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Originally published as JCO Early Release 10.1200/JCO.2006.09.7030 on December 8 2006 © 2007 American Society of Clinical Oncology.
Clinical Cancer Advances 2006: 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 reprint requests 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 second consecutive 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 developed this report to demonstrate the enormous progress being made on the front lines of cancer research today. The report is intended to give all those with an interest in cancer care—the general public, cancer patients and physicians, policymakers, oncologists, and other medical professionals—an accessible summary of the year's most important cancer research advances. These pages report on new targeted therapies that are improving survival and response rates in hard-to-treat cancers such as kidney cancer, HER-2–positive breast cancer, head and neck cancer, and chronic myelogenous leukemia; the FDA’s approval of the world's first preventive vaccine for human papillomavirus (HPV), which has the potential to dramatically reduce the global burden of cervical cancer; and advances in the fast-growing field of personalized medicine, including a new lung cancer test that could help physicians better target treatments and predict prognosis. These advances are only part of the landscape. Survival rates are on the rise, the number of cancer deaths in the United States began declining for the first time since 1930, and new research is showing that the rates of certain common cancers, such as those of the breast and colon, have stabilized, and may have even begun to decline. However, cancer research still faces a number of major obstacles. At a time of extraordinary scientific potential, declining federal funding of cancer research threatens to stall or even reverse recent progress. Such funding cuts have already led to fewer clinical trials, fewer talented young physicians entering the field, and a growing bottleneck of basic science discoveries waiting to be "translated" into useful therapies and diagnostics. In addition to highlighting the major research advances over the past year, this report also identifies key barriers to accelerating the pace of cancer research and outlines ASCO's recommendations for overcoming them. Despite these and other challenges, there is much good news on the front lines of cancer research. This report demonstrates the essential role of clinical cancer research in finding new and better ways to treat, diagnose, and prevent a group of diseases that strike half of men and one-third of women in the United States. I want to thank the Editorial Board members, the Specialty Editors, and the ASCO Cancer Communications Committee and Cancer Research Committee for their dedicated work to develop this report. I hope you find it useful. Sincerely, Gabriel N. Hortobagyi, MD, FACP 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 last 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 number of U.S. cancer deaths dropped slightly in 2003, the first such decline since 1930, and today, there are nearly 10 million cancer survivors in the United States. This report documents the most significant advances on the front lines of cancer research. This year, major research advances can be grouped in three categories:
While much progress has been made, cancer still takes a tremendous toll, and new, more effective prevention and treatment strategies are urgently needed. With extraordinary recent advances in the understanding of the human genome and the inner workings of cancer cells, researchers have never been in a better position to accelerate progress against cancer. Yet significant obstacles stand in the way of realizing this potential. In addition to identifying the major clinical research advances of the year, this report outlines some of the most significant barriers to accelerating the pace of cancer research, and ASCO's recommendations for overcoming them.
Summary of Findings FDA Approves First Vaccine to Prevent HPV Infection. The most significant advance over the past year in both gynecologic oncology and in cancer prevention was the U.S. Food and Drug Administration (FDA) approval of the first vaccine to prevent infection with HPV, a virus present in virtually all cervical cancers. The vaccine has the potential to profoundly reduce the burden of cervical cancer, which is diagnosed in nearly 500,000 women each year globally, including nearly 10,000 women in the United States. The vaccine, known as Gardasil (Merck & Co Inc, Whitehouse Station, NJ), was shown to be 100% effective in preventing HPV 16–and 18–related cervical precancers in women who were not previously exposed to these strains of the virus. These strains together account for approximately 70% of cervical cancer cases worldwide. In addition, an analysis of three large international studies suggests that the vaccine may also be very effective in preventing HPV-related vaginal and vulvar precancers. The approval of the HPV vaccine is a major advance for cancer prevention. Critical to success of the vaccine will be ensuring that women in the world's poorest countries—where cervical cancer is most common—have rapid and affordable access to this life-saving new tool. (See p. 152) Targeted Therapies Effective in Hard-to-Treat Cancers. Several studies stand out as advances that will change the standard of care for a number of hard-to-treat cancers. These include studies demonstrating improved survival and response rates in kidney cancer, HER-2–positive breast cancer, and chronic myelogenous leukemia, as well as a study showing that an existing targeted therapy can improve survival in head and neck cancers—the first new treatment for this disease in 45 years. New therapies prove effective in kidney cancer—Treatment regimens for kidney cancer have not changed in more than two decades. By improving survival rates, the therapies tested in the following two studies represent major advances in the treatment of this disease. (See p. 151)
