Featured Article

Organ Transplant Recipients Are at Increased Risk for a Range of Cancers

NCI researchers have found higher risks for 32 types of cancer among a group of transplant recipients in the Transplant Cancer Match Study.

Patients who have received a solid organ transplant, such as a kidney, lung, or heart transplant, are twice as likely to develop cancer as the general population, and the risk extends to a broad range of cancers, according to research ²⁹ published November 1 in JAMA.

Doctors have known since the early days of organ transplantation that cancer is a possible complication of this often life-saving procedure. The new study gives researchers the first overview of cancer risk ³⁰ patterns in a large population of solid organ transplant recipients in the United States, including risk patterns for less common cancers.

"The risk is increased for quite a broad group of cancers," said lead investigator Dr. Eric Engels of NCI's Division of Cancer Epidemiology and Genetics ³¹ (DCEG). "By clarifying the spectrum of these cancers, the results of this study encourage us to think about why that might be."

He and his colleagues found higher risks for 32 types of cancer among a group of nearly 176,000 transplant recipients in the Transplant Cancer Match Study ³². Although the risks varied depending on the type of cancer, the overall risk estimate was in line with previous studies.

Much of the increased risk of cancer among organ transplant recipients has been attributed to the medications these patients use to prevent the immune system from rejecting a donor's organ. Suppressing the immune system raises the risk for certain cancers, particularly cancers caused by an infectious agent, such as a virus.

In the current study, non-Hodgkin lymphoma ³³, which can be caused by the Epstein-Barr virus ³⁴, was the most common cancer, and the risk was greatly increased in organ transplant patients compared with the general population. The researchers also found an increased risk of cancers with no established links to infection, including melanoma ³⁵, lip cancer ³⁶, and thyroid cancer ³⁷.

Cancers of the lung ³⁸, kidney ³⁹, and liver ⁴⁰ were also common and occurred at increased rates compared with risks in the general population.

This study underscores the important role of the immune system in the prevention of cancer, noted Dr. Claire Vajdic of the University of New South Wales, Australia, whose research involves organ transplantation and cancer but who was not involved in the study.

"The findings very clearly demonstrate that this population has an increased risk for a remarkably wide range of solid and hematological cancers," she wrote in an e-mail message. "Strategies for preventing cancer in this high-risk population are of paramount importance."

A better understanding of cancer risk in transplant recipients would help clarify the role of the immune system, infections, and other factors in the development of malignancies, the study authors noted. This could also reveal ways to improve the safety of organ transplantation, they added.

Dr. Engels and his colleagues analyzed data on solid organ transplant recipients from the U.S. Scientific Registry of Transplant Recipients (1987–2008) and data from 13 state and regional cancer registries. Most previous studies were not large enough to develop risk profiles for less common cancers.

"We are very excited about this study," said Dr. James Bowman, medical director of the Division of Transplantation within the Health Resources and Services Administration ⁴¹. "Until now, we have not had a way to attach reliable numbers to these less common cancers."

Eventually, Dr. Bowman added, information about cancer risks could help primary care physicians "remain alert" to the potential cancer risks for their patients who have received organ transplants.

The study found high rates of some common cancers within the first 6 months of transplantation, Dr. Vajdic noted. But she cautioned that these rates may include cancers that were present but undetected in organ recipients at the time of transplantation, rather than cancers that resulted from the procedure and immune system suppression.

News reports have occasionally described cases where a patient may have developed cancer after receiving an organ from a donor who had an undiagnosed tumor. But in the current study, Dr. Engels said, this type of transmission probably accounted for no more than a very small fraction of cases, if any.

An unexplained finding from the study was an increased risk of kidney cancer in patients who received organs other than a kidney. Investigators in the United Kingdom recently reported ⁴² a similar result.

"The explanation for this is not known, but our results may lead researchers to ask new questions about why cancers develop in transplant recipients," said Dr. Engels. "It's not just suppression of the immune system that is increasing the risk of cancer; other factors are likely to be involved."

More than four decades have passed since Dr. Israel Penn first reported cancers occurring in transplant recipients. A pioneer in organ transplantation, he started a national registry ⁴³ that spurred research on cancer risks in transplant recipients and laid the groundwork for the current study.

"Organ transplantation is one of the miracles of modern medicine, and it represents a new lease on life for patients with organ failure," said Dr. Engels. "We will continue to do research to learn how to minimize the burden of cancer in these patients."

—Edward R. Winstead ⁴⁴

Cancer Research Highlights

Annual Screening with Chest X-Ray Does Not Reduce Lung Cancer Deaths

Annual screening for lung cancer ³⁸ using a standard chest x-ray does not reduce the risk of dying from lung cancer when compared with no annual screening, according to findings from the NCI-led Prostate, Lung, Colorectal, and Ovarian ⁴⁵ (PLCO) screening trial. The results ⁴⁶ from a median ⁴⁷ of nearly 12 years of follow-up were published online October 26 in JAMA.

