The Heartland Cancer Center's collaborative approach to patient care and research aids in many significant breakthroughs.  Our newsstand section offers the latest local news from the Center and from abroad:

Experimental Drug Improves Survival in Previously Treated Metastatic Colorectal Cancer

Drug Shows Promise against Hard-to-Treat Chronic Lymphocytic Leukemia

Two Drugs that Hit One Target Show Efficacy against Metastatic Breast Cancer

Lung Cancer's Hidden Victims: Those Who Never Smoked

The Emerging Evidence about the Role of Obesity in Cancer

Study Confirms Letrozole Prevents More Breast Cancer Recurrences than Tamoxifen

Chemotherapy That is Less Toxic to the Heart May Be an Option for Some Women with HER2-Positive Breast Cancer

Rising Oropharyngeal Cancer Rated Linked to HPV Infection

In Breast Cancer, Moving Toward More Personalized Hormone Therapies

FDA Approved New Drugs to Treat Skin, Blood, and Lung Cancers

Smokers at Greater Risk of Bladder Cancer than Previously Estimated

Mobile Phone Use Does Not Raise Cancer Risk in Children and Adolescents

Studies Reveal the Genetic Complexity of Head and Neck Squamous Cell Cancers

Toward a New Understanding of Cancers in Adolescents and Young Adults 

 Quality Assurance at a Clinical Research Site: A Pratical Guide  

Experimental Drug Improves Survival in Previously Treated Metastatic Colorectal Cancer

Treatment with the investigational agent regorafenib modestly improved survival for patients with metastatic colorectal cancer  whose disease had progressed after multiple prior treatments, according to clinical trial results presented last week at the 2012 Gastrointestinal Cancer Symposium.

The trial’s Data and Safety Monitoring Committee stopped the trial after a preplanned interim analysis showed a 1.4-month improvement in median overall survival, said the trial’s lead investigator, Dr. Axel Grothey of the Mayo Clinic Cancer Center in Minneapolis.

In the trial, called CORRECT, 760 patients were randomly assigned to receive regorafenib in combination with best supportive care—that is, care designed to treat symptoms but not to cure the underlying disease—or a placebo and best supportive care. Regorafenib, which comes in pill form, targets several specific enzymes known as kinases that regulate key tumor cell processes, including cell growth and proliferation.

The median overall survival was 6.4 months for patients who received regorafenib and 5 months for patients who received the placebo. After the randomized phase of the trial was stopped, patients in the placebo arm could choose to cross over and receive regorafenib.

Approximately two-thirds of the patients in the trial had received at least four prior treatments. Common side effects of regorafenib included skin rash, fatigue, diarrhea, and hypertension, which could be managed with medications and dose reductions, Dr. Grothey explained.

Fewer than 2 percent of the patients who received regorafenib experienced significant tumor shrinkage. But 44 percent of patients who received regorafenib had no measurable tumor growth or worsening of symptoms compared with 15 percent of patients treated with placebo.

Unlike many chemotherapy drugs and targeted agents, which are cytotoxic—that is, they kill cancer cells—regorafenib appears to be primarily cytostatic, meaning it arrests tumor growth, Dr. Grothey noted.

Other primarily cytostatic agents are in development. Traditional measures of treatment efficacy, such as tumor shrinkage, will have to be reconsidered, Dr. Grothey noted, or “we might miss agents that are cytostatic” and can help control tumor growth and progression.

Last year the Food and Drug Administration granted regorafenib, which is manufactured by Bayer, "fast trac" designation for the treatment of patients with metastatic colorectal cancer whose disease has progressed despite multiple treatments with FDA-approved drugs. The fast-track process is designed to expedite the agency’s review of treatments for diseases with unmet needs.


The Web site of the National Cancer Institute (http://www.cancer.gov/).

Drug Shows Promise against Hard-to-Treat Chronic Lymphocytic Leukemia

Vacitoclax, an experimental drug that inhibits a group of proteins that promote cell survival, has shown encouraging results in a phase I trial in patients with difficult-to-treat chronic lymphocytic leukemia (CLL). The drug targets several related proteins in the BCL2 family, which are present in many types of tumor cells and which block the natural tendency of abnormal cells to undergo programmed cell death, or apoptosis.

Among 26 patients who received navitoclax after their cancer had relapsed or stopped responding to other treatments, nine experienced a partial response and seven maintained stable disease for more than 6 months, an international research team reported December 19 in the Journal of Clinical Oncology. And of 21 patients with lymphocytosis (an increase in the number of lymphocytes in the blood) at the start of the trial, 19 had a reduction in lymphocyte count of at least 50 percent. The main dose-limiting toxicity was thrombocytopenia.

This study “provides the first convincing clinical validation of BCL2 as a useful therapeutic target in CLL,” wrote the authors, Dr. Andrew W. Roberts of the Royal Melbourne Hospital in Australia and his colleagues.

The response to navitoclax was “impressive” considering that the drug was given as a single agent to patients who had received multiple prior therapies, Dr. Peter Hillmen of St. James’s Institute of Oncology in the United Kingdom commented in an accompanying editorial.

The strategy of inhibiting anti-apoptotic BCL2 family members “seems likely to herald the beginning of a revolution in the treatment of CLL,” Dr. Hillmen continued. He added that navitoclax is one of several investigational agents now in clinical development that target different aspects of CLL biology. The next steps, he went on, are to determine how to combine these new agents most effectively. “The logical combination of these agents promises to dramatically alter the treatment of CLL and may eventually lead to therapy that is both more effective and less toxic,” he wrote.

Previous phase I studies have demonstrated the safety and preliminary efficacy of navitoclax in patients with difficult-to-treat lymphomas and small-cell lung cancer, wrote Dr. Loren D. Walensky of the Dana-Farber Cancer Institute in an accompanying article describing the biological pathway of navitoclax in CLL. The drug now “advances to phase II testing as a single agent and in combination to combat cancer chemoresistance, he noted.

The Web site of the National Cancer Institute (http://www.cancer.gov/).

Two Drugs that Hit One Target Show Efficacy against Metastastic Breast Cancer

Combining two drugs that target the HER2 protein, trastuzumab (Herceptin) and the investigational agent pertuzumab, with chemotherapy may be a new treatment option for women with HER2-positive metastatic breast cancer, according to results from a large clinical trial.

