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  • 1. Published Ahead of Print on November 15, 2010 as 10.1200/JCO.2010.33.2742 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2010.33.2742 JOURNAL OF CLINICAL ONCOLOGY A S C O S P E C I A L A R T I C L E Clinical Cancer Advances 2010: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology Mark G. Kris,* Steven I. Benowitz, Sylvia Adams,† Lisa Diller,† Patricia Ganz,† Morton S. Kahlenberg,† Quynh-Thu Le,† Maurie Markman,† Greg A. Masters,† Lisa Newman,† Jennifer C. Obel,† Andrew D. Seidman,† Sonali M. Smith,† Nicholas Vogelzang,† and Nicholas J. Petrelli*From the American Society of ClinicalOncology, Alexandria, VA. A MESSAGE FROM ASCO’S PRESIDENTSubmitted October 15, 2010; accepted Like many health professionals who care for people with cancer, I entered the field because of specific patientsOctober 21, 2010; published online who touched my heart. They still do. In an effort to weave together my personal view of what the Americanahead of print at www.jco.org on Society of Clinical Oncology (ASCO) stands for and the purpose the organization serves, my presidential themeNovember 8, 2010. this year is “Patients. Pathways. Progress.”Executive Editor* Patients come first. Caring for patients is the most important, rewarding aspect of being an oncology professional.Specialty Editor† At its best, the relationship between doctor and patient is compassionate and honest—and a relationship ofCorresponding author: Steven I. mutual respect. Many professional organizations have an interest in cancer, but no other society is so focusedBenowitz, MA, American Society of on the entire spectrum of cancer care, education, and research. Nor is any other society as particularly interestedClinical Oncology, 2318 Mill Road, Suite in bringing new treatments to our patients through clinical trials as ASCO is. Clinical trials are the crux for improving800, Alexandria, VA 22314; e-mail: treatments for people with cancer and are critical for continued progress against the disease.steven.benowitz@asco.org “Pathways” has several meanings. Some pathways are molecular—like the cancer cell’s machinery of© 2010 by American Society of Clinical destruction, which we have only begun to understand in recent years. But there are other equallyOncology important pathways, including the pathways new therapies follow as they move from bench to bedside0732-183X/10/9999-1/$20.00 and the pathways patients follow during the course of their diseases. Improved understanding of these pathways will lead to new approaches in cancer care, allowing doctors to provide targeted therapies thatDOI: 10.1200/JCO.2010.33.2742 deliver improved, personalized treatment. The best pathway for patients to gain access to new therapies is through clinical trials. Trials conducted by the National Cancer Institute’s Cooperative Group Program, a nationwide network of cancer centers and physicians, represent the United States’ most important pathway for accelerating progress against cancer. This year, the Institute of Medicine released a report on major challenges facing the Cooperative Group Program. Chief among them is the fact that funding for the program has been nearly flat since 2002. ASCO has called for a doubling of funding for cooperative group research within five years and supports the full implementation of the Institute of Medicine recommendations to revitalize the program. ASCO harnesses the expertise and resources of its 28,000 members to bring all of these pathways together for the greater good of patients. Progress against cancer is being made every day—measurable both in our improved understanding of the disease and in our ability to treat it. A report issued in December 2009 by the National Cancer Institute, the Centers for Disease Control and Prevention, the American Cancer Society, and the North American Association of Central Cancer Registries found that rates of new diagnoses and rates of death resulting from all cancers combined have declined significantly in recent years for men and women overall and for most racial and ethnic populations in the United States. The pace of progress can be and needs to be hastened. Much remains to be done. Sustained national investment in cancer research is needed to bring better, more effective, less toxic treatments to people living with cancer. Pathways to progress continue in the clinic as doctors strive to find the right treatments for the right patients, to understand what represents the right treatments, and to partner with patients and caregivers for access to those treatments. This report demonstrates that significant progress is being made on the front lines of clinical cancer research. But although our nation’s investment in this research is paying off, we must never forget the magnitude of what lies ahead. Cancer remains the number two killer of Americans. Future progress depends on continued commitment, from both ASCO and the larger medical community. George W. Sledge Jr, MD President American Society of Clinical Oncology J Clin Oncol 99. © 2010 by American Society of Clinical Oncology © 2010 by American Society of Clinical Oncology 1 Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on November 29, 2010 from 186.137.29.43 Copyright © 2010 American Society of Clinical Oncology. All rights reserved. Copyright 2010 by American Society of Clinical Oncology
  • 2. Kris et al EXECUTIVE SUMMARY Table 1. Cancer Incidence and Mortality: 2010 EstimatedThe American Society of Clinical Oncology (ASCO) conducts an New Estimatedannual, independent review of advances in clinical cancer research to Cancer Type Cases Deathsidentify those that have had the greatest impact on patient care. This All 1,529,560 569,490year’s Clinical Cancer Advances features 53 of the most significant Tongue 10,990 1,990studies, including 12 that the editors consider major advances. Mouth 10,840 1,830 Despite the National Cancer Institute (NCI) report in 2009 that Pharynx 12,660 2,410 Other oral cavity 2,050 1,650overall cancer rates are on the decline in the United States, more than Esophagus 16,640 14,5001.5 million new diagnoses are expected in 2010, and nearly 570,000 Stomach 21,000 10,570Americans are expected to die as a result of the disease this year alone. Small intestine 6,960 1,100This year’s Clinical Cancer Advances outlines recommendations for Colon 102,900 51,370increasing the rate of progress against cancer and for a significant Anus, anal canal, and anorectum 5,260 720increase in funding for and improvements to the clinical research Liver and intrahepatic bile duct 24,120 18,910 Gallbladder and other biliary 9,760 3,320system to accelerate the pace of discoveries that will lead to improved Pancreas 43,140 36,800mortality rates and quality of care. Larynx 12,720 3,600 Lung and bronchus 222,520 157,300Summary of Findings Bones and joints 2650 1,460 Soft tissue (including heart) 10,520 3,920 Cancer cases, death rates decline in United States. A new report Melanoma (skin) 68,130 8,700issued in late 2009 by leading health and cancer organizations found Breast 209,060 40,230that overall rates of new diagnoses of and death resulting from all Uterine cervix 12,200 4,210cancers combined declined significantly in recent years for most racial Ovary 21,880 13,850and ethnic populations in the United States. Vulva 3,900 920 The report, issued by the NCI, the US Centers for Disease Vagina and other genital (female) 2,300 780 Prostate 217,730 32,050Control and Prevention, the American Cancer Society, and the Testis 8,480 350North American Association of Central Cancer Registries, showed Penis and other genital (male) 1,250 310that the number of new cancer cases declined, on average, by nearly Urinary bladder 70,530 14,6801% per year between 1999 and 2006. In addition, death rates Kidney and renal pelvis 58,240 13,040dropped 1.6% annually from 2001 to 2006, primarily as a result of Ureter and other urinary organs 2,490 830reductions in new cases and death rates for the three most common Eye and orbit 2,480 230 Brain and other nervous system 22,020 13,140cancers in men (lung, prostate, and colorectal cancers) and for two Endocrine system 46,930 2,570of the three leading cancers in women (breast and colorectal can- Thyroid 44,670 1,690cers; Tables 1 and 2). Hodgkin lymphoma 8,490 1,320 Hard-to-treat cancers. Although some cancers defy early detec- Non-Hodgkin’s lymphoma 65,540 20,210tion and are more often diagnosed in advanced stages, many cancers Myeloma 20,180 10,650are simply inherently resistant to therapy. Advances in such hard-to- Acute lymphocytic leukemia 5,330 1,420 Chronic lymphocytic leukemia 14,990 4,390treat cancers in the last year follow. Acute myeloid leukemia 12,330 8,950 Chemotherapy combination increases survival in elderly pa- Chronic myeloid leukemia 4,870 440tients with advanced lung cancer: The same combination of chem- NOTE. Number of cases rounded to the nearest 10; estimated new casesotherapy drugs (carboplatin and paclitaxel) that is commonly used exclude basal and squamous cell skin cancers and in situ carcinomas exceptin younger patients with lung cancer improved survival in elderly urinary bladder. Source: American Cancer Society: Cancer Facts and Figurespatients compared with single-agent therapy (gemcitabine or vinorel- 2010. Atlanta, GA, American Cancer Society, 2010.bine). Although older patients are often given less aggressive forms oftherapy, the authors of a multicenter, phase III study reported that themore aggressive combination therapy was both more effective and well-tolerated. Bevacizumab extends progression-free survival for women Chemotherapy combination dramatically improves survival with advanced ovarian cancers: A phase III trial found that addingfor patients with metastatic pancreatic cancer: A randomized, the antiangiogenesis drug bevacizumab, which targets tumorphase III trial in patients with metastatic pancreatic cancer is the blood vessel growth and development, to the standard chemother-first trial, to our knowledge, to demonstrate a significant survival apy drug combination of carboplatin and paclitaxel helped womenimprovement in individuals with stage IV adenocarcinoma of the with advanced ovarian cancers live significantly longer without thepancreas. The authors found that treatment with FOLFIRI- disease progressing compared with women treated with chemo-NOX—a combination of the chemotherapy drugs fluorouracil, therapy alone. These extremely difficult-to-treat types of cancers in-leucovorin, irinotecan, and oxaliplatin—resulted in better response clude epithelial ovarian cancer, primary peritoneal ovarian cancer, andrates, progression-free survival, and overall survival compared with fallopian tube cancer. Researchers found that giving chemotherapy andstandard single-drug treatment with gemcitabine (Gemzar; Lilly, In- bevacizumab, followed by longer-term treatment with bevacizumab, wasdianapolis, IN). the most effective strategy.2 © 2010 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on November 29, 2010 from 186.137.29.43 Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