Lapatinib improves treatment of advanced breast cancer—An international phase III trial showed for the first time that giving the targeted therapy lapatinib (Tykerb; GlaxoSmithKline, Research Triangle Park, NC) with capecitabine (Xeloda; Hoffmann-La Roche Inc, Nutley, NJ) controlled cancer growth more effectively than capecitabine alone in women with advanced HER-2–positive breast cancer that grew despite prior treatment with the drug trastuzumab (Herceptin; Genentech, South San Francisco, CA). The research indicates that lapatinib could be an additional tool for fighting breast cancer that overexpresses the HER-2/neu protein, which accounts for 20% to 25% of all breast cancer cases, and is particularly aggressive and difficult to treat. The FDA is currently reviewing an application for the approval of lapatinib for the treatment of advanced HER-2 breast cancer patients who did not respond to previous therapy, including trastuzumab. (See p. 149) Dasatinib effective in leukemia patients resistant to imatinib—A phase I clinical trial of the new targeted therapy dasatinib (Sprycel; Bristol-Myers Squibb Company, New York, NY) in patients with chronic myelogenous leukemia (CML) who could not tolerate or had become resistant to the drug imatinib (Gleevec; Novartis Pharaceuticals, East Hanover, NJ) showed that 92.5% of these poor prognosis patients had no evidence of disease after receiving dasatinib. In addition, 70% of patients with a more advanced form of leukemia experienced a significant decrease in the number of abnormal blood cells after receiving dasatinib. Following publication of this study, the FDA approved dasatinib for CML in June 2006. (See p. 149) Cetuximab provides first new treatment for head and neck cancer in 45 years—A multinational study found that adding the targeted therapy cetuximab (Erbitux; ImClone Systems Inc, New York, NY) to standard high-dose radiation therapy in patients with locally advanced head and neck cancer slowed cancer growth and prolonged survival, compared with patients who received radiation therapy alone. Patients on cetuximab lived an average of 49 months, compared with 29.3 months for patients who received radiation therapy alone. Following publication of this study, the FDA approved cetuximab to treat head and neck cancer, making it the first drug to be approved for this disease in 45 years. (See p. 153) Researchers Create Genetic Test to Predict Lung Cancer Prognosis—The most significant advance in lung cancer over the past year occurred in the fast-growing field of personalized medicine—the development of new ways to predict the effectiveness or side effects of therapy based on an individual's genetic profile. As scientists learn more about the human genome and each individual's particular genetic make-up, the creation of diagnostic tests and targeted therapies specific to the individual will allow oncologists to better target treatments and predict prognosis. One of the most significant advances in this area over the past year was the creation of a novel gene profiling test that can predict which patients with early-stage non–small-cell lung cancer (NSCLC) are most likely to be cured, as well as those who are most likely to experience a relapse of their disease. The test, called the "lung metagene model," was 72% to 79% accurate in predicting recurrence—a rate more accurate than considering clinical characteristics, such as tumor size, alone. The test was especially helpful in identifying patients with stage "IA" lung cancer for whom chemotherapy after surgery might be appropriate. Current standard treatment for stage IA NSCLC is surgical removal of the tumor, but up to 25% of patients treated with surgery alone experience a recurrence of their disease. Additional studies are planned to confirm the accuracy of this model. If confirmed accurate, the tool could provide an effective means of estimating a patient's risk of recurrence, enabling physicians and patients to make more informed decisions about the use of chemotherapy for early-stage lung cancer. A similar test has been developed and is in clinical use in breast cancer, and a large randomized phase III trial launched in 2006 will examine its ability to select breast cancer patients most likely to benefit from chemotherapy.
Recommendations: Accelerating Cancer Research However, much more needs to be done to ensure that such discoveries move rapidly through the cancer research process. A growing backlog of basic science discoveries are waiting to be studied to determine if they can be "translated" into potentially useful therapies for cancer patients. This problem is compounded by the fact that federal funding of clinical and translational research has been flat for the last several years, and additional budget cuts are possible for fiscal year 2007. To accelerate the pace of cancer research, ASCO recommends two key action steps over the coming year: 1. Increase Funding of Cancer Research. Congress' doubling of the National Institutes of Health (NIH) budget between 1998 and 2003 yielded major new discoveries in all areas of biomedical research, including cancer. However, flat funding since 2003, and possible cuts in 2007, threaten to derail this progress. To avoid losing critical ground in cancer research, ASCO supports annual minimum increases of 5% for NIH, beginning in fiscal year 2007. 2. Advance Research From the Lab to the Clinic: Increasing Access to Biospecimens. Human biospecimens—samples of tissue and blood taken from patients during surgeries, biopsies, or routine tests—play a critical role in the translation of basic science discoveries into clinical applications by allowing researchers to study the molecular characteristics of cancer cells. However, ready access to biospecimens for use in cancer research has become a major challenge. Following are ASCO's recommendations for improving access to human biospecimens a. Standardized collection and storage of biospecimens: There are no common procedures for collecting and storing biospecimens and no consistent quality-control measures. ASCO recommends the development of national guidelines to standardize procedures for collection, storage, and use of biospecimens, and the development of a national database linking National Cancer Institute (NCI)–supported repositories to allow for the sharing of information and expertise across institutions. b. Impact of privacy laws on cancer research: Under the Health Insurance Portability and Accountability Act (HIPAA), in order to use biospecimens, researchers are required to get authorization from every patient for each research project. While ASCO agrees that preserving a patient's right to privacy is important, variations in the interpretation of such privacy regulations have inadvertently made it much more difficult to conduct cancer research. Because the extent of HIPAA's impact is unclear, ASCO recommends that an independent body, such as the Institute of Medicine (IOM), conduct a rigorous review of the law's effect on cancer research, and calls on the U.S. Department of Health and Human Services to issue clear guidance on the implementation of HIPAA provisions across research settings. c. Intellectual property rights: Debate over intellectual property rights—including who owns human biospecimen samples and who owns the right to any discoveries made using the samples—has also limited access to biospecimens. ASCO recommends the creation of a centralized database for biospecimens, which could greatly speed scientific discovery in cancer research. In addition, ASCO calls for a new collaborative effort involving cancer institutions, industry, government, and patient groups to identify ways such information could be shared for the benefit of all parties in cancer research, while maintaining appropriate protection for intellectual property.