The phase III CLEOPATRA trial showed that combining both of the HER2-targeting agents with the chemotherapy drug docetaxel as an initial treatment led to a 6-month improvement in progression-free survival compared to treatment with docetaxel and trastuzumab alone. The results were presented at the San Antonio Breast CAncer Symposium and published in the New England Journal of Medicine last week.

Targeting HER2 with two different drugs has shown promise in multiple trials, said the trial’s lead investigator, Dr. Jos Baselga of Harvard Medical School and the Massachusetts General Hospital, during a press briefing. “I think dual HER2 blockade is coming soon, and it will be in our daily practices.”

Although both drugs target the HER2 protein on the surface of cancer cells, they do so in different ways. Laboratory studies have indicated that the drugs may have a synergistic effect on HER2-positive tumors, which Dr. Baselga explained, are “addicted” to HER2 signaling.

More than 800 women were enrolled in the randomized trial; half received all three drugs and half received trastuzumab and docetaxel, a standard first-line treatment for women with metastatic HER2-positive breast cancer, plus a placebo. Progression-free survival was 18.5 months in the three-drug arm and 12.4 months in the two-drug plus placebo arm. More women who received the three-drug combination experienced significant shrinkage of their tumors than women who received trastuzumab, docetaxel, and the placebo, Dr. Baselga reported.

Although there is a trend toward better overall survival in women treated with pertuzumab, the trial hasn’t been running long enough to clearly determine whether the three-drug combination helps women live longer, Dr. Baselga said.

Trastuzumab has been associated with significant cardiac side effects in some women, but no increase in such side effects was seen in women in the trial who received both HER2-targeted drugs.

Genentech, which manufactures pertuzumab and trastuzumab and funded the trial, has submitted an application to the Food and Drug Administration for approval of pertuzumab for use as an initial treatment in women with HER2-positive metastatic breast cancer.

The Web site of the National Cancer Institute (http://www.cancer.gov/).

Lung Cancer's Hidden Victims: Those Who Never Smoked
More than 32,000 Americans who never lit up will die each year, with women at higher risk, experts say

By E.J. Mundell
HealthDay Reporter

FRIDAY, Dec. 2 (HealthDay News) -- Opera legend Beverly Sills never smoked. Neither did actress and health advocate Dana Reeve, wife of the late actor Christopher Reeve.

And yet in 2007 and 2006, respectively, both joined the ranks of about 32,000 Americans each year who never touch a cigarette but die of lung cancer anyway.

In fact, experts say, one in every five cases of the leading cancer killer occurs in nonsmokers. The annual death toll among this group now approaches that of breast cancer (about 40,000 per year) and is roughly equal to that of prostate cancer (32,000). Many never-smoking women may also be unaware that they are more than twice as likely to die of lung cancer as they are of ovarian cancer (14,000 deaths per year).

Numbers like those have experts calling for a shift in the public's thinking on lung cancer, away from its label of "the smoker's disease."

"We say, 'If you have a lung, you can get lung cancer,'" said Linda Wenger, executive director of Uniting Against Lung Cancer (UALC), a nonprofit advocacy group aimed at reaching a better understanding of lung cancer. The group was founded after the death in 2001 of Joan Scarangello, an ABC and NBC journalist and lifelong nonsmoker who fell victim at age 47 to lung cancer.

"She was very healthy, she was a runner," Wenger said, but the disease claimed Scarangello as it has many never-smokers. "We need to look at lung cancer as being a cancer like any other," Wenger added.

Many experts believe that the stigma around smoking that accompanies lung cancer -- that its victims somehow "brought it on themselves" -- has dampened public sympathy for patients and hindered funding for research.

"The lung cancer research field is definitely the stepchild in the [cancer research] family, and we're sure a lot of that has to do with stigma," said Holli Kawadler, UALC's scientific program director. She noted that, in terms of funding received from the U.S. National Cancer Institute, "the numbers are $27,000 in research per cancer death for breast cancer, compared to only about $1,400 per cancer death for lung cancer."

"It's very disheartening for the whole field," Wenger said. "We have a partner out there, his wife has lung cancer but she never smoked. And she has the attitude that 'I never smoked, but cigarettes are going to kill me' because the money is not there for research, because of the smoking stigma."

Lung cancer's lethal nature may also be hindering efforts to boost awareness and funding for research, experts add.

"Unlike other cancers where there is better funding, lung cancer patients aren't well enough to really advocate for themselves," explained Dr. James Dougherty, medical and scientific advisor for the Lung Cancer Research Foundation (LCRF), based in New York City. "When they get the diagnosis they often get sick pretty quickly, so they aren't about to publicly take on the role of saying 'Look, I have a problem, I need help.'"

Still, even with limited funding, scientists are slowly uncovering clues to the origins and distinct nature of lung cancer in never-smokers. One obvious starting point is the fact that women are affected far more often than men.

"Among never-smokers with lung cancer, women outnumber men two-to-one," Wenger said.

According to experts at the LCRF, the reasons for the disparity aren't clear, but early research is suggesting that, much like breast tumors, lung tumor aggressiveness in women appears linked to estrogen. Other factors, as yet unknown, may also be at play.

"We're also learning much more about the differences in the biology of [lung cancer in] smokers and nonsmokers," Dougherty added. He pointed to LCRF-funded research under way at M.D. Anderson Cancer Center in Houston, "specifically looking at some new potential markers on the [tumor] cells of people who have never smoked. Hopefully that will lead to the identification of better treatment options for nonsmokers."

Determining risk factors that might place certain never-smokers at especially high risk for lung cancer is another focus of research. The dream, experts said, is to somehow devise an accurate "panel" of biological and other factors that could serve as a basis in pinpointing at-risk individuals who may need closer monitoring.

All of these research advances will depend on much better funding, however. In the meantime, the stigma of smoking that overshadows never-smokers newly diagnosed with lung cancer continues.

"We hear a lot from people that the first thing they are asked after diagnosis is, 'Did you smoke?'" said Kawadler. "That's very tough."

More information

Find out more about ongoing efforts to fight lung cancer at the Lung Cancer Research Foundation.

