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Originally published as JCO Early Release 10.1200/JCO.2007.15.4088 on December 17 2007 © 2008 American Society of Clinical Oncology.
Clinical Cancer Advances 2007: Major Research Advances in Cancer Treatment, Prevention, and Screening—A Report From the American Society of Clinical Oncology
From the American Society of Clinical Oncology, Alexandria, VA Address correspondence to: Todd Bentsen, American Society of Clinical Oncology, 1900 Duke St, Suite 200, Alexandria, VA 22314; e-mail: bentsent{at}asco.org
A MESSAGE FROM ASCO'S PRESIDENT: For the third year, the American Society of Clinical Oncology (ASCO) is publishing Clinical Cancer Advances: Major Research Advances in Cancer Treatment, Prevention, and Screening, an annual review of the most significant cancer research presented or published over the past year. ASCO publishes this report to demonstrate the important progress being made on the front lines of clinical cancer research today. The report is intended to give all those with an interest in cancer care—the general public, cancer patients and organizations, policymakers, oncologists, and other medical professionals—an accessible summary of the year's most important cancer research advances. These pages report on the use of magnetic resonance imaging for breast cancer screening, the association between hormone replacement therapy and breast cancer incidence, the link between human papillomavirus and head and neck cancers, and the use of radiation therapy to prevent lung cancer from spreading. They also report on effective new targeted therapies for cancers that have been historically difficult to treat, such as liver cancer and kidney cancer, among many others. A total of 24 advances are featured in this year's report. These advances and many more over the past several years show that the nation's long-term investment in cancer research is paying off. But there are disturbing signs that progress could slow. We are now in the midst of the longest sustained period of flat government funding for cancer research in history. The budgets for the National Institutes of Health and the National Cancer Institute (NCI) have been unchanged for four years. When adjusted for inflation, cancer research funding has actually declined 12% since 2004. These budget constraints limit the NCI's ability to fund promising cancer research. In the past several years the number of grants that the NCI has been able to fund has significantly decreased; this year, in response to just the threat of a 10% budget cut, the nation's Clinical Trials Cooperative Groups reduced the number of patients participating in clinical trials by almost 2,000 and senior researchers report that many of the brightest young minds no longer see the promise of a career in science, choosing other careers instead. It's time to renew the nation's commitment to cancer research. Without additional support, the opportunity to build on the extraordinary progress to date will be lost or delayed. This report demonstrates the essential role that clinical cancer research plays in finding new and better ways to care for the more than 1.4 million people expected to be diagnosed with cancer this year. I want to thank the Editorial Board members, the Specialty Editors, and the ASCO Cancer Communications Committee for their dedicated work to develop this report. I hope you find it useful. Sincerely, Nancy E. Davidson, MD President American Society of Clinical Oncology
Clinical Cancer Advances is an independent annual review of the top advances in cancer treatment, prevention, and screening across all cancer types, conducted by the American Society of Clinical Oncology (ASCO). Over the past three decades, investment in clinical cancer research, prevention, and screening has reduced cancer incidence and death rates, increased survival rates, and significantly reduced the symptoms and side effects of cancer and its treatment. The latest statistics show that cancer death rates decreased by 2.1% per year from 2002 to 2004, almost twice the annual decline of 1.1% per year from 1993 to 2002. Today, there are more than 10 million cancer survivors in the United States. This report documents 24 of the most significant advances on the front lines of cancer research over the past year, including six that the editors of this report consider major advances. This year, major advances can be grouped into two categories:
While much progress has been made, cancer still takes a tremendous toll, and new, more effective prevention and treatment strategies are urgently needed. The United States is currently in the midst of the longest sustained period of flat government funding for cancer research in the country's history. When adjusted for inflation, the budget of the NCI has actually declined 12% since 2004. Without additional support, the opportunity to build on the extraordinary progress to date will be lost or delayed.
Summary of Findings Prevention and Screening Advances. Several studies helped expand knowledge about how to best screen for certain cancers, and how to prevent cancer from both forming and spreading. Role of MRI for Breast Cancer Screening. The use of magnetic resonance imaging (MRI) to detect breast cancer has generated significant debate. While some studies have suggested that MRI may be better able to detect some breast cancers compared with mammography, the cost, high rate of false-positives, and inconsistent standards for performing MRIs have made broad use impractical. This year, new guidelines and findings from several studies provided additional guidance about how MRI should be used for breast imaging:
It is important to note that despite the benefits of breast MRIs for women in high-risk groups, MRI is not yet recommended for the majority of women as a screening tool for breast cancer because of the cost, lack of standards, and high rate of false positives, which can lead to unnecessary biopsies. Mammograms are still considered the best screening tool for women who are at normal risk for breast cancer. Role of HPV Infection in Head and Neck Cancers. Two studies shed light on the role that HPV (the virus present in virtually all cervical cancers) plays in the development of head and neck cancers. The studies suggest a possible role for the recently approved HPV vaccine in preventing head and neck cancers.
