The Mathematics Of Cancer


Larry Norton sees some of the toughest cases as deputy physician-in-chief for breast cancer at Memorial Sloan-Kettering Cancer Center. He has access to the most advanced imaging machines, the best surgeons and numerous new tumor-fighting drugs. But often the fancy technology helps only temporarily. Sometimes a big tumor will shrink dramatically during chemotherapy. Then all of a sudden it comes back in seven or eight locations simultaneously.

Norton thinks adding more mathematics to the crude science of cancer therapy will help. He says that oncologists need to spend much more time devising and analyzing equations that describe how fast tumors grow, how quickly cancer cells develop resistance to therapy and how often they spread to other organs. By taking such a quantitative approach, researchers may be able to create drug combinations that are far more effective than the ones now in use. “I have a suspicion that we are using almost all the cancer drugs in the wrong way,” he says. “For all I know, we may be able to cure cancer with existing agents.”

His strategy is unusual among cancer researchers, who have tended to focus on identifying cancer-causing genes rather than writing differential equations to describe the rate of tumor spread. Yet adding a dose of numbers has already led to important changes in breast cancer treatment. The math of tumor growth led to the discovery that just changing the frequency of chemo treatments can boost their effect significantly.

In the future Norton’s theorizing may lead to new classes of drugs. Researchers have always assumed tumors grow from the inside out. His latest theory, developed in collaboration with Sloan-Kettering biologist Joan Massagué, asserts that tumors grow more like big clusters of weeds. They are constantly shedding cells into the circulatory system. Some of the cells form new tumors in distant places. But other wayward cells come back to reseed the original tumor, making it grow faster. It’s like hardened terrorists returning to their home villages after being radicalized abroad and recruiting even more terrorists, says Massagué, who in December showed that the self-seeding process happens in laboratory mice. If this model works in humans, it will open up new avenues for treatment. It suggests that to cure cancer, doctors need to come up with drugs that stop the seeding process. These drugs may be different from the current crop of drugs, which are designed to kill fast-dividing cells.

Among other mysteries, self-seeding may explain why tumors sometimes regrow in the same location after being surgically removed: not necessarily because surgeons failed to remove part of the original tumor but because some itinerant cancer cells returned later to their original home to start a new tumor in the same place.

Norton, 62, got a degree in psychology from the University of Rochester, then an M.D. from Columbia University. For a while during college he thought he would make a career as a saxophonist and percussionist. The remnant of that dream is a vibraphone in his office in Memorial’s new 16-story breast cancer center.

Ever since he was a fellow at the National Cancer Institute in the 1970s he has been trying to come up with mathematical laws that describe tumor growth. He treated a lymphoma patient whose tumor shrank rapidly during chemotherapy. A year later the cancer returned worse than ever. The speed with which the tumor grew back didn’t jibe with the prevailing notion that most tumors grew in a simple exponential fashion.

Working with NCI statistician Richard Simon, Norton came up with a new model of tumor growth based on the work of the 19th-century mathematician Benjamin Gompertz. The concept (which other researchers proposed in the 1960s) holds that tumor growth generally follows an S-shape curve. Microscopic tumors below a certain threshold barely grow at all. Small tumors grow exponentially, but the rate of growth slows dramatically as tumors get bigger, until it reaches a plateau. A corollary of this: The faster you shrink a tumor with chemo, the quicker it will grow back if you haven’t killed it all.

Based on these rates of growth, Norton argued that giving the same total dose of chemotherapy over a shorter period of time would boost the cure rate by limiting the time tumors could regrow between treatments. The concept got a skeptical reaction initially. “People said it was a total waste of time,” he recalls. It took decades before Norton was able to prove his theory. But in 2002 a giant government trial showed that giving chemotherapy every two weeks instead of every three lowered the risk of breast cancer recurrence by 26% over three years, even though the two groups got the same cumulative dose.

Today Norton’s “dose-dense” regimen is common practice for certain breast cancer patients at high risk of relapse after surgery. Timing adjustments are also showing promise in other tumor types. Last October a Japanese trial found that ovarian cancer patients lived longer if they received smaller doses of chemotherapy weekly rather than getting larger doses every three weeks, according to results published in The Lancet.

“Larry has been one of the real thinkers in this area,” says Yale University professor and former NCI head Vincent DeVita. But designing better treatment schedules doesn’t get as much credit as the glamorous business of inventing drugs.

Norton’s latest theory about how tumors grow is derived from Massagué’s pioneering research. It is consistent with Gompertz’s growth curves and ties together two essential features of cancer that researchers had long considered separate–cell growth and metastasis.

Their collaboration started five years ago, when Massagué called Norton and shared a startling finding that was emerging from his laboratory. Massagué was studying how tumors spread from an organ such as the breast to the lungs, brain and other faraway places. He took human breast tumor cells, implanted them in mice and waited for metastases to occur. He analyzed cells that had metastasized to see what genes were overactive. None of the genes implicated in the spread of cancer to distant organs had to do with excessive cell division, it turned out. Instead, they all related to the ability to infiltrate and adapt to new environments.

The finding seemed to contradict doctors’ impression that the fastest-growing tumors are also the most likely to spread. Pondering how to reconcile the two ideas, Norton and Massagué theorized that tumor cells released into the bloodstream sometimes are attracted back to the original tumor and help it expand.

Self-seeding may explain why large tumors tend to grow (in percentage terms) more slowly than small tumors: It could be that growth is a function of surface area rather than volume. Tumors that are efficient seeders may kill people by promoting the seeding process, not because they have a higher exponential growth rate.