SOURCES: Linda Wenger, executive director, and Holli Kawadler, Ph.D., scientific program director, Uniting Against Lung Cancer, New York City; James Dougherty, M.D., medical and scientific advisor, Lung Cancer Research Foundation, New York City

 The Emerging Evidence about the Role of Obesity in Cancer

Concern about the public-health consequences of obesity has risen as its prevalence has increased worldwide. Obesity rates have more than doubled since 1980, according to the World Health Organization. In the United States alone, the 2007–2008 National Health and Nutrition Examination Survey results show that 34.2 percent of adults 20 years of age or older are overweight, 33.8 percent are obese, and 5.7 percent are extremely obese. In 1988–1994, in contrast, only 22.9 percent of adults were obese.

A recent NIH research initiative, based on simulation modeling, estimated the public health and economic consequences of the continued rise in obesity among the aging populations of the United States and the United Kingdom. The researchers found that, by 2030, 65 million more U.S. residents will be obese, and that this increase will carry associated costs of $48 to $66 billion per year for treating obesity-related diseases. Clearly, the costs of obesity are substantial and increasing rapidly.

Many people are familiar with the evidence that obesity increases the burden of common chronic diseases such as diabetes, cardiovascular disease, asthma, and arthritis. Surprisingly, despite decades of research indicating a strong association between obesity and cancer incidence and prognosis, obesity's contribution to cancer has been widely recognized only recently.

Before effective cancer screening and treatments were commonly available, many people were not diagnosed until their cancer was advanced, when they may have already experienced weight loss and cachexia. In addition, patients undergoing cancer treatment often experienced significant nausea and vomiting, which led to further weight loss. Cancer was thus considered to be associated with weight loss, rather than with obesity.

Research during the 1970s in animal models and epidemiologic studies examining factors influencing breast cancer began to suggest, however, that higher body mass index (BMI) ratings increased the risk of breast cancer. Since then, extensive research at the basic, clinical, and population levels by investigators around the world has shown that obesity is associated with an increased risk of cancers of the endometrium, postmenopausal breast, gastrointestinal tract (colon, pancreas, adenocarcinoma of the esophagus, and gallbladder), kidney, and thyroid, as well as aggressive forms of prostate cancer. Adult weight gain and increased amounts of abdominal body fat have also been associated with increased risk for several cancers.

During the last two decades, an extensive body of research has begun to identify an association between obesity and worse prognosis and outcomes among some cancer patients, particularly those with breast, prostate, and colon cancer. In interpreting the research on cancer risk and prognosis, it is important to understand that obesity is associated with physical inactivity and poor dietary practices that may also increase the risk for cancer.

Researchers are exploring the many potential mechanisms by which obesity may influence cancer risk and prognosis. Early research focused on the effect of obesity on adverse changes in sex hormones such as estrogens and androgens, particularly during puberty, pregnancy, and menopause.

More recent research has examined mechanisms related to insulin and related growth factors, adipokines (cytokines secreted by fat tissue), other metabolic and growth factors, inflammatory factors, altered immune response, and oxidative stress, relative to all phases of cellular growth and cell death. Researchers are also looking at the effects of obesity and of energy expenditure and intake—at the cellular and whole-body level—on many other mechanisms that may influence cancer. Other research indicates that sleep, alterations in circadian rhythms, and changes in the microbiome may also influence obesity and cancer.

Although important findings have already been made about the links between obesity and cancer, much research remains to be done in a number of areas. For example, relatively few studies of obesity and cancer risk have adjusted for the potential effects of physical activity; more have adjusted for dietary factors that may influence cancer risk, such as total calories or amount and types of dietary fat consumed. In addition, no clinical research to date has examined the effect of weight loss on the initial development of cancer; nor have clinical trials been funded to test the effect of weight loss on the likelihood of dying from cancer once diagnosed.

This special issue of the NCI Cancer Bulletin explores how NCI is supporting extensive research at the cellular, animal, and clinical levels to address these gaps in our knowledge about the role of obesity in cancer. NCI's initiatives include partnerships with institutes across NIH, that seek to advance research to understand the environmental, policy, and social forces that may be contributing to the worldwide obesity epidemic.

For example, given the substantial evidence showing how difficult it is to reverse obesity once it occurs, much research is focused on obesity prevention in children, families, and the communities in which they live, play, and work. NCI is working with its partners at NIH, the U.S. Department of Agriculture, the Centers for Disease Control and Prevention, and the Robert Wood Johnson Foundation on the National Collaborative on Childhood Obesity Research. This initiative seeks to enhance the implementation and effectiveness of research to identify multilevel individual, social, environmental, and policy factors that may help to reverse the rising trends in childhood obesity, particularly among populations that are at the greatest risk of obesity and its adverse consequences.

Obesity prevention efforts, such as the Let's Move campaign, are also important, not just because they seek to help control childhood obesity, but because they may also reduce cancer-related morbidity and mortality in the United States.

Dr. Rachel Ballard-Barbash
Associate Director, Applied Rearch Program
NCI Division of Cancer Control and Population Science

The Web site of the National Cancer Institute (http://www.cancer.gov/).

Study Confirms Letrozole Prevents More Breast Cancer Recurrences than Tamoxifen

After a median of 8 years of follow-up from a large randomized trial, women with estrogen-receptor positive breast cancer who received 5 years of treatment with the aromitase inhibitor letrozole were less likely to have their cancer recur or to die during follow-up than women who had 5 years of treatment with tamoxifen. In addition, 5 years of sequential treatment—either 2 years of letrozole followed by 3 years of tamoxifen or 2 years of tamoxifen followed by 3 years of letrozole—was not better than 5 years of letrozole alone at preventing recurrence or death. These results, from the BIG 1-98 trial, were published online October 20 in Lancet Oncology.

Researchers from 27 countries enrolled 8,010 postmenopausal women with invasive breast cancer that could be removed surgically in the trial. After surgery, the women were randomly assigned to one of four groups: 5 years of letrozole (letrozole monotherapy), 5 years of tamoxifen (tamoxifen monotherapy), or one of the two sequential treatment groups. Novartis, the maker of letrozole, provided funding for the trial, along with NCI and the International Breast Cancer Study Group.

In 2005, preliminary results from the trial showed that letrozole alone was better than tamoxifen at preventing early recurrences, and when given the option to cross over, 619 of the 2,459 women in the tamoxifen-only arm chose to cross over to receive letrozole. Since crossover can complicate interpretation of trial results, the researchers performed a traditional intention-to-treat analysis (which includes only data from the original treatment assignments) and a type of analysis designed to account for crossover.