To demonstrate the impressive progress being made in clinical cancer research, the American Society of Clinical Oncology—the leading medical society representing nearly 25,000 oncologists and other professionals who care for people with cancer—has developed this report to chronicle the major clinical cancer advances over the previous year, and to identify emerging trends and current issues 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 is written for all those with an interest in cancer care: the general public, cancer patients and organizations, policymakers, oncologists, and other medical professionals. This report, now in its second year, was developed under the guidance of a 20-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 (November 2005-October 2006). 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. Cancers 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 (also called "hematologic" cancers) include leukemias, lymphomas, multiple myeloma, and myelodysplastic syndromes. A number of promising advances involving novel targeted therapies for hematologic cancers were made in the last year, including a particularly important advance in the treatment of leukemias resistant to imatinib (Gleevec). In addition, the FDA approved two new therapies for hematologic malignancies: dasatinib (Sprycel; Bristol-Meyers Squibb, Princeton, NJ) for chronic myelogenous leukemia and lenalidomide (Revlimid; Celgene, Summit, NJ) for myelodysplastic disorders and multiple myeloma.
MAJOR ADVANCE Imatinib was approved by the FDA in 2001 and proved highly effective for the treatment of CML. The oral drug blocks an enzyme produced by a mutation in the BCR-ABL gene, which is involved in the development of certain forms of leukemia. However, some patients develop additional mutations in this gene, causing their cancers to become resistant to the drug. Dasatinib targets these secondary mutations. Following publication of this study, the FDA approved dasatinib in June 2006. Physicians believe that optimal treatment of diseases like CML may involve the combination or sequencing of targeted drugs, or the selection of drugs based on the particular BCR-ABL mutation in the leukemia cells.
OTHER NOTABLE RESEARCH
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 prognosis for women living with the disease. According to the 2006 Annual Report to the Nation on the Status of Cancer, the number of new breast cancer cases in the United States began stabilizing in 2001, and there are signs that it may be declining. In addition, major strides have been made in the treatment of more aggressive forms of breast cancer, such as HER-2 breast cancer with the targeted therapy trastuzumab (Herceptin). Now, new research has identified an additional tool for treating advanced HER-2 breast cancer that is resistant to trastuzumab, while other research is resulting in important confirmatory evidence that trastuzumab can reduce the risk of breast cancer recurrence in women with early-stage HER-2–positive breast cancer. In addition, an NCI-sponsored study from seven institutions underscores the importance of regular screening for breast cancer, showing that both mammograms and adjuvant therapy (chemotherapy following surgery) have played a key role in declining breast cancer mortality over the last decade.
MAJOR ADVANCE In this study, researchers compared the time it took for cancers to grow and spread (time to progression) in 160 women randomly assigned to receive lapatinib plus capecitabine, and 161 women who received capecitabine alone. Time to progression was almost twice as long in the lapatinib/capecitabine group: 36.9 weeks versus 19.7 weeks. Side effects were generally similar between the two groups, though women in the lapatinib group were somewhat more likely to experience mild to moderate diarrhea and rash.3
OTHER NOTABLE RESEARCH
Mammograms and Adjuvant Therapy Played Key Role in Declining Breast Cancer Mortality A study investigating the causes of declining breast cancer deaths indicates that mammograms accounted for 28% to 65% of the decline in deaths over the last several decades, with the remainder due to improvements in chemotherapy treatment after surgery ("adjuvant therapy"). The study, sponsored by the NCI, was designed to assess the effect of mammography and adjuvant treatment on the reduction in breast cancer mortality in the United States from 1975 to 2000. The death rate was nearly flat from 1975 to 1990, before dropping nearly 24% between 1990 and 2000. In the study, a consortium of investigators from seven different institutions developed independent statistical models of breast cancer incidence and mortality to assess the effect of mammography and adjuvant treatment on the reduction in breast cancer mortality. Despite differences in methodology, all seven groups concluded that screening and treatment have contributed to the observed decline in the rate of death from breast cancer and that the decline can be explained by a combination of screening and adjuvant therapy and not by either one alone.7
Primary brain tumors represent a unique clinical challenge. While clinical trials over the last 25 years have evaluated a variety of drugs and treatment delivery systems, the prognosis for people with brain tumors has remained largely unchanged. In 2006, two studies in patients with a type of brain tumor called oligodendroglioma demonstrated that certain molecular characteristics of the tumor may be associated with a better prognosis—a finding that could eventually help physicians select treatment based on the specific genetic profile of the tumor.
NOTABLE RESEARCH The trials, which were designed to assess overall survival between the two treatments, found that patients receiving chemotherapy plus radiotherapy did not live significantly longer than patients who received radiotherapy alone. However, in a secondary finding, researchers discovered that patients whose tumors lacked the 1p and 19q alleles lived longer, indicating that tumors with this genetic profile may be less aggressive, more responsive to therapy, or both. (An allele is an alternative form of a gene.) These trials are the first large phase III studies to validate a link between 1p/19q deletions and patient outcome.
Gastrointestinal 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. While there were no practice-changing studies in 2006, several studies provided information about the most effective treatments for pancreatic cancer and gastrointestinal stromal tumor (GIST).