It took Massagué four years of work to prove that self-seeding occurs in laboratory mice. Now comes the tricky part: coming up with drugs that block tumor seeding. Massagué and Norton have identified four genes involved in seeding and are testing for drugs to block them. Convincing drug companies to go along could be difficult; it’s easier to see whether a drug shrinks tumors than to see whether it stops evil cells from spreading. But Norton believes that doing this hard work may be the key to a cure.

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How Doctors Deliver Bad News


The doctor in the grainy video is standing up, shifting uncomfortably as he spouts medical jargon that members of his patient’s family don’t understand.

 

When the reality sets in—that their father and husband is dead—the family’s intense emotions fluster the doctor. He awkwardly suggests an autopsy before rushing away to respond to his chirping beeper.

It is a low-budget training video that Andrew Epstein, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, uses often as he teaches medical students the art of breaking bad news.

“If you don’t balance out the physiological basis of disease and treatment of disease with the psychosocial side of medicine, you’re at risk” of alienating patients and their families, Dr. Epstein tells a group of students at a training session last week.
Doctors are trying new ways of solving an old problem—how to break bad news, which is as much a staple of doctors’ lives as ordering blood work and reviewing scans. One issue: Patients and their families, of course, aren’t all going to respond in the same way. Research into the effectiveness of training doctors in how to deliver bad news has turned up mixed results, with patients often not noticing any benefit.

“How much do people want to know? What techniques should be used? It’s a moving target,” says Dr. Epstein, who is also trained in palliative medicine.

Among pointers his students are taught: Always deliver bad news in a private, quiet area. Ask patients what they already know about their medical situation and if it is OK to share the news you have. Use silence to acknowledge sadness or other emotions. Avoid medical jargon. Speak clearly but sensitively.

And empathize. “This is clearly terrible news that I have given you. I can’t imagine what you’re going through,” says Dr. Epstein, giving the students an example of empathetic statements.

The skills can also be useful in daily life outside medicine as most people find themselves at times having to deliver unwelcome news.

“Breaking bad news is actually a golden opportunity to deepen the patient-doctor relationship,” says Nila Webster, a stage-IV lung-cancer patient in Revere Beach, Mass. “For a doctor to be willing to be emotionally available is a tremendous gift for any patient.”

Ms. Webster, 51 years old, left the cancer center at Massachusetts General Hospital this year because she was saddened at how a doctor told her about a setback. A drug trial was under way at the hospital that might have helped her, but she was told there was no room for her.

The oncologist “suggested I go try a couple of other hospitals,” Ms. Webster says. “It was like this long relationship was over and the doctor was ready to pawn me over to another hospital.”

Dr. Andrew Epstein, left, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, leads a monthly seminar for medical students on how to discuss bad medical news with patients and their families. ‘If you don’t balance out the physiological basis of disease and treatment of disease with the psychosocial side of medicine, you’re at risk’ of alienating patients and their families, Dr. Epstein tells the students at a recent session. ENLARGE
Dr. Andrew Epstein, left, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, leads a monthly seminar for medical students on how to discuss bad medical news with patients and their families. ‘If you don’t balance out the physiological basis of disease and treatment of disease with the psychosocial side of medicine, you’re at risk’ of alienating patients and their families, Dr. Epstein tells the students at a recent session.
Perhaps no specialty deals with having to break bad news to patients more than oncology. One study estimated an oncologist breaks bad news as many as 20,000 times over a career. Patient and family reactions can run the gamut from extreme sadness and weeping to shock and disbelief to anger. Some doctors tell of patients—or more frequently their family members—punching walls, yelling at them or even threatening to shoot them, in extreme cases.

“Often what happens is clinicians just keep talking and it’s just white noise for the patient,” says James Tulsky, chief of Duke Palliative Care at Duke University. “You need to attend to the fact that this is really serious news and attend to the emotion.”

Dr. Tulsky is one of the developers of VitalTalk, a nonprofit that trains medical professionals in communication skills and empathy, with the aim of developing healthier connections between patients and clinicians. He says doctors delivering bad news should be brief, clear and to the point. “Pause after delivering the bad news. Allow the patient to process that. Generally the patient should be the first one to speak after you deliver the news.”

At Sloan Kettering, Dr. Epstein’s session includes teaching two mnemonics, acronyms often taught in medical school to help students remember information like treatment protocols. One mnemonic he uses is SPIKES, aimed at helping doctors break bad news to patients, and NURSE, for exploring emotions. Dr. Epstein said he includes the memory prompts “because I think we need all the help we can get.”

(SPIKES stands for setting, patient perspective, information, knowledge, empathize/explore emotions and strategize/summarize. NURSE stands for name emotion, understand, respect, support and explore emotions.)

Kate Hogan Green, on right, holding Lorelei, decided to continue with the pregnancy despite learning the baby had Down syndrome. But she says she left her perinatologist after being abruptly told the fetus had a separate, fatal condition. The condition eventually cleared up, and Lorelei is now 14 months old. On the left are Ms. Green’s husband, Bryan, and 3-year-old Adelaide.
Kate Hogan Green, on right, holding Lorelei, decided to continue with the pregnancy despite learning the baby had Down syndrome. But she says she left her perinatologist after being abruptly told the fetus had a separate, fatal condition. The condition eventually cleared up, and Lorelei is now 14 months old. On the left are Ms. Green’s husband, Bryan, and 3-year-old Adelaide.
Kate Hogan Green, of Westerville, Ohio, was 12 weeks pregnant when she learned she was going to have a baby girl who had tested positive for Down syndrome. The 40-year-old decided to continue with the pregnancy. At 18 weeks she saw a perinatologist who told her at an ultrasound appointment that her baby also had nonimmune fetal hydrops, a separate condition in which fluid accumulates and that often results in death.