In the intention-to-treat analysis, women who received letrozole alone had a disease-free survival rate of 73.8 percent at 8 years, compared with a rate of 70.4 percent for women who received tamoxifen alone. Women who received letrozole alone also had better overall survival at 8 years than women receiving tamoxifen alone (83.4 versus 81.2 percent). The differences between the groups were slightly greater in the analysis accounting for the crossover. Neither of the two sequential treatments provided better results than letrozole alone.

Although these updated results show that letrozole reduces risk of relapse and improves survival compared with tamoxifen, "use of a sequence might be reasonable for patients at low-to-intermediate risk of relapse, those for whom starting or continuing letrozole is contraindicated, or in cases where 5 years of letrozole might not be available," concluded the authors.

"These two drugs have different side effects, and this study shows that a woman has options," said Dr. Jo Anne Zujewski, head of Breast Cancer Therapeutics in NCI's Division of Cancer Treatment and Diagnosis, who was not involved in the research. "If the side effects from letrozole are intolerable, benefits are maintained by switching to tamoxifen rather that stopping hormonal therapy altogether."

Further reading: Letrozole More Effective Than Tamoxifen in Early Breast Cancer: Results from the BIG 1-98 Trial

The Web site of the National Cancer Institute (http://www.cancer.gov/).

Chemotherapy That is Less Toxic to the Heart May Be an Option for Some Women with HER2-Positive Breast Cancer

A nonanthracycline-containing chemotherapy regimen combined with the targeted therapy trastuzumab (Herceptin) may be an option for some women with HER2-positive breast cancer, according to results from the Breast Cancer International Research Group 006 (BCIRG-006) trial. These results, the first from a large randomized breast cancer trial to test nonanthracycline chemotherapy with trastuzumab, were reported October 6 in the New England Journal of Medicine.

Anthracyclines are effective anticancer drugs, but they can produce long-term side effects, including heart damage and second primary cancers. Because trastuzumab can also cause heart damage, combining the two drugs may further increase the risk to the heart.

The nonanthracycline regimen tested in BCIRG-006 was based on laboratory data that showed synergy between trastuzumab and docetaxel or platinum-based chemotherapy drugs. “It was also anticipated that [the regimen] might circumvent the cardiac toxicity seen with anthracycline-based regimens,” wrote the study authors, led by Dr. Dennis Slamon, director of Clinical/Translational Research at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

Researchers in 41 countries enrolled 3,222 women with HER2-positive breast cancer in the trial. Participants were randomly assigned to receive one of three chemotherapy regimens after surgery: doxorubicin (an anthracycline), cyclophosphamide, and docetaxel (AC-T); AC-T plus trastuzumab; or docetaxel and carboplatin plus trastuzumab (TCH). The trial was sponsored by Sanofi-Aventis, the maker of docetaxel, with additional support from Genentech, the maker of trastuzumab.

At a median follow-up of 5.4 years, women in both groups receiving trastuzumab had better 5-year disease-free survival rates (84 percent for AC-T plus trastuzumab and 81 percent for TCH) than women who received AC-T alone (75 percent). The differences for both trastuzumab-containing regimens were statistically significant. (The researchers defined disease-free survival as the length of time without a breast cancer recurrence, a second primary cancer, or death from any cause.)

Although no significant difference in the rate of disease-free or overall survival was seen between the two trastuzumab-containing regimens, the study was designed to test both trastuzumab-containing regimens against treatment without trastuzumab, not against each other.

Therefore, there is no definitive answer to whether one of the trastuzumab-containing regimens is better than the other, explained Dr. Sally Hunsberger, an investigator with the Biometric Research Branch in NCI's Division of Cancer Treatment and Diagnosis (DCTD). Instead, the authors looked at the tradeoff between disease-free events and cardiac events by comparing the excess of breast cancer events to the excess of high-grade congestive heart failure events.

A total of 144 women receiving TCH had a distant recurrence of their cancer compared with 124 women receiving AC-T plus trastuzumab (a difference of 20 events). However, 21 women receiving AC-T plus trastuzumab had high-grade congestive heart failure compared with 4 women who received TCH (a difference of 17 events). In addition, 18.6 percent of women receiving AC-T plus trastuzumab had a nonsymptomatic loss of heart function compared with 9.4 percent of women who received TCH.

Patients who receive TCH probably have a few more cancer recurrences, “but is it worth the cardiac events to use an anthracycline?” asked Dr. Hunsberger. Individual women and their doctors will need to decide which treatment is more relevant to their circumstances, balancing the risk of late side effects with the risk of recurrence, she said. “If a woman has heart disease, then TCH is probably a valid regimen to use.”

Taken together, the data from this trial “do not clearly favor one regimen over the other,” wrote Dr. Daniel F. Hayes of the University of Michigan Comprehensive Cancer Center in an accompanying editorial. “These observations establish TCH as another (but not ‘the’) standard of care for adjuvant treatment of HER2-positive early-stage breast cancer,” he concluded.

“I agree that both trastuzumab-containing regimens could be considered ‘standard’,” said Dr. Jo Anne Zujewski, head of Breast Cancer Therapeutics in DCTD. “This study confirms again that trastuzumab-based therapy—whether combined with TC or AC-T as a chemotherapy backbone—has marked benefits in patients with tumors that overexpress HER2.”

It will be important, said Dr. Slamon, to keep following these and other women who have received the combination of an anthracycline and trastuzumab to better understand the long-term effects on the heart. “We don’t have long-term safety data on a lot of these studies, and that’s a real problem,” he explained.

The BCIRG-006 researchers plan to follow their participants for a median of 10 years to gather additional data on efficacy and safety.

—Sharon Reynolds

The Web site of the National Cancer Institute (http://www.cancer.gov/).

Rising Oropharyngeal Cancer Rates Linked to HPV Infection

A new study provides evidence that human papillomavirus (HPV) infection may be responsible for the rise in incidence of oropharyngeal squamous cell carcinoma (OPSCC), a type of head and neck cancer. The research suggests that if these trends continue, by 2020 HPV-positive OPSCC will likely surpass cervical cancer as the most common HPV-associated cancer in the United States. The findings were published online October 3 in the Journal of Clinical Oncology.

Originally thought to be a single disease, OPSCC is now recognized as two distinct tumor types: HPV-positive and HPV-negative. HPV-negative tumors are associated with tobacco and alcohol use, older age at diagnosis, and a poorer prognosis, whereas HPV-positive cancers have risk factors related to sexual behavior, are diagnosed in younger people, and tend to have better survival rates.