NOTABLE RESEARCH The trial, conducted by the Eastern Cooperative Oncology Group (ECOG), involved 833 patients who were randomized to receive one of the three regimens. None of the patients had previously received chemotherapy, and the primary end point of the trial was overall survival. Researchers found that the median overall survival for the three arms was 5 months for standard gemcitabine regimen, 6 months for fixed dose-rate gemcitabine, and 6.5 months for GEMOX. The differences were not statistically significant, however. This study adds to several previous studies showing that adding another chemotherapy agent to gemcitabine does not provide any advantage over gemcitabine alone.10 Activity of Sunitinib in Patients With GIST Linked to Mutation Status A new study examining the relationship between the genetic profile of a tumor and the activity of sunitinib (Sutent) in patients with imatinib-resistant GIST found that response to sunitinib is associated with the presence of mutations in the KIT and PDGFRA genes. Imatinib (Gleevec) is a first-line treatment for patients with GIST, but it does not work for all patients, and many develop resistance to the drug over time. Sunitinib, which inhibits enzymes called kinases that play a role in angiogenesis (the growth of blood vessels that feed tumors), has been shown to improve survival in patients whose tumors don't respond to imatinib, and in January 2006 was approved by the FDA for this indication. The trial involved tumor specimens from 97 patients with advanced imatinib-resistant GIST who were taking sunitinib during phase I/II trials. Tumor specimens were collected before and following imatinib therapy and analyzed for KIT and PDGFRA mutations. Researchers found that while all patients benefited from the drug, the benefit was significantly influenced by the type of mutation a patient had. Progression-free survival and overall survival were significantly longer for patients with a primary KIT exon 9 mutation or those lacking KIT or PDGFRA mutations. (An exon is the segment of a gene that contains instructions for making a protein.)11
Genitourinary cancers include cancers of the prostate, kidney, testicles, and bladder/urethra. The most significant research findings this year were in the treatment of kidney cancer. Patients with advanced kidney cancer or kidney cancer not cured by surgery have historically had few treatment options, with just 15% responding to the standard therapies interferon-a or interleukin-2. In December 2005, the FDA approved the targeted therapy sorafenib tosylate (Nexavar) for the treatment of advanced kidney cancer, after studies indicated that the drug slowed disease progression and improved survival. Now, new research is demonstrating that two additional targeted therapies can improve survival and response rates in kidney cancer, providing additional hope for patients living with the disease. In addition, a study in patients with germ cell tumors (primarily testis cancers) provides additional information regarding the risks and benefits of high-dose chemotherapy.
MAJOR ADVANCES The study had three treatment arms—207 patients received interferon-a, 209 received temsirolimus, and 210 received a combination of the two drugs. Median overall survival for the three groups was 7.3 months, 10.9 months, and 8.4 months, respectively. Progression-free survival was 1.9 months, 3.7 months, and 3.7 months, respectively. The most common side effect in all groups was asthenia (weakness and fatigue), which was lower in the temsirolimus group. Temsirolimus had other mild side effects which were easily controlled. The relatively mild toxicity associated with the drug suggests it has the potential to be combined with other agents in future studies.12 Sunitinib Improves Progression-Free Survival in Advanced Kidney Cancer A phase III international trial involving 750 patients with advanced renal cell carcinoma showed that sunitinib (Sutent) improved progression-free survival and response rates when compared with standard treatment, interferon-a. Sunitinib was approved by the FDA in January 2006 as a second-line treatment for advanced renal cell cancer in patients whose cancer had progressed following treatment with immune therapies. This study was the first to assess the drug in previously untreated patients. In the trial, none of the patients had received previous chemotherapy, although most had undergone surgery to remove the affected kidney. Half were given sunitinib and half were given interferon-a. Progression-free survival was 47.3 weeks for the sunitinib group, compared with 24.9 weeks for the interferon-a group. Response rates were 24.8% for sunitinib, compared with 4.9% for interferon-a. Researchers will continue to follow the patients in the study to determine the difference in overall survival between the two treatments.13
OTHER NOTABLE RESEARCH In this study, 219 patients were randomized to conventional chemotherapy followed by high-dose chemotherapy or conventional chemotherapy alone. At 1 year, 52% of patients on the high-dose regimen had a complete response, compared with 48% of patients who received conventional-dose chemotherapy only. At a median follow-up of 51 months, there was no difference in survival between the two groups. Patients on the high-dose regimen experienced more side effects than those who received conventional chemotherapy; however, these side effects could be managed and were not associated with increased mortality.14
Gynecologic cancers include cancers of the cervix, uterus, ovaries, fallopian tubes, vulva, and vagina. Ovarian and cervical cancers are two of the most common types of gynecologic cancers in the United States. Cervical cancer, which is closely associated with HPV, is even more prevalent in the developing world, where screening with the Pap test is not widely available, and many precancerous lesions go unnoticed and untreated. Ovarian cancer is difficult to detect in its early stages and, as a result, the majority of women are diagnosed during advanced stages of disease. One of the most significant advances in gynecologic cancer over the past year was the FDA approval of the world's first vaccine to prevent HPV infection. The implications for the prevention of cervical cancer among women are significant, both in the United States and abroad.
MAJOR ADVANCE The Gardasil findings resulted from four phase II and phase III clinical trials, which together evaluated more than 20,000 women between the ages of 16 and 26 years from a number of different countries, for up to 5 years. The studies showed that Gardasil prevented all HPV 16–and 18–related cervical precancers: no cases occurred among 8,487 women who received Gardasil, compared with 53 cases among 8,460 women who received a placebo. Gardasil was also shown to be 99% effective in preventing cases of genital warts caused by HPV type 6 or 11. Vaccine May Also Protect Against Most Vaginal and Vulvar Cancers. A separate study showed that Gardasil prevented 100% of HPV-related vaginal and vulvar precancers after 2 years. Such cancers are becoming increasingly common among young women. The study, known as FUTURE II, combined data from three clinical trials evaluating the HPV vaccine in 18,150 women from North and South America, Europe, and Asia who were randomly assigned to receive the vaccine or a placebo. After 2 years, researchers found that none of the women who received the vaccine developed HPV-related vaginal or vulvar precancers, compared with 24 women in the placebo group.16 In addition, a candidate vaccine known as Cervarix (GlaxoSmithKline, Research Triangle Park, NC), which targets HPV strains 16 and 18, has shown promise in clinical trials, and is expected to be considered for approval by the FDA in early 2007.
