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In a novel retrospective study comparing robot-assisted radical prostatectomy (RARP) and radical retropubic prostatectomy (RRP), in men with high-risk prostate cancer, the authors found equivalent oncologic outcomes. Recurrence-free survival was similar at 2 years (84% and 79%) and at 4 years (68% and 66%) after RRP and RARP, respectively (log-rank, 

 = .53) among 410 men who were treated at the University of California San Francisco (UCSF) from 2002 and 2011.

Sanoj Punnen, MD, clinical fellow in the Department of Urology at UCSF, reported these results for colleagues along with Peter Carroll, MD, at the 2012 Society for Urologic Oncology annual meeting in Bethesda, Maryland.

Within the study cohort, 177 patients underwent RRP and 233 patients had received the robotic procedure. The mean patient age was 61.6 years. Median follow-up was 27 months, with a range of 2 to 112 months.

There were no between-group differences by surgical approach, pathological grade, stage, or positive margin rates. However, Punnen stated, there was a trend towards higher positive margin rates with RARP in the early experience of robotic surgery, but this rate is now equivalent to open surgery (

Some other differences were observed between RRP and RARP. For example, RARP patients experienced less blood loss and more often underwent complete bilateral nerve sparing (54% RARP; 34% RRP, 

Although its adoption for urologic surgery has expanded significantly over the past decade, the use of robotic prostatectomy for patients with high-risk prostate tumors has remained under debate. This study provides reassurance that RARP may be a consideration for an additional group of men with prostate cancer. Therefore, the choice between open versus robotic surgery should depend on the experience and comfort level of the surgeon performing the procedure. It is well-performed surgery, whether robotic or open, that determines the outcome—not the technique or approach used.

		Table. Positive Margin Rates Between Open and Robotic Surgery

Articles

A novel retrospective study comparing robot-assisted radical prostatectomy and radical retropubic prostatectomy, in men with high-risk prostate cancer, found equivalent oncologic outcomes.

RARP Oncologic Outcomes Equivalent to Open Surgery for High-Risk Prostate Tumors

		Leonard G. Gomella, MD, professor and chair of the Department of Urology at Thomas Jefferson University, consults with Edouard J. Trabulsi, MD, far right, an associate professor and specialist in urologic oncology.

For patients diagnosed with localized prostate cancer, the good news is that a variety of treatment options are available. Yet that benefit can also be a stumbling block. To learn about potential therapies, men often must visit a series of doctors with different specialties, sometimes hearing divergent opinions about their care. Then, it’s up to the patients to weigh all the information as they choose a treatment that will forever affect their quality of life.

Leonard G. Gomella, MD, professor and chair of the Department of Urology at Thomas Jefferson University Hospital (TJU) in Philadelphia, noticed that pattern in the mid-1990s, and it occurred to him that there was a better way to handle such cases.

“Sometimes patients would see the surgeon on a Monday, the radiation oncologist on a Wednesday, and the medical oncologist on a Friday,” he said. “We thought that coordinating the care of these men might be something good to try.”

So Gomella and Richard K. Valicenti, MD, MA, then director of the Radiation Oncology Department’s genitourinary (GU) program, spent a year pilot-testing a multidisciplinary clinic for patients with prostate and other genitourinary cancers.

“Our model was that we were all in the same place at the same time evaluating the patients, discussing the patients, and sharing information,” Gomella said. As a result, he said, clinic doctors were able to collaborate to give each patient a definitive treatment recommendation in a single visit.

Seventeen years later, the clinic remains an important part of the way the hospital treats patients with GU cancers, and has served as a model for other departments there interested in providing multidisciplinary care.

			Pathology review of submitted slides with report generated before visit

			• Review of other ancillary services (integrative medicine, etc)

			• Physician evaluation based on nature of problem

			Clinical trials eligibility assessment

				Treatment plan and/or additional evaluation

				Follow-up call to patient 2-3 days after visit

			Treatment scheduled at Kimmel Cancer Center

		Adapted from Gomella LG, Lin J, Hoffman-Censits J, et al. Enhancing prostate cancer care through the multidisciplinary clinic approach: a 15-year experience. 

	Results From the Clinic’s First Decade

Particularly in prostate cancer, for which new treatments are continually being developed, Gomella believes the multidisciplinary approach has become more important than ever.

Launched in 1996, the GU clinic has been operating longer than any other clinic of its kind at a National Cancer Institute (NCI)-designated cancer center in the United States, according to leaders at the Kimmel Cancer Center at TJU. They shared the wisdom of their experience in a 2010 paper about outcomes for patients with prostate cancer (

While the clinic also helps guide treatment decisions in those with urologic cancers including bladder and kidney cancers, 83% of its patients have prostate cancer. TJU’s 2010 analysis looked strictly at the program’s success in treating those affected by stage III or IV locally advanced prostate cancer, a population that constituted 11.5% of the 384 patients per year who visited the clinic for treatment advice between 1995 and 2006.