A previous study by the same authors showed that OPSCC diagnoses had been increasing since the early 1970s, even as rates of other oral cancers dropped. “We expected that the oral cancers would decline in incidence,” explained lead author Dr. Anil Chaturvedi of NCI’s Division of Cancer Epidemiology and Genetics, “because cigarette smoking, which is a strong risk factor for these cancers, has declined in the United States. The increasing incidence of oropharyngeal cancers during the same time suggested that there could be another risk factor. We hypothesized that HPV infection could be leading to the rise in oropharyngeal cancer incidence.”

To evaluate the prevalence of HPV in OPSCC tumors over time, the researchers used tissue samples from three registries in the Surveillance, Epidemiology, and End Results Residual Tissue Repository Program. They used several molecular techniques to detect HPV DNA, viral load, and mRNA in 271 OPSCC tumor samples collected between 1984 and 2004.

The prevalence of HPV in tumor samples (as assessed by HPV DNA) surged from 16.3 percent in the second half of the 1980s to 72.7 percent during the early 2000s, the researchers found. “These increases may reflect changes in sexual behavior, including increases in oral sex,” said senior author Dr. Maura Gillison of the Ohio State University in a news release.

The researchers also discovered that the incidence of HPV-positive OPSCC in the population more than doubled between the late 1980s and early 2000s, while that of HPV-negative cancers fell 50 percent.

Patients with HPV-positive OPSCC were more likely than patients with HPV-negative OPSCC to be younger and male, and they had better long-term survival rates (median survival of 131 months, versus 20 months for HPV-negative cancers), especially if they were treated with radiation therapy. But “not everyone with HPV-associated cancers is cured,” said Dr. Arlene Forastiere of the Johns Hopkins University, “and we are seeking to understand the molecular genetics of that [patient] subset.”

These findings are not likely to result in immediate treatment changes for OPSCC patients, but they can enroll in clinical trials specifically studying HPV-positive OPSCC, noted Dr. Forastiere.

Since the majority of the HPV-positive tumors contained HPV type 16 DNA, vaccination against this type prior to exposure—in men and women—also may be beneficial, as no screening techniques currently exist. But studies are needed to evaluate the efficacy and cost-effectiveness of vaccination, Dr. Chaturvedi added.

The Web site of the National Cancer Institute (http://www.cancer.gov/).

In Breast Cancer, Moving Toward More Personalized Hormone Therapies

After treatment for early-stage breast cancer, many postmenopausal women with estrogen-receptor positive tumors decide to take drugs, such as an aromitase inhibitor or tamoxifen, to prevent or delay a recurrence of their disease. Selecting which treatment strategy may be best for the individual patient is difficult, in part because there is conflicting scientific evidence.

Guidelines, such as those from the American Society of Clinical Oncology, suggest that all post-menopausal women should receive an aromatase inhibitor either alone or before or after tamoxifen, but they do not suggest an optimal approach.

Clear recommendations may eventually come from ongoing clinical trials. In the meantime, a new study suggests doctors should consider the potential side effects of the drugs as well as a patient's health history when making a selection.

The study, published in the September 7 Journal of the National Cancer Institute (JNCI), largely confirmed what is known about these drugs. Compared with tamoxifen, the longer use of aromatase inhibitors was associated with higher rates of heart disease and bone fractures but with lower rates of blood clots and endrometrial cancer.

Aromatase inhibitors and tamoxifen, often referred to as adjuvant hormonal therapies, are designed to interfere with the body's production of estrogen and the promotion of breast tumor growth by estrogen, respectively. Estrogen is a naturally occurring hormone that can contribute to the growth of breast cancer.

The new findings highlight the need for physicians to select a therapy based on more than its ability to prevent a recurrence of breast cancer, the study authors said.

"Because the risks of these adjuvant therapies are relatively low, physicians don't spend a lot of time thinking about side effects," said lead investigator Dr. Eitan Amir of the Princess Margaret Hospital in Toronto. But there are clearly serious side effects associated with both approaches, he continued, noting that doctors should be able to identify patients at risk for some of these toxicities before selecting therapies.

"Don't Ditch the Switch"

Based on an analysis of seven clinical trials using these antihormonal therapies, the researchers concluded that switching from one type of therapy to another could offset the potential cumulative side effects of individual drugs and allow many women to experience the maximum benefits with lower side effects.

"We know that the one-size-fits-all approach does not work for every woman," said Dr. Shannon Puhalla of the University of Pittsburgh Cancer Institute, who co-authored an accompanying editorial entitled "Adjuvant Endocrine Therapy for Breast Cancer: Don't Ditch the Switch."

"As oncologists, we always focus on preventing cancer from recurring, but it is important to look at other causes of morbidity and mortality in our patients," Dr. Puhalla continued. As she and her co-authors wrote in the editorial, the field needs a risk model that can help clinicians select the most appropriate treatment for an individual.

The current study, she added, "is a first step in trying to personalize hormonal therapies."

Serious side effects from adjuvant hormonal therapies are rare but may occur more frequently in patients with certain health conditions, such as a history of heart problems, the researchers said.

"This study provides further validation that both of these options are very good for patients," said Dr. Tito Fojo of NCI's Center for Cancer Research who was not involved the research. "So it becomes incumbent on the doctor to think about toxicities and about which drug is best for an individual patient."

An Aromatase Inhibitor Puzzle

Clinical trials have shown that, compared with tamoxifen, aromatase inhibitors are better at delaying the time until disease recurs (disease-free survival or recurrence-free survival). But none of the trials has demonstrated improved overall survival for aromatase inhibitors.

The researchers hypothesized that the cumulative toxicity of aromatase inhibitors may lead to deaths from causes other than breast cancer. They tested their hypothesis by assessing the risks of six adverse events associated with therapies used by more than 30,000 women to interfere with cancer growth-promoting hormones.

The analysis suggested that the cumulative toxicity of aromatase inhibitors, when used as a first-line treatment, may explain the lack of an overall survival benefit despite improvements in disease-free survival.

Dr. Amir stressed that the findings should be considered preliminary and need to be validated. In the meantime, information about the potential risk of side effects should be clearly communicated to patients, he said.

"The key is to provide a more holistic assessment of the patient not just for preventing breast cancer, but also as it relates to the side effect profiles of drugs," Dr. Amir added.

