leadership role in moving things forward. In this disease, the numbers run against you. Despair is deep, but there is real hope if we invest in the research. This Johns Hopkins team is making great progress.
Maybe success is five years away, or maybe it doesn’t come for 20-30 years, but someone has to do this or we’ll never get there.”
Other champions of the cause include the Goldman family, who have most recently provided lead funding for a pancreatic cancer genome study, the largest gene study
every conducted, and whose earlier gift established the Sol Goldman Pancreas Cancer Research Center.
The Commonwealth Foundation supports both cancer vaccine research and C.Novyi-NT research, and the Lustgarten Foundation, the Skip Viragh Charities and the Viragh Family
Foundation have been major contributors to pancreatic cancer research, patient care and clinical studies.
Just as important to the fight are donors like Russell Weisman. Weisman came up with $100,000 to cover the costs of therapy for a friend whose insurance company had denied
payment. When the insurance company finally came through, instead of taking his money back, Weisman donated it to the Kimmel Cancer Center.
MAKING THE CUT
For GI cancers, the critical role of surgery cannot be overstated. With gastric cancers, it all comes down to the lymph nodes. These bean-size organs of the immune system located throughout the body can be filters for cancer cells, gathering them up and providing the vehicle for them to travel from the main tumor to other tissues and organs. The number of lymph nodes containing cancer can tell if it has just begun to spread or it has already made a complete escape.
The American Society of Clinical Oncology (ASCO) reports, however, that a quarter of surgeons (and many experts believe it is actually as high as one-half) do not take out the
adequate number of lymph nodes during surgery, and as a result, they don’t get an accurate assessment of the cancer and how far it has progressed. Yet data show that the number of lymph nodes removed directly correlates with longer survival, says gastric cancer expert Mark Duncan, so patients suffer when surgeons aren’t aggressive enough.
“It’s simple math,” he says, “I would be more confident that the cancer was not widespread if I found that just two out of 19 lymph nodes were positive for cancer as opposed to two out of nine. Maybe two out of nine was really three out of 21. Or zero
out of six could really be two out of 21. You won’t know unless you take out the right number of lymph nodes,” says Duncan.
Duncan, who performs more than 300 gastric surgeries a year, says patients need to be aware that it does matter where they go to be treated. The ASCO report found that surgeons outside of major medical and academic centers were not even getting lymph nodes adjacent to the stomach.
Johns Hopkins surgeons take an aggressive approach because the current statistics are dismal for the rare cancer. Of the more than 21,000 people diagnosed each year, only
about 25 percent will be cured. The rest—75 percent—will die from the cancer.
Surgery may be the only opportunity to cure the patient because, for now, chemotherapy and radiation have shown minimal benefits. So, Duncan and colleagues take out all
lymph nodes near and around the stomach in an effort to change the direction of these numbers.
“Gastric cancers all behave the same and respond to the same anticancer drugs, so we are looking for better drugs,” he says. Duncan is experimenting with treating patients with
chemotherapy and radiation before surgery. He is also working with epigenetic experts Jim Herman and Stephen Meltzer to better understand the biology of these cancers.
Patients can give an extra tube of blood during their regular blood work so that Herman and Meltzer can explore the DNA for markers of the cancer that could be targets for early detection and treatment.
“It probably won’t lead to a clinical change within the next five years, but it could make a real difference in 10,” says Duncan.
Gastric cancers occur either in the bottom of the stomach or at the top where the stomach joins the esophagus. When the cancer is in the bottom of the stomach, the surgeon removes the tumor and pieces the stomach back together. When the cancer occurs at the junction of the stomach and esophagus, the surgeon removes the esophagus, and pulls the stomach up to create a new one joined directly to the intestine.
Duncan cautions patients to be wary of hospitals that tout minimally invasive gastric surgeries.“The incision for minimally invasive surgery in stomach cancer is just slightly
smaller than the incision for an open procedure,” Duncan says. “So, there really is not much additional benefit to the patient. The goal should be safe operation. Surgeons should
not be committed to a minimally-invasive or open procedure.
Sometimes you need a little of both. The key is to do what is best for the patient.”Leading esophageal cancer surgeon Stephen Yang feels the same way about minimally-invasive esophageal operations.
“They don’t really change the hospital stay,” he says.
“It’s about 7-10 days either way.” Yang operates on one to two esophageal cancer patients each week, and his mortality rates, less than 1 percent, are excellent.