  • 3. Clinical Cancer Advances 2010 Targeted therapies and personalized medicine. As researchers Table 2. Trends in 5-Year Relative Survival Rates, 1975-2005 (select cancers) continue to better understand the basic biology and behavior of can- 5-Year Survival (%) cers, they are also increasingly successful in developing treatment strategies that are tailored to the genetics of individual patients and Cancer Type 1975-1977 1984-1986 1999-2005 their tumors. Major advances in personalized medicine and targeted All 50 54 68 therapies in the past year follow. Brain 24 29 36 Breast (female) 75 79 90 Novel ALK inhibitor shows high response in group of patients Colon 52 59 66 with lung cancer: A phase I trial showed that a high percentage of Esophagus 5 10 19 patients (about one in 20 patients with lung cancer) with a specific Hodgkin’s lymphoma 74 79 86 ALK gene mutation responded to treatment with the ALK inhibitor Kidney 51 56 69 crizotinib, and more than two thirds experienced some tumor shrink- Larynx 67 66 63 Leukemia 35 42 54 age. Phase I trials are typically aimed at gauging toxicity and rarely Liver and bile duct 4 6 14 show dramatic clinical activity. More than 90% of the 82 patients Lung and bronchus 13 13 16 enrolled onto the study responded to the drug; either the disease Melanoma of the skin 82 87 93 stopped growing, or there was some tumor shrinkage. Myeloma 26 29 37 New targeted treatment shows promise for patients with ad- Non-Hodgkin’s lymphoma 48 53 69 vanced melanoma with BRAF gene mutation: In a study that bodes Oral cavity and pharynx 53 55 63 well for the future use of targeted therapies against melanoma, re- Ovary 37 40 46 searchers showed that the majority of patients with advanced mela- Pancreas 3 3 6 noma with a specific BRAF gene mutation (V600E mutant BRAF) Prostate 69 76 100 responded to a new BRAF inhibitor, PLX4032. In the second part of a Rectum 49 57 69 Stomach 16 18 27 phase I trial, tumors either completely or partially regressed, including Testis 83 93 96 metastases in the bone and liver, for 81% of patients. Thyroid 93 94 97 Quality of life. Several important studies this year contributed to Urinary bladder 74 78 82 improving the lives of people with cancer. Uterine cervix 70 68 72 Adding palliative care to chemotherapy improves survival in Uterine corpus 88 84 84 patients with lung cancer: A randomized clinical trial of patients with NOTE. Survival rates are adjusted for normal life expectancy and are based oncases diagnosed in the SEER 9 areas from 1975-77, 1984-86, and 1999-2005 advanced lung cancer showed that those individuals who receivedand then followed through 2006. Source: American Cancer Society: Cancer standard chemotherapy coupled with palliative care immediately afterFacts and Figures 2010. Atlanta, GA, American Cancer Society, 2010. Abbreviation: SEER, Surveillance, Epidemiology, and End Results. diagnosis lived significantly longer and had a better quality of life than The difference in rates between 5-year survival rates for patients diagnosed those who received chemotherapy alone. Patients who regularly sawbetween 1975 and 1977 and those diagnosed between 1999 and 2005 isstatistically significant (P .05). palliative care specialists reported less depression and pain and better mobility and were less likely to undergo fruitless and expensive aggres- sive therapy at the end of life than individuals who were treated with chemotherapy alone. This research was supported by a Career Devel- Antibody ipilimumab improves survival in advanced melanoma: opment Award from the ASCO Cancer Foundation.In what was, to our knowledge, the first-ever phase III randomized Sleep problems impact large majority of patients with cancertrial to show a survival benefit for patients with advanced melanoma, who receive chemotherapy: In what was, to our knowledge, the firstresearchers found that an experimental immune therapy using ipili- large study to evaluate the prevalence of insomnia in patientsmumab—a human monoclonal antibody that keeps the immune undergoing chemotherapy, researchers found that more than threesystem’s T cells activated, including those that target melanoma quarters of patients have insomnia and other sleep disorders—cells—resulted in patients living 34% longer after 2 years. The study nearly three times the rate found in the general population. Thealso found that the melanoma was kept in check for 6 months in nearly researchers showed that sleep problems were more prevalent in30% of those receiving the drug, compared with 11% of controls. patients younger than age 58 years and that patients reporting Reducing cancer recurrence. Although many cancers can betreated successfully at first, staving off the return of cancer may be a insomnia were also significantly more likely to report depressiondaunting challenge. When a cancer recurs, often it is resistant to and fatigue than those without insomnia.treatment and leads to death. There was a major advance over the last New drug approvals. Important clinical studies resulted in newyear in reducing recurrence in breast cancer, which showed that a drug approvals by the US Food and Drug Administration this year,briefer course of radiation is just as effective in preventing recurrence including two drugs for prostate cancer (Table 3).in early-stage breast cancer. A shorter, three-week course of higher- Sipuleucel-T approved for treating advanced prostate cancer:dose radiation—an approach called hypofractionated therapy—was The US Food and Drug Administration approved sipuleucel-T (Prov-just as effective as the standard five-week course for women with enge; Dendreon, Seattle, WA), a cancer vaccine for metastaticearly-stage breast cancer. After 10 years, the risk of local recurrence hormone-refractory prostate cancer early in 2010. Unlike a preventiveamong two groups of more than 600 women, who were randomly vaccine, which is given to stimulate the immune system to fight offassigned to receive the shortened course or to the standard radiation infections and prevent disease, Provenge is a therapeutic vaccine thatcourse, was nearly the same. boosts the body’s immune system to attack cancer cells in the body.www.jco.org © 2010 by American Society of Clinical Oncology 3 Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on November 29, 2010 from 186.137.29.43 Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
  • 4. Kris et al Table 3. FDA Approvals of Anticancer Agents, September 2009 –September 2010 Anticancer Agent Trade Name Indication Date of Approval Newly approved agents Cabazitaxel Jevtana (sanofi-aventis, mHRPC June 17, 2010 Bridgewater, NJ) Sipuleucel-T Provenge (Dendreon, Seattle, WA) Asymptomatic or minimally symptomatic metastatic April 29, 2010 castration-resistant prostate cancer† Romidepsin Istodax (Celgene, Summit, NJ) CTCL‡ November 5, 2009 Ofatumumab Arzerra (GlaxoSmithKline, For treatment of patients with CLL refractory to October 26, 2009 Philadelphia, PA) fludarabine and alemtuzumab Pazopanib Votrient (GlaxoSmithKline) Advanced renal cell carcinoma October 19, 2009 Pralatrexate Folotyn (Allos Therapeutics, For relapsed or refractory peripheral T-cell lymphoma September 25, 2009 Westminster, CO) (PTCL)§ Expanded indications for existing agents Nilotinib Tasigna (Novartis Oncology, For adult patients with newly diagnosed Philadelphia June 17, 2010 Florham Park, NJ) chromosome–positive chronic myeloid leukemia Erlotinib Tarceva (Genentech, South San Maintenance treatment for patients with locally April 16, 2010 Francisco, CA) advanced or metastatic NSCLC Rituximab Rituxan (Genentech) For patients previously treated for CD20-positive CLL in February 18, 2010 combination with fludarabine and cyclophosphamide Lapatinib Tykerb (GlaxoSmithKline) For use with letrozole to treat certain January 29, 2010 postmenopausal women with hormone receptor– positive metastatic breast cancer Rasburicase Elitek (sanofi-aventis) For the initial management of plasma uric acid levels October 16, 2009 in adult patients with leukemia, lymphoma, and solid tumor malignancies Abbreviations: FDA, US Food and Drug Administration; mHRPC, metastatic hormone-refractory prostate cancer; CTCL, cutaneous T-cell lymphoma; CLL, chroniclymphocytic leukemia; NSCLC, non–small-cell lung cancer; PTCL, peripheral T-cell lymphoma. FDA approved for use in combination with prednisone for treatment of patients with mHRPC previously treated with a docetaxel-containing regimen. †FDA-approved autologous cellular immunotherapy for the treatment of asymptomatic or minimally symptomatic castration-resistant (hormone-refractory) prostatecancer. ‡FDA approved for CTCL in patients who have received at least one prior systemic therapy. §The Office of Oncology Drug Products granted accelerated approval to pralatrexate injection (Folotyn) for the treatment of patients with relapsed orrefractory PTCL. Cabazitaxel approved for advanced prostate cancer: Cabazitaxel them. The IoM’s recommendations focus on improving the speed,(Jevtana; sanofi-aventis, Bridgewater, NJ) became the first chemother- efficiency, and flexibility of cooperative group clinical trials whileapy drug that we know of that is available for men with advanced, maximizing the involvement of patients and physicians.hormone-refractory prostate cancer who have already