—Edward R. Winstead

The Web site of the National Cancer Institute (http://www.cancer.gov/).

FDA Approves New Drugs to Treat Skin, Blood, and Lung Cancers

In the last 2 weeks of August, the Food and Drug Administration (FDA) approved three new cancer drugs: vemurafenib (Zelboraf), for patients with unresectable or metastatic melanoma whose tumors harbor a specific genetic mutation in the BRAF gene; brentuximab vedotin (Adcetris), for some patients with Hodgkin lymphoma and anaplastic large cell lymphoma; and crizotinib (Xalkori), for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors have a gene fusion  caused by a chromosomal translocation involving the ALK gene.

The three drugs were approved all well in advance of the time allotted for their review. By comparison, from the beginning of 2010 until the week of August 15, 2011, the agency had approved just six new cancer drugs.

Some common themes ran through the approvals. Crizotinib and brentuximab, for example, were accelerated approvals, meaning that they were approved because clinical trials showed an improvement in a surrogate endpoint, such as tumor response, that is reasonably likely to predict clinical benefit. Both drugs have to be tested in confirmatory trials to verify their safety and clinical effectiveness.

Crizotinib and vemurafenib, meanwhile, were approved with companion diagnostics for each drug. These companion tests are used to identify patients who are most likely to benefit from the drugs, based on the presence of a specific genetic abnormality or other molecular marker.

All three drugs also have one more important feature in common, stressed Dr. Richard Pazdur, director of the Office of Oncology Drug Products in FDA's Center for Drug Evaluation and Research: "They all appear to have a more favorable benefit-to-risk analysis than conventional chemotherapy agents." The greater benefit-to-risk ratio "reflects a true understanding of the biology of the disease," Dr. Pazdur continued.

Although targeting specific genetic aberrations is not a new therapeutic approach, greater knowledge of the underlying biology of many cancers means that "there are more targets out there, and researchers better understand how to hit [those targets] and the ramifications of hitting them," said Dr. Jeff Allen, executive director of Friends of Cancer Research, an advocacy organization that promotes research collaborations. "To see that coming to clinical benefit with greater frequency is very encouraging."

In addition, all three drugs have demonstrated or strongly suggested that they are effective for diseases for which effective treatments have been difficult to find. Brentuximab, for instance, is the first new drug approved for Hodgkin lymphoma in 30 years.

A Refined Approach

Dr. Paul Bunn, a lung cancer expert from the University of Colorado Medical Center, said during a press briefing on crizotinib that the drug's approval represents "a new paradigm for drug development, where a small but well-defined fraction of people get a very well-defined drug."

The same holds true for vemurafenib. The FDA based its approval for both drugs on trials that included only patients who harbored the molecular aberrations that the drugs target.

In the case of crizotinib, only 3 to 5 percent of patients with NSCLC harbor the ALK translocation. (A recent study suggests, however, that as many as 8 percent of patients with the adenocarcinoma type of NSCLC may have the translocation.) Even though the percentage of patients with the translocation is small, as many as 16,000 NSCLC patients per year may be candidates for the drug, said Dr. Mark Kris of Memorial Sloan-Kettering Cancer Center during the briefing.

The subset of melanoma patients who are candidates for vemurafenib is substantially larger; about half of patients with metastatic melanoma harbor the BRAF mutation.

Such a sizable subset of patients who are candidates for a new molecularly tailored therapy will likely be more of an exception than the rule, said Dr. Razelle Kurzrock, chair of the Department of Investigational Cancer Therapeutics at the University of Texas M. D. Anderson Cancer Center.

For common cancers like lung cancer, Dr. Kurzrock added, it is particularly unlikely that a large percentage of patients will be found to carry a specific genetic alteration. "Common cancers may be more common because there are more pathways for developing the disease than in less common and rarer cancers," she said.

Had crizotinib been developed in the more traditional manner, Dr. Kurzrock said, with the trials including any patient with NSCLC rather than just those with the ALK translocation, the drug could very well have been abandoned because of poor responce rates.

Essential Companions

When there is a marker that clearly identifies a subset of patients who may benefit from a drug, "companies have become very proactive in the development of companion diagnostics," said Dr. Helen Chen of NCI's Division of Cancer Treatment and Diagnosis.

From fairly early in the development process of vemurafenib and crizotinib, in fact, the drugs' developers, Pfizer and Plexxikon, began working with diagnostics companies to develop tests that would identify appropriate patients to include in clinical trials.

"There has been a great deal of concern in the oncology community about the difficulty of developing diagnostics along with the drug," said Dr. Pazdur. "These are both excellent examples that it can be done…. You can develop your in vitro diagnostic [test] with the drug simultaneously and move through the approval process fairly easily."

Go Forth and Multiply

The rapid development and approval of these drugs can have a multiplier effect. Crizotinib's approval is particularly important, Dr. Kurzrock believes. "It provides a real incentive to look for these small subsets of patients, because now it's been shown that it can really pay off."

It can also accelerate the continued development of the approved agents. Brentuximab is already being tested in patients with earlier-stage Hodgkin lymphoma, as well as in CD30-positive non-Hodgkin lymphoma. And vemurafenib will be tested in trials in combination with a recently approved drug for advanced melanoma, the immunotherapy drug ipilimumab (Yervoy).

With numerous patients experiencing complete disappearance of their tumors, at least for a time, in the clinical trials that led to these new approvals, all three drugs are already helping patients.

Jeff Wigbels took his first dose of crizotinib last October. His lung cancer had spread to multiple places in his body, including his throat. He had to eat through a tube, he explained during the briefing on the drug's approval.

A week after taking the first dose, some friends came to visit him. They ordered pizza. And he could eat it.

"It was an amazing experience for me that [the drug] could work that quickly," he said.