With the article, the cancer center became the first in the United States to publish peer-reviewed data demonstrating that such patients, in follow-ups of at least five years after their clinic visits, boasted survival rates that exceeded national averages, said Gomella, an author of the article.

Patients who were treated for T3 NO MO prostate cancer had a five-year survival probability of approximately .90 as compared with a likelihood nationally of about .79 (

 = .0007 according to a log-rank analysis and .0012 according to a Wilcoxon analysis). For patients with T4 NO MO prostate cancer, the survival probability was .70 at 60 months as compared with an approximate .50 nationally (

 = .0847 log-rank and .1073 Wilcoxon). A 

 value below .05 was considered statistically significant.

In the paper, Gomella et al posited several reasons for the survival improvement: “technical expertise from fellowship-trained urologic oncologists and robotically assisted surgeons, radiation oncologists with specific academic interest in [prostate cancer] supported by strong dosimetry and radiation physicists, appropriate medical management and other supportive care, patient education, and patient’s socioeconomic status.”

The authors added that “the close real-time interaction may more appropriately identify patients who may benefit from combined modalities such as radiation with hormonal therapy or postoperative adjuvant radiation therapy, or clinical trials. It is our belief that the coordination of care provided by the multidisciplinary team is a factor to strongly consider in assessing the reasons for improved patient outcomes.”

When it came to patients with stage I or II prostate cancer, meanwhile, clinic outcomes matched those reflected in national averages described in NCI Surveillance Epidemiology and End Results (SEER) data, with 10-year survival data approaching 100%.

By administering a six-item questionnaire to patients, clinic leaders also found that most of the men they helped with treatment decisions considered the consultation experience “good” or “very good” and would recommend the program to others.

“We looked at parameters like wait time, whether patients felt they got good information, and whether treatment recommendations were reasonable, and our scores were generally above 90% to 93%, which is extraordinarily high,” Gomella said. “That tells us the patients were happy with the encounter.”

While TJU did not track the rate of treatment regret among its patients with prostate cancer, the authors of the paper pointed to other data supporting the idea that multidisciplinary care can protect patients from regretting their treatment choices.

A problem faced by prostate cancer patients, they wrote, is that there’s often a lack of definitive evidence supporting one mode of treatment over another. Citing two studies, the authors suggested that doctor specialty, rather than patient preference, frequently guides decisions about the treatment of the disease.

Complicating the matter is that there are so many treatment options available, Gomella said. Since the early 2000s, medical oncology has played a larger role as chemotherapeutic agents have been incorporated into the treatment of prostate cancer; robotically assisted laparoscopic prostatectomy has been added to the list of surgical options; and radiation therapy has evolved to include brachytherapy and the use of fiducial markers to track patients who are getting external beam radiation, he said.

A multidisciplinary setting can help patients navigate that confusing landscape, Gomella and his colleagues wrote. They said that a primary goal of the multidisciplinary GU cancer clinic approach “is to provide this balanced information in an open and interactive fashion, with all clinical specialists present at the same time,” they wrote. “Shared decision making through a discussion with different specialists about the risks and benefits of each treatment can decrease distress and posttreatment regret.”

Between 2000 and 2009, changing trends in the treatment of prostate cancer became evident within TJU’s clinic, according to the authors.

One example, they wrote, is that patients to be treated with radiation therapy became slightly more likely to choose external beam radiation over brachytherapy. In 2000, about 60% of such patients chose external beam radiation; in 2009, about 85% chose it, the authors explained.

A bigger change has occurred among patients who opt for radical prostatectomies; in recent years, patients have become much more likely to choose robotically assisted surgery, Gomella said.

In 2005, when the procedure was relatively new, about 5% of clinic patients who opted for radical prostatectomy chose the robotically assisted procedure, according to the paper. The very next year, 65% of such patients chose the new technology, and by 2009, that number had jumped to about 90%.

“It’s been a nationwide trend since about 2001, when the da Vinci Surgical System got approved, and there’s been a gradual increase in the number of patients who undergo it,” Gomella said. “In the literature, the risks and benefits of the different forms of radical prostatectomy are debated, and so this is really driven by patients, who view it as more minimally invasive. Clearly, it has some advantages—in the first 24 hours there’s less blood loss, and the likelihood of discharge from the hospital 12 to 24 hours sooner&mdash;but at the end of the day, radical prostatectomy is about disease control and quality of life, and the debate is whether the expense of the robot is worth it when you look at the long-term results not being that different.”

		Thomas Jefferson University Hospital in Philadelphia, above, offers the genitourinary cancer clinic in an outpatient facility.

Yet another change has been a shift in the composition of the patient population at the clinic, which typically sees between 600 and 700 patients with GU cancers each year. While the number of patients with bladder cancer has been rising, there’s been a drop in the number of patients with prostate cancer, Gomella said.

“Recently, there have been some stark decreases in the frequency of screening and biopsy for prostate cancer nationwide,” the doctor said, “so over the 2012-2013 calendar year we’re seeing a dropoff of 15% to 20% of our prostate cancer patients.”