Participants in the trial who were randomly assigned to receive an annual chest x-ray for 4 consecutive years had nearly the same mortality rate from lung cancer as participants randomly assigned to receive usual care—that is, care they would typically receive in their own community.

PLCO is one of the largest cancer screening trials ever conducted. The trial involved nearly 155,000 participants between the ages of 55 and 74. Participants were screened for four different cancers at one of 10 designated centers between November 1993 and July 2001.

Unlike participants in the National Lung Screening Trial ⁴⁸ (NLST)—the results of which were initially presented ⁴⁹ late last year—PLCO participants were not at increased risk of cancer. Only 10 percent of participants were current smokers and 42 percent were former smokers. Among participants in the screening arm of the PLCO trial, 91.3 percent were screened at least once and 83.5 percent had all four chest x-rays. Only 11 percent of patients in the usual care, or control, arm of the trial had a chest x-ray to screen for lung cancer during the 4-year intervention period.

In NLST, screening with low-dose helical computed tomography ⁵⁰ (CT) was compared to chest x-ray in patients who were at increased risk of lung cancer, primarily because of their smoking history. The results showed a 20 percent reduction in lung cancer mortality associated with CT. When PLCO researchers looked at the subset of about 30,000 patients in their trial who would have been candidates for NLST based on their smoking history, there was a suggestion of a slight reduction in lung cancer mortality risk associated with screening at 6 and 13 years of follow-up. This finding, however, did not achieve statistical significance ⁵¹.

Only 18 percent of the lung cancers diagnosed in the screening arm of PLCO were diagnosed during the trial's intervention period. But, according to Dr. Christine Berg, of NCI's Division of Cancer Prevention ⁵², the principal investigator of the PLCO and NLST, a longer screening period most likely would not have made a difference given the lack of a mortality reduction in higher-risk participants.

Results from the trial "are as definitive as most studies get," Dr. Berg continued. "They really indicate that lung cancer screening with chest x-ray is of no benefit for reducing lung cancer mortality, regardless of an individual's risk profile."

Research groups are still analyzing the NLST results, Dr. Berg added, including the implications of the high false-positive rate associated with CT screening in that trial.

Radiation Therapy after Breast-Conserving Surgery Improves Survival

Radiation therapy ⁵³ after breast-conserving surgery ⁵⁴ substantially reduces the risk of cancer recurring in the breast and moderately reduces the risk of death from the disease, according to updated results from a meta-analysis ⁵⁵ by the Early Breast Cancer Trialists' Collaborative Group.

The results ⁵⁶, published online October 19 in The Lancet, are based on data from nearly 11,000 women who participated in 17 randomized trials ⁵⁷ that compared breast-conserving surgery with and without radiation therapy. Radiation therapy may help prevent breast cancer ⁵⁸ from recurring or spreading to other parts of the body by eliminating microscopic disease that remains in the breast after surgery.

Overall, the authors reported, radiation therapy was associated with a 16 percent drop in the absolute risk ⁵⁹ of breast cancer recurring in the first decade (from 35 percent to 19 percent); it was also associated with a 4 percent drop in the absolute risk of dying from breast cancer in the first 15 years after surgery (from 25 percent to 21 percent).

The success of radiation in reducing the recurrence of breast cancer depended on which biological subtype of the disease a woman had, the study found. Patients with estrogen receptor-positive ⁶⁰ tumors benefited more than women with estrogen receptor-negative ⁶¹ and triple-negative ⁶² disease.

The nearly 50 percent reduction in the relative risk ⁶³ of a 10-year recurrence of breast cancer exceeds that achieved with chemotherapy alone or hormonal therapy alone, wrote Dr. Thomas Buchholz of the University of Texas M. D. Anderson Cancer Center in an accompanying commentary ⁶⁴. The improvement, he continued, was roughly equivalent to the benefits of trastuzumab ⁶⁵ (Herceptin) for patients with HER2 ⁶⁶-positive breast cancer. 

Screening ⁶⁷, surgery, pathology, radiation therapy ⁵³, and systemic therapy ⁶⁸ have all changed substantially since most of the women entered the trials included in this analysis. Therefore, the absolute reduction in recurrence with radiation therapy in future patients might differ greatly from that recorded in these trials, the authors noted.

Nevertheless, the benefit was seen in a wide range of patients with very different absolute risks. This suggests that the approach might have similar benefits for future patients who receive breast-conserving surgery but who are not comparable with the women included in the trials analyzed here, the authors concluded.