received treat-ment with the chemotherapy drug docetaxel. ABOUT THIS REPORTSummary of Recommendations This year’s Clinical Cancer Advances report highlights the most Every year significant progress is made in the fight against cancer.significant advances that have been made in cancer research in 2010. Because hundreds of cancer clinical trials are completed each year,For the past 50 years, the NCI Cooperative Group Program has served identifying the most notable advances in cancer research in any givenas one critical link between these scientific discoveries and improved year can be challenging. Six years ago, ASCO stepped in to fill thistreatment for patients with cancer (Table 4). Unfortunately, stagnant information gap and undertook the compilation and publishing offunding and numerous administrative and oversight challenges Clinical Cancer Advances.threaten the program’s ability to continue to serve in this role. Developed under the direction of a 14-person editorial board In conjunction with the release of the Institute of Medicine (IoM) comprised of prominent oncologists, only studies that significantlyreport,1 ASCO makes the following recommendations: altered the way a cancer is understood or had a direct effect on patient Double funding for cooperative clinical research: ASCO calls on care were included. The editors–including specialty editors for each ofNCI to double funding for Cooperative Group Program trials in the the disease- and issue-specific sections–reviewed research presented atacademic and community settings from its current level of $250 mil- major scientific meetings and studies published in peer-reviewed scien-lion to $500 million by 2015. Funding for cooperative clinical research tific journals during a 1-year period (October 2009-September 2010).has been virtually flat since 2002, forcing the NCI Cooperative Group Although important research is underway in all cancer types,Program to limit patient enrollment onto clinical trials. A recent advances that met the above criteria were not demonstrated in all typesASCO survey found that one third of Cooperative Group Program of cancer during the past year. Studies included in this year’s report areparticipants plan to limit participation in federally funded clinical grouped as follows.trials as a result of inadequate patient reimbursement. ● Blood and lymphatic cancers Implement IoM report recommendations: ASCO urges all stake- ● Breast cancerholders affected by the report’s recommendations to implement ● Cancer disparities4 © 2010 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on November 29, 2010 from 186.137.29.43 Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
  • 5. Clinical Cancer Advances 2010 Table 4. 2010 Clinical Cancer Advances Cooperative Group Studies Cooperative Group Cancer Type Research National Surgical Adjuvant Breast and Bowel Project Breast Negative sentinel node adequate to confirm lack of cancer spread13 American College of Surgeons Breast Immunohistochemistry to find micrometastases in bone marrow Oncology Group and sentinel lymph nodes unnecessary12 American College of Surgeons Breast Removing fewer lymph nodes in sentinel node-positive breast Oncology Group cancer does not impair survival10 North Central Cancer Treatment Group† Cancer disparities Race associated with response to chemotherapy for advanced colorectal cancer18 Southwest Oncology Group† Cancer disparities Disparities in cancer survival most significant in hormonally-driven cancers14 American College of Surgeons GI GIST mutations predict recurrence risk, may guide treatment Oncology Group choices22 Gynecologic Oncology Group Gynecologic Bevacizumab extends progression-free survival for women with advanced ovarian cancer28 American College of Surgeons Oncology Group Head and neck Sentinel node biopsy shows potential for early-stage oral cancer33 Radiation Therapy Oncology Group† Head and neck Survival is better with HPV-related oropharyngeal tumors30 Radiation Therapy Oncology Group Lung Stereotactic radiation a potential alternative for patients with inoperable early-stage lung cancer38 North Central Cancer Treatment Group† Melanoma Meta-analysis shows adding interferon alfa after surgery improves overall survival in patients with melanoma41 Children’s Oncology Group Pediatrics Adding imatinib to chemotherapy improves event-free survival in high-risk ALL46 Abbreviations: GIST, GI stromal tumors; HPV, human papillomavirus; ALL, acute lymphoblastic leukemia. Research conducted under cooperative groups. †Research on the basis of the analysis of cooperative group studies. ● GI cancers were reported. A pair of studies showed two second-generation drugs ● Genitourinary cancers were more effective than the current standard for chronic myeloid ● Gynecologic cancers leukemia. Another reported on the potential benefit of mainte- ● Head and neck cancers nance therapy for multiple myeloma, a disease in which relapse is a ● Lung cancer constant threat. Two more reports described the potential benefits ● Melanoma of adding antibody therapy to established treatments for follicular ● Pediatric cancers lymphoma. The past year also brought several new US Food and ● Prevention and screening Drug Administration approvals of drugs to treat rare forms of ● Quality of life and quality of cancer care lymphoma and leukemia. The advances detailed in each section are categorized as majorand notable, depending on the impact on patient care and survival. Notable AdvancesThe research considered for this report covers the full range of clinical Tyrosine kinase inhibitors provide additional options to imatinib forcancer issues: front-line chronic myeloid leukemia. For the vast majority of patients ● Epidemiology with chronic myeloid leukemia (CML), the current standard drug, ima- ● Prevention tinib (Gleevec; Novartis Oncology, Florham Park, NJ), is extremely effec- ● Screening tive. Yet a small but growing number of patients either don’t respond or ● Early detection develop resistance to imatinib. Therefore, researchers have sought alter- ● Traditional treatment (surgery, chemotherapy, radiation) natives for those patients for whom imatinib is ineffective. ● Targeted therapies Two separate studies this year showed the second generation ● Immunotherapy tyrosine kinase inhibitors dasatinib (Sprycel; Bristol-Myers Squibb ● Genetic research Oncology, Princeton, NJ) and nilotinib (Tasigna; Novartis Oncology, ● Personalized medicine Florham Park, NJ), which target the same genetic pathway as imatinib, ● Access to care may provide even more effective options against CML as first-line ● Quality of life ● End-of-life care therapies. These treatments were previously found to be effective in patients with CML for whom disease persisted despite treatment with imatinib or for those patients who cannot tolerate imatinib. In both BLOOD AND LYMPHATIC CANCERS cases, the newer drugs elicited faster and stronger responses and were better tolerated than imatinib.Cancers of the blood and lymphatic system include leukemia, lymphoma, ● In one phase III trial, 519 newly diagnosed patients withand multiple myeloma. During the past year, several important studies chronic phase CML were randomly assigned to receive eitherwww.jco.org © 2010 by American Society of Clinical Oncology 5 Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on November 29, 2010 from 186.137.29.43 Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
  • 6. Kris et al dasatinib or imatinib. The researchers measured the patients’ previous treatment with high-dose therapy and autologous stem-cell complete cytogenetic response, which is considered a good transplantation, followed by 2 months of lenalidomide treatment after marker for long-term survival, and the rate of major molecu- initial therapy to achieve a complete remission. Investigators found lar response (MMR), another marker of drug effectiveness. that adding lenalidomide maintenance therapy almost doubled 3-year After 1 year, 77% of patients receiving dasatinib reached a progression-free survival; 68% of patients in the lenalidomide main- complete cytogenetic response compared with 66% of those tenance group did not experience disease progression compared with receiving imatinib. The rate of MMR was also higher for 35% of patients in the placebo group who did not experience disease dasatinib (46%) compared with imatinib (28%). Researchers progression. Overall survival at 2 years was similar in both groups plan to observe these patients to assess long-term overall (95%), and analysis is ongoing. These findings suggest that this ap- survival and progression-free survival.2 proach can improve quality of life for patients with multiple myeloma ● In the other trial, called the ENESTnd (Evaluating Nilotinib by delaying the need for intensive therapy to treat a relapse. Efficacy and Safety in Clinical Trials of Newly Diagnosed New chemotherapy agent, better use of rituximab, may improve Philadelphia Chromosome–Positive CML Patients) trial,3 846 survival, delay relapse in follicular lymphoma. This year, two studies patients with newly diagnosed chronic-phase CML were ran- provided important new insights on potential advances in treating domly assigned to receive either nilotinib (doses of either 300 follicular lymphoma, a slow-growing but usually incurable cancer. 