However, he says, there is a marketing benefit to community hospitals that attract patients with the idea of smaller incisions and shorter hospital stays. He recalls a community
hospital that widely publicized that it was the first to perform minimally invasive esophageal cancer surgery. What it didn’t report was that the patient ended up at Johns Hopkins with Yang to undergo extensive reconstructive surgery to repair the botched, minimally-invasive attempt. It took Yang five operations to correct the mistakes made in the minimalist approach in which the sole aim was to give the patient a shorter hospital stay and recovery time.
“Don’t be fooled,” Yang warns patients. “Good advertising does not necessarily equal good care.” When it comes to surgery, study after study shows that higher volumes translate to better outcomes, says Yang, who recently participated in another study that found teaching hospitals to be the best place for these surgeries.
That study was prompted by repeated questions from patients concerned about having surgery at a teaching hospital where a resident could be operating. Yang believed that a
teaching hospital was the best place to have surgery, particularly for difficult operations such as those performed to remove cancers, but he wanted to back his hunch with realdata. So, he and a group of Johns Hopkins surgeons crunched the numbers for lung cancer, tracking discharge and death information from different types of hospitals. They found that patients treated at hospitals with residents-in-training have a 17 percent less chance of dying after lung cancer surgery compared with patients having their surgery at non-teaching hospitals.
“It’s like cooking,” Yang says, “I can take a recipe from Emeril and follow it step by step, but it’s probably going to taste better if Emeril makes it. It’s the same with surgery.
There is a lot of complex reconstruction involved in these surgeries, and expertise through volume of surgeries does relate to better outcome. Academic centers do better. The data
prove it. We have excellent surgical results at Johns Hopkins because we have developed expertise. We do these procedures over and over.”
Yang also has received national attention for his willingness to treat older patients turned away by other hospitals and achieving outcomes comparable to those of younger patients.
This proficiency, as well as good supportive care, has translated into the lowest morbidity and mortality rates in Maryland.
His surgical expertise and aggressive approach to cancer surgery have resulted in some of the highest patient volumes in the region for Johns Hopkins, but only about 5 percent to
10 percent will be cured with surgery alone. About 30 percent to 40 percent of patients will need chemotherapy and radiation therapy to shrink their tumors before Yang can even
attempt to cut them out.
Esophageal cancers are not very common, and they are hard to detect. By the time there are symptoms, surgery is often not going to cure them. So, with incidence and death
rates from esophageal cancer almost equal, and with rates increasing among younger people in their 30s and 40s and in women, Yang and a multidisciplinary team of esophageal cancer experts that includes Arlene Forastiere, Ros Juergens, and
Larry Kleinberg are eager to bring new ideas to the clinic.
The team is working with surgeon Malcolm Brock and cancer biologist Jim Herman on a test that can predict a patient’s response to anticancer drugs, known as taxanes.
Taxanes work by stopping cancers cells ability to divide and grow. In a study of esophageal tumor specimens, Brock and Herman found that a particular gene was affected by a cellular function known as methylation. The methylation of the gene translated to greater sensitivity to taxanes and, as a result, improved survival.
“Methylation of this gene,” says Forastiere, “is a major indicator of long-term survival, actually doubling survival time.”
Patients get chemotherapy and radiation therapy before surgery, and if a biopsy of their tumor reveals the methylated gene, they are treated with taxanes. This one finding is expected to increase survival rates in patients with the gene alteration from 30 percent to up to 70 percent. Methylation may also be the key to early detection. Barrett’s esophagus, a condition in which the cells lining the esophagus begin to change their composition, can sometimes progress to esophageal cancer. Herman believes that epigenetic markers may be the key to sorting it all out, that dangerous lesions that are likely to progress to esophageal cancer have a unique molecular signature characterized by methylation of the p16 and APC genes. When analyzed over time in laboratory studies, led by Jean Wang from the Division of Gastroenterology, lesions with no methylation of p16 or APC rarely progressed to cancer, while those with methylation of
the genes did. The team is evaluating the use of demethylating agents in Barrett’s esophagus patients who have the molecular signature as way to stop progression to esophageal cancer.
The team also is eager to bring to esophageal cancer the “DNA forensics” that Brock and Herman have pioneered in lung. The duo uses methylation patterns deciphered from
patients’ tumors to pinpoint cancers that are likely to come back. Patients with these markers may benefit from more aggressive surgery and chemotherapy.
MANY APPROACHES MEANS MORE CURES
With all of the gastrointestinal cancers, it is clear that a single approach will not cure most of them. By creating disease-specific GI cancer clinics, we have gathered together the wealth of knowledge and expertise that exists at Johns Hopkins and funneled it towards these relentless cancers. Our approach just might cure these cancers—even the metastatic ones.