Targeted Therapy Shows Benefit in Rare Type of Thyroid Cancer

Treatment with the multitargeted agent vandetanib ⁶⁹ (Caprelsa) improved progression-free survival ⁷⁰ in patients with medullary thyroid cancer ⁷¹ (MTC), according to findings from a randomized clinical trial ⁵⁷. Earlier this year, the Food and Drug Administration (FDA) approved vandetanib for the treatment of patients with MTC based on initial findings from the phase III trial ⁷². MTC is a rare cancer, accounting for only 5 percent of all thyroid cancer cases, and radiation and chemotherapy have limited effects once the cancer progresses to an advanced stage.

The trial's results ⁷³ were published online October 24 in the Journal of Clinical Oncology.

At 24 months of follow-up, median ⁴⁷ progression-free survival had not yet been reached for patients who received vandetanib, reported Dr. Samuel Wells of the Medical Oncology Branch ⁷⁴ in NCI's Center for Cancer Research and his colleagues. Estimated progression-free survival for the patients treated with vandetanib was 30.5 months, compared with 19.3 months for patients who received a placebo.

The double-blinded ⁷⁵ trial enrolled 331 patients with MTC who were randomly assigned to receive vandetanib or a placebo. All patients had locally advanced disease ⁷⁶ or distant metastases ⁷⁷. If there was evidence that their disease was progressing, patients in the placebo arm could opt to receive open-label ⁷⁸ vandetanib.

In addition to the improvement in progression-free survival, the objective response ⁷⁹ rate was higher and several other disease-related measures were better in the vandetanib arm than in the placebo arm. One of the drug's targets is RET kinase ⁸⁰, and the measurable response rate appeared to be higher in patients with RET mutations than in those without mutations. Because so few patients were defined as not having a RET mutation, the response rate in RET mutation-negative patients remains uncertain.

Because 52 patients in the placebo arm received open-label vandetanib, the authors explained, it may not be possible for the trial to show an improvement in overall survival.

A number of side effects were more common in patients who received vandetanib, including diarrhea, nausea, and hypertension; 12 percent of patients stopped taking the drug because of side effects.

Vandetanib's side-effect profile should influence which patients with MTC receive the drug, wrote Drs. Benjamin Solomon and Danny Rischin of the Peter McCallum Cancer Center in Australia in an accompanying editorial ⁸¹. The 8 percent of patients treated with vandetanib who had QTc prolongation, a type of heart rhythm disturbance, is "particularly concerning," they continued. Because of the risk of QTc prolongation, vandetanib is only available under a Risk Evaluation and Mitigation Strategy ⁸².

Patients with advanced MTC who are not exhibiting symptoms should simply be monitored for evidence of disease progression, Drs. Solomon and Rischin advised. "In contrast, patients who are symptomatic, have a high disease burden, or have rapidly progressing disease stand to benefit the most from treatment with vandetanib."

Study Confirms Letrozole Prevents More Breast Cancer Recurrences than Tamoxifen

After a median ⁴⁷ of 8 years of follow-up from a large randomized trial, women with estrogen-receptor positive ⁶⁰ breast cancer who received 5 years of treatment with the aromatase inhibitor ⁸³ letrozole ⁸⁴ were less likely to have their cancer recur ⁸⁵ or to die during follow-up than women who had 5 years of treatment with tamoxifen ⁸⁶. 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 ⁸⁷, from the BIG 1-98 trial, were published online October 20 in Lancet Oncology.

Researchers from 27 countries enrolled 8,010 postmenopausal ⁸⁸ 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 ⁸⁹ 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 ⁹⁰ 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 ⁹¹ 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."

Study Suggests Smaller Melanoma Excision Margins May Be Option for Some Patients

A randomized controlled trial ⁵⁷ of patients with stage IIA–C cutaneous ⁹² melanoma ³⁵ thicker than 2 mm found that a 2-cm surgical resection margin is sufficient and is as safe for patients as a 4-cm margin in terms of overall survival ⁹¹, according to a report ⁹³ published online October 21 in The Lancet.

The study, which took place from 1992 to 2004 in nine European clinics, assigned 936 patients to receive treatment with either a 2-cm or a 4-cm resection margin. After a median ⁴⁷ follow-up of 6.7 years, 181 patients in the 2-cm margin group and 177 in the 4-cm group had died. Both groups had a 5-year overall survival rate of 65 percent.

Controversies and discussions about optimal surgical excision margins for patients with thick melanomas have lasted many years, according to the study's authors, led by Dr. Peter Gillgren of the Karolinska Institute in Sweden. Wide excisions can lead to poor cosmetic results, lymphedema ⁹⁴, long hospital stays, frequent need for skin grafts, or complicated skin flap reconstructions. "A trade-off exists between a wide excision, with consequent surgical difficulties, and the relapse risk with a narrow excision, which could compromise disease-free survival or, worse, overall survival," the researchers noted.

Several recent studies and a meta-analysis ⁹⁵ by the Cochrane Collaboration have found no significant differences in the rate of local recurrence or in overall survival with smaller excision margins for melanoma. However, prior to the current study "no randomised controlled trial of equal size has been done comparing surgical excision margins of 2 cm and 4 cm for patients with cutaneous melanoma thicker than 2 mm," the researchers wrote.