In addition to reflecting nationwide changes in the approach to prostate cancer treatment, TJU’s clinic has been at the forefront of a growing trend toward multidisciplinary care. Since it opened its doors, numerous other multidisciplinary clinics have sprung up.

Within TJU alone, seven have been spawned since the GU clinic was launched.

“The brain tumor center is a tremendous example of patients interacting with not only surgeons and radiation oncologists, but medical oncologists,” Gomella said. “We’ve also spun off a small renal mass program that focuses on patients who may not need major surgery or chemotherapy or other agents for kidney cancer, and they come into a small renal clinic where they’re seen by interventional radiologists, as well as the urologic surgeons, to discuss management.”

The multidisciplinary clinic for patients with prostate and other GU cancers at Thomas Jefferson University Hospital has served as a model for other departments interested in providing multidisciplinary care.

Integrating Care for Prostate Patients: Multidisciplinary Model Pioneered

		Figure. Snapshot of HPV-Related Cancers

		The pie chart depicts overall number of new cases of human papillomavirus (HPV)-associated cancers by body site in the US in 2009.

The patterns characterizing oropharyngeal cancers associated with the human papillomavirus (HPV) are bucking broad trends in oncology statistics in the United StatesâŽ¯and not in a positive way, according to the Annual Report to the Nation on the Status of Cancer.

While overall cancer rates have declined among men and stabilized among women, the rate of oropharyngeal cancers is on the rise, the report indicated. Researchers based their observations on data from several federal registries for 1975 through 2009.

Investigators found that HPV DNA was detected in 71.7% of oropharyngeal tumors diagnosed from 2000- 2004, up from 16.3% from 1984-1989. ”The increasing trend for HPV-associated oropharyngeal cancer rates is in stark contrast with the overall decreasing trend for tobacco-related oropharyngeal cancers, largely because of declines in cigarette smoking,” the report said.

In further analysis, researchers noted that the increase in HPV-related oropharyngeal cancers stems from a rise of the malignancy among white men and women. They said the reasons for this development are unclear, and pointed out that there is a paucity of historical data about the infection, and about the tumor type by race and ethnicity.

Overall, HPV-associated malignancies accounted for 3.3% of all cancer cases among women and 2.0% among men diagnosed in 2009, the report said. Oropharyngeal cancers comprised 78.2% of HPV-related cancer in men and 11.6% for women. The virus also causes cancers of the cervix, anus, vagina, vulva, and penis (

Although the impact of HPV is on the rise, vaccination rates continue to lag, with only about 32% of girls age 13 to 17 years receiving all three doses in 2010, approximately four years after the Advisory Committee on Immunization Practices (ACIP) recommended its adoption for adolescent girls. ACIP added vaccination recommendations for adolescent boys and young men in 2011.

The report was produced through a collaboration of the American Cancer Society, the Centers for Disease Control and Prevention, the National Cancer Institute, and the North American Association of Central Cancer Registries.

	1. Jemal A, Simard EP, Dorell C, et al. Annual Report to the Nation on the Status of Cancer, 1975-2009, Featuring the Burden and Trends in Human Papillomavirus (HPV)-Associated Cancers and HPV Vaccination Coverage Levels [published online ahead of print January 7, 2013]. 

The patterns characterizing oropharyngeal cancers associated with the human papillomavirus are bucking broad trends in oncology statistics in the United StatesâŽ¯and not in a positive way.

Oropharyngeal Cancer Links to HPV Detailed

Working in the laboratory and the clinic, Shaji K. Kumar, MD, has made a discovery: that there aren’t enough hours in a day.

That’s why the translational researcher, who spends his time solving the mysteries of multiple myeloma (MM), is determined to make every moment count.

The 42-year-old, who joined the Division of Hematology at the Mayo Clinic in Rochester, Minnesota, in 2003, was named a professor at the school’s College of Medicine in September 2012, in recognition of his achievements.

The doctor’s level of involvement was also reflected in December 2012 at the annual meeting of the American Society of Hematology (ASH), where he was listed as a coauthor of 45 abstracts or posters scheduled for presentation.

Through that work and more, Kumar has provided new insights about subgroups of patients with MM and a blood disease that is noncancerous yet similar—amyloidosis&mdash; and how the conditions should best be treated. In both diseases, he has conducted studies that have helped identify patients whose prognoses are either better or worse than average, based on biomarkers or response to stem cell transplant.

Specifically, the doctor and his colleagues came up with a new staging system for patients with amyloidosis; identified a group of patients with MM who tend to survive longer after autologous stem cell transplant; described a subgroup of patients with amyloidosis who should not undergo stem cell transplant because of a high risk of early mortality; and demonstrated that younger patients with MM tend to have poorer outcomes, and need novel treatments to prolong their survival.