“I’m sitting there with jelly on my stomach and he’s telling me the baby has this condition. I didn’t have a clue what that was,” she recalls. “He said the baby will likely not survive. He said that we could terminate.” Ms. Green recalls being handed scratchy paper towels as she sobbed.

She switched specialists and about a month later the fluid cleared up. She now has a 14-month-old daughter, Lorelei Clair Green, who has Down syndrome.

A 2011 study in the Annals of Internal Medicine found that giving oncologists feedback on recorded conversations they had with patients made them twice as likely to use more empathic statements in future talks than were doctors who didn’t receive feedback. Patients also reported greater trust in the doctors who had gotten feedback. The study, led by Dr. Tulsky, involved 48 oncologists and 300 recorded conversations with patients.

However, a 2013 study found that doctors and nurse practitioners who received communication-skill training focused on end-of-life care were rated no higher by patients than medical professionals who didn’t receive the training. The study, published in JAMA, included 391 doctors and 91 nurse practitioners.

Another study, published online in February in JAMA Oncology, found the majority of about 100 cancer patients who watched videos with actors playing doctors preferred the on-screen physicians who relayed a more optimistic message. The finding appears to run counter to most doctors’ advice that bad news should be given sensitively but not sugar coated. The researchers said the study underscores the importance of doctors building a relationship with patients so delivering bad news doesn’t have too much of a negative impact.

Helen Riess, a psychiatrist at Massachusetts General Hospital, says she has seen the importance of empathy training for doctors. “I noticed that my patients were spending way too much time feeling upset after their medical visits,” she says.

Dr. Riess, who is the director of the hospital’s empathy and relational science program, founded Empathetics, which offers online empathy courses. The training includes interpreting and managing patients’ emotions through facial expressions and body language. It also teaches doctors how to manage their own emotions during serious patient discussions. “Delivering bad news unsettles everybody, not just the patient,” she says.

Cancer Immunotherapy Named Science Magazine “Breakthrough of the Year”


Each year, Science magazine announces one pivotal scientific achievement as the “Breakthrough of the Year.” Memorial Sloan-Kettering researchers have played a leading role in pioneering this year’s winner: cancer immunotherapy.

Pictured: T cells

“Immunotherapy marks an entirely different way of treating cancer — by targeting the immune system, not the tumor itself,” Science said in choosing this burgeoning field. Based on the idea that the immune system can be trained to attack tumors in the same way that it targets infectious agents, cancer immunotherapy exploits the ability to harness different types of immune cells circulating in the body.

A Rich History at Memorial Sloan-Kettering

Although cancer immunotherapy is being touted as a recent breakthrough in cancer treatment, its origins at Memorial Sloan-Kettering go back more than a century. In the 1890s, William Coley, a surgeon at New York Cancer Hospital (the predecessor to Memorial Sloan-Kettering) discovered cancer patients who suffered from infections after surgery often fared better than those who did not. His finding led to the development of Coley’s toxins, a cocktail of inactive bacteria injected into tumors that occasionally resulted in complete remission. But eventually the use of this treatment fell out of favor.

In the 1960s, research by Memorial Sloan-Kettering investigator Lloyd Old led to the discovery of antibody receptors on the surface of cancer cells, which enabled the development of the first cancer vaccines and led to the understanding of how certain white blood cells, known as T cells or T lymphocytes, can be trained to recognize cancer.

Helping Patients Today

One of the pivotal milestones cited in the Science article is the work of immunologist James Allison in identifying a protein receptor on the surface of T cells called CTLA-4, which puts the brakes on T cells and prevents them carrying out immune attacks. He later identified an antibody that blocks CTLA-4 and showed that turning off those brakes allows T cells to destroy cancer in mice. (Dr. Allison, who spent nearly a decade of his career at Memorial Sloan-Kettering until last year, is now at MD Anderson Cancer Center in Houston.)

Anti-CTLA-4 eventually became ipilimumab (YervoyTM), a drug approved in 2011 for the treatment of metastatic melanoma, the most deadly form of skin cancer. Dr. Allison, together with Memorial Sloan-Kettering physician-scientist Jedd Wolchok, helped guide the development of ipilimumab from the first laboratory studies through the late-stage clinical trials that led to the drug’s approval.

Dr. Wolchok’s research on immune therapies for melanoma continues, including a study earlier this year that found that more than half of patients with advanced skin melanoma experienced tumor shrinkage of more than 80 percent when given the combination of ipilimumab and the antibody drug nivolumab, another promising immunotherapy drug under investigation, suggesting that these two drugs may work better together than on their own.

The other major area of research highlighted in the Science story is the development of chimeric antigen receptor (CAR) therapy, based on the idea that a patient’s own immune cell type, called T cells, can be collected from blood, engineered to recognize cancer cells and acquire stronger antitumor properties, and reinfused to circulate through the bloodstream and attack those cancerous cells. Memorial Sloan-Kettering has been a leading center in developing this technology.