5 mg or 400 mg) or imatinib. By a median follow-up time of 18 ● A phase III German trial showed that bendamustine (Treanda; months, both patient groups receiving nilotinib had experi- Cephalon Oncology, Frazer, PA), a novel chemotherapeutic agent, enced more MMRs (69% for those receiving 300 mg and combined with the antibody rituximab (Rituxan; Genentech, 63% for those receiving 400 mg). Only 36% of the patients South San Francisco, CA) increased the rate of complete re- receiving imatinib had experienced MMRs. By 24 months, sponse in follicular and other types of lymphomas compared the patients who received nilotinib were still doing better— with the commonly used cyclophosphamide, doxorubicin, vin- the corresponding MMR rates were 86%, 88%, and 48%, cristine, and prednisone (CHOP) plus rituximab regimen. In the respectively. Patients treated with nilotinib were less likely to study, 513 patients with late-stage, slow-growing lymphomas experience disease progression to more dangerous phases (most of which were follicular lymphoma) were randomly as- compared with patients treated with imatinib. signed to treatment with either the bendamustine plus rituximab The results of both trials offer more choices for patients with or CHOP plus rituximab combination. Researchers found thatnewly diagnosed chronic phase CML. Nilotinib was granted acceler- the group treated with bendamustine plus rituximab lived signif-ated approval by the US Food and Drug Administration in 2010 icantly longer without the disease progressing (54.9 months)(Table 3) and is now indicated for use in front-line chronic phase compared with the patients treated with CHOP plus rituximabCML. These data suggest that second-generation inhibitors could (34.8 months). The patients treated with bendamustine experi-become the new standard of care for chronic phase CML. However, enced better overall responses than those in the CHOP group,many experts caution that longer follow-up is needed before either but there were no differences in overall survival. Patients treatednilotinib or dasatinib universally replace imatinib for this indication. with the CHOP plus rituximab combination experienced signif- Adverse effects are common with all tyrosine kinase inhibitors. icantly more toxicities and complications resulting from infec-Compared with imatinib, nilotinib more frequently caused rash, tions than did those treated with the bendamustine regimen.headache, liver function abnormalities, high cholesterol, hyperglyce- Bendamustine is not toxic to the heart, whereas doxorubicin ismia, increased serum lipase, and abnormal electrolyte levels. In addi- known to be cardiotoxic and may increase the risk of hearttion, there was prolongation of the QT interval, warranting a failure. These findings suggest that the bendamustine plus ritux-postapproval monitoring mandate from the US Food and Drug Ad- imab combination could become a new standard of care forministration. Dasatinib was more likely than imatinib to cause throm- previously untreated patients with follicular lymphoma.bocytopenia and pleural effusions. All three agents can cause ● The phase III international PRIMA (Primary Rituximab andsignificant myelosuppression. Maintenance) trial6 found that 2 years of rituximab (Rituxan) Lenalidomide maintenance therapy slows myeloma progression. maintenance therapy reduces the risk of follicular lymphomaMultiple myeloma, a cancer of plasma cells in the bone marrow, is recurrence by 50% for patients who responded to initial chem-typically treated with high-dose chemotherapy and autologous stem- otherapy plus rituximab. Patients with stage III or IV follicularcell transplantation, a procedure in which some of a patient’s own lymphoma whose disease was reduced or eliminated by rituximab-blood stem cells are removed and returned after treatment to rebuild based combination chemotherapy were randomly assigned to re-the immune system. Despite this aggressive approach, more than 90% ceive rituximab maintenance therapy (n 505) or noof patients eventually experience relapse. maintenance therapy (n 513) for 2 additional years. After a New findings from a phase III trial4 showed that adding mainte- median follow-up time of 25 months, the lymphoma progressednance therapy with the drug lenalidomide (Revlimid; Celgene, Sum- in 18% of the patients in the rituximab maintenance groupmit, NJ) in patients who had achieved remission after initial therapy compared with nearly double that (34%) among those whoslowed disease progression by 54%. Maintenance therapy is longer- didn’t receive the drug. The researchers noted that further obser-term treatment given after patients successfully complete initial ther- vation is needed to confirm the benefits of maintenance ritux-apy with the goal of prolonging remission. imab therapy for reducing the risk of lymphoma relapse. In this study, investigators evaluated more than 600 patients who Rituximab maintenance therapy was well-tolerated, and qualitywere randomly assigned to receive maintenance lenalidomide or pla- of life was similar between the two groups. On the basis of thesecebo until they experienced disease relapse. All patients had received findings, the manufacturer of rituximab has applied for approval6 © 2010 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on November 29, 2010 from 186.137.29.43 Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
  • 7. Clinical Cancer Advances 2010 in the United States and Europe for an expanded indication for conserving surgery significantly reduces deaths resulting from breast rituximab as maintenance therapy for these patients. cancer compared with surgery alone. Still, as many as 30% of women New targeted therapies approved for peripheral T-cell lymphoma who undergo such surgery in North America do not opt for radiation,and recurrent chronic lymphocytic leukemia. Two new drugs were partly as a result of its inconvenience.approved by the US Food and Drug Administration this year for But this year, Canadian researchers reported that a shorter, three-peripheral T-cell lymphoma and recurrent chronic lymphocytic leu- week course of higher-dose radiation—an approach called hypofrac-kemia (CLL). The approvals were based on significant response data in tionated therapy—may be just as effective as the standard five-weeksmall numbers of patients. course for women with early-stage disease.9 After 10 years, the risk of ● Pralatrexate (Folotyn; Allos Therapeutics, Westminster, CO) local recurrence among 622 women randomly assigned to receive the received US Food and Drug Administration approval as a shortened course was 6.2% compared with 6.7% among 612 women single-agent therapy for relapsed or refractory peripheral who were treated with the standard radiation course. In addition, T-cell lymphoma, a relatively rare and aggressive type of non- 71.3% of patients in the standard radiation group experienced good or Hodgkin’s lymphoma that is diagnosed in nearly 9,500 US excellent cosmetic outcomes after 10 years compared with 69.8% of patients annually. This drug is the first, to our knowledge, women receiving the briefer therapy. approved for peripheral T-cell lymphoma works by inhibiting RFC-1, a protein that is overexpressed in T-cell lymphoma Notable Advances cells. The approval was based on findings from the phase II Removing fewer lymph nodes in sentinel node-positive breast cancer PROPEL (Pralatrexate in Patients With Relapsed or Refractory does not impair survival. When cancer is detected in the sentinel node, Peripheral T-Cell Lymphoma) trial, which showed that 29 of 109 surgeons frequently remove additional lymph nodes (axillary node patients (27%) with peripheral T-cell lymphoma who received dissection) under the arm to look for more cancer. Although this has pralatrexate experienced some tumor shrinkage.7 been shown to control breast cancer spread locally, its effect on sur- ● The US Food and Drug Administration approved ofatu- vival has been controversial. New findings suggest that despite evi- mumab (Arzerra; GlaxoSmithKline, Philadelphia, PA), a dence of cancer in the sentinel lymph node, removal of axillary lymph monoclonal antibody drug targeting the CD20 protein on B nodes may not provide a survival benefit. cells, for treating relapsed or resistant CLL. The approval was In the largest phase III study of axillary node dissection in women based on findings from a single-arm trial including 154 pa- with sentinel node–positive disease to date to our knowledge, re- tients with relapsed or resistant CLL. In a subgroup of 59 patients searchers randomly assigned 891 women who had clinically node- with CLL who were resistant to two drugs—fludarabine and negative disease, fewer than three cancer-positive sentinel nodes, and alemtuzumab—researchers found that treatment with ofatu- breast-conserving surgery and radiation into two groups.10 The first mumab resulted in a 42% overall response rate with a median group received further sentinel node biopsy, and the second was response duration of 6.5 months. This response rate is en- treated with both sentinel node biopsy and axillary node dissection. couraging in a population of patients that has been heavily After a median follow-up of six years, the researchers found that pretreated and immunocompromised and that has few non- no survival advantage resulted from removing more lymph nodes. myelosuppressive options.8 The 5-year survival for those who had extra lymph nodes removed was 91.9% compared with 92.5% for women who had only the sentinel node removed. Disease-free survival was similar as well (82.2% for BREAST CANCER those who had the axillary node removed v 83.8% for those who had only the sentinel node removed).Breast cancer remains the most commonly diagnosed cancer for The study closed early because of lower-than-expected enroll-women in the United States, and significant progress continues to be ment, and further study is needed. However, the results raise themade against the disease. Women are living longer, healthier lives, possibility that, for select individuals such as the elderly and womenthanks to improvements in surgery, chemotherapy, and radiation with certain accompanying conditions or diseases, doctors couldtherapies. Recent insights into the molecular pathways critical to the safely forgo additional lymph node removal.behavior of specific breast cancers and the subclassification of breast Novel drug based on marine sponge chemical improves overall sur-cancers on the basis of genomic profile (as opposed to histologic vival in metastatic breast cancer. Metastatic breast cancer kills approx-features seen under the microscope) have been key in advancing imately 40,000 women in the United States each year, but there areunderstanding and treatment of the disease. But many challenges currently no curative treatments. For the first time to our knowledge,remain; certain forms of breast cancer continue to be difficult to treat. researchers have found that the chemotherapy agent eribulin mesy- Important advances of the past year include smarter radiation late, which is a new type of microtubule inhibitor that is an analog of atherapy approaches for early-stage disease; a new chemotherapy chemical derived from a marine sponge, helped patients with recur-agent for women with advanced breast cancer whose disease has rent or metastatic disease live longer compared with patients treatedprogressed despite other treatments; and new information on the with the physician’s choice of other standard treatments.most effective, least invasive way to detect cancer spread in the The phase III international study, called EMBRACE (Eisai Met-underarm lymph nodes. astatic Breast Cancer Study Assessing Physician’s Choice Versus Eribulin E7389), found that women who received eribulin had aMajor Advance median overall survival of 13.1 months compared with 10.7 months Briefer course of radiation just as effective in preventing recurrence for women who received their physician’s choice of therapy.11 Afterin early-stage breast cancer. Radiation of the entire breast after breast- one year, 53.9% of patients were alive after treatment with eribulinwww.jco.org © 2010 by American Society of Clinical Oncology 7 Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on November 29, 2010 from 186.137.29.43 Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