In addition to unraveling the intricacies of the two diseases, Kumar investigates new therapies to treat them. For instance, in a clinical trial whose results drew attention at ASH (abstract 332), the doctor and his colleagues demonstrated that the proteasome inhibitor MLN9708, administered along with lenalidomide and dexamethasone in previously untreated patients with MM, showed comparable efficacy—with greater convenience and tolerability&mdash;than the typical results for a standard drug in the same class, bortezomib, used in a similar combination regimen.

To manage his schedule, which includes seeing patients and teaching residents and fellows, Kumar is focused on effectively organizing his timeâŽ¯not in order to work less, but as a means of getting more done.

That’s because his career is a labor of love for Kumar, even when he finds it difficult to strike a balance between his professional life and time with his wife and two daughters.

“It’s a lot of work, but I’ve enjoyed every bit of it,” Kumar said. “It’s hard to say it’s a sacrifice when you enjoy what you’re doing.”

Kumar spends about half his working hours providing patient care, tending both to outpatients who have MM or amyloidosis, and to inpatients with those diseases who undergo stem cell transplant.

When it comes to conducting research, the doctor splits his time between his lab, which includes a staff of three and a rotation of fellows, and clinical trials.

In some cases, the trials are “homegrown,” investigating ideas generated in Kumar’s lab. For example, a phase I/II clinical trial now accruing (NCT00918333) will move a combination of panobinostat and everolimus from the doctor’s lab to patients with recurrent MM, non-Hodgkin lymphoma, or Hodgkin lymphoma, to evaluate the efficacy and side effects of the pairing. Panobinostat is a histone deacetylase inhibitor that also may modulate angiogenesis- related genes, while everolimus inhibits the key regulatory kinase mTOR, according to the National Cancer Institute. The hypothesis is that the two drugs may block some of the enzymes necessary for the growth of cancer cells.

The rest of Kumar’s trials look at drugs, or drug combinations, developed in other labs, including proteasome inhibitors and novel compounds. The doctor is especially excited about an investigational cyclindependent kinase inhibitor, dinaciclib, which he’s testing alone (NCT01096342) and in combination with bortezomib and dexamethasone (NCT01711528) in patients with refractory MM.

Finally, Kumar is pursuing long-term, grant-supported research projects, including one funded by the National Institutes of Health (NIH) concerning the onset and biomarkers for progression of monoclonal gammopathies, the umbrella of diseases that includes MM. The aim is to “identify the markers that predict why somebody would go from having gammopathy of undetermined significance to having MM,” he said. “If we know who will get it, maybe we can intervene early or figure out ways to try and prevent that progression or transition from happening.”

In a project funded by the Multiple Myeloma Research Foundation and set to stretch into 2020, Kumar will assess the relationship between outcomes, treatment regimens, and molecular profiles in patients with newly diagnosed MM

One goal “is to figure out how to improve the survival of patients with high-risk MM,” Kumar said. “There are 15% to 20% of patients with MM who don’t live beyond two or three years after diagnosis, and the medications we have now tend to stop working very fast—the myeloma just breaks through. We’re trying to understand why they behave the way they do by developing clinical trials looking at combinations and approaches for those patients.”

Growing up in Aluva, India, Kumar was always fascinated by the field of medicine.

“Right from the beginning,” he recalled, “it seemed like something fun and intriguing at the same time.”

The son of a homemaker and a chemical engineer, and particularly good at math and physics, Kumar became one of 45 students countrywide chosen annually to attend the All India Institute of Medical Sciences in New Delhi, the top medical school in India.

“Clearly, being able to go to that medical school was a turning point,” said Kumar, who had previously graduated as a premed major from Union Christian College, in his hometown. “Being able to go there really opened up doors for me.”

Kumar graduated from the medical school with an MB BS in 1991 and stayed on to complete an internship, followed by a residency in internal medicine. As part of those programs, Kumar took care of several patients with cancer, sparking his interest in oncology and motivating him to work in a cancer hospital during his time as a senior resident, from 1996 to 1997.

“I found it quite challenging, but at the same time I felt that we were really helping people,” he said.

After completing his residencies and earning his MD, Kumar set his sights on coming to the United States to pursue oncology.

“The field was still quite in its infancy in India,” he said, “with very few options for training, and treatments out of reach for the vast majority of patients.”

To pursue his specialty, the doctor knew he’d be required to complete another residency in America. He applied to the Mayo Graduate School of Medicine, in Rochester, was selected, and arrived in 1997 to begin a two-year clinical residency in internal medicine. Kumar followed that with a fellowship in hematology/oncology at the school from 1999 to 2003.

“I showed up for the interview in the middle of a snowstorm,” recalled Kumar, who’d only seen a hint of snow once before, in northern India. “Culturally, it was a big change, too, but Rochester being a small city softened the impact of moving out of India to a different country. The Mayo Clinic is also very diverse ethnically and culturally, so it was a lot easier to get used to the place. Now my wife and I feel more at home here than back home.”

Kumar was named an assistant professor of Medicine and Oncology at Mayo in 2002, and a year later, as a Mayo Foundation Scholar, spent 18 months in a lab at the Dana-Farber Cancer Institute in Boston, Massachusetts. There, the doctor conducted research on myeloma, which he had already chosen as his field of interest.