The first successes in this field have come in the treatment of leukemia. In March, Memorial Sloan-Kettering investigators reported that genetically modified T cells had been successful in rapidly inducing complete remissions in patients with relapsed B cell acute lymphoblastic leukemia (ALL), an aggressive form of blood cancer.

“This is a very exciting finding for patients with B cell ALL, directly borne out of our basic research on CARs for over a decade, and a landmark proof of concept in the field of targeted immunotherapy,” says Michel Sadelain, Director of Memorial Sloan-Kettering’sCenter for Cell Engineering, who led the study, along with medical oncologist Renier Brentjens.

Memorial Sloan-Kettering continues to study this approach and now has clinical trials under way investigating it in other types of leukemia, lymphoma, and prostate cancer, with several more trials slated to begin soon.

Looking toward the Future

Today, investigators in Memorial Sloan-Kettering’s Immunology Program in the Sloan-Kettering Institute are conducting a diverse range of studies aimed at developing the next generation of immune-based cancer treatments.

For example, Immunology Program Chair Alexander Rudensky is focused on studying a subset of T lymphocytes called regulatory T cells, which are critical for keeping other white blood cells in check and therefore play an important role in controlling immune system reactions. Understanding how these cells function, and how to inhibit them will offer novel and effective ways to treat cancer.

The research also has implications for treating conditions characterized by an overactive immune system — including autoimmune disorders such as rheumatoid arthritis, psoriasis, and diabetes.

Follow-Up Care Crucial for Pediatric Cancer Survivors.


Today 80 percent of children with cancer survive for five years or longer after their diagnosis, and most young survivors grow up to lead long lives. But many deal with after-effects of cancer for their entire lifetimes. Nearly three-quarters of these childhood cancer survivors will later develop a chronic health problem as a delayed effect of treatment, making long-term health monitoring critical to their well-being.

Pictured: Charles Sklar

Pediatric endocrinologist Charles Sklar directs Memorial Sloan-Kettering’s Long-Term Follow-Up Program, which has screened and managed the health of about 2,000 pediatric cancer survivors since its launch in 1990. Dr. Sklar is an active participant in a national research group known as the Childhood Cancer Survivor Study, which monitors the health of pediatric cancer survivors into adulthood to analyze the late effects of cancer treatment and determine how to better detect and treat them.

In a recent interview, Dr. Sklar discussed the Long-Term Follow-Up Program’s role in raising awareness of these lingering effects and why lifelong vigilance is essential.

Are parents of pediatric survivors typically prepared for dealing with late effects of treatment that can impact their child long-term or for the rest of their lives?

Most families that come to us now have heard of these effects, which is somewhat different than when our program started. Oncologists typically discuss most of these potential late effects at the time of diagnosis.

That being said, when you’re the parent of a child with a life-threatening illness, there’s only a limited amount of information you can take in. And often the survivors themselves are not aware because they may have been very young at the time of diagnosis, so these aren’t things that were necessarily discussed with them directly. That’s something we often need to do when we see them in our clinic.

What are the most common delayed effects of cancer treatment such as chemotherapy or radiation on children?

It’s difficult to generalize because treatments are very different for different diseases, and younger children have different vulnerabilities compared to older children. Endocrine, growth, and reproductive problems are very common. Heart and lung problems certainly do occur, but only in select groups of people, and there are very few people who actually suffer from clinically important heart or lung impairments.

How do you diagnose and treat late effects?

Every patient gets a tailored treatment summary that looks at all the therapies they received – including the types and doses of chemotherapy or radiation – as well as the patient’s gender and age at the time of treatment.

We develop a care plan based both on our own experience as well as published guidelines we were instrumental in developing, and we begin a screening program. Some screenings require a yearly blood test; specialized testing like echocardiograms or pulmonary function testing; or sending patients to experts for tests such as neurocognitive testing.

If the tests continue to be normal, there’s obviously nothing to do but continue the screening. Along the way we educate families and survivors about the need to do many of these tests for the rest of their lives.

If we see abnormalities in our screening tests, we treat them or send the patients to specialists who can treat them or perhaps follow them with more sophisticated testing.

How has research on late effects of cancer treatment changed the way that pediatric cancer patients are now treated after their initial cancer diagnosis?

Many changes in treatment have been informed by these types of studies. It’s important to understand that the full scope of late effects and a complete understanding of their prevalence can take 20 to 30 years to come about, so there’s a lot we don’t know yet.

But now we do know, for example, that radiation to the brain – which used to be a standard treatment for almost all children with leukemia – put these children at risk for learning, growth, and endocrine problems. Today, radiation to the brain is only given to a very tiny fraction of children with leukemia, the most common cancer that we see in children.

Radiation to the chest, particularly for young women with Hodgkin’s disease, has now been associated with a very high risk of breast cancer as well as heart problems for both men and women. So the volume, dose, and even the use of radiation has been reduced among these patients over the last 20-plus years.

Are there any new findings from the Childhood Cancer Survivor Study that you find especially compelling?

One study just coming out looked at the interaction between traditional cardiovascular risk factors like high blood pressure, diabetes, and high cholesterol in patients who had cancer treatments that put them at risk for heart problems, such as radiation to the heart area.

While we knew that these children are at risk for certain kinds of heart problems as they age, now we also know that adding in traditional cardiovascular risk factors increases their cardiovascular risks several fold. Their lifetime risk for heart problems and death from heart disease can be significantly reduced if appropriately managed.

What challenges remain in helping childhood cancer survivors?