Decreasing Use of Hormone Replacement Therapy Linked to Declines in Breast Cancer Cases. Two studies this year reported that the recent significant reduction in breast cancer incidence appears to be associated with the declining use of hormone replacement therapy (HRT) in menopausal women. The use of HRT declined beginning in 2002, following a report from the National Institutes of Health (NIH)–sponsored Women's Health Initiative that linked the use of estrogen plus progestin during and after menopause with a number of adverse effects, including an increased risk for invasive breast cancer. While other factors that could have played a role in the decreased incidence (eg, recent declines in mammography screening rates and changes in diet) could not be completely ruled out as contributors, the association with HRT was strong. Preventive Radiation Therapy Improves Survival for Patients With Small-Cell lung Cancer. Researchers reported for the first time that radiation therapy to the head for patients with advanced small-cell lung cancer cuts the risk that the cancer will spread to the brain by about two-thirds, and as a result extends patients' lives. In this study, radiation prevented the deterioration of physical and psychological functioning that can occur when cancer spreads to the brain. Previous studies have showed that radiation therapy to the head can extend survival in patients with earlier stage small-cell lung cancer, but this was the first study to evaluate the treatment in patients with advanced disease who have a higher likelihood of developing brain metastases and lower survival rates.
Two studies of anticancer therapies that target specific molecular defects of cancer cells stood out as advances that have the potential to change the standard of care for some liver and kidney cancers, which have proven particularly hard to treat. Sorafenib Improves Survival in Liver Cancer. Primary liver cancer (cancer starting in the liver rather than spreading to the liver from other organs or sites) is the third leading cause of cancer death globally, often resulting in death within a year of diagnosis. In a significant advance in the treatment of the disease, a large study found that patients who took the targeted therapy sorafenib (Nexavar) for hepatocellular carcinoma (the most common type of liver tumor) lived approximately 44% longer than patients who did not receive the anticancer drug. Sorafenib is currently approved by the US Food and Drug Administration (US FDA) for treating a form of advanced kidney cancer and is being evaluated in patients with other cancers as well. Bevacizumab Improves Treatment of Advanced Kidney Cancer. A large multicenter study showed adding bevacizumab (Avastin) to interferon-alfa2a (an older kidney cancer drug) as a first-line treatment for advanced kidney cancer improves progression-free survival—the length of time during and after treatment that the cancer does not grow. Adding bevacizumab nearly doubled progression-free survival, from 5.4 months to 10.2 months. Bevacizumab is approved by the US FDA for the treatment of metastatic colorectal cancer and non–small-cell lung cancer. Historically, there have been few effective treatments for renal cell carcinoma, the most common type of kidney cancer. In the past 2 years, however, three targeted therapies have proven effective at either increasing survival or increasing progression-free survival and have received US FDA approval—sorafenib, sunitinib (Sutent), and temsirolimus (Torisel). Future trials are expected to either compare bevacizumab to these drugs or evaluate it in combination with these new therapies.
The American Society of Clinical Oncology—the leading medical society representing more than 25,000 oncologists and other professionals worldwide who care for people with cancer—has developed this report to demonstrate the important progress being made in clinical cancer research and to highlight emerging trends in the field. The report is also intended to fill a gap in cancer literature. It is the only published report to highlight the major advances in clinical cancer research and care each year, and it is written for everyone with an interest in cancer care: the general public, cancer patients and organizations, policymakers, oncologists, and other medical professionals. This report, now it its third year, was developed under the guidance of a 21-person editorial board made up of leading oncologists and other cancer specialists, including specialty editors for each of the disease-specific and issue-specific sections. The editors reviewed research published in peer-reviewed scientific journals and the early results of research presented at major scientific meetings over a 1-year period (October 2006 to September 2007). Only studies that significantly altered the way a cancer is understood or had an important impact on patient care were included. Research in each section is divided into "major advances" and "other notable research," depending on the impact of the advance on patient care and survival. While important research is underway in all cancer types, advances that met the above criteria were not demonstrated in all types of cancer over the past year. Studies included in this year's report are grouped as follows:
The research considered for this report covers the full range of clinical cancer issues:
Cancers of the Blood and Lymphatic System. Cancers of the blood and lymphatic system (also called "hematologic" cancers) include leukemias, lymphomas, multiple myeloma, and myelodysplastic syndromes. A number of promising advances for hematologic cancers were made in the past year, including treatments for multiple myeloma and two types of leukemia—acute promyelocytic leukemia and chronic myelogenous leukemia.