In an accompanying editorial ⁹⁶, Dr. John Thompson of the Melanoma Institute Australia and Dr. David Ollila of the University of North Carolina at Chapel Hill noted that the current study's conclusions about the comparability of 2-cm versus 4-cm excision widths "need to be tempered by the knowledge that the originally planned equivalence trial design had a target accrual of 2,000 patients, yet fewer than 1,000 were enrolled."

As a result, they explained, the trial lacked the statistical power to prove the two treatment options are equivalent. Instead, the study showed that a 2-cm margin was not inferior to a 4-cm margin. The editorialists also noted that a new clinical trial is being planned to test whether a 1-cm margin is equivalent or noninferior to a 2-cm margin.

HPV Vaccine Reduces Anal HPV Infection and Precancerous Lesions

Results of a study of men who have sex with men revealed that vaccination with the human papillomavirus ⁹⁷ (HPV) vaccine Gardasil ⁹⁸, which protects against HPV types 6, 11, 16, and 18, reduced their risk of persistent anal HPV infection and decreased the incidence of anal intraepithelial ⁹⁹ neoplasia ¹⁰⁰, a lesion known to precede anal cancer ¹⁰¹. The findings ¹⁰² were published October 27 in the New England Journal of Medicine.

The incidence ¹⁰³ of anal cancer has been growing by around 2 percent a year in the general population. Anal cancer is especially prevalent in men who have sex with men.

In the study, researchers led by Drs. Joel Palefsky and Anna Giuliano of the H. Lee Moffitt Cancer Center and Research Institute randomly assigned 602 men between the ages of 16 and 26 to receive the HPV vaccine or a placebo ¹⁰⁴. After 36 months of follow-up, men who received all three doses of the vaccine had 77.5 percent fewer cases of anal intraepithelial neoplasia related to HPV types 6, 11, 16, and 18. The risk of persistent anal infection with the same HPV types was reduced by 94.9 percent. No serious vaccine-related side effects were reported.

Although the study was not long enough to measure the vaccine's effect on anal cancer directly, these results, in agreement with a previous study ¹⁰⁵, suggest that the HPV vaccine may reduce the risk of anal cancer, which is caused by HPV-16 and -18.

"There is currently no routine screening and treatment of anal intra-epithelial neoplasia of grade ¹⁰⁶ 2 or 3 to reduce the risk of anal cancer," the authors explained. "Vaccination may be the best long-term approach to reducing the risks of both anal cancer and anal condyloma ¹⁰⁷."

Special Report

Study Shows Aspirin Reduces Colorectal Cancer in Those at High Risk

High doses of aspirin decreased colorectal cancer incidence in those with Lynch syndrome by nearly 60 percent.

Findings from the first large clinical trial of its kind indicate that taking high doses of aspirin daily for at least 2 years substantially reduces the risk of colorectal cancer ¹²¹ among people at increased risk of the disease.

Conducted in the United Kingdom, the trial, dubbed CAPP2, showed a nearly 60 percent decrease in colorectal cancer incidence ¹⁰³ among men and women with hereditary nonpolyposis colon cancer ¹²² (HNPCC), also known as Lynch syndrome, who took 600 mg of aspirin daily compared to a placebo ¹⁰⁴. HNPCC is an inherited condition in which mutations ¹²³ in certain genes substantially increase the risk of colorectal cancer as well as several other cancers. People with hereditary mutations in these genes, which are involved in a type of DNA repair process called mismatch repair, typically begin developing cancer in their 40s; approximately 15 percent of all colorectal cancers are attributed to defects in mismatch repair genes.

Published October 27 online in The Lancet, the findings ¹²⁴ update the trial's initial results ¹²⁵, published in 2008. At that time, based on a mean ¹²⁶ follow-up of 29 months, use of daily aspirin was not found to reduce the incidence of colorectal cancer or precancerous lesions.

The updated results are based on a mean follow-up of nearly 56 months for 861 participants with HNPCC. Overall, there was a strong trend toward a reduction in colorectal cancer incidence among participants taking aspirin, but the reduction did not reach statistical significance ⁵¹. 

Among participants who took aspirin for at least 2 years (258), however, colorectal cancer incidence fell nearly 60 percent compared to that among participants who took a placebo for the same length of time. At least 2 years of aspirin use was also associated with a 55 percent reduction in other cancers associated with HNPCC, which can include stomach ¹²⁷, ureter ¹²⁸, biliary tract ¹²⁹, skin ¹³⁰ (sebaceous glands), and endometrial ¹³¹ cancers, as well as glioblastoma ¹³².