We need to educate and train physicians and other health care providers to be experts in survivorship. We now have a fellowship here in pediatric survivorship offering specialized, in-depth training to people who want to have a career in taking care of survivors. It’s just now becoming available as a formal area of medical specialization.

New Diagnostic Test for Blood Cancers Will Help doctors.


Pictured: Ross Levine
Physician-scientist Ross Levine

A new diagnostic test that identifies genetic alterations in blood cancers will enable physicians to match patients with the best treatments for leukemias, lymphomas, and myelomas. Co-developed by Memorial Sloan-Kettering and cancer genomics company Foundation Medicine, the test analyzes samples from patients with the blood diseases and provides information about hundreds of genes known to be associated with these disorders.

The genetic profile will help physicians make more-accurate prognoses and also guide them in treatment recommendations — from deciding whether to take an intensive approach with existing drugs such as chemotherapy to enrolling patients in clinical trials investigating novel therapies. The new test is produced commercially by Foundation Medicine and is expected to be available by the end of this year.

Medical oncologist Ross Levine, who led research at Memorial Sloan-Kettering contributing to the development of the test along with physician-scientists Marcel van den BrinkAhmet Dogan, and Scott Armstrong, presented results demonstrating its accuracy today at the annual meeting of the American Society of Hematology in New Orleans.

A Tool with Broad Impact

The test will play an essential role in the clinical care of most patients with blood disorders at Memorial Sloan-Kettering and, it is expected, in the care of patients throughout the United States. According to the Leukemia and Lymphoma Society, an estimated 1.1 million people in the nation are currently living with, or in remission from, leukemia, lymphoma, and myeloma, and an estimated combined total of more than 148,000 will be diagnosed with one of these diseases in 2013.

“Our hope is that this test becomes available to all patients in the country with these malignancies,” Dr. Levine says. “We were particularly excited that we weren’t just developing a tool for the relatively small number of people who are treated at our institution, but providing access to state-of-the-art cancer genomics more broadly.”

The diagnostic test was developed and validated using more than 400 samples from Memorial Sloan-Kettering patients with the three blood disorders. Dr. Levine explains that it is far more comprehensive than existing tests, which focus on a small number of genetic mutations associated with specific blood cancer types. The new test analyzes more than 400 cancer-related genes, and unlike most standard tests, it looks for alterations in both DNA and RNA.

Sequencing RNA along with DNA is especially useful in the detection of certain kinds of genetic alterations that commonly occur in blood cancers. These include translocations (which occur when pieces of DNA are exchanged between two chromosomes) and fusion genes (new genes that include parts of two different genes). In addition to improving the treatment of patients, Memorial Sloan-Kettering will use information gleaned from the test to further advance research into blood cancers.

Clinically Relevant Mutations

Dr. Levine explains that Memorial Sloan-Kettering researchers worked with Massachusetts-based Foundation Medicine to annotate, or define, every gene in the panel to correlate it with clinical data and to provide insight into how this information can be used to guide clinical decision making.

“What’s vital about the test is that it’s not just reporting the presence of specific alterations but also indicating how a particular genetic event detected in a patient can guide either prognosis or therapy,” he says. “We identified clinically relevant mutations that were not found using standard tests. These mutations are ‘actionable,’ meaning that targeting them can change the course of the disease, including directing patients to innovative clinical trials.”

Initially, the goal for the test is to produce the full genetic profile from a patient sample within three to four weeks. “With the exception of someone who has very acute leukemia that requires immediate treatment decisions, this test is going to be valuable in clinical care,” Dr. Levine says.

 

New Information about Mesothelioma Diagnosis and Treatment at Memorial Sloan-Kettering.


Most oncologists see very few people withmesothelioma, a relatively rare cancer. The illness originates in a membrane called the mesothelium, which forms a lining that protects many of the body’s internal organs. It has been linked to exposure to asbestos once commonly used in building materials and is diagnosed in just 2,000 to 3,000 people in the United States each year.

As a hospital with one of the nation’s largest volumes of patients with mesothelioma, Memorial Sloan-Kettering offers a unique breadth of understanding and experience in diagnosing and treating the disease.

In our newly updated guide to mesothelioma you can learn about improvements in treatments and supportive care that have dramatically lengthened and improved the quality of life for patients over the past few decades.

High Volume and Advanced Care

Our surgeons have been leaders in establishing surgical approaches used to treat pleural mesothelioma, a common subtype of the disease that forms in the pleura, the sac that protects the lungs. Pleural mesothelioma can cause symptoms such as shortness of breath and pain in the chest area.

We oversee a vast patient database — the world’s largest — that generates information helpful to physicians in selecting not only who is a good candidate for surgery, but which type of operation will be most effective.

In addition, we have pioneered a multimodal approach for pleural mesothelioma that combines surgical removal of cancerous tissue along with chemotherapy or radiation treatment. Our radiation oncologists have developed cutting-edge radiation techniques, such as intensity-modulated radiation therapy (IMRT) that enables radiation to be targeted to tumors with better precision while minimizing damage to the normal tissue.

Our surgical and medical oncology experts also collaborate in advancing the treatment ofperitoneal mesothelioma, a subtype that affects the lining of the abdomen and can lead to abdominal swelling and pain, diarrhea, and constipation. We are actively attempting to identify genetic mutations that might help us find new treatments for these cancers.

A Team Approach

Because we diagnose and treat a relatively large number of people with mesothelioma, we are able to offer many patients the option to enroll in clinical trials that test new drugs and novel approaches.