OTHER NOTABLE RESEARCH However, women in the study who received intraperitoneal therapy experienced more toxic side effects—including some that were life-threatening—and were more likely to report poorer quality of life, compared with women who received only intravenous therapy. Only 42% of women in the combined chemotherapy group were able to complete all six cycles of therapy, compared with 83% of those who received intravenous chemotherapy alone. Such toxicity has limited the widespread use of intraperitoneal therapy. Researchers noted that subsequent studies should examine the effect of delivering lower doses or other agents through intraperitoneal administration.
Cancers of the head and neck—those affecting the nose, mouth, tongue, throat, and larynx—are usually treated with a combination of surgery, chemotherapy, and/or radiation therapy. In the past year, several studies identified new treatment regimens that could slow the growth of head and neck cancers and improve survival for these patients, without causing significant additional side effects. Head and neck cancers have traditionally been very difficult to treat, and these studies represent some of the most significant advances in the management of head and neck cancer in decades.
MAJOR ADVANCE Cetuximab was approved for the treatment of metastatic colorectal cancer in combination with chemotherapy in 2004. Following publication of this study, the FDA this year approved the drug for use in combination with radiation therapy to treat squamous cell cancer of the head and neck, making it the first drug to be approved for this disease in 45 years. Additional studies are now underway to compare a regimen of cetuximab, platinum-based chemotherapy, and radiation versus radiation and chemotherapy alone (another commonly used treatment regimen for this group of patients).
OTHER NOTABLE RESEARCH In the study, 538 patients were randomized between the two treatments. Induction therapy was followed by ongoing chemotherapy and radiation, and for some patients, surgery. Patients were followed for an average of 41.9 months. Researchers found that overall survival for the group at 3 years was 62.1% compared with 48.1% for the control group. The majority of late side effects were related to radiation therapy. This trial represents the first large multicenter effort to show that the addition of docetaxel to induction therapy, when followed by chemoradiotherapy, improves survival.19 Chemotherapy and "Re-Irradiation" After Salvage Surgery Slows Cancer Growth This study showed that giving the chemotherapy drugs fluorouracil and hydroxyurea with additional radiation therapy to patients who underwent "salvage" surgery for second head and neck cancers or head and neck cancers that had returned extended the time it took for their cancers to grow by 60%, compared with patients who had no treatment after salvage surgery. "Salvage" surgery is the term used to describe surgery to remove cancerous tissue after a tumor has returned, or a new cancer has developed in an area previously treated for cancer. All of the patients had previously received radiation therapy for head and neck cancer. Overall survival did not significantly differ between the two groups.20 These data are the first to compare the effectiveness of such "reirradiation" and chemotherapy in patients with head and neck cancer following salvage surgery. The additional treatment was not associated with significant side effects.
Lung cancer incidence and mortality have begun declining in recent years, due to a decrease in smoking rates over the last several decades, particularly among men. However, the disease remains the leading cancer killer in the United States, with an estimated 162,460 deaths expected in 2006. There has also been recent progress in treating the disease. Some targeted therapies are proving effective against lung cancer, and research has shown that giving chemotherapy after surgery for more advanced lung cancer can prolong survival. At the same time, not all patients with lung cancer are benefiting from these advances. Researchers are learning that specific characteristics of an individual's tumor may help predict prognosis and response to treatment. In the last year, several studies have pinpointed specific genetic alterations that suggest whether a patient is likely to respond to a given drug. In addition, researchers have developed a test to identify patients whose cancers are likely to have been cured after surgery, and those that have a high risk of recurrence—individuals who could potentially benefit from chemotherapy following surgery.
MAJOR ADVANCE Additional studies are planned to confirm the accuracy of this model. If confirmed accurate, the tool could provide an effective means of estimating a patient's risk of recurrence, enabling physicians and patients to make more informed decisions about the use of chemotherapy for early-stage lung cancer.21
OTHER NOTABLE RESEARCH While previous studies have shown that chemotherapy after surgery can help some patients with NSCLC, until now there has been no way to predict which patients are most likely to benefit. This study suggests that ERCC1 could be an important predictive marker, and if confirmed in prospective, randomized trials, could one day help oncologists better identify patients most likely to benefit from cisplatin-based chemotherapy after surgery. Studies Confirm Erlotinib and Gefitinib Active in Lung Cancers With EGFR Mutations For the first time, four prospective studies indicate that erlotinib (Tarceva; Genentech, South San Francisco, CA) and gefitinib (Iressa; AstraZeneca Pharmaceuticals, Wilmington, DE) may be particularly effective in lung cancer patients whose tumors have mutations in the EGFR gene. Previous studies have shown that response to these therapies is just 8% to 10% among lung cancer patients without mutations in the EGFR gene.23 Both drugs, called tyrosine kinase inhibitors, inhibit an enzyme called the EGFR tyrosine kinase on the surface of many tumor cells—including some lung cancers—and may control the growth of the tumor. Although past research indicated that these drugs might be effective in treating non–small-cell lung cancers with EGFR mutations, only retrospective studies supported this claim. The following four prospective studies demonstrate that erlotinib and gefitinib are active in non–small-cell lung cancers that contain mutations in the EGFR gene, particularly those with deletions in exons 19 and 21. (An exon is the segment of a gene that contains instructions for making a protein.)