Notable Research In 2007, a study showed that the drug is more effective than standard therapy when added to treatment for patients newly diagnosed with APL as well. A multi-institutional phase III clinical trial found that the addition of arsenic trioxide to standard therapy significantly increases survival among adult patients with newly diagnosed APL. In this trial, overall survival was 86% in the arsenic trioxide arm versus 77% in the standard arm (which involves three stages of treatment known as induction, consolidation, and maintenance therapy).1 Dasatinib Active As a First-Line Treatment for Chronic Myelogenous Leukemia. Results of a phase II trial showed that dasatinib (Sprycel) results in high hematologic and cytogenetic response rates when used as a first-line treatment for early-stage chronic myelogenous leukemia (CML). This is the first study to look at dasatinib as a first-line treatment in patients newly diagnosed with the most common stage of CML, called chronic phase. The patients in the study received dasatinib orally every day. After 3 months, complete hematologic response, defined as normal blood counts and no enlargement of the spleen, occurred in 81% of patients. Complete cytogenetic response, defined as no evidence of the "Philadelphia" chromosome (which encodes the bcr/abl protein implicated in CML) in the bone marrow, occurred in 73% of patients. After 6 months, 95% of patients had complete cytogenetic response. Dasatinib was approved by the US FDA in 2006 as a second-line treatment for CML patients who have developed resistance to imatinib (Gleevec), the standard first-line treatment. Both drugs are targeted therapies that bind to and inhibit bcr/abl, the mutated protein that causes CML. Imatinib binds to the protein only when it is in its "closed" form, while dasatinib binds to the protein in both its closed and "open" forms.2 Lenalidomide and Bortezomib More Effective Together for Myeloma. Multiple myeloma, a cancer of the bone marrow, has historically been difficult to treat. A phase I clinical trial found that the combination of two drugs designed to treat multiple myeloma may be more effective together than when the drugs are used individually. The trial tested the drugs bortezomib (Velcade) and lenalidomide (Revlimid) in patients with myeloma whose disease had recurred and was progressing despite prior treatment with other therapies. The researchers found that 58% of patients responded to lenalidomide and bortezomib, including 6% who had complete remission. The median duration of remission was 6 months, with some patients experiencing remission for up to 2.5 years. Bortezomib, which was approved by the US FDA in 2003, interferes with the ability of myeloma cells to break down and dispose of certain proteins, a process they need to grow and spread. Lenalidomide, approved by the US FDA for myeloma in 2006, disrupts the way tumor cells interact with surrounding tissue in the bone marrow.3
Over the past few decades, improvements in early detection and the development of more effective treatments have led to significant declines in breast cancer deaths and improved outlook for women living with the disease. Increasingly, breast cancer is being treated as a group of diseases rather than as a single disease. The molecular characteristics of each person's tumor cells are taken into account when treatment options are considered. For example, identifying whether specific hormone receptors are present in a patient's cancer cells can help determine whether therapies targeted at those receptors will help an individual patient. Improved prognostic methods also help determine how aggressive a patient's treatment should be. This year, magnetic resonance imaging (MRI) was recommended for breast cancer screening in specific groups of patients. In addition, a decline in breast cancer incidence rates was linked to a reduction in the use of hormone replacement therapy. Another large trial looked at the best way to deliver radiation therapy to patients after they have had surgery for early-stage disease.