“Mayo in Rochester is one of the bestknown institutions in the world for myeloma, and we have a large group of people interested in this disease,” he said. “When I started my internship there, that was when I got interested in myeloma.”

The doctor added that his two mentors at Mayo, S. Vincent Rajkumar, MD, and Morie A. Gertz, MD, helped spark his interest in studying the disease.

			Graduated from medical school alongside his wife, Seema Kumar, MD, and now works with her at the Mayo Clinic; she’s a pediatric endocrinologist.

			Enjoyed the book Getting Things Done: The Art of Stress-Free Productivity, by David Allen. “You always think you figure out your own ways of doing things efficiently, but this book gives a different perspective about how you can organize—not by recycling all the things you have to do, but by making a checklist in your mind,” Kumar said. “It’s been helpful.”

			Cites as a favorite movie The Pursuit of Happyness, starring Will Smith, about a single dad bringing up his son. “There were some valuable lessons in there in terms of persistence and hope, and the fact that you always have to think positive and work hard,” Kumar said.

			Appreciates the wisdom in the saying “A goal without a plan is only a wish.”

			As hobbies, enjoys photography and building “souped-up, state-of-the-art” computers.

			Has never held a job outside the field of medicine.

			Is part of the Eastern Cooperative Oncology Group’s Myeloma Committee, and is on the steering committee of the Multiple Myeloma Research Consortium, a nonprofit that facilitates early-stage clinical trials by bringing together researchers and industry.

			Believes that funders should prioritize cancer research that can be applied directly to patient care, and that they should encourage scientists and institutions to work more collaboratively in order to drive swifter results.

Back in the fold at Mayo, Kumar earned the positions of senior associate consultant in the Division of Hematology and associate professor of Medicine several years later. He moved up the ladder to consultant in 2008, and to professor last year.

Having risen through the ranks at the institution, Kumar has learned some valuable lessons about cancer patients.

“The thing that has always struck me is that, when confronted with a disease that is potentially or almost always fatal, the majority of the patients find courage that even they didn’t know they had,” he said. “It takes a lot of time to come to terms with that, but most of the patients eventually accept this and really want to do their best to try and beat the disease.”

Dealing with such prognoses isn’t easy for doctors, either, Kumar said.

Oncologists who care for cancer patients “tend to open up and learn more about them,” he said, “and that’s a double-edged sword, because you get close and then you lose them. But you really get a sense of what they want in life, and can try to strike a balance between that and the reality of what they can look forward to.”

Kumar likes to pass along that message to the students he teaches.

“Early in their careers, they don’t always take into account what the patients want,” he said of the residents and fellows. “You have to get a sense of how much patients are willing to sacrifice, or the quantity versus quality of life they are striving for, before you set out on a path of treatment.”

Kumar also leaves his students with an additional piece of wisdom.

“Not everybody necessarily wants to do research, but it’s important,” he said. “When you’re treating the patient in front of you, you’re just touching one patient. When you research, you touch a lot more patients. Doing research opens up new vistas and makes you think more, and think beyond just doing one thing at a time. You learn a new language, so when you’re taking care of patients and read about a new development, you’re able to interpret that information in a better fashion.”

In his own research, Kumar isn’t looking forward to any specific breakthroughs, but to “a series of small steps” that will move him closer to his goal.

“My aim is to continue to improve the survival of patients with myeloma,” he said, “by helping to develop better, safer treatments so that patients can live a normal life—not just in lifespan, but in quality.”

Working in the laboratory and the clinic, Shaji K. Kumar, MD, has made a discovery: that there aren't enough hours in a day.

Making Time for Innovation: Myeloma Expert Sets Brisk Pace of Discovery

As with other types of cancer, the molecular drivers of multiple myeloma (MM) are of intense interest to researchers. In his laboratory at Mayo Clinic in Rochester, Minnesota, Shaji K. Kumar, MD, is working to understand the genomic intricacies of MM, particularly the role played by activity associated with the 

 gene. He expects to publish the results of several such projects in 2013.

, a research associate in Kumar’s lab, Vijay G. Ramakrishnan, PhD, offered some details about those projects, which are funded by the National Institutes of Health, the Multiple Myeloma Research Foundation, and Mayo Clinic.

One of the lab’s research interests is identifying the reasons behind, and potential new treatments for, high-risk MM. Please discuss the team’s efforts to solve this problem.

Of particular interest and focus is the impact of p53 deletion in myeloma, because it’s known that a significant proportion of patients with this deletion do poorly when compared with those who don’t have the deletion. To better understand this, we’re doing gene expression profiling on high-risk patients who have the deletion, and on those who don’t. The goal is to identify the genes that could be associated with p53 deletion. This would not only enable us to predict outcomes for specific patients, but would identify genes that would make likely targets for future treatments.

To get this information, we extract total RNA from patient cells and check the expression levels of all the expressed genes. This will present us with a global view of the genes of these two groups of patients and the genes associated with p53 deletion.