—Carmen Phillips

The Price of Success The approval of these three and several other new cancer drugs in the last year has generated a great deal of excitement. But there is also a mounting concern about their high cost. Crizotinib, for example, costs $9,600 per month. Brentuximab costs $13,500 per dose. The price of vemurafenib and ipilimumab, another melanoma drug, are in the same ballpark, as is sipuleucel-T  (Provenge), which was approved last year to treat metastatic prostate cancer. For 1 year of treatment with many of these drugs, the cost is $100,000 or more. Pfizer, Roche (which owns development and distribution rights to vemurafenib), and Seattle Genetics have all established patient assistance programs to help cover the cost of the drugs for those who are under- or uninsured. The available data suggest that such help is needed. A study published earlier this year found that as patient co-pays for cancer drugs rose, the likelihood of patients filling even the initial prescription fell. In addition to the burden of high drug costs on individual patients, costs are expanding for society as a whole. A recent NCI study  estimated that Americans spent $125 billion on cancer treatment in 2010 and the authors projected that costs could reach nearly $180 billion by 2020. Numerous factors influence drug prices, including well-documented issues related to development and regulatory approval. When it's possible, the ability to limit trials to a smaller group of patients whose tumors have specific molecular markers may bring down development costs, which could translate to lower prices, Dr. Kurzrock said. But that's not a certainty. From a population-wide perspective, such targeted drugs may offer potential savings, Dr. Allen stressed. In the case of drugs like vemurafenib and crizotinib, he said, "we'll be saving money by not giving them to patients who we know won't benefit."

The Web site of the National Cancer Institute (http://www.cancer.gov/).

Smokers at Greater Risk of Bladder Cancer than Previously Estimated

Current cigarette smokers have a higher risk of bladder cancer than previously reported, and the proportion of bladder cancers due to smoking in women is now comparable to that in men, according to a study by researchers in NCI’s Division of Cancer Epidemiology and Genetics (DCEG). Their findings were published August 17 in JAMA.

This latest study included data from more than 450,000 participants in the NIH-AARP Diet and Health Study, a questionnaire-based study that began in 1995, with follow-up through the end of 2006.

“Current smokers in our study had a fourfold excess risk of developing bladder cancer, compared to a threefold excess risk observed in previous studies,” said study co-author Dr. Neal Freedman. “The stronger association between smoking and bladder cancer is possibly due to changes in cigarette composition or smoking habits over the years.”

In the current study, former smokers were twice as likely to develop bladder cancer than those who never smoked. As with many other smoking-related cancers, the risk of bladder cancer fell after people quit smoking.

Previous studies had indicated that only 20 to 30 percent of bladder cancer cases in women were caused by smoking, but the new data indicate that smoking is responsible for about half of bladder cancer cases among women, a proportion similar to that found in men in this and previous studies.

The increase in the proportion of smoking-induced bladder cancer cases among women may be because smoking rates in men and women are now similar. The majority of the earlier studies were conducted at times or in places where smoking was much less common among women than men.

“Our findings provide additional evidence of the importance of preventing smoking initiation and promoting cessation for both men and women,” said senior author Dr. Christian Abnet.

The Web site of the National Cancer Institute (http://www.cancer.gov/).

Mobile Phone Use Does Not Raise Cancer Risk in Children and Adolescents

The first-ever study of mobile phone use by children and adolescents carried out in four European countries found no increased risk of brain cancer, according to a report published online July 27 in the Journal of the National Cancer Institute (JNCI).

Investigators in Denmark, Sweden, Norway, and Switzerland conducted a multicenter case-control study involving children and adolescents 7 to 19 years of age who were diagnosed with a brain tumor between 2004 and 2008. The investigators, led by Dr. Denis Aydin of the Swiss Tropical and Public Health Institute in Basel, conducted interviews with 352 brain tumor case patients, 646 healthy control subjects, and their parents.

The children who regularly used mobile phones were not statistically significant more likely to have been diagnosed with brain tumors than nonusers, the researchers reported. In addition, those who used mobile phones for at least 5 years did not have a statistically significantly higher risk of developing brain tumors. Moreover, the investigators found no increased risk of brain tumors in the parts of the brain that typically receive the highest levels of mobile-phone radiation exposure.

For some of the children, the investigators were also able to obtain data from mobile phone service providers. In these children, brain tumor risk rose with the amount of time since the family began its mobile phone subscription but not with the amount of mobile phone use as recorded by the service providers, the researchers added.

Previous epidemiologic studies among adult users have found no overall increased risk of brain cancer from mobile phone use. This study addressed concerns that the developing brains and nervous systems of children and adolescents might be more vulnerable to the potential adverse health effects of mobile phone use.

“Researchers continue to monitor trends in brain cancer and mobile phone use,” commented Dr. Martha Linet, chief of the Radiation Epidemiology Branch in NCI’s Division of Cancer Epidemiology and Genetics. “Other ongoing research includes a large study of rodents exposed to mobile phone frequencies that is being conducted by the National Toxicology Program; a prospective study recruiting 250,000 mobile phone users in five European countries; and a case-control study comparing 2,000 young people between the ages of 10 and 24 who were diagnosed with brain tumors and an equal number of control subjects from 13 countries.”

Further reading: “A Conversation with Dr. Martha Linet on Cell Phone Use and Cancer Risk”

The Web site of the National Cancer Institute (http://www.cancer.gov/).

Studies Reveal the Genetic Complexity of Head and Neck Squamous Cell Cancers

Two independent, multi-institution research teams have identified a large number of previously unknown genetic defects associated with head and neck squamous cell carcinoma (HNSCC), the most common form of head and neck cancer. The researchers sequenced the entire protein-coding regions, or exomes, of the DNA in dozens of patient tissue samples, and the findings were published online July 28 in two papers in Science (here and here).

The studies were led by researchers from the Broad Institute of MIT and Harvard, the University of Pittsburgh Cancer Institute, the Johns Hopkins Kimmel Cancer Center, and the University of Texas M. D. Anderson Cancer Center.

Tobacco use, excessive alcohol consumption, and human papillomavirus (HPV) infection are known risk factors for HNSCC, which includes cancers arising in the mouth and throat. The 5-year survival rate for many types of HNSCC has improved little over the past 40 years.

To search for gene defects, or mutations, that may play a role in HNSCC, the researchers compared whole-exome sequences of tumor tissue with those of matched normal tissue from the same patients. Both research teams confirmed genetic abnormalities that were previously implicated in HNSCC, including mutations in the TP53 tumor suppressor gene, which were by far the most common.

The two teams also identified a large number of unexpected gene mutations in HNSCC, most notably in the NOTCH1 gene and other genes involved in squamous cell differentiation—the process by which less mature, rapidly dividing cells develop into more specialized squamous cells that divide more slowly.

“The degree of differentiation—that is, tumor cell grade —has never consistently been shown to be a clinical prognostic factor” in HNSCC, said Dr. Jennifer Grandis of the University of Pittsburgh, a senior author of one of the studies. “So it was surprising to find mutations in a series of genes that…appear to contribute to differentiation.”