  • 8. Kris et alcompared with 43.7% of those receiving the physician’s choice of States, and ongoing research seeks to better understand the complextherapy. The results could potentially establish eribulin as a new stan- causes of these differences. Although socioeconomic disadvantages indard for this group of patients. access to cancer care and services are more prevalent among racial and Immunohistochemistry to find micrometastases in bone marrow ethnic minorities—and are widely assumed to account for most ofand sentinel lymph nodes unnecessary. Doctors frequently use an these cancer outcome differences—increasing attention has focusedextra-sensitive test called immunohistochemistry (IHC) to detect the on the potential effects of newly discovered, inherited susceptibilitiesspread of hidden breast cancer, with the goal of predicting risk of to certain cancers.recurrence and guiding therapy choices. However, a large observa- Key studies published during the past year showed that equaltional trial of women with early-stage breast cancer found that using cancer treatment results in equal outcomes, regardless of racial orIHC to find micrometastases in both the bone marrow and sentinel ethnic identity for most cancers. However, several recent breast cancerlymph nodes did not have an impact on survival.12 These results argue studies have demonstrated provocative differences in the biologicagainst the frequent use of IHC testing, which could save money and characteristics and survival rates in women with African ancestry bothspare women from potentially unnecessary therapy prescribed on the within the United States and in continental Africa compared withbasis of such tests. white women. Other research provided a new perspective on the In this prospective, multicenter study, researchers examined the underlying factors affecting racial differences in survival for patientspotential clinical significance of IHC-detected cancer in the bone with colon cancer.marrow and sentinel node in more than 5,500 women with early-stage, clinically node-negative disease. All underwent sentinel node Notable Advancesbiopsies and bone marrow aspiration to look for micrometastases, and Disparities in cancer survival most significant in hormonally driventhose whose diseases were found to be negative by these standard cancers. In a groundbreaking study examining the root causes ofpathology tests were tested with IHC. Standard pathology detected racial disparities in cancer survival among patients in clinical trials,cancer in 23.9% of the sentinel nodes, and IHC found cancer in anadditional 10.5%. researchers found that cancer outcomes were indeed similar for pa- Despite the fact that IHC detected more cancer, the 5-year sur- tients with cancer receiving equal treatment within the context of avival rate was statistically similar between the two groups. In the IHC clinical trial, regardless of racial/ethnic identity. This was true with thegroup, 95.1% of the women with positive sentinel nodes lived 5 years exception of trials designed for hormonally driven cancers such ascompared with 92.8% of women with positive nodes found by stan- breast, prostate, and ovarian cancer. For hormonally driven cancers,dard pathology. For patients with bone marrow metastases detected survival rates were worse for African American patients than for whiteby IHC, median 5-year overall survival was lower (90.2% compared patients. These differences persisted even after controlling for prog-with 95.1% for women with IHC-negative bone marrow) and statis- nostic, treatment, and socioeconomic factors.tically significant. Although the detection of bone marrow metastases Investigators closely examined the records of nearly 20,000 adultby IHC identified patients with an increased risk for death, it was not patients with cancer, including 2,308 African Americans from 35predictive of overall survival in a multivariate analysis. Southwest Oncology Group phase III trials that were conducted dur- Negative sentinel node adequate to confirm lack of cancer spread. ing a 27-year period.14 They studied outcomes for cancers of theIn recent years, the standard practice has been to examine the breast’s breast, lung, colon, ovaries, and prostate along with lymphoma, leu-sentinel lymph node— usually under the woman’s arm—to look for kemia, and multiple myeloma. Results were stratified according tohidden cancer that may have spread there. This procedure can avoid cancer pathology and stage. The study findings showed that Africanthe need for axillary node dissection in women who have no palpable American heritage was associated with increased risk of death in pa-disease or evidence of spread to the lymph node. Axillary node dissec- tients with early-stage premenopausal and postmenopausal breasttion, which is a surgical procedure to remove all axillary lymph nodes cancer, advanced-stage ovarian cancer, and advanced-stage prostateunder the arm, can cause pain, swelling, and scarring. cancer. The 10-year survival rates for African American patients with A National Surgical Adjuvant Breast and Bowel Project trial early-stage premenopausal breast cancer compared with all other pa-randomly assigned 5,611 women with clinically node-negative breast tients with early-stage premenopausal breast cancer were 68% andcancer to either have both sentinel and axillary nodes removed (group 77%, respectively. Those rates were 52% and 62%, respectively, for1) or have sentinel node surgery only, with axillary dissection only if early-stage postmenopausal breast cancer; 13% and 17%, respec-cancer was found (group 2).13 Of the 5,611 women, only the 3,989 in tively for advanced ovarian cancer; and 6% and 9%, respectively,groups 1 and 2 whose diseases were found to be sentinel node–negative for advanced prostate cancer. These findings suggest that tumorwere observed for an average of 95 months. The researchers did not biologic, hormonal, and other inherited factors could be contrib-find any statistically significant differences in local and regional recur- uting to race- and ethnicity-associated survival differences in hor-rence or in overall survival between groups 1 and 2. monally driven cancers. Two studies reveal an association between African ancestry and risk of triple-negative breast cancer. African American women have a CANCER DISPARITIES lower lifetime incidence of breast cancer compared with white women, but they have significantly higher breast cancer mortalityAlthough progress continues to be made in cancer detection, screen- rates. A key to explaining the mortality disparity is the fact that Africaning, and treatment, these advances do not necessarily benefit all groups American women are more likely to be diagnosed with tumors,to the same degree. Disparities in cancer outcomes are well- known as triple-negative tumors, that are negative for the estrogendocumented between various racial and ethnic groups in the United receptor, the progesterone receptor, and the HER2/neu protein.8 © 2010 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on November 29, 2010 from 186.137.29.43 Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
  • 9. Clinical Cancer Advances 2010Triple-negative breast cancers are also highly correlated with the in- disparities in colon cancer mortality rates by evaluating differences inherently aggressive basal breast cancer subtype, and they do not re- response to chemotherapy. Researchers studied race- and ethnicity-spond to targeted, biologic systemic treatment for breast cancer, such related variations in pharmacogenetics by analyzing a group of partic-as endocrine therapy or the drug trastuzumab (Herceptin; Genentech, ipants in the North Central Cancer Treatment Group trial N9741,18 aSouth San Francisco, CA). randomized controlled trial comparing three different colon cancer This year, two studies added important new insights to the body regimens: irinotecan and fluorouracil, fluorouracil and oxaliplatin,of knowledge on the association between racial and ethnic identity and and irinotecan and oxaliplatin.the risk for triple-negative breast cancer. Both studies evaluated breast Investigators compared adverse events, response rates, time totumors of Western African women, which is particularly relevant to progression, and overall survival for 1,412 white and African Ameri-inherited breast cancer risk in contemporary African American can participants. In addition, pharmacogenetic analyses were per-women because of the hypothesized shared ancestry with Western formed on blood samples from 486 patients for whom such samplesAfrican women. were available. After controlling for stage at diagnosis and treatment ● In a first-of-its-kind study, to our knowledge, researchers assessed arm, the investigators found that overall survival and time to disease the distribution of molecular subtypes of invasive breast cancers in progression were similar for the two groups. However, response