MRI for Breast Cancer Detection. The use of MRI to detect breast cancer has generated significant debate. While some studies have suggested that MRI may be better able to detect some breast cancers compared with mammography, the cost, high rate of false-positives, and inconsistent standards for performing MRIs have limited its potential usefulness. This year, findings from several studies led to new guidelines about the use of MRI for breast imaging:
Despite the benefits of breast MRIs for women in high-risk groups, however, MRI is not yet recommended for the majority of women as a screening tool for breast cancer because of the cost and inconsistent standards for performing MRI. MRIs are also highly sensitive and not specific, resulting in a high rate of false-positives, which can lead to unnecessary biopsies. It has not yet been shown that MRI screening improves overall survival or other outcomes. Decreasing HRT Use Linked to Declines in Breast Cancer Incidence. Two studies this year reported a link between the recent reduction in breast cancer incidence and the decline in the use of HRT in menopausal women. HRT use declined beginning in 2002, following a report from the NIH-sponsored Women's Health Initiative that linked the use of estrogen plus progestin during and after menopause with a number of adverse effects, including an increased risk for invasive breast cancer. In 2007, one large study found that rates of breast cancer declined by 13% from 2001 to 2003. Both studies found that declines in breast cancer occurred only in women aged 50 years or older, and were more significant in breast cancers that are estrogen receptor–positive, the type of cancer whose growth could be fueled by the use of additional hormones. Both studies analyzed large databases of patients and examined other factors that could have played a role in the decreased incidence, such as mammography screening rates and changes in diet. While those factors could not be completely ruled out as additional contributors, the association with HRT was strong, warranting further study.8,9
Other Notable Research Conventional radiation therapy for women with early breast cancer is typically given at a consistent dose, delivered in 25 installments (fractions), 5 days a week over a period of 5 weeks. Physicians hypothesized that it may be possible to reduce the overall radiation dose and the treatment period without compromising the safety or effectiveness of therapy. This trial comprised two different studies that looked at different variations in radiation dose. After an average follow-up of 5 to 6 years, the incidence of local recurrence remained low among all patients in both trials (3.4% of patients had local relapse with no significant difference between radiation regimens).10
Treating tumors of the CNS and the brain in particular represents a unique clinical challenge. Although clinical trials over the past 25 years have evaluated a variety of drugs and treatment delivery systems, the prognosis for people with brain tumors has remained largely unchanged. This year, a clinical trial showed for the first time that a combination of drugs shrinks gliomas, the most common form of brain cancer, which has been particularly difficult to treat. Another study showed that radiation therapy can benefit elderly patients with glioblastoma.
Notable Research Radiotherapy Improves Survival of Elderly Patients With Glioblastoma. A study found that patients 70 years of age or older with glioblastoma (a fast-growing, often fatal type of brain tumor) who received radiotherapy in addition to supportive care to relieve symptoms lived 53% longer than those who received supportive care alone. Median survival for the radiotherapy group was 29 weeks versus 17 weeks for the group that received supportive care alone. There were no severe side effects related to the radiation treatments, and the quality of life and cognitive functions did not differ between those receiving radiation and those receiving supportive care alone. The study is significant because there is currently no standard treatment for patients in this age range.
GI cancers include those of the esophagus, stomach, liver, pancreas, biliary tract, colon, rectum, and anus. The ability to effectively treat these cancers varies significantly. For example, while many colorectal cancers can be diagnosed in their early, more curable stages using colonoscopy, no such screening tests exist for less common cancers of the digestive tract—such as those of the pancreas, which are often diagnosed when they are advanced and difficult to treat effectively. In 2007, research investigated the use of targeted therapies to treat a variety of GI cancers. In addition, a large study found a link between diets high in fat and an increased risk of recurrence and death in patients with colorectal cancer that had spread to the lymph nodes.
Major Advance In this study, patients who received sorafenib lived a median of 10.7 months compared with 7.9 months for those who received a placebo. Time to cancer progression was also significantly longer in the treatment group: 5.5 versus 2.8 months. The study was terminated early due to the positive results.13
Other Notable Research The study was the first to evaluate this combination, providing a new treatment option and enabling more patients to have their tumors surgically removed. Cetuximab is currently approved by the US FDA as second-line or third-line therapy, meaning it is used to treat advanced colorectal cancer that has continued to grow despite previous therapy.14 High-Fat Diets Linked to Recurrence of Colon Cancer. A large observational study of patients with stage III colorectal cancer (cancer that has spread to the lymph nodes) found that some dietary patterns were linked to a higher risk of disease recurrence and death following surgery than others. The study was designed to evaluate the benefits of two forms of adjuvant chemotherapy (additional treatment given after the primary treatment for disease). Because both treatments resulted in identical outcomes, researchers were able to study the entire study population as a single group. The investigators compared the likelihood of recurrence among those who ate a more traditional "Western" diet, characterized by high intakes of meat, fat, refined grain, and dessert, to those who ate a "prudent" diet, in which patients consumed large quantities of fruits, vegetables, poultry, and fish. Patients on the Western diet were 3.25 times more likely to have their cancer return or to die compared with the patients on the prudent diet. Further research is needed to determine which specific nutrients or food types may have the strongest link to patient outcome.15
Genitourinary cancers include cancers of the prostate, kidneys, testicles, and bladder/urethra. The most significant research finding this year identified a new potential treatment for kidney cancer. Research showed that bevacizumab, a drug that has been approved by the US FDA for the treatment of metastatic colorectal cancer and non–small-cell lung cancer, was also effective against renal cell carcinoma. Historically, there have been few effective treatments for renal cell carcinoma, the most common type of kidney cancer. In the past 2 years, however, three targeted therapies have proven effective in increasing survival and have received US FDA approval—sorafenib, sunitinib, and temsirolimus.