Both studies found far fewer mutated genes in HPV-positive tumors than in HPV-negative tumors, supporting the idea that HPV-positive HNSCC, which has a better prognosis, is a distinct disease and thus merits different treatment.

The results of multidisciplinary collaborations such as these “will allow us for the first time to understand the complex biology of head and neck cancer,” Dr. Grandis said. “It’s clearly not one disease. It’s many diseases, despite appearing identical under the microscope.

“It’s right to be cautiously pessimistic,” Dr. Grandis said. But she believes that delving into the biological complexity of cancers such as HNSCC will ultimately reveal new therapeutic targets.

“We’re still in just the baby steps of these genetic findings,” she continued. The most important next step, she explained, is to identify the subset of mutations that drive tumor formation and figure out how to target them. “These are the patients’ tumors—they are speaking to us. Whether we understand what they say is a different question.”

The Web site of the National Cancer Institute (http://www.cancer.gov/).

Toward a New Understanding of Cancers in Adolescents and Young Adults

My personal motivation to improve the understanding and care of cancer among adolescents and young adults (AYAs) comes from reflection on my own diagnosis of a prototypical young adult cancer, testicular cancer, at age 28.

Having just begun my training as an academic oncologist, I found myself asking a wide range of questions: Why does testicular cancer predominantly affect young adults? Why is there a separate disease staging system in the pediatric versus the adult clinic? How does a young adult balance a cancer diagnosis with a new career and a new family? What resources exist to support young adults during their cancer journey? How does a cancer diagnosis affect long-term survivorship?

Striving to answer these questions led me to form the Adolescent and Young Adult Oncology program in the Knight Cancer Institute at Oregon Health and Science University and to work with the Lance Armstrong Foundation's LIVESTRONG Young Adult Alliance.

More than 72,000 adolescents and young adults (ages 15 to 39) learn they have cancer each year in the United States, a number up to seven times larger than the number diagnosed under the age of 15. Cancers that are common in AYAs often are rare in the traditional adult oncology clinic—germ cell tumors, leukemias and lymphomas, melanoma, thyroid cancer, and sarcomas.

AYAs face unique medical issues. For instance, diagnosis is often delayed because physicians rarely think of a young adult as having cancer. A lack of health insurance also makes access to medical care more difficult for some patients in this age range, although the new health care law that allows children to stay on their parents' insurance until the age of 26 should help in this regard.

Sometimes AYA patients receive treatments that may not be the most effective for their cancer. For instance, recent clinical trials indicate that, in at least some cases, AYA patients with acute lymphoblastic leukemia (ALL) may have better outcomes when treated with pediatric, rather than adult, regimens. Young adults also face issues around the availability and timing of fertility preservation techniques and often report a sense of isolation within the traditional pediatric or adult cancer clinic setting, where they see very few other patients their own age.

Until recently, many physicians have been unaware of these issues, compounding the difficulties faced by young people with cancer. Perhaps as a result of this lack of awareness and other factors, survival rates for AYAs have stagnated in recent decades, while survival rates for young children and older adults have improved.

The report of NCI's Adolescent and Young Adult Oncology Progress Review Group, published in 2006, provided the stimulus, the legitimacy, and the framework to pursue work in AYA oncology. The report, titled "Closing the Gap: Research and Care Imperatives for Adolescents and Young Adults with Cancer," presented five key recommendations for improving outcomes:

1.Characterizing the distinguishing features of the AYA cancer burden. More research is needed on the biology of tumors in AYA patients given that, in some types of cancer, tumors appear to be different from those in children and older adults. These biological differences may require different treatment regimens to achieve the best possible outcomes. In addition, more research is needed to understand the psychosocial effects of diagnosis, treatment, and survivorship in this age group, and how intellectual, emotional, cultural, and other factors influence medical outcomes.


2.Providing education and training. Health care providers who work with AYAs must be educated about the types of cancers that occur most commonly among this age group, monitoring for late effects among survivors, and the psychosocial needs of AYA patients and survivors. Broader public and professional education campaigns are also needed to raise awareness about AYA cancers in general and risk factors in particular.


3.Creating tools to study AYA cancers. The report recommended creating a database on all AYA cancer patients, increasing the number of tissue samples available for research from this population, and expanding the number of clinical trials appropriate for and available to AYAs.


4.Ensuring excellence in care delivery. The first step toward achieving this goal is the development of standards of care for AYA patients. Once these standards have been developed, they must be disseminated to and implemented by all stakeholders in the AYA community, including researchers, health care providers, and advocates.


5.Bolstering advocacy and support. Effective support services for AYA cancer patients and survivors need to be based on an understanding of how cancer may affect their self esteem, spirituality, body image, life goals, and stage of development, among other factors.
In the 5 years since these goals were set, we have made progress in each area. Research projects have been started, tissue samples collected and analyzed, and clinical trials focused on AYAs launched. Preliminary work laying the foundation for standards of care has been completed.

In the area of awareness and education, programs and workshops for health care providers have been set up and advocacy groups are spreading the word. In the past year, LIVESTRONG has partnered with the American Society of Clinical Oncology to produce the "Focus Under Forty" educational series.

I believe that understanding "outlying" cancers such as those occurring in the AYA age range will lead to new treatments and more supportive approaches to care. We have seen examples in applying pediatric principles to the treatment of young adult ALL, characterization of and differing treatment approaches for premenopausal breast cancer, and genetic screening for early-onset colorectal cancers.

As an oncologist, a cancer researcher, and a survivor of cancer as a young adult, I am proud of the work aimed at improving outcomes for AYA patients, encouraged by the spirit of collaboration to continue seeking answers to the questions I faced, and eager to participate in these continued efforts.

Dr. Brandon Hayes-Lattin
Medical Director, AYA Oncology Program, Knight Cancer Institute,
Oregon Health and Science University
Senior Medical Advisor, Lance Armstrong Foundation

The Web site of the National Cancer Institute (http://www.cancer.gov/).

 Quality Assurance at a Clinical Research Site: A Practical Guide

Alan Lyss, MD, provides advice for implementing a quality assurance program at a clinical research site. Dr. Lyss explains the importance of quality assurance and provides practical tips based on his experience as a community-based clinical investigator. He is an oncologist and investigator at the Missouri Baptist Cancer Center and member of the ASCO Cancer Research Committee. Click here to locate this video and others on the web.