"Our results, taken in conjunction with recent research, provide a basis for recommendation of aspirin chemoprevention in Lynch syndrome as a standard of care," wrote the trial's lead investigator, Dr. John Burn of Newcastle University, and his colleagues. "The optimum dose and duration of treatment remain to be established."

The findings are the latest to demonstrate aspirin's potential as a cancer prevention agent. Last year, two meta-analyses of findings from other clinical trials involving aspirin (but in which cancer incidence was not a pre-defined endpoint) showed substantial reductions ¹³⁵ in overall cancer risk and colorectal cancer risk associated with regular aspirin use for an average of 4 years.

The only other randomized trial of aspirin that had cancer incidence as a pre-specified endpoint, the Women's Health Study, did not show ¹³⁶ a reduction in overall cancer incidence or any specific cancers. Participants in that trial, however, were not at elevated risk for cancer and took only a 100 mg dose of aspirin every other day, although over a longer period than participants taking high-dose aspirin daily in CAPP2.

The continued follow-up of CAPP2 participants was a pre-specified component of the trial, the researchers explained. "This concept of delayed cancer chemoprevention was apparent in observational studies, in which protection against cancer in regular aspirin users took about 10 years to emerge," they wrote. The longer-term results, they continued, "support the hypothesis of a delayed effect of aspirin on colorectal cancer."

In an accompanying Lancet commentary ¹³⁷, Drs. Scott Lippman and Andrew Chan, of the University of Texas M. D. Anderson Cancer Center and Harvard Medical School, respectively, agreed that the findings "provide a strong rationale for routine use of aspirin in individuals with Lynch syndrome." This should be in addition to continued "intensive cancer surveillance" with standard screening tools, they added.

With the lower incidence of other HNPCC-related cancers among trial participants taking aspirin, further research is also needed on the optimal dose and duration "that gives maximum benefits with minimal side effects" in others at elevated cancer risk, said Dr. Asad Umar of NCI's Division of Cancer Prevention.

Unlike the sporadic forms of colorectal cancer, inflammation does not appear to considerably influence cancer development in people with HNPCC, added Dr. Umar, whose research in the 1990s identified that the genetic mutations associated with this syndrome hindered key DNA repair processes in cells. The primary mechanism of action of aspirin and other nonsteroidal anti-inflammatory drugs, or NSAIDs, is to inhibit the COX1 and COX2 proteins, lynchpins in the body's inflammatory response.

"This work really suggests that, at least in people with HNPCC, aspirin may be working by a very different mechanism of action," Dr. Umar said. (See the sidebar.)

The updated findings from CAPP2 did not include any information on side effects, in particular gastrointestinal bleeding, that have been associated with aspirin and other anti-inflammatory drugs. Determining whether a lower dose could have the same cancer prevention effect will be important, Dr. Umar stressed, because it could limit any toxicity caused by either short- or long-term aspirin use for cancer prevention.

The CAPP2 research team, Dr. Burns said in a Lancet podcast ¹³⁸, will be analyzing tumor samples from participants in the trial's aspirin and placebo arms to see if they can identify differences that can provide some insight into the mechanism. And the CAPP3 trial ¹³⁹ is being launched to test different aspirin doses in people with HNPCC.

—Carmen Phillips ¹⁴⁰

A Closer Look

Tackling the Conundrum of Cachexia in Cancer

By some estimates, nearly one-third of cancer deaths can be attributed to a wasting syndrome called cachexia ¹⁴¹ that can be devastating for patients and their families. Characterized by a dramatic loss of skeletal muscle mass and often accompanied by substantial weight loss, cachexia (pronounced kuh-KEK-see-uh) is a form of metabolic mutiny in which the body overzealously breaks down skeletal muscle and adipose tissue, which stores fat. Patients suffering from cachexia are often so frail and weak that walking can be a Herculean task.

Cachexia occurs in many cancers, usually at the advanced stages ¹⁴² of disease. It is most commonly seen in a subset of cancers, led by pancreatic and gastric cancer, but also lung, esophageal, colorectal, and head and neck cancer.

Despite cachexia's impact on mortality and data strongly suggesting that it hinders treatment responses and patients' ability to tolerate treatment, researchers who study muscle wasting say it has not received the attention it deserves. No effective therapies have been developed to prevent or hamper its progression. Even for patients who are able to eat—appetite suppression or anorexia is a common cachexia symptom—improved nutrition often offers no respite.

And yet, over the last few years, researchers have begun to better understand the underlying biology of cancer-related cachexia. Findings from several studies point to potentially powerful therapeutic approaches, and a number of clinical trials of investigational drugs and drugs approved for other uses have been conducted or are under way.

"It's exciting to see several avenues of investigation coming to the forefront and trials moving forward," said Dr. Aminah Jatoi, a medical oncologist at the Mayo Clinic Comprehensive Cancer Center.