Through our multidisciplinary team approach we are able to design customized and timely treatment plans for each of our patients.

We have found that the quality and length of life of people with mesothelioma is also improved by the follow-up care and support provided by our team of physicians as well as our nurses and social workers. For relief from symptoms such as pain, fatigue, and shortness of breath, for example, many people also take advantage of our symptom and pain management services.

Source: MSKCC

Too Much Information? Geneticist Mark Robson Discusses Accidental Genetic Findings.


Genetic testing of tumors is becoming increasingly common in cancer care. The molecular alterations found in a tumor can provide critical information for making an accurate diagnosis and determining the best treatment.

Although current clinical testing usually focuses on a panel of specific mutations, cancer centers are developing programs to analyze entire cancer genomes routinely — an approach made possible by cheaper sequencing costs — in order to individualize care. This process raises a thorny issue: What happens when a genome analysis of a person’s tumor reveals that he or she is at risk for developing a different type of cancer or other disease?

Recently, Memorial Sloan-Kettering Clinical Genetics Service Chief Kenneth Offit, Clinical Genetics Service Clinic Director Mark E. Robson, and researcher Yvonne Bombardpublished a viewpoint in the Journal of the American Medical Association regarding this question of incidental genetic findings, which cancer researchers have dubbed the “incidentalome.”

We asked Dr. Robson to discuss some of the issues surrounding accidental genetic findings and what Memorial Sloan-Kettering is doing to address them.

What is an example of a genetic variation that might be discovered by accident while sequencing the genome of a patient’s tumor?

For instance, you could be sequencing a lung cancer tumor in search of an EGFR mutation to target with an anticancer drug, and find a mutation in BRCA1, which is associated with increased risk for breast and ovarian cancer. Since most of a tumor’s DNA sequence is identical to the sequence of a normal cell from that same patient, this additional variation is probably inherited — and is what is called a germline mutation.

In that situation, are you obligated to inform the patient? It’s a very complex question. There are many variables to consider, such as individual preference, whether anything can be done to control risk, and whether other people — such as close relatives — may be affected.

Has this actually become a problem for doctors and researchers, or is it still a hypothetical situation for now?

Right now, most clinical testing of tumors is for a relatively limited number of specific mutations, not the full genome. But soon we’re going to be testing for a much broader panel of genes, increasing the chances of incidental findings.

On the research side, it’s quickly becoming an issue. Many tumor samples that have been stored in tissue banks for years or decades are now being fully sequenced. If incidental discoveries are made during that process, is there an obligation to try to find those patients and inform them? This has not been established, and there are obvious practical barriers. We need to lay the intellectual groundwork now for how we’re going to respond to these questions.

What steps have been taken at Memorial Sloan-Kettering to address the issue?

This summer, our Institutional Review Board (IRB), which oversees all of our patient-related research, updated part of our patient consent policy. When patients agree to have a tissue sample taken, they are asked whether they are open to being re-contacted if an investigator finds something that might affect their health.

Under the new procedure, if a researcher finds something that might be important to communicate to the patient, the specific question will be put before the IRB and carefully considered. If there is agreement the information should be conveyed, and the patient has indicated that he or she wants to be re-contacted, we’ll reach out to that person. We think this protects the people participating in our studies without restricting important research.

With all the genetic research taking place at Memorial Sloan-Kettering, is the IRB facing a deluge of these cases?

So far, no. The way the analyses are being conducted is that the computer looks for mutations in specific spots and subtracts all other information about the inherited genetic sequence before the investigator sees it. In other words, if you have genetic variants present in the tumor that are also in the normal cells, they are being filtered out by the software. The investigator ends up seeing variants that are only in the tumor.

As we pointed out in the JAMA paper, this is one way of limiting potential incidentalome issues.

But some researchers don’t have the germline DNA sequence available for comparison purposes, so while sequencing the tumor they see potentially relevant variations. For example, they could be sequencing a prostate cancer genome and see a mutation in theBRCA1 gene, which increases risk of other cancers.

The question becomes, under what circumstances do you tell the patient, and what about the patient’s siblings or children who may carry the mutation as well? In addition, sometimes multiple variants associated with disease risk may be found — and how do we provide counseling for all of them at once?

Have you gotten a sense from patients about what their preference usually is regarding being informed of these incidental genetic discoveries?

Commonly, people say, “I want to know everything,” but the devil’s in the details when you start considering the risk for diseases that can’t be prevented or treated. We are setting up focus groups of patients and unaffected people to try to understand how people think when they are confronted with these situations and how they prioritize different types of genetic information. We also have an active IRB protocol in which we are giving people who had their sequence determined as part of research studies the opportunity to learn their results.

Right now, it’s not clear what the dividing lines are. We want to reach a point where mutations are sorted into different categories, where certain incidental findings are nearly always appropriate to communicate to patients, others almost never so, and some require more context to determine.

We’re moving from the traditional model of asking patients if they would like to hear the results of a specific test before that test is performed, to this brave new world where we’re trying to help people make decisions about genetic information revealed by accident that is not possible to fully anticipate. It’s a very complicated issue, but it also offers a tremendous opportunity to benefit patients.

If you are interested in participating in the focus group, call 646-888-4867. Everyone is welcome, including patients, relatives, Memorial Sloan-Kettering employees, and the general public. No sequencing is provided.

Source: MSKCC

 

 

 

High-risk features in radiation-associated breast angiosarcomas.