This is especially important because not all patients with the p53 deletion do poorly. Dr Kumar has already demonstrated that there are other compensatory mechanisms, like trisomies in the myeloma cells, which ameliorate the effect of a p53 deletion. So in those patients, the question is: Does this happen because specific genes are present abundantly, and does that somehow overcome the expected bad response?

Are you conducting any other investigations that focus on the p53 deletion?

Yes, as part of the development of a novel drug, we are working in the lab to use molecules to upregulate p53, since it functions as a tumor suppressor. The drug we’re testing is an MDM2 inhibitor designed by a pharmaceutical company to kill cancer cells by increasing their levels of p53.

We’re conducting these experiments on established human MM cell lines and myeloma patient-derived plasma cells.

If not ultimately useful for the patient with a p53 deletion, we hope the drug might still help p53 wild-type patients.

Is your lab investigating any other drivers of MM?

We’re analyzing the phenotypic differences between plasma cells from individuals with premalignant conditions and active MM disease. Such studies will help us to discover markers of prognostic relevance and help us to identify individuals with a high risk of progression to an active disease stage.

In addition, we are looking at the role of the tumor microenvironment in disease progression. It’s known that angiogenesis increases with disease progression. Specifically, we are trying to identify angiogenesis-related genes/proteins that are differentially expressed in patient plasma cells across disease stages. More recently, we have identified a few of these proteins that are of interest.

Now, we’ll start doing functional assays, in which we’ll be overexpressing and knocking down those proteins in the cell to see their effects on angiogenesis, tumor growth, and apoptosis. Such studies will help validate the role of angiogenesis in MM, the importance of the identified proteins in angiogenesis, and the benefits of inhibiting angiogenesis in patients with active disease.

Shaji K. Kumar, MD, is working to understand the genomic intricacies of multiple myeloma, particularly the role played by activity associated with the TP53 gene.

Putting the Focus on p53 in Multiple Myeloma

Senior vice president for Clinical Affairs and National Director for Medical Oncology

		Cancer Treatment Centers of America, Eastern Regional Medical Center

One measure of the maturation of molecular diagnostics in defining optimal management of malignant disease is the fact that new reports that may be of considerable clinical significance tend to generate relatively limited notice. Yet over time, our use of these tools will more critically define the clinical situations where specific targeted therapeutics are indicated, and will suggest new opportunities for favorably impacting outcomes.

Consider, for example, the continuing unfolding story of the influence of epidermal growth factor receptor (

) mutations in the management of non-small cell lung cancer (NSCLC). It was less than a decade ago that the initial reports appeared noting that the presence of a sensitizing mutation in 

 helped to define a population of patients with NSCLC who had a realistic opportunity to benefit clinically from the administration of a small-molecule tyrosine kinase inhibitor directed to this receptor.

This observation was quickly followed by reports demonstrating the relatively high objective response rates associated with the delivery of this class of agents, where the cancers were documented to contain such mutations. Subsequent paradigm-changing randomized phase III trials revealed the superiority associated with EGFR inhibitors over standard chemotherapy employed as first-line therapy in metastatic NSCLC known to contain sensitizing 

 For example, in a recently reported phase III trial conducted in a European patient population, initial treatment with erlotinib substantially improved progression-free survival (median 9.7 months vs 5.2 months; HR = 0.37, 

 < .0001) compared with treatment with cytotoxic chemotherapy.

Perhaps not surprisingly, such impressive and clinically meaningful results have led some to suggest that it might be reasonable to treat all patients who present with advanced or metastatic NSCLC with an EGFR inhibitor—without examination of the tumor’s 

 mutation status—and only deliver standard cytotoxic chemotherapy at the time of subsequent disease progression.

However, a recently reported phase III trial has clearly revealed the general inadvisability of this approach.

 Patients with advanced NSCLC, unselected for their 

 mutation status, were randomized to receive erlotinib followed by platinum-based chemotherapy at the time of disease progression or standard chemotherapy followed by the EGFR inhibitor at progression. In this trial, the patients who received erlotinib as initial treatment experienced a statistically significant inferior survival compared with individuals administered primary chemotherapy (median 8.7 months vs 11.6 months).

Thus, while erlotinib has been shown to produce outcomes deemed “statistically equivalent” to chemotherapy when employed as a second-line treatment option in NSCLC,

 the body of clinical evidence suggests that documenting the existence of a sensitizing 

 mutation and subsequently preferentially delivering an EGFR inhibitor in the presence of such an abnormality, with chemotherapy being administered in its absence, would be a far more rational therapeutic strategy.

Finally, a provocative retrospective analysis involving more than 150 patients with NSCLC whose tumors possessed a sensitizing 

 mutation has suggested that initial treatment with an EGFR inhibitor may be associated with a lower rate of central nervous system progression compared with the use of upfront cytotoxic chemotherapy.

 If confirmed by other investigators, these data suggest the delivery of this class of drugs may be able to prevent or at least substantially delay the development of a particularly ominous complication of the malignancy.