"It's important that oncologists be aware of these trials and offer participation to their patients," said Dr. Jatoi, a member of an international group of clinicians and researchers who earlier this year published a consensus statement ¹⁴³ to more precisely define cancer-related cachexia. The publication also provided a preliminary classification system for the condition—akin in some respects to the staging system ¹⁴⁴ used for tumors. (See the sidebar.)

Cachexia isn't limited to cancer. It is commonly seen in people with AIDS and chronic forms of kidney disease and heart failure, among other conditions, as well as in those who have suffered severe trauma and burns, said Dr. Alfred Goldberg of the Harvard University School of Medicine, whose research on muscle wasting and protein degradation eventually led to the development of the cancer drug bortezomib ¹⁴⁵ (Velcade). With so many potential clinical applications, Dr. Goldberg said, "There really is an enormous therapeutic opportunity here."

Why and How Cachexia Happens

The consensus statement is a good beginning, according to another co-author, Dr. Mellar Davis of the Cleveland Clinic Taussig Cancer Center. But researchers still need to dig deeper into how cachexia develops in patients with cancer, Dr. Davis continued, and how its course is influenced by everything from nutrition and physical activity to disease-specific factors, such as reduced testosterone levels caused by cancer therapy or opioids to treat pain.

Multiple factors are clearly at play in cachexia development and progression, Dr. Goldberg explained. He believes that at its core cachexia is "more of a host response that's evolved to fight fasting, injury, or disease," he said. During this response, the body is trying to obtain additional energy stores from muscle, in the form of amino acids, to convert into glucose to keep the brain functioning. The problem, he continued, "is that we can't turn off this response to the cancer, even when we can provide the patient with essential nutrients."

Many studies suggest that inflammation "is a unifying theme of cachexia across many diseases, including cancer," said Dr. Teresa Zimmers of the Jefferson Kimmel Cancer Center in Philadelphia.

The inflammation is caused in part by the body's immune response to the tumor, which results in the production of pro-inflammatory cytokines ¹⁴⁷, explained Dr. Konstantin Salnikow, of NCI's Division of Cancer Biology ¹⁴⁸ (DCB). Although these cytokines can help to kill tumor cells, some also appear to tilt the body's metabolism ¹⁴⁹ toward catabolism, the breakdown of muscle proteins and fat.

Elevated levels of several cytokines in particular have been closely associated with cachexia and mortality in cancer patients. In NCI-supported mouse model studies, for example, Dr. Zimmers has shown that elevated levels of the cytokine IL-6 ¹⁵⁰ can induce cachexia. She and others have begun to unravel ¹⁵¹ some of the potential mechanisms by which IL-6 may do this.

Searching for Treatments

Despite the incomplete understanding of the underlying biology of cancer-related cachexia, a few potential therapies are moving into early human trials.

More than one drug will likely be needed to successfully combat cachexia, particularly if it's at an advanced stage, said Dr. Barbara Spalholz, also of DCB. "We may have to hit different combinations of targets, depending on the type of cancer and other factors," she said.

The agent that appears to be the furthest along is the selective androgen ¹⁵² receptor modulator GTx-024 ¹⁵³ (Ostarine), developed by GTx Inc., based in Memphis, TN. In August, GTx launched two phase III clinical trials ⁷² of the investigational agent, dubbed POWER1 ¹⁵⁴ and POWER2 ¹⁵⁵, for the prevention or treatment of cachexia in patients with advanced non-small cell lung cancer. 

Researchers and several pharmaceutical and biotechnology companies have increasingly trained their sights on agents that target several members of a family of growth regulators ¹⁵⁶ that appear to have an outsized influence on muscle growth, in particular the proteins activin and myostatin. Myostatin's primary function is to serve as a brake on muscle growth. Sheep, mice, dogs, and cattle with mutations in the gene that produces myostatin are excessively brawny. A case report ¹⁵⁷ published in 2004 found that a German child who at birth "appeared extraordinarily muscular, with protruding muscles in his thighs and upper arms" had a genetic mutation in the myostatin gene.

Two mouse-model studies published last year, one led by Dr. Zimmers and the other by Dr. H.Q. Han at the biotechnology company Amgen, provided strong proof of principle that blocking the activity of myostatin and activin can have a significant impact on cachexia. Both studies used different versions of an investigational agent—an engineered form of a cellular receptor for myostatin and activin called ActRIIB—that acts as a decoy, mopping up these proteins in the circulatory system.

Dr. Zimmers' study ¹⁵⁸ showed that the drug could potently reverse cachexia in a mouse model of colon cancer. Working with a similar mouse model, Dr. Han and his colleagues showed that the treatment not only reversed cachexia but, in a finding ¹⁵⁹ that Dr. Goldberg, a study co-author, called "quite remarkable," allowed treated mice to live substantially longer than untreated mice, even as their tumors continued to grow normally. The study was also the first to demonstrate that targeting myostatin and activin could reverse cachexia-induced heart muscle loss.