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% 30 years ago. An estimated 12,500 new cases of cancer are expected to occur among infants, children, and adolescents under the age of 21 in 2006. An estimated 2,760 cancer-related deaths are expected among children this year, with approximately one-third of these deaths due to leukemia. The most significant developments this year were the FDA's approval of two drugs for the treatment of pediatric hematologic cancers.
NOTABLE RESEARCH FDA Approves Nelarabine for Rare Leukemia and Lymphoma In October 2005, the FDA approved nelarabine (Arranon; GlaxoSmithKline, Research Triangle Park, NC) for the treatment of children with T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL), whose cancer has not responded to or has returned following two chemotherapy regimens. In a study of 39 pediatric patients with resistant or recurrent T-ALL/T-LBL, 23% experienced complete remission of disease, which lasted from 3.3 to 9.3 weeks.29,30 Nelarabine is the first drug to treat this limited population of patients, and was approved under the FDA's accelerated approval program, which allows the agency to approve products for life-threatening illnesses based on early evidence of a drug's effectiveness. As a condition of accelerated approval, the trial sponsor is completing additional studies to confirm the drug's clinical benefit.
More than 1 million cases of skin cancer are diagnosed in the United States every year. While the vast majority of these are basal cell or squamous cell skin cancers, which are relatively easy to treat, there has been a steady increase in the incidence of melanoma in the last several decades. Though less common, melanoma is significantly more invasive, can spread quickly, and is more likely to be life-threatening than other types of skin cancers. Most skin cancers are caused by exposure to ultraviolet radiation from the sun, though other risk factors for melanoma have been identified recently, such as family history, suggesting that the development of melanoma may involve interactions among a variety of factors. Several studies in the last year identified clinical and genetic factors that contribute to our understanding of the biology of melanoma, which is key to identifying more effective approaches to both treat and prevent the disease. In addition, researchers have developed a new tool to help physicians assess an individual's risk of developing melanoma and plan for potential interventions.
NOTABLE RESEARCH The study involved 1,269 patients with intermediate-thickness melanoma (1.2 to 3.5 mm) who were randomly assigned to one of two treatment strategies: surgery to remove the tumor, followed by sentinel-node biopsy in the nearby lymph nodes, with immediate removal of surrounding lymph nodes if cancer cells were found in the sentinel node; or surgery to remove the tumor, followed by observation, with immediate removal of the lymph nodes if cancer was found in the lymph nodes, as determined by physical examination.31 Cancer cells in the lymph nodes were found a median of 16 months earlier by sentinel-node biopsy than by physical examination. In addition, the presence of cancer cells in the sentinel node was the most significant factor predicting a patient's survival. Overall, patients with melanoma who underwent sentinel-node biopsy had a significantly lower rate of cancer recurrence 5 years after diagnosis (21.7%) than patients whose lymph nodes were monitored after surgery by physical examination (26.9%). The rate of death from melanoma after 5 years, however, was similar between the two groups (87.1% versus 86.6%, respectively). These findings support the use of sentinel-node biopsy as standard practice for the staging of cancer in patients with intermediate-thickness melanoma. Studies Suggest Melanomas Arise Through Distinct Pathways Two new studies in melanoma suggest that the disease arises through distinct genetic pathways. In the first study, Australian researchers collected data from more than 300 melanoma patients, finding that melanomas of the head and neck are associated with chronic patterns of sun exposure, while those of the trunk are more closely linked to intermittent patterns of sun exposure.32 The second study, an international multicenter investigation, found that genetic alterations in melanoma tumors differed according to where on the body the melanomas developed and the patients' level of sun exposure. Researchers found that 81% of melanomas in parts of the body not damaged by the sun had mutations in the BRAF and N-RAS genes, while melanomas in parts of the body heavily exposed to the sun did not have these mutations. In addition, melanomas with normal BRAF and N-RAS genes frequently had more copies of the genes for two enzymes called CDK4 and CCND1. The researchers concluded that these findings indicate that melanomas can develop through different genetic pathways.33 New Tool Developed to Identify People at High Risk for Melanoma In this multicenter study led by the NCI, researchers used data from over 1,600 melanoma patients to develop a tool to estimate an individual's risk of developing melanoma over the next five years. Based on data from more than 1,600 non-Hispanic whites with the disease, the model computes this risk by using information on an individual's skin complexion, sun exposure, and results of a physical examination of the back and shoulders (including the number of dysplastic nevi—moles with the greatest potential of becoming cancerous).34 The authors noted that the results of the tool can be used by health professionals to identify people with an increased risk of melanoma and to help them plan for potential interventions, such as reducing sun exposure, having regular skin exams, and participating in clinical trials of new agents to prevent the disease.
Cancer prevention research involves studying lifestyle changes to reduce the risk of cancer, such as smoking cessation, exercising, or following a balanced diet and maintaining a healthy weight, as well as researching certain drugs, vaccines, and dietary supplements that may lower the risk of developing cancer, often called "chemoprevention." It may also involve research on interventions to eliminate environmental causes of cancer. The most significant advances in cancer prevention in the last year were in the field of chemoprevention, including the FDA approval of a vaccine to prevent HPV infection, and the findings of the first head-to-head comparison of tamoxifen and raloxifene to reduce the risk of developing breast cancer.