Radiation-associated breast angiosarcoma (RT-AS) is an uncommon malignancy with an incidence of less than 1% of all soft tissue sarcomas. The overall prognosis is quite dismal with high rates of recurrences and poor overall survival. There is an obvious paucity of data regarding clinical outcomes of patients with breast RT-AS.

methods:

We identified all patients with RT-AS treated at the Memorial Sloan-Kettering Cancer Center between 1982–2011 and collected their correlative clinical information.

results:

We identified 79 women with RT-AS with a median age of 68 (range 36–87). The median interval between radiation and development of RT-AS was 7 years (range 3–19). The median time to local and distant recurrence was 1.29 years (95% CI 0.72–NA) and 2.48 years (95% CI 1.29–NA), respectively. The median disease-specific survival was 2.97 years (95% CI 2.21–NA). Independent predictors of worse disease-specific survival included age greater than or equal to68 years (HR 3.11, 95% CI 1.20–8.08,P=0.020) and deep tumors (HR 3.23, 95% CI 1.02–10.21, P=0.046.)

conclusion:

RT-AS has high local/distant recurrence rates, limited duration on standard chemotherapy and poor disease-specific survival.

Source: BJC

Cornell dots show promise in targeting cancer cells during surgery.


The U.S. Food and Drug Administration (FDA) has approved the first clinical trial of a new technology that uses radiolabeled nanoparticles to brighten cancer cells so they can be detected by a PET-optical imaging camera.

Researchers from Memorial Sloan-Kettering Cancer Center (MSKCC) and Cornell University are collaborating with Hybrid Silica Technologies, a Cornell start-up company, and Dutch optical imaging developer O2view on the project and clinical trial.

The FDA’s investigational new drug (IND) approval for the study represents the first inorganic particle platform of its class to be used for multiple clinical indications, according to co-researcher Dr. Michelle Bradbury, a neuroradiologist at MSKCC and assistant professor of radiology at Weill Cornell Medical College.

The trial will explore the applications of cancer targeting and future therapeutic diagnostics, as well as cancer disease staging and tumor burden assessment through lymph node mapping.

Multiple applications

“Cancer has largely been the heavy hitter for nanoparticle probes, and I think there are overlaps with other diseases where institutions could make use of such types of particles,” Bradbury toldAuntMinnie.com. “We are developing the [therapeutic diagnostic] probes and using them for surgical applications, mainly lymph node mapping.”

The so-called “Cornell dots” are silica spheres approximately 6 nm in diameter that enclose several dye molecules. The silica shell, which is essentially glass, is chemically inert and small enough to pass through the body and exit in the urine. For clinical applications, the dots are coated with neutral molecules — polyethylene glycol (PEG) — so the body will not recognize them as foreign substances and activate a patient’s immune system to reject them.

To make the nanoparticles adhere to tumor cells, organic molecules that bind to tumor surfaces or specific locations within tumors can be attached to the PEG shell. When exposed to near-infrared light, the dots become brighter and help identify the targeted cancer cells.

Nanoparticle half-life

Nanoparticles in general can linger in the bloodstream for many hours and even days, depending on their size. Given their 6-nm size, the nanoparticles have a half-life of approximately six hours in the bloodstream before evacuation through the kidneys. “Within a 24-hour period,” Bradbury said, “50% may be cleared through the kidneys.”

Among the researchers’ goals in this trial is to validate the pharmacokinetics and dosimetry of the nanoparticles and PET-optical imaging technology for safe use in humans. Researchers also will collect blood and urine samples to see how different parts of the body, besides organs, react to the nanoparticles.

The study will include five metastatic melanoma patients as its first enrollees. “If all goes well with a few patients, we hope to proceed with a targeted study,” Bradbury said.

Surgical information

The technology, the researchers believe, could be particularly beneficial during surgical treatment, allowing surgeons to see the invasive or metastatic spread to lymph nodes and distant organs and illustrating the extent of treatment response.

Initially, the surgical applications will include cancer within the complex area of the head and neck. With the help of the nanoparticles and PET-optical imaging camera, surgeons will be able to detect the activity of the lymph nodes.

Currently, Bradbury explained, physicians have little or nothing to refer to during surgery other than a preclinical scan — and compared to the scan, the patient is now in a totally different position on the table.

“How would they know where they are in the neck?” she asked. “They just don’t [know], so they want tools so they can see what they are doing and see the nodes in relation to vital structures, such as nerves. They don’t want to pick up activity from a lymph node plus an adjacent tumor, which would be easy to do, if you don’t know where you are exactly.”

Nanoparticles in mice

Researchers have already had some success with the nanoparticles and the PET-optical imaging technology in a preclinical study in mice. Among the conclusions is that the nanoparticles have been “optimized for efficient renal clearance” and “concurrently achieved specific tumor targeting” (Journal of Clinical Investigation, July 2011, Vol. 121:7, pp. 2768-2780).

In addition, the multimodal silica nanoparticles exhibit “what we believe to be a unique combination of structural, optical, and biological properties,” wrote lead study authors Dr. Miriam Benezra and Dr. Oula Penate-Medina and colleagues.

To be clinically successful, the group added, the “next generation of nanoparticle agents should be tumor selective, nontoxic, and exhibit favorable targeting and clearance profiles. Developing probes meeting these criteria is challenging, requiring comprehensive in vivo evaluations.”

