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.

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.

 

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

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

 

Genome Sequencing of One Patient’s Tumor Could Lead to New Treatment Options for Some Bladder Cancer Patients.


In mapping the entire genome of a tumor from a patient with advanced bladder cancer, researchers at Memorial Sloan-Kettering have uncovered a genetic weakness that could potentially be targeted with an existing drug. Published in the journal Science on August 21, the findings could lead to new and potent therapies for a subset of patients with the disease.

In addition, the investigators hope that their study might encourage more research on cases in which a cancer drug is shown to work in a small number of patients but further investigation has not been pursued because the treatment was found to be ineffective in the majority of patients.

The findings were made after an early-stage clinical trial in which Memorial Sloan-Kettering physicians treated advanced bladder cancer patients with everolimus (Afinitor®), a targeted therapy already used in the treatment of kidney cancer, among other cancer types. While the drug did not help the vast majority of patients enrolled in the trial, the doctors were encouraged by the outcome of one patient – a 73-year-old woman – whose condition radically improved.

“Her response is absolutely remarkable,” affirms physician-scientist David B. Solit, of Memorial Sloan-Kettering’s Human Oncology and Pathogenesis Program, who led the study. “Most impressively, more than two years after starting the treatment, she continues to do well on everolimus, and all signs of her disease are gone.”

By comparison, the health of the other patients on the trial typically worsened two to three months into the study.

Focusing on the Exceptional Case

It is not uncommon for a new cancer drug to have mixed results when tested in patients. One or several trial participants may have good outcomes while others receive no benefit from the treatment. “When favorable responses are seen in only a small fraction of patients, the therapy is often deemed ineffective, and further research studies are not pursued,” says Dr. Solit.

In particular, the investigators noted in their report, cases where only a single patient does remarkably well in a trial have traditionally been “dismissed as failing to provide meaningful clinical evidence” of benefit.

But according to the researchers the findings of the everolimus study suggest that trials in which a drug appears to be successful in only one or several exceptional cases might in fact warrant further scrutiny. In determining the underlying reason why one patient in the largely negative everolimus trial had responded favorably to the drug, the researchers gained new insights about how this therapy could be used to its full advantage to benefit a small subset of bladder cancer patients.

Combing through the Genome

Everolimus works by targeting a cellular process called the mTOR pathway, which often goes awry in cancer cells. Although the researchers did not know why the drug had worked so well for one patient in the study, they hypothesized that a genetic abnormality in the patient’s tumor might be altering this pathway, making her cancer cells vulnerable to the therapy.

Initially, they tested samples of the patient’s tumor for a number of known gene changes. “We didn’t find any of these ‘usual suspects,’” Dr. Solit says. “There are thousands of genes that may be disrupted in cancer. Identifying the mutation that caused her disease to respond so profoundly to everolimus was like looking for a needle in a haystack.”

However, more-powerful technologies for whole-genome sequencing have recently become available, allowing scientists to determine the entire DNA sequence of a tumor or blood sample within weeks or days. As Dr. Solit puts it, “we are now able to discover new mutations by taking the entire haystack apart.”

Using this method, the investigators found that the woman’s tumor carried a mutation in a gene called TSC1, which is known to be involved in the mTOR pathway. “All of a sudden, it made perfect sense that her disease would be so sensitive to everolimus,” says Dr. Solit.

Incremental Progress

Dr. Solit and his colleagues were then able to confirm that mutations in the TSC1 gene were linked to a tumor’s sensitivity to everolimus by analyzing additional tumor tissue from patients in the trial. They found that three other patients whose tumors had partly shrunk in response to the drug also had a mutation in TSC1, while the participants whose disease had not improved did not have this genetic change.

“This tells us that everolimus might be an option for the minority of bladder cancer patients whose tumors have TSC1 mutations, even though the drug was not effective in most patients with this disease,” explains Dr. Solit. The researchers are now planning a new clinical trial in which the drug will be offered only to patients whose cancer cells test positive for TSC1 mutations. He estimates that such mutations are likely to be present in approximately one out of ten people with bladder cancer.

“Over time,” he adds, “as other mutations are found that can be targeted therapeutically, we believe that doctors will be able to offer more-effective treatments to a growing number of patients.”