MAJOR ADVANCE
OTHER NOTABLE RESEARCH Tamoxifen is approved by the FDA for three purposes—to treat metastatic breast cancer, to reduce the risk of breast cancer recurrence, and to reduce the risk of developing the disease in both pre- and postmenopausal women at high risk for breast cancer. Raloxifene is approved to prevent osteoporosis, and has also been shown in previous clinical trials to reduce breast cancer risk in postmenopausal women. The STAR trial, conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP), included 19,747 postmenopausal women at increased risk of breast cancer at more than 500 centers in the United States and Canada. Starting in July 1999, participants were randomly assigned to receive 60 mg of raloxifene or 20 mg of tamoxifen once daily for 5 years. After a median follow-up of 4 years, researchers found no significant difference in the number of invasive breast cancers between the tamoxifen group (163 cases) and the raloxifene group (167 cases). However, there were fewer noninvasive breast cancers, such as ductal carcinoma in situ or lobular carcinoma in situ, in the tamoxifen group (57 cases), compared with the raloxifene group (81 cases). The number of uterine cancers was greater among women on tamoxifen (36) than in those who received raloxifene (23). Although both drugs are known to increase the risk of blood clots, the risk was 29% lower in the raloxifene group compared with the tamoxifen group. Rates of heart problems, stroke, bone fracture, or death were similar in both arms of the study. The women are continuing to be followed, and women in the tamoxifen group were given the option to switch to raloxifene.35
According to the NCI, there are now more than 10 million cancer survivors living in the United States. The current five-year relative survival rate for all cancers diagnosed between 1995 and 2001 is 65%, up from 50% in 1974 to 1976. This marked improvement in survival has been fueled by a growing knowledge of the inner workings of cancer cells, which has brought about improved treatments and diagnostic techniques. However, with progress in treating cancer comes an emerging challenge—ensuring the long-term health and quality of life of the growing number of cancer survivors. The effects of cancer, and cancer treatment, can last for years after the completion of therapy. Continued advances in cancer research, coupled with a growing and aging population, suggests that both the number of cancer survivors and the needs of this population will continue to increase. Breast cancer survivors represent the largest group of cancer survivors in the United States. One of the most common side effects of breast cancer treatment is fatigue, and past research has indicated that such fatigue can persist up to 5 years after diagnosis and treatment. This year, a study of breast cancer patients found that fatigue can continue as much as 10 years after diagnosis.
NOTABLE RESEARCH Between 1994 and 1997, researchers recruited 1,957 women who had been diagnosed with early-stage breast cancer 1 to 5 years earlier, were free of disease, and had completed all cancer therapies other than tamoxifen (which is often taken for 5 years following initial therapy to reduce the risk of recurrence). In 1998, the researchers recontacted women who were at least 5 years postdiagnosis, and distributed questionnaires to those who expressed interest in participating in the follow-up survey. Seven hundred sixty-three women completed questionnaires during both study periods. Researchers compared levels of fatigue during two periods: 1 to 5 years and 5 to 10 years after diagnosis. Using a standardized survey, women provided information on three general areas of health-related quality of life: physical, emotional, and social well-being. This study focused on reported levels of vitality and physical pain. Researchers found that a similar percentage of women scored in the fatigued range in both the 1-to-5 years (35%) and 5-to-10 year (34%) periods. Among women classified as fatigued in the first assessment, 63% continued to score in the fatigued range at the second assessment. Overall, approximately 21% of women reported being fatigued during both assessment periods, suggesting that persistent fatigue may be a common issue for breast cancer survivors.36
As this report demonstrates, significant progress has been made across every area of cancer research—treatment, prevention, survivorship, and quality of life. Much of the progress seen in recent years can be attributed to a far greater understanding of basic biology and the role of genes and proteins in the origin and progression of disease. Such advances in basic science have been particularly important in understanding the genetic characteristics that lead to cancer growth, development, metastasis, recurrence, and responsiveness to treatment, and are critical for progress in the development of personalized therapy for cancer patients. However, much more needs to be done to ensure that such discoveries move rapidly through the cancer research process. Cancer research faces a number of obstacles, including a growing bottleneck of basic science discoveries waiting to be "translated" into useful therapies and diagnostics, and declining federal funding of translational and clinical cancer research. Another critical issue hampering cancer research is the increasingly limited access to "biospecimens" (samples of tissue and blood taken from patients during surgeries, biopsies, or routine tests). Such samples are central to most cancer research and vital to development of therapeutic clinical trials. To accelerate the pace of cancer research, ASCO recommends action steps in two key areas over the coming year:
1. Increase Funding for Cancer Research In addition, using the biologic "keys" discovered in the lab to unlock the door for cancer treatment will require additional funding for clinical trials, and the participation of many thousands of patients. Although hundreds of clinical trials are taking place at any one time, researchers estimate that today it takes as long as 10 years between the identification of a target for cancer therapy and the availability of that therapy for patients, depending on the type of cancer being studied and the end points being measured. In order to take full advantage of new knowledge about the biology of cancer, we must accelerate the pace of clinical research and shorten this time frame. But without adequate funding, that timeline could become even longer and some promising new therapies might never be studied at all. Recommendation:
2. Advance Research From the Lab to the Clinic: Increasing Access to Biospecimens Standardized Collection and Storage of Biospecimens—To conduct a single study, researchers must obtain a large number of high-quality biospecimen samples with accompanying clinical information about the patient's disease, prior treatment, and other health problems. While many existing repositories in the United States house millions of biospecimens, there are no common procedures for collecting and storing specimens, and no consistent quality-control measures. Samples are often stored under varying conditions and may not have accompanying clinical information about the patient, making it difficult for researchers to pool, share, or compare results. In addition, many of these samples do not have appropriate authorization from the donor for use in research studies, and retroactive authorization is costly and difficult to obtain. Recommendations: There is an urgent need for national guidelines to standardize procedures for the collection, storage, and use of biospecimens and their accompanying data.