Source: http://www.auntminnie.com

Making Clinical Trials More Efficient, Informative, and Effective


recent op-ed in the New York Times by journalist and cancer advocate Clifton Leaf asked the question, do clinical trials work? The answer is a straightforward yes. A clinical trial is a tool that when correctly employed can identify more-effective treatments for patients with cancer and other diseases.

It is important to acknowledge that some clinical trials have not been as informative as we would like. Some have shown “improvements” that might not be considered groundbreaking. But others have truly changed the standard of care for a given disease in a single day.

The questions today are, how do we increase the number of informative trials that can change practice and save lives? How do we evaluate promising therapies in the shortest possible time? And when do we stop and move on when the results are not as positive as expected? A well-designed clinical trial can accomplish these goals.

My colleagues and I are focusing on streamlining our clinical research program, which will allow more patients to participate in more trials, and also bring novel compounds and therapies to those who can benefit from them in a timely manner. At Memorial Sloan-Kettering, patients and researchers are typically involved in more than 900 total clinical trials at any given time.

The Traditional Paradigm

The standard approaches for developing most cancer treatments have been built on a rigid sequence of clinical trials. Historically these studies advanced the field slowly over time with incremental improvements. Each step reset the benchmark to which subsequent treatments were compared. This approach served us for many years as standard chemotherapy agents with broad applicability across many patients and diseases were being developed.

The development of agents such as cisplatin, carboplatin, and paclitaxel all occurred in this way and these agents still form the backbone of many cancer treatments.

The traditional paradigm of evaluating agents required them to move through phase I, II, and III trials, often over a protracted period of time. The phase I trial was intended to establish a dose — the “maximum tolerated dose” — and to establish safety. These phase I trials were generally small, and an assessment of the effectiveness of the agent was usually not the goal.

The next step involved a phase II trial classically with 35 or so patients enrolled to see if a certain group of patients would have tumor shrinkage and for what period of time. We often accepted a rather low number of patients showing improvement as evidence of activity.

If results of the phase II trial were positive, the investigation would move to randomized phase III trials with large numbers of patients, known in clinical trials as cohorts. Large numbers are required to detect a difference between a new and old treatment, particularly if the differences are expected to be small. Phase III trials often are done at many medical centers around the nation, and sometimes around the world, making orchestration complex, and the time required to get results can be long.

Rethinking the Large Trial

Just as the computing tools we used five years ago would seem completely inadequate to support us now, the rigid clinical trial paradigm described above has also become outmoded in many situations. Clinical trials remain the best way to improve cancer treatments, but what we need to rethink and avoid is the large clinical trial with long follow-up looking for very small improvements. (Several examples were discussed in the op-ed by Mr. Leaf.)

In particular, this approach will not serve us well in the era of mechanism-based or targeted therapies in which the therapy being tested may only work in a small group of patients but may be highly effective in that group.

The idea of aligning patients who carry a specific therapeutic target with a specific drug has resulted in higher response rates than have been previously seen, and now combination therapy is being considered to overcome the resistance that tumors often develop to anticancer drugs. New cancer drugs are initially tested in phase I trials, but we have become more nimble in confirming these responses early on rather than moving down the traditional paradigm.

The Basket Trial

The development of the “basket” trial is one example. Instead of starting with multiple clinical trials in different diseases (which requires duplication of regulatory and infrastructure efforts), we start with one trial — the basket — and one or more targets, and allow patients with multiple diseases to enroll in cohorts or groups.

If one group shows good response, we expand this group to immediately assess whether others could benefit from the new therapy. If another group is unfortunately not showing evidence of effectiveness, this group may be closed and the patients can move on to consider other therapy. In this way, the exploration of the effectiveness of a treatment occurs early, quickly, and in one trial.

The optimal phase I trial today often explores drugs with innovative mechanisms. When a robust response rate is seen and the group is expanded sufficiently (called an expansion cohort), this can sometimes bring enough confidence of effectiveness in the phase I trial that smaller randomized trials can be immediately done to confirm the findings.

For example, a recent Memorial Sloan-Kettering study of nivolumab and ipilimumab in patients with advanced melanoma, conducted by medical oncologist Jedd Wolchok and colleagues, was expanded so that 53 patients received the combination therapy in the initial trial. In this study, 53 percent of patients had significant reduction in tumor size by 80 percent or more. This trial rapidly confirmed the activity of this combination without having to go to a traditional phase II trial.

Smaller, Smarter Trials

There are two ways to increase the likelihood that a new treatment shows benefit in contemporary clinical trials. The first is to align the right patient with the right target in trials of therapeutic agents that target a specific mutation or pathway. The second is to identify biomarkers for response — for example, an abnormality measurable in the blood or detectable in the tumor specimen that when present can predict response to a particular agent — as a critical part of new drug development. In this way, we can give a new treatment to those people who are most likely to benefit.

We also need to continue to develop new statistical designs. One of these is called the Bayesian approach, where treatment arms in a given trial are frequently reviewed. The ones that are better performing will enroll more patients, and those doing less well get closed as soon as possible.

We are essentially moving toward smaller and smarter trials looking for clearly meaningful improvements. This allows us to evaluate strategies faster and, most importantly, increase the chance of benefit for individual patients.

When a clinical trial is well designed — whether the results are positive or negative — we learn important next steps. In addition, if we can match the right patient to the right trial, the number of successful approaches will continue to rise.

The clinical trial remains our best tool to identify new therapies, but as with all tools, innovation is required if trials are to remain relevant. We have more novel agents and approaches to consider than ever before, and well-designed clinical trials remain the best way forward.

Source: http://www.mskcc.org