In summary, despite all we have learned about the importance of sensitizing EGFR mutations in defining the management of advanced NSCLC, our education regarding the relevance of this molecular target in optimizing clinical outcomes continues.

			Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. [published online ahead of print April 29, 2004]. 

. 2004;350(21):2129-2139. doi:10.1056/NEJMoa040938.

			Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy [published online ahead of print April 29, 2004]. 

. 2004; 304(5676):1497-1500. doi: 10.1126/ science.1099314.

			Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma [published online ahead of print August 19, 2009]. 

. 2009; 361(10):947-957. doi: 10.1056/NEJMoa0810699.

			Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial [published online ahead of print]. 

 2012;13(3):239-246. doi: 10.1016/S1470- 2045(11)70393-X.

			Gridelli C, Ciardiello F, Gallo C, et al. First-line erlotinib followed by secondline cisplatin-gemcitabine chemotherapy in advanced non-small cell lung cancer: the TORCH randomized trial [published online ahead of print July 9, 2012]. 

 2012;30(24):3002-3011. doi: 10.1200/JCO.2011.41.2056.

			Ciuleanu T, Stelmakh L, Cicenas S, et al. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study [published online ahead of print January 24, 2012]. 

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			Heon S, Yeap BY, Lindeman NI, et al. The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations [published online ahead of print June 25, 2012]. 

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Despite all we have learned about the importance of sensitizing EGFR mutations in defining the management of advanced NSCLC, our education regarding the relevance of this molecular target in optimizing clinical outcomes continues.

EGFR's Evolution: New Insights Refine Role of Mutation in NSCLC

			Associate Professor, Clinical Neurology, University of Virginia School of Medicine,

		How does the research in your laboratory relate to Notch signaling and cancer?

		Why does Notch make a promising target for cancer therapy?

	Working in a laboratory at the National Institutes of Health, Benjamin W. Purow, MD, became the first researcher to demonstrate that the Notch pathway plays a role in gliomas. Today, he is pursuing the pathway at the University of Virginia School of Medicine in Charlottesville. He spends the majority of his time in the lab, where his research focuses on glioblastomas, the most common and most lethal primary brain tumors, with the ultimate goal of developing new therapies for this deadly disease. The remainder of his time is spent in the clinic and with patients in whom these treatments may one day be applied.	

	Our primary focus is on glioblastoma brain tumors, and we are interested in a number of novel therapeutic approaches to these and other kinds of cancer. One of the foci of the lab is targeting the Notch pathway in these tumors. But we are also interested in other novel targets such as microRNAs, which we transitioned into through some of our Notch studies several years ago. We are interested in microRNAs both upstream and downstream of Notch (in other words, those that could regulate Notch or that are themselves being regulated by Notch). We have found some microRNAs that suppress the Notch pathway and offer a potential therapeutic angle in these tumors, though we face the significant challenge of efficient delivery to brain tumors.	

	Notch has been attracting increasing interest in oncology in recent years, although the first evidence came from some much older studies that showed that if you engineered a constitutively active form of the Notch protein into mice it could lead to T-cell leukemia. That was a beautiful indication that Notch activity could be causal or at least tumor−promoting in certain cancers. Since then, Notch has actually been found to play opposing roles in different kinds of cancer. In certain cancers, such as gliomas/glioblastomas, Notch seems to play a pro-tumor role. Interestingly, though in some cancers (such as T-cell leukemia) it plays a “classic” oncogenic role, in others it displays tumor-promoting activity without common mutations or amplifications in the gene. Then there are other cancers where it plays more of a tumor−suppressive role, such as skin and lung cancers and possibly B-cell malignancies, in which the Notch pathway is suppressed to foster tumorigenic activity.

	Another reason that interest in the Notch pathway has been enhanced is that we had small-molecule inhibitors ready and waiting in the wings that had originally been developed for use in Alzheimer patients: the gamma secretase inhibitors (or GSIs), which block the enzymatic processing of a number of different proteins, including Notch. A lot of clinical research thus far has focused on testing these inhibitors in various cancers.

		What is the most significant recent development relating to Notch signaling in cancer?

		In your opinion, which of the Notch-targeted agents holds the most promise?

		What are the major hurdles to the development of Notch-targeted anticancer agents?

	Finally, we tend to think of cancers as very primitive kinds of cells, stem cells gone awry, or mature cells that have reverted to a more primitive state, and, since Notch has a key role in maintaining the stem-cell state, it makes sense that it may have a role in fostering the development of cancers. Furthermore, in recent years we have realized that not all cancer cells are the same and in a lot of cancers there seems to be a subset called cancer stem cells, which may be the original cells that got the tumor going and replenish the tumor after treatment with traditional therapies. By targeting Notch, we may be able to get leverage against these cells and sensitize cancers to chemotherapy or radiation treatment.	