rates native West African women by creating tissue microarrays from were significantly higher among the white participants (41%) compared the tumors of 507 Nigerian and Senegalese women.15 They found with the African American participants (28%). Additionally, several that approximately three quarters of these tumors were hormone highly significant associations were identified between racial and ethnic receptor–negative, and more than half were either a basal subtype identity and drug-metabolizing enzyme genotypes, but no definitive or an unclassified triple-negative subtype. conclusions could be drawn regarding the impact of these associations ● Another study concluded that the extent of African ancestry is on drug toxicity and effectiveness as a result of inadequate sample size. associated with risk for developing triple-negative breast can- cer on the basis of a comparative analysis of 581 African American patients, 1,008 white American patients, and 75 GI CANCERS Ghanaian patients with breast cancer.16 The highest propor- tion of triple-negative breast cancer was seen among the Gha- GI cancers include those of the esophagus, stomach, liver, pancreas, naian women (82%), and the lowest frequency was seen biliary tract, colon, rectum, and anus. Important advances in the past year among the white women (16%); African American women included a pair of studies showing progress against two types of metastatic had an intermediate risk frequency of 26%. A similar pattern was pancreatic cancer, and reports showing the potential value of analyzing observed for proportions of estrogen receptor–negative tumors, for gene mutations in GI stromal tumors and metastatic colon cancer. which the frequencies were 76%, 36%, and 22% among Ghana- ian, African American, and white women, respectively. Major Advance These studies strengthen the understanding of disparities in Chemotherapy combination dramatically improves survival for pa-breast cancer outcome, and they may ultimately contribute to the tients with metastatic pancreatic cancer. Adenocarcinoma of the pan-clinical applications of targeted breast cancer treatment and creas (the most common type of pancreatic cancer) is extremelyrisk assessment. aggressive and often detected after it has spread to other parts of the Study confirms socioeconomic status plays major role in racial dis- body. Treatment options for patients diagnosed with stage IV pancre-parities in colon cancer outcomes. Past studies have shown differences atic cancer are limited, making treatment challenging. But a recentbetweenstage-specificcoloncancertreatmentsgiventoAfricanAmerican randomized phase III trial of 250 patients with metastatic pancreaticand white patients. These disparities in care have been presumed to be cancer is the first to demonstrate a significant survival improvement inrelated to socioeconomic disadvantages and poorer health care access, this population.19 It found that first-line treatment with FOLFIRI-thereby at least partially explaining the higher colon cancer mortality rates NOX—a combination of the chemotherapy drugs fluorouracil, leu-that are observed among African American patients. A recent analysis covorin, irinotecan, and oxaliplatin—resulted in better response rates,supports this theory. In a population of patients with colon cancer and progression-free survival, and overall survival compared with stan-similar socioeconomic status and insurance coverage, patients received dard single-drug treatment with gemcitabine. The trial was haltedthe same quality of care regardless of race and experienced similar out- early at an interim analysis on the basis of these positive results.comes,confirmingthatsocioeconomicstatusplaysamajorroleinrace-or The median overall survival for patients treated with FOLFIRI-ethnicity-associated disparities in colon cancer outcomes. NOX was 11.1 months compared with 6.8 months for those receiving To examine the effects of race on colorectal cancer outcomes in a gemcitabine, marking the longest-ever survival advantage observed, tosingle hospital, investigators retrospectively analyzed records from our knowledge, in a clinical trial for advanced pancreatic cancer.365 patients (175 African American patients and 190 white patients) Approximately 48% of patients on FOLFIRINOX were alive at 1 yeardiagnosed with stage II, III, or IV colon cancer.17 After adjusting for comparedwith20%ofpatientswhoreceivedgemcitabine.Patientsonthedemographics such as socioeconomic status, health insurance cover- FOLFIRINOX arm also lived nearly twice as long without a worsensing ofage, gender, age, and marital status, the investigators examined racial disease; median progression-free survival was 6.4 months for those ondifferences in the quality (timeliness and effectiveness) of stage- FOLFIRINOX and 3.3 months for those treated with gemcitabine.specific colon cancer therapy. They found no difference in patient care Although common in the FOLFIRINOX group, adverse effectsor outcomes between African American patients and white patients. were not severe enough that patients had to stop treatment. Patients Race and ethnicity associated with response to chemotherapy for who received FOLFIRINOX experienced longer preservation of qual-advanced colorectal cancer. Another study offered further clues to ity of life, although toxicities were higher compared with gemcitabine.www.jco.org © 2010 by American Society of Clinical Oncology 9 Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on November 29, 2010 from 186.137.29.43 Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
  • 10. Kris et alNotable Advances Previously researchers had shown that 1 year of imatinib therapy Sunitinib delays spread of cancer for patients with pancreatic neu- after surgery significantly prolonged survival without recurrence forroendocrine tumors. An international study showed that patients with patients with GIST compared with patients with GIST who received aadvanced pancreatic neuroendocrine tumors lived twice as long with- placebo. In this study, researchers analyzed tumor and molecularout disease progression when treated with the tyrosine kinase inhibitor characteristics in 513 patients with GIST who were randomly assignedsunitinib (Sutent; Pfizer, New York, NY) as did those who received a to receive either imatinib or a placebo. Researchers found that highplacebo. Pancreatic neuroendocrine tumors, which sometimes secrete mitotic rate, small bowel location, and large tumor size were associ-excessive amounts of various hormones, make up only about 5% of all ated with worse recurrence-free survival. Patients whose tumors ex-pancreas tumors, and they grow slower than adenocarcinoma of pressed exon 11 mutations and who were treated with adjuvantthe pancreas. imatinib were significantly less likely to suffer disease recurrence within 2 In this multicenter phase III trial, 171 patients whose tumors had years than those who received a placebo; 91% of those with exon 11progressed in the previous 12 months were randomly assigned to mutations were relapse-free compared with 65%. Likewise, patients withreceive either sunitinib or placebo.20 All patients received supportive mutations in the PDGFRA gene were also less likely to experience recur-care, which could include antinausea medication, nutritional support, rence when treated with imatinib. In contrast, imatinib did not seem toand antibiotics for infections. Overall, patients in the sunitinib group influence recurrence for patients with wild-type tumors.were more likely to be alive after six months than were those treated BRAF status, tumor site, time to relapse help predict overall survivalwith placebo (92.6% v 85.2%). Researchers also found that median after colon cancer relapse. Researchers have previously evaluated theprogression-free survival was longer in the sunitinib group than in the prognostic value of eight selected molecular markers on relapse-freeplacebo group (11.4 v 5.5 months). The trial was halted early as a result survival in stage II and III colon cancer. In this study, they examinedof the superiority of sunitinib over placebo. The results suggest that the prognostic value of the same eight markers on survival after relapsesunitinib can delay disease progression and help patients live longer. in 392 of 990 patients who experienced disease relapse.23 The authors BRAF status prognostic marker for metastatic colon cancer survival found that, although BRAF gene status and tumor site had no prog-with chemotherapy plus cetuximab. Two large trials, the CRYSTAL nostic value on relapse-free survival, both, along with time to relapse,(Cetuximab Combined With Irinotecan in First-Line Therapy for were strong determinants of overall survival of patients with colon cancer after disease relapse. In their data set, patients with BRAF-Metastatic Colorectal Cancer) and the OPUS (Oxaliplatin and Cetux- mutated tumors had a median survival of 7.5 months compared withimab in First-Line Treatment of Metastatic Colorectal Cancer) stud- 25.2 months for patients with BRAF wild-type tumors. The median sur-ies, showed that adding the targeted drug cetuximab (Erbitux; vival after relapse of patients with right-sided tumors was 16.2 monthsImClone Systems, Branchburg, NJ) to initial chemotherapy improved compared with 28.4 months for those patients with left-sided tumors.outcomes compared with chemotherapy alone for those patients with Finally,patientswhosediseaseexperiencedlaterelapselivedmorethan2.5metastatic colon cancer tumors that do not have KRAS gene mutations. years compared with 1.5 years for those who experienced early relapse. In a follow-up analysis, researchers pooled data from both trial Researchers suggest that the markers evaluated in this study should bepopulations (which included 1,645 patients, although only 1,378 used in stratifying patients with metastatic colon cancer for clinical trials.evaluable samples) and assessed outcomes on the basis of both KRASand BRAF gene mutation status.21 They found that adding cetuximabto chemotherapy improved outcomes for all patients with normal GENITOURINARY CANCERSforms of KRAS, regardless of BRAF status, but that those patients withnormal forms of both the KRAS and