Major Advance Bevacizumab targets a protein called vascular endothelial growth factor (VEGF), which stimulates new blood vessel formation. When bevacizumab binds to VEGF, the protein cannot stimulate the growth of blood vessels, cutting off oxygen and other nutrients the tumor needs to grow. Future studies are likely to test bevacizumab as a single agent for first-line treatment of kidney cancer by directly comparing it against sorafenib, sunitinib, and temsirolimus as well as evaluating it in combination with those and other drugs.
Gynecologic cancers include cancers of the cervix, uterus, ovaries, fallopian tubes, vulva, and vagina. Endometrial cancer, which makes up approximately 95% of all uterine cancers diagnosed, is the most common gynecologic cancer in the United States, affecting about 39,000 women each year.
Notable Research About half of the women received EBRT after surgery and half did not. After a median follow-up of more than 4 years, neither overall survival nor likelihood of recurrence differed significantly between the two groups. However, the incidence of side effects in the radiation therapy group was nearly double that in the surgery group: 61% compared with 31%. The most common side effects were fatigue, diarrhea, and increased urinary frequency.17
Cancers of the head and neck—those affecting the nose, mouth, throat, tongue, and larynx, as well as the thyroid gland—are usually treated with a combination of surgery, chemotherapy and/or radiation therapy. In the past year, there were two major findings that explored the link between head and neck cancers and human papillomavirus (HPV), the virus that causes the majority of cervical cancer cases. In addition, targeted therapies showed promise for a number of different types of head and neck cancer.
Major Advance
Other Notable Research Axitinib Shows Activity Against Advanced Thyroid Cancer. The standard treatment for thyroid cancer is surgery and/or radioactive iodine, which cures a large percentage of patients. But there are currently few treatments for patients who do not respond to those therapies. This year, the first phase II clinical trial to evaluate the experimental drug axitinib in patients with advanced thyroid cancer showed that the drug has substantial antitumor activity. In this study, 22% of patients experienced tumor shrinkage, which lasted from 1 to 16 months. In another 50% of patients, tumors stopped growing. All of the patients had thyroid cancer that had advanced despite other treatments. Axitinib, which is given orally as a pill, inhibits receptors of vascular endothelial growth factor, which plays a role in tumor formation by promoting the growth of blood vessels that feed tumors.21
Lung cancer incidence and mortality have slowly but steadily declined in recent years, due to a decrease in cigarette smoking over the past several decades, particularly among men. However, the disease remains the leading cause of cancer deaths in the United States, and is expected to kill more than 160,000 people in 2007. Progress has also been made in lung cancer treatment. Some targeted therapies are proving effective against lung cancer, and research has shown conclusively that giving chemotherapy after surgery can extend patients' lives. Researchers are learning that specific characteristics of an individual's tumor may help predict prognosis and response to treatment—a treatment approach known as personalized medicine. In 2007, research showed that, in addition to early-stage cancer, patients with advanced small-cell lung cancer benefit from preventive radiation therapy to the head to decrease the spread of cancer to the brain and prolong survival. Small-cell lung cancer is difficult to cure and is diagnosed in nearly 30,000 people (or about 15% of all patients with lung cancer) in the United States each year.
Major Advance This is important because when cancer spreads to the brain, it leads to the deterioration of physical and psychological functioning. Previous studies showed that radiation therapy to the head can extend survival in patients with earlier stage small-cell lung cancer, but this was the first study to evaluate the treatment in patients with advanced disease, who have an even higher risk of developing brain metastases. After 1 year, the radiation therapy group had significantly fewer brain metastases-causing symptoms (15%) than the control group (40%). Moreover, 27% of the patients in the radiation therapy group were alive after 1 year, compared with only 13% of patients who did not receive the treatment.22,23
Significant progress has been made over the past several decades in treating childhood cancer, with overall 5-year survival now at nearly 80%, compared with 58% about 30 years ago. This is due, in part, to the fact that most childhood cancer patients are treated in clinical trials, where they have access to cutting-edge therapies, and are closely monitored. However, long-term side effects of cancer treatment continue to be a problem. This year, a large international trial found that the intensity of treatment for the rare childhood cancer neuroblastoma can be greatly reduced, maintaining high survival rates while lowering major side effects such as organ damage and hearing loss. Another study looked at programs for improving childhood cancer treatment in low- and middle-income countries and found that relatively small monetary investments aimed at the specific needs of each country can improve the treatment of children with cancer.
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