	There have been a lot of really fascinating developments in recent years. With respect to the end goal of getting agents approved for use in patients, the trials in T-cell leukemia were actually somewhat disappointing. There were some serious toxicity issues with the GSIs. Researchers are now finding ways to get around thisâŽ¯ with weekly dosing, for exampleâŽ¯and there are ongoing clinical trials in a number of different cancers. Some of the pharmaceutical companies have been somewhat discouraged by the results of trials with a Notch inhibitor as a single agent, but it seems there may be increasing enthusiasm for combining Notch with other agents to sensitize cancer cells to chemotherapy or other anticancer agents. Also, Notch (specifically the delta-like ligand 4 [DLL4]) has been found to play an important role in angiogenesis (new blood vessel development). Monoclonal antibodies directed against DLL4 have been shown to significantly disrupt the tumor vasculature. One caveat of this is that it may lead to a certain kind of blood vessel tumor, so further work is clearly needed.	

	The gamma-secretase inhibitors are very nonspecific. They block processing of a number of proteins and affect a whole range of cellular processes, as well as being very nonspecific within the pathway itself, inhibiting all of the different Notch receptors. There have been hints that we might gain benefits from more selective and targeted inhibition of a single Notch receptor or ligand, and a number of pharmaceutical companies are working on developing antibodies to block these proteins. Interestingly, antibodies that activate certain Notch family members are also being looked at, and these may have interesting applications in tumors where Notch has a tumor-suppressive role. I think these more specific agents probably hold the most promise at the moment.	

	Notch is not an enzyme, so developing drugs to block it has been a challenge. Enzymes, like kinases, are much more easily druggable. It was a bit of luck really that there is a druggable protein that processes Notch, namely gamma-secretase. Another issue has been the diversity and sheer level of complexity within the pathway; there are four Notch receptors and several different ligands as well, and it’s starting to become clear that they can have different functions within the cell. A third issue is the toxicity I mentioned. It is not harmless to block Notch, with side effects like severe diarrhea. All of these present significant challenges in the pursuit of Notch-targeting agents.

Benjamin W. Purow, MD, a researcher whose focus is on glioblastomas, discusses the Notch pathway and the development of Notch-targeted anticancer agents.

Notch Holds Promise, but Presents Obstacles as Cancer Target

		Associate Professor, Section of Hematology/Oncology, Department of Medicine, Co-Director, Head and Neck Cancer Program, Director, Hematology/Oncology Fellowship Program, University of Chicago Medical Center, Chicago, IL

Oncologists who treat patients with head and neck cancer are aware that those whose disease has been caused by human papillomavirus (HPV) have significantly better outcomes than those whose disease is caused by other factors such as smoking. However, new research suggests that there may be five distinct subgroups in which specific genetic profiles may be utilized to guide treatment decisions in patients.

“Currently, we treat all patients with head and neck cancer in essentially the same way,” said Ezra E. W. Cohen, MD, co-director of the Head and Neck Cancer Program at the University of Chicago Medical Center. “But we do know that the prognosis for patients who are HPV-positive is much better.”

To determine whether patients’ genetic profiles differed, Cohen and his colleagues at the University of Chicago, led by researcher Tanguy Seiwert, MD, took approximately 130 tumor samples from patients with stage IV squamous cell carcinoma of the head and neck and performed gene expression (mRNA) analysis.

The samples were gathered before patients received therapy, and all of the participants subsequently were treated with a 5-fluorouracil, hydroxyurea, and concurrent radiation (FHX)-based regimen. This way, the researchers could determine the outcome as a function of gene expression in the groups identified through the analysis, since patients received the same treatment across all the subgroups eventually identified. Cohen said that patients were enrolled regardless of whether they were HPV-positive or HPV-negative.

Based on these findings, the University of Chicago team was able to classify head and neck cancer into five different subgroups: hypoxic, basal, classical, HPV-associated type A, and HPV-associated type B.

The first three typesâŽ¯hypoxic, basal, and classicalâŽ¯are not associated with HPV. Cohen said hypoxia occurs in about one out of five head and neck cancer cases, and it can lead to increased resistance to therapy, supporting the notion that HPV-negative cancers are associated with poorer prognoses. The basal type is associated with epithelial cell differentiation and involves the RAB3 pathway, while the classical type can involve cell cycle disruptions. Cohen said that in these subgroups, the survival was worse, although the exact reasoning behind the poorer prognosis is not yet known.

“Biologically, these tumors are more resistant to standard therapy,” Cohen said. “We do not know exactly why that is.”

Cohen noted that while the prognosis is better in HPV-positive cases of head and neck cancer, better outcomes were observed in tumors that were classified as HPV-associated type A compared with type B. In type A, researchers found alterations associated with immune response, and the analyses revealed some potential targets for which treatments have been or are currently being developed, including the programmed death-1 (PD-1) pathway.

Type B had some similarities to the basal type of head and neck cancer, Cohen said.

New research suggests that there may be five distinct subgroups of head and neck cancer in which specific genetic profiles may be utilized to guide treatment decisions in patients.

February 2013 | Oncology Live®