Impact of Privacy Laws on Cancer Research—The Health Insurance Portability and Accountability Act (HIPAA), enacted by Congress in 1996, established new protections for the use and disclosure of patient health information. While ASCO supports the overall principles of HIPAA and agrees that preserving a patient's right to privacy is important, variations in the implementation and interpretation of such privacy regulations have inadvertently made it much more difficult to conduct critical cancer research. For example, researchers report that these regulations have led to delayed or limited access to human biospecimens needed for large-scale studies. Under HIPAA, in order to use human biospecimens, researchers are required to get authorization from every patient for each research project. Scientists report that this requirement has made research significantly more complex than it was before HIPAA was enacted. Some examples from a recent IOM report include:
In addition, important rules governing research—FDA regulations, the Common Rule, and HIPAA—often diverge. (The Common Rule is the 1991 federal regulation that provides basic procedures and principles that are to be followed in the conduct of human subject research sponsored by federal agencies. It requires a review of proposed research by an institutional review board, the informed consent of research subjects, and institutional assurances of compliance with regulations.) These discrepancies have caused confusion and widely variable implementation across research institutions and settings. Such variation—in large part the product of institutions' concern about liability—has added to delays and barriers mentioned above.
Recommendations:
Tissue Ownership and Intellectual Property Rights—Debate over tissue ownership and intellectual property rights has also limited access to biospecimens. Controversy exists over who owns samples—the repository or the patient who donated the sample—as well as who owns the right to any discoveries made using the samples. Such debates have also made it difficult for researchers to pool samples or to compare the results across institutions. As researchers and industry sponsors have sharply increased their demand for biospecimens, some institutions have begun asserting control over biospecimens, associated data, and research findings.
•Recommendation: The creation of a centralized database for biospecimens could greatly speed scientific discovery in cancer research. ASCO calls for a new collaborative effort involving leaders from cancer institutions, government, industry, and patient groups to identify ways that such information could be shared for the benefit of all parties in cancer research, while maintaining appropriate protection for intellectual property.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: James Bonner, Bristol-Myers Squibb, ImClone; Walter J. Curran Jr, Bristol-Myers Squibb, Aventis, Eli Lilly, Genentech, AstraZeneca; Roy S. Herbst, AstraZeneca, Eli Lilly, Genentech; Maurie Markman, Eli Lilly, GlaxoSmithKline, Merck, MGI Pharma; Robert F. Ozols, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Johnson and Johnson, Eli Lilly, Novartis, Telik, Unither; Derek Raghavan, Isis Pharmaceuticals, Bristol-Myers Squibb, YM Biosciences (Canada), Revolution Health Care Website; Richard L. Schilsky, BioNumerik Pharmaceuticals, Bristol-Myers Squibb, Chiron, Geron, Immunogen, Nektar, Neopharm, Viventia; John W. Sweetenham, Genentech Stock: Burton L. Eisenberg, Novartis; Robert F. Ozols, Biogen Idec, Celgene, Pfizer, Theradex Honoraria: James Bonner, Bristol-Myers Squibb, ImClone; Julie Gralow, Genentech, Novartis, Roche; Roy S. Herbst, Amgen, AstraZeneca, Eli Lilly, Genentech; Robert F. Ozols, Bristol-Myers Squibb, Genentech, Eli Lilly; Richard L. Schilsky, BioNumerik Pharmaceuticals, Bristol-Myers Squibb, Geron, Immunogen, Nektar, Neopharm, Viventia; John W. Sweetenham, Genentech Research Funds: Burton L. Eisenberg, Novartis; Roy S. Herbst, Amgen, AstraZeneca, Genentech, Sanofi; Derek Raghavan, Eli Lilly, Abraxis; Richard L. Schilsky, Novartis Testimony: Maurie Markman, AstraZeneca Other: N/A
Conception and design: Yolonda L. Colson, Julie Gralow, Roy S. Herbst, Robert F. Ozols Data analysis and interpretation: James Bonner, Yolonda L. Colson, Walter J. Curran Jr, Burton L. Eisenberg, Patricia A. Ganz, Julie Gralow, Roy S. Herbst, Barnett S. Kramer, Mark G. Kris, Maurie Markman, Robert J. Mayer, Robert F. Ozols, Derek Raghavan, Gregory H. Reaman, Raymond Sawaya, Lynn M. Schuchter, John W. Sweetenham, Linda T. Vahdat, Rodger J. Winn Manuscript writing: James Bonner, Yolonda L. Colson, Walter J. Curran Jr, Burton L. Eisenberg, Partricia A. Ganz, Julie Gralow, Roy S. Herbst, Barnett S. Kramer, Mark G. Kris, Maurie Markman, Robert J. Mayer, Robert F. Ozols, Derek Raghavan, Gregory H. Reaman, Raymond Sawaya, Lynn M. Schuchter, John W. Sweetenham, Linda T. Vahdat, Rodger J. Winn Final approval of manuscript: James Bonner, Yolonda L. Colson, Walter J. Curran Jr, Burton L. Eisenberg, Patricia A. Ganz, Julie Gralow, Roy S. Herbst, Barnett S. Kramer, Mark G. Kris, Maurie Markman, Robert J. Mayer, Robert F. Ozols, Derek Raghavan, Gregory H. Reaman, Raymond Sawaya, Richard L. Schilsky, Lynn M. Schuchter, John W. Sweetenham, Linda T. Vahdat, Rodger J. Winn
published online ahead of print at www.jco.org on December 8, 2006.
* Executive Editor/Editorial Board Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
EXECUTIVE SUMMARY
Specialty Editor 
) as first-line systemic therapy for patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol 24:18s, 2006 (abstr LBA3)