An Uphill Climb

Despite the enticing results in mice, unanswered questions and challenges remain, stressed Dr. Se-Jin Lee of Johns Hopkins University, who discovered myostatin and co-developed the first form ¹⁶⁰ of the ActRIIB agent in 2005, in collaboration with scientists from the pharmaceutical company Wyeth, now part of Pfizer.

"One of the most informative studies would be to get muscle samples from patients experiencing wasting and see if the pathway [regulated by activin and myostatin] has been activated," Dr. Lee said.

The ActRIIB agent may need to be refined for use in humans, he continued, because it binds other proteins besides myostatin and activin (one of the reasons it is so potent in mice), which could produce unanticipated and unwelcome side effects.

At least one company, Massachusetts-based Acceleron, has an ActRIIB-targeted agent in two human phase II trials for the treatment of a form of muscular dystrophy. The trials were stopped earlier this year because of treatment-related bleeding issues in patients. Amgen representatives did not respond to inquiries about the developmental status of the agent used in its previous mouse model studies.

"The appeal of targeting this pathway," Dr. Lee said, "is that even if it's not playing a causative role [in muscle wasting], hitting it could have a major clinical benefit in terms of preserving muscle mass."

Dr. Salnikow noted that targeting cachexia could have a spillover effect on the tumor, perhaps robbing cancer cells of molecules they use for energy that are produced by the excess breakdown of muscle. He has other hopes as well.

"If we can identify the early switch to cachexia, we could really prevent the extended cachexic effects and improve patients' ability to withstand therapy," he said.

—Carmen Phillips ¹⁴⁰

Featured Clinical Trial

Cetuximab and Radiotherapy for HPV-Associated Oropharynx Cancer

Name of the Trial
Phase III Randomized Study of Radiotherapy with Cisplatin or Cetuximab in Patients with Human Papilloma Virus-Associated Oropharyngeal Cancer (RTOG-1016). See the protocol summary ¹⁶¹.

Drs. Andy M. Trotti and Maura Gillison

Principal Investigators
Dr. Andy Trotti, Radiation Therapy Oncology Group
Dr. Maura Gillison, Ohio State University Comprehensive Cancer Center

Why This Trial Is Important
Oropharyngeal squamous cell carcinoma ¹⁶² (OSCC) is a type of head and neck cancer ¹⁶³ that forms in the middle part of the throat, which includes the base of the tongue, the tonsils, and the soft palate. Although OSCC was once thought to be a single disease, recent research has revealed that it has two distinct types: cancers that test positive for human papillomavirus ⁹⁷ (HPV) and those that are HPV-negative.

Oropharyngeal tumors negative for HPV have been linked to tobacco and alcohol abuse, whereas HPV-positive malignancies may be related to sexual behavior. Patients with HPV-associated OSCC are likely to be younger at the time of diagnosis and have a better prognosis ¹⁶⁴ than those with HPV-negative malignancies. In contrast with the rates of other oral cancers, which have fallen as smoking rates have declined, the incidence of HPV-positive OSCC is on the rise ¹⁶⁵.

Current treatment strategies for oropharyngeal cancer are based on tumor stage ¹⁶⁶, rather than HPV status, and consist of surgery or radiation with or without cisplatin ¹⁶⁷-based chemotherapy ¹⁶⁸. Cancer response rates ¹⁶⁹ following cisplatin-based chemotherapy and radiotherapy ¹⁷⁰ are generally good, but studies have shown ¹⁷¹ that this combination treatment approach dramatically increases toxic side effects. Since more than 80 percent of patients with HPV-positive tumors survive at least 5 years after diagnosis, these patients may do just as well on a less-toxic regimen.

One study ¹⁷² investigating the combination of cetuximab ¹⁷³, a monoclonal antibody ¹⁷⁴ directed against a protein called EGFR ¹⁷⁵, and radiotherapy in head and neck cancer demonstrated improved patient survival compared with radiation alone. The use of this combination increased skin irritation, but otherwise it had the same side effects as radiotherapy alone. An analysis ¹⁷⁶ of patients in this trial revealed that those with OSCC who were male and younger, a group that mirrors the HPV-positive population, benefited most from the combination therapy. These results suggested that radiation plus cetuximab, instead of cisplatin-based chemotherapy, may reduce treatment toxicity without compromising cancer control for patients with HPV-positive OSCC.

In this clinical trial, patients with HPV-positive OSCC will be randomly assigned to receive cisplatin chemotherapy plus intensity-modulated radiation therapy ¹⁷⁷ (IMRT) or cetuximab plus IMRT. Prior to treatment, patients will complete a computer-administered survey on head and neck cancer risk factors, including tobacco exposure, alcohol use, and oral hygiene. During and after treatment, patients will also report the toxic side effects they experience. Clinicians will monitor the patients for tumor response, toxicity ¹⁷⁸, quality of life, progression-free survival ⁷⁰, and overall survival ⁹¹.