BRAF genes benefited most. This past year saw important advances in the treatment and under- standing of genitourinary cancers, which include those in the prostate, Median survival for patients with normal KRAS and BRAF who bladder, kidney, testes, ureters, and urethra. A major study providedwere treated with chemotherapy and cetuximab was 24.8 months evidence on the feasibility of watchful waiting for prostate cancer andcompared with 21.1 months for chemotherapy alone. For patients the importance of regular biopsies. The US Food and Drug Adminis-with normal KRAS and BRAF mutations, adding cetuximab increased tration also approved two new drugs for metastatic hormone-resistantmedian survival from 9.9 to 14.1 months. These data demonstrate that prostate cancer: a first-ever therapeutic vaccine, to our knowledge,BRAF mutations are prognostic—patients whose tumors harbor and a new chemotherapy drug for patients whose disease has pro-BRAF mutations have significantly shorter progression-free and over- gressed despite other forms of chemotherapy. In addition, the USall survival. However, patients with a normal KRAS gene and a BRAF Food and Drug Administration also approved a drug for advancedmutation still seem to benefit from cetuximab, and treatment deci- renal cell cancer.sions regarding the use of cetuximab should not be made based on thepresence of BRAF mutations. Major Advances GI stromal tumor mutations predict recurrence risk, may guide Sipuleucel-T approved for treating advanced prostate cancer. Thetreatment choices. An American College of Surgeons Oncology US Food and Drug Administration approved sipuleucel-T (Prov-Group trial—to our knowledge the largest trial of patients with GI enge), a cancer vaccine for metastatic hormone-refractory prostatestromal tumors (GIST) observed prospectively after surgery—found cancer, in April 2010. Unlike a standard vaccine, which is given tothat patients whose tumor cells have certain gene mutations are at stimulate the immune system to fight off infections and prevent dis-higher risk of recurrence and are more likely to benefit from adjuvant ease, sipuleucel-T is a therapeutic vaccine that boosts the body’s im-therapy with the tyrosine kinase inhibitor imatinib (Gleevec).22 The mune system to attack cancer cells in the body.findings suggest that analyzing GIST mutations may help guide treat- The approval of sipuleucel-T was based on results from a ran-ment strategies after surgery. domized, phase III trial of 512 patients with metastatic prostate cancer10 © 2010 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on November 29, 2010 from 186.137.29.43 Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
  • 11. Clinical Cancer Advances 2010that was resistant to other therapies. Those who received the vaccine GlaxoSmithKline, Philadelphia, PA) for the treatment of advancedexperienced an improvement of 4.1-months in median survival when renal cell cancer in October 2009. Pazopanib is an oral drug that blockscompared with patients receiving a placebo (25.8 v 21.7 months).2,24 multiple cancer cell receptors that are associated with tumor growth Cabazitaxel approved for advanced prostate cancer. Cabazitaxel and angiogenesis (development of blood vessels that feed tumors).(Jevtana), a second-line chemotherapy drug for advanced, hormone- This approval was based on data from a phase III study of 435 patientsrefractory prostate cancer in men who have already received treatment with advanced renal cell carcinoma that showed that patients whowith the chemotherapy drug docetaxel, was approved by the US Food received pazopanib lived significantly longer without disease progres-and Drug Administration in June 2010. Before this approval, there sion (9.2 months) compared with those who received a placebowere no effective treatments that we know of in this setting. (4.2 months).27 The approval was based on data from the randomized, phase IIITROPIC (Treatment of Hormone-Refractory Metastatic ProstateCancer Previously Treated With a Taxotere-Containing Regimen) GYNECOLOGIC CANCERSclinical trial, conducted among 755 patients in 26 countries.25 Allpatients had advanced hormone-refractory prostate cancer, and all Gynecologic cancers include cancers of the cervix, uterus, ovaries,had previously been treated with docetaxel. In the clinical trial, pa- fallopian tubes, vagina, and vulva. Two reports this year could havetients were randomly assigned to receive either cabazitaxel or another important implications for treating and screening for ovarian cancer,cancer drug, mitoxantrone. Men who received cabazitaxel lived a which is the most deadly form of gynecologic cancer. In one study,median of 15.1 months, a 30% increase in survival compared with a researchers reported on the first effective targeted therapy to ourmedian of 12.7 months for those who received mitoxantrone. knowledge, bevacizumab, for advanced ovarian cancer, and other research showed promising results from a novel screening techniqueNotable Advances in women at normal risk for ovarian cancer. Watchful waiting an option for low-risk patients, better tools neededto identify aggressive disease. Early-stage, low-risk prostate cancer can Major Advancebe a slow-growing disease; in some cases it takes as long as 25 years to Bevacizumab extends progression-free survival for women withrequire any treatment. As a result, many men opt for a watchful advanced ovarian cancer. Although two chemotherapy drugs, carbo-waiting approach, in which surgery or treatment is delayed, and men platin and paclitaxel, have been the standard treatment for advancedinstead undergo frequent prostate-specific antigen (PSA) testing and ovarian cancer for the past decade, this cancer has remained extremelyoccasional biopsy to determine when and if treatment is needed. difficult to treat, and most women eventually die as a result of the In a single-arm study reported this year, researchers assessed disease. But a new strategy for treating epithelial ovarian cancer, pri-the feasibility of watchful waiting by prospectively observing 450 mary peritoneal ovarian cancer, and fallopian tube cancer has shownpatients with low-risk prostate cancer. 26 In the study, the decision promising results. A Gynecologic Oncology Group trial has found thatto treat was based on rising PSA or changes in tumor pathology (on adding the antiangiogenesis drug bevacizumab to the standard chem-the basis of a biopsy). PSA testing was performed every 3 months otherapy drug combination helped women live significantly longerfor 2 years. All men underwent confirmatory biopsy 6 to 12 months without disease progression. The Gynecologic Oncology Group is partafter an initial biopsy and then every 3 or 4 years with a median of the NCI Cooperative Group Program that serves as one critical linkfollow-up of 6.8 years. Those whose PSA levels doubled in 3 years between these scientific discoveries and improved treatment for can-or fewer were offered treatment. cer patients. Investigators found that, overall, 30% of patients had to be reclas- In this double-blind phase III study, investigators randomlysified as higher risk and offered treatment on the basis of rates of PSA assigned nearly 1,900 women with stage III or IV disease who haddoubling. Of the 117 patients treated with surgery, 50% (or 13% of not undergone previous treatment to one of three groups: standardpatients overall) experienced rising PSA scores again and a recurrence chemotherapy (paclitaxel plus carboplatin) and placebo followedof cancer, suggesting that they might have benefited from earlier, more by placebo maintenance; standard chemotherapy with bevaci-aggressive treatment. Still, researchers found that men in this trial were zumab followed by placebo maintenance; or standard chemother-more likely to die of causes other than prostate cancer, reporting a apy with bevacizumab followed by bevacizumab maintenance.28prostate cancer–specific survival rate of 97.6% (overall survival of Maintenance therapy was defined as a longer-term treatment givenpatients in the study was 78.6%). after standard chemotherapy with the goal of extending cancer The findings also suggest that watchful waiting is particularly progression–free survival.feasible and safe for men older than age 70 years who have low-to- In conclusion, the researchers found that patients in the thirdintermediate-risk disease. In this group, the investigators reported that group lived a median of 14.1 months without disease progressionthe risk of death as a result of other causes was almost 19-fold greater compared with 10.3 months for patients in the group that received chem-than that of prostate cancer. otherapy alone. Patients who received initial chemotherapy and bevaci- The researchers concluded that, although watchful waiting was fea- zumab with placebo maintenance did not experience a significant benefitsible and few men died of prostate cancer, more regular biopsies could be compared with those who were treated with chemotherapy alone.helpful for better detection of progressing cancer, and additional studies,including genetic tests of the tumors, are needed to better identify when Notable Advancepatients have more aggressive disease despite an initial low-risk status. New ovarian cancer screening strategy promising for postmeno- Pazopanib approved for patients with kidney cancer. The US pausal women at average risk. More than 70% of ovarian cancers areFood and Drug Administration approved pazopanib (Votrient; diagnosed at an advanced stage, and researchers would like to identifywww.jco.org © 2010 by American Society of Clinical Oncology 11 Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on November 29, 2010 from 186.137.29.43 Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