Source: Source: MCKCC

 

 

Stem Cell Transplant Experts Discuss the Procedure and How to Become a Stem Cell Donor.


This morning, Good Morning America co-host Robin Roberts announced that she will undergo a bone marrow transplant at Memorial Sloan-Kettering Cancer Center. Learn about the treatment and recovery process from Memorial Sloan-Kettering experts.

Over the course of three decades, Memorial Sloan-Kettering physicians have performed more than 4,000 bone marrow transplants – nearly 400 annually in recent years. This procedure, also known as a stem cell transplant, is used to replenish bone marrow and hematopoietic stem cells that have been destroyed due to a variety of reasons, such as certain types of cancer, cancer treatments, blood diseases, or immune disorders. Hematopoietic, or blood-forming, stem cells are produced in the bone marrow.

Our investigators have also been at the forefront of research in stem cell transplantation since 1973, when our doctors performed the world’s first successful transplant between a patient and an unrelated donor. Many of the transplant approaches and supportive care regimens widely used today were pioneered at Memorial Sloan-Kettering.

In a recent interview, experts on our Adult Bone Marrow Transplantation Service talked about the procedure, the recovery process, and how to become a bone marrow or stem cell donor.

What does a stem cell transplant involve?

There are two main types of transplants. In an autologous transplant, a patient’s own stem cells are collected and then transplanted back. In an allogeneic transplant, the stem cells are obtained from another person or from donated umbilical cord blood and then given to the patient.

Before either type of transplant, the patient receives high doses of chemotherapy or a combination of chemotherapy and radiation therapy to kill any cancerous cells and hematopoietic stem cells in the bone marrow. Healthy blood stem cells are then transplanted into the bloodstream through an intravenous catheter, in a process similar to a blood transfusion.

The stem cells migrate to the bone marrow, where after several weeks they usually begin to develop into new infection-fighting white blood cells, oxygen-rich red blood cells, and blood-clot-forming platelets.

How do doctors decide that a person should receive a transplant?

We carefully select patients for this procedure because transplantation can be extremely challenging for a patient and his or her family. This is both because of the toxicity of the high-dose regimens before the transplant and because the patient’s immune system must be suppressed for an extended period of time after the procedure to prevent a rejection of the transplanted cells.

Despite the risks, outcomes have dramatically improved over the past decades, and stem cell transplants can often cure a person’s disease. In fact, a recent study conducted by the National Marrow Donor Program found that Memorial Sloan-Kettering significantly exceeded its predicted one-year survival rate for patients undergoing an allogeneic transplant.

What is the recovery process like for a patient?

Most patients remain in the hospital for several weeks to receive medical support. To protect against infection, everyone who enters the patient’s room is required to wear gloves, masks, and sometimes disposable gowns, and to wash their hands with antiseptic soap. Patients can’t have any fresh fruit, flowers, or plants in their rooms, as these can carry disease-causing molds and bacteria.

The first year after the transplant is critically important because it’s the period when complications – such as infection or rejection – are most likely to happen. Patients are typically able to get back to their regular activities after a year, with a lower risk of developing an infection.

How do you identify donors for patients who need an allogeneic transplant?

Finding an appropriate donor is critical to the success of an allogeneic transplant. Because the immune system can identify and destroy any cells perceived as foreign, a donor’s tissue type should match the patient’s as closely as possible. The process of tissue typing is based on analyzing proteins called human leukocyte antigens (HLA), which are found on the surface of white blood cells and tissues.

We work closely with our patients to find a bone marrow match. Often, the ideal donor is a sibling who has inherited the same HLA. The majority of patients do not have a brother or sister who is a match, so we can look for other family members who may be a partial match. But because family size is getting smaller in North America, it is becoming more challenging to find appropriate family member donors.

We often look to volunteer donor registries, such as the National Marrow Donor Program, and in some cases we consider using umbilical cord blood stored in public banks, such as through National Cord Blood Program. It can also be difficult to find stem cells from people of mixed ethnic or minority backgrounds through these registries, so we encourage more people to consider becoming a donor.

How can I register to become a bone marrow or stem cell donor?

You can join the Be The Match Registry or DKMS Americas. Everyone who is medically able should consider becoming part of a marrow registry. Learn more about who can donate, donor requirements, and medical guidelines from the National Marrow Donor Program.

Source: MSKCC.