"This is the first randomized phase III trial specific to the HPV-positive patient population," said Dr. Gillison. "There are a lot of quality of life outcomes incorporated [into the trial] about both acute toxicity and long-term toxicity, and the patients are reporting their toxicity experience directly on things like nausea, vomiting, ability to swallow, pain, and energy level using touch-screen surveys.

"It also includes things that we have never looked at before, which will allow us to do a cost-effectiveness analysis. The first potential outcome is that one of the treatments is better than the other. Then we get an answer in terms of disease control. If the two treatments are equivalent, then we see which one gives the patient the best quality of life. There is also the possibility that they are equal and one of them has a cost-benefit to society over the other," Dr. Gillison added.

For More Information

See the lists of entry criteria ¹⁷⁹ and trial contact information ¹⁸⁰ or call the NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). The toll-free call is confidential.

CDC Update

Committee Recommends Routine HPV Vaccination for Boys

On October 25, the Advisory Committee on Immunization Practices ¹⁸¹ (ACIP) voted to recommend the routine vaccination of 11- and 12-year-old boys with the quadrivalent human papillomavirus ⁹⁷ (HPV) vaccine, Gardasil ⁹⁸. The committee stated that vaccination could begin in boys as young as 9 and that males between the ages of 13 and 21 who have not yet received the vaccine should also be vaccinated.

The ACIP provides advice to government agencies to reduce the incidence of vaccine-preventable diseases and to increase the safe use of vaccines and related biological products. The Centers for Disease Control and Prevention (CDC) will review the committee's recommendations before deciding whether to approve them. (The guidelines will become official when published in CDC's Morbidity and Mortality Weekly Report).

HPV is the most common sexually transmitted infection in the United States, with approximately 20 million Americans currently infected. Most infections are cleared by the immune system, but some persist. These persistent infections are associated with genital warts, as well as with cancers of the cervix, vulva, vagina, penis, anus, and head and neck. The HPV vaccine works by preventing infections by specific HPV virus types and is most effective when given before exposure to the virus.

In 2009, the committee voted to support ¹⁸² the use of Gardasil to prevent genital warts in males but did not recommend routine vaccination of boys. Last week, the committee strengthened its 2009 vaccine recommendation for boys because new data from clinical trials demonstrated the vaccine's effectiveness in males. Given the low rates of HPV vaccination in girls ¹⁸³, the committee also noted that vaccinating boys should reduce the rate of HPV infections in females.

CDC Launches Initiative to Prevent Infections among Cancer Patients

¹⁸⁴

Some cancer patients undergoing chemotherapy have a very low white blood cell ¹⁸⁵ count, called neutropenia, which leaves them less able to fight infections. As a result, these patients are at increased risk of serious infections. In patients with neutropenia, infections that would ordinarily be minor can become life-threatening.

To help cancer patients and doctors become aware of—and lower—the risk of infection, the Centers for Disease Control and Prevention have launched a new website ¹⁸⁴. The website features questionnaires for patients and caregivers about the risk of neutropenia, offers tips for preventing infection, highlights the signs and symptoms of an infection, and offers advice on what patients should do if they think they might have an infection.

Cancer.gov Update

Recovery Act Funds Advances in Breast Cancer Detection, Treatment, and Prevention

¹⁸⁶

The NCI Recovery Act website ¹⁸⁷ features a new article ¹⁸⁸ about how Recovery Act funding is enabling researchers to address the public health burden of breast cancer ⁵⁸. The article highlights three Recovery Act-funded projects, each addressing a different challenge associated with the disease.

The article discusses researchers who are working to improve breast cancer treatment and survival while also avoiding the use of aggressive surgery or chemotherapy when less-intensive treatment would provide equal benefit to the patient. It also covers investigators focused on breast cancer prevention and understanding how behavioral and neighborhood factors help identify specific populations that may require more interventions, and how to tailor those interventions strategically.

Through Recovery Act-funded research, scientists are making strides in understanding the complexities of breast cancer, how breast cancer affects different people, and how to address these variables.

Online Education and Training for Health Professionals Now Easily Accessible

¹⁸⁹

NCI has organized its education and training materials for health professionals in one convenient location. The resources found on the Education and Training for Health Professionals webpage ¹⁹⁰ are designed to help meet the cancer educational needs of health care providers, public health program planners, researchers, and cancer registrars. The targeted training resources will help these audiences increase their capacity to deliver state-of-the-art cancer care and up-to-date cancer information to the public.

The training materials cover a range of critical cancer topics, including clinical trials, patient care, evidence-based cancer control program planning, translational research ¹⁹¹, and cancer registries and their operation. Courses are available in several formats, including online self-study, CD/DVD, downloadable material, webinars, podcasts, and animated tutorials.