  • 12. Kris et ala reliable screening test for early-stage disease. For years, levels of the nificantly better 3-year overall survival (82.4% v 57.1%) thanCA-125 protein, found through a blood test, have been known to those with HPV-negative tumors.30increase during ovarian cancer development. But the CA-125 protein ● The second trial compared standard radiotherapy and cispla-test has not proved to be a reliable indicator for documenting the tin with the same treatment plus a second drug, tirapazamine,presence of early-stage ovarian cancer. A recent study, however, which is a cytotoxin. Although this study noted that the out-showed the feasibility of a novel and promising new screening ap- come of the experimental treatment was not better than thatproach for postmenopausal women at average risk for ovarian can- of the standard treatment, it found that patients with HPV-cer.29 The new approach uses a mathematical model, called the Risk of positive oropharyngeal cancer had significantly better overallOvarian Cancer Algorithm (ROCA), that combines trends in CA-125 survival than those with HPV-negative tumors.31blood test results, a patient’s age, and results from a transvaginal As a result of these large studies, future head and neck trials willsonogram (TVS) and finally referral to a gynecologic oncologist, enroll patients according to the HPV status of the tumor. HPV-as necessary. positive trials will focus on treatment deintensification and thus allow The study included 3,238 postmenopausal women age 50 to 74 improved quality of life for those patients who are likely to have ayears with no significant family history of breast or ovarian cancer who better prognosis, whereas HPV-negative trials will focus on intensify-were observed for up to 8 years. On an annual basis, researchers found ing treatment to improve survival in this patient group, which appearsthat less than 1% of women required TVS. Eight women underwent to have a poorer prognosis.surgery on the basis of the ROCA results, three of whom had invasive Accelerated radiotherapy schedule is more effective in head and neckbut early-stage ovarian cancers, two had borderline ovarian tumors, cancer in resource-poor countries. Several large, randomized studies inand three had benign ovarian tumors. The specificity of ROCA fol- Western countries have shown that accelerated fractionated radio-lowed by TVS for referral to surgery was 99.7%, indicating that the therapy, which shortens the overall radiation course without compro-approach experienced few false-positive results. mising the total dose, can improve local and regional tumor control in A large-scale study of ROCA involving more than 200,000 patients with locally advanced head and neck cancer. A large, multi-women is underway in the United Kingdom; the results are expected center, randomized trial at nine centers located in countries within 2015. limited resources showed that this treatment was more effective than conventional fractionation and can be feasibly delivered to a large number of patients without requiring additional resources.32 HEAD AND NECK CANCERS In the trial, 908 patients with squamous cell carcinoma of the larynx, pharynx, or oral cavity were randomly assigned to receiveHead and neck cancers—including those commonly found in the either an accelerated regimen of 6 radiation fractions per week for 6mouth, larynx, pharynx, and sinus/nasal tract—account for approxi- weeks (median, 40 days) or the conventional schedule of 5 fractionsmately 5% of all diagnosed cancers in the United States. The incidence per week for 7 weeks (median, 47 days). After 5 years of follow-up, theof head and neck cancer is increasing globally and is now the fourth accelerated radiation treatment was superior to the conventionalmost common malignancy in the world, with more than 70% of all treatment in local and regional control (42% v 30%) and 5-yearcases found in developing countries. disease-specific survival (50% v 40%). There was also a trend for This year, the most significant research included two large clinical improved overall survival with the accelerated treatment (35% vtrials that demonstrated the importance of human papillomavirus (HPV) 28%). Accelerated treatment was associated with more adverse effectsinfection on head and neck cancer prognosis and treatment outcomes. (skin reaction, mucosal inflammation, and temporary feeding tubeOther studies reported promising results using accelerated radiotherapy use) but not with increased late toxicity.toimproveoutcomesinresource-limitedcountriesanddemonstratedthe Sentinel node biopsy shows potential for early-stage oral cancer.usefulness of sentinel node biopsies to determine the spread of oral cavity For patients with early-stage oral cavity cancer that has a high risk forcancers. Finally, a study showed the influence of radiation quality on spreading to the lymph nodes in the neck, standard treatment isoverall survival for patients with head and neck cancer. surgery without necessarily checking the sentinel nodes. Sentinel node biopsy has been shown to be highly accurate and useful in the man-Notable Advances agement of early-stage breast cancer and melanomas, but it has not Survival is better with HPV-related oropharyngeal tumors. Most been well-tested in squamous cell carcinoma of the head and neck.head and neck cancers have been closely linked to excessive tobacco This year, a prospective multicenter trial tested this concept inand alcohol use. More recently, there has been an increase in HPV-related 140 patients with early-stage oral cavity cancer.33 The study foundhead and neck cancers, which are caused by infections with the same that sentinel node biopsy could serve as a useful tool for staging oralhigh-risk HPV subtypes that cause cervical cancer. Prior studies have cavity cancer rather than performing a larger, more invasive necksuggested a link between tumor HPV status to overall and surgery to determine whether the cancer has spread. These findingsprogression-free survival among patients with oropharyngeal cancer. are important because such neck surgery can be disfiguring and is also ● Researchers examined the connection between the HPV status of associated with swallowing and shoulder dysfunction. oropharyngeal cancer and survival among patients with stage III In the study, researchers found that of 106 sentinel node biopsies or IV tumors who participated in two large, randomized clinical that were pathologically negative for cancer, 100 patients had no other trials. One trial compared two types of radiotherapy (standard pathologically positive lymph nodes, yielding a negative predictive 7-week course v accelerated 6-week course) that were both deliv- value of 94%. Through additional testing, a negative sentinel lymph ered together with the chemotherapy drug cisplatin. They found node biopsy correctly predicted a lack of metastases to the neck in 96% that patients with HPV-positive oropharyngeal cancer had sig- of cases. Experts caution that, although these results are promising, it is12 © 2010 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on November 29, 2010 from 186.137.29.43 Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
  • 13. Clinical Cancer Advances 2010too early to call for the routine use of such testing, and more research receiving the combination lived nearly twice as long (6.3 v 3.2 months)is needed. without disease progression as well. Radiotherapy quality and protocol compliance are keys to head and Crizotinib shows high response rate in patients with lung adenocar-neck cancer survival. In the context of an international phase III cinoma with EML4-ALK translocations. A phase I trial showed that aclinical trial of radiotherapy and chemotherapy in patients with locally high percentage of patients with lung adenocarcinoma with a specificadvanced head and neck cancer, for the first time to our knowledge, ALK gene mutation responded to an investigational ALK inhibitor,researchers showed that radiation quality and adherence to radiother- crizotinib.36 More than half of these patients experienced some tumorapy guidelines impact tumor control and translate into a survival shrinkage. Phase I trials are typically aimed at gauging toxicity of andifference.34 The trial aimed to test the benefit of adding a hypoxic cell experimental agent and rarely show dramatic clinical activity.cytotoxin, tirapazamine, to concurrent cisplatin-based chemotherapy When the ALK gene fuses with another gene, it promotes lungand radiation. Participating centers submitted imaging and radiation cancer cell growth by encoding the production of a tumor-specifictreatment plans to a centralized quality assurance center for initial protein called anaplastic lymphoma kinase (ALK), an enzyme that isreview and feedback after one week of starting radiation treatment and instrumental to cancer cell growth and development. Crizotinib, which isthen submitted for final review after treatment was completed. taken orally, inhibits the ALK enzyme. About one in 20 patients with In the study, 208 (approximately 25%) of 820 patients received lung cancer, or approximately 11,000 people, in the United States areradiation treatment that was noncompliant with the protocol. Of estimated to be diagnosed with ALK-positive lung cancer each year.these, 87 patients received doses less than 60 Gy and had radiation In the study, more than 90% of the 82 patients enrolled re-treatment deficiencies that were predicted to have an adverse impact sponded to the drug; either their disease stabilized, or there was someon tumor control. These patients had significantly poorer tumor con- tumor shrinkage. On the basis of these findings, phase III trials com-trol rate and, more importantly, worse 2-year overall survival (50% v paring crizotinib to chemotherapy are ongoing.70%) than those treated with compliant plans. Adding routine management by a palliative care team to chemo- Researchers also found that centers with low patient enrollment therapy improves survival in patients with lung cancer. A randomizedonto the trial were more likely than centers with high enrollment to clinical trial of patients with advanced lung cancer showed that thosehave noncompliant plans. Centers that enrolled fewer than five pa- individuals who received standard chemotherapy coupled with pallia-tients in the trial had 29.8% of the submitted radiation plans that were tive care immediately after diagnosis lived significantly longer and hadpredicted to have an adverse impact on tumor control, whereas those a better quality of life than those who received chemotherapy alone.37enrolling more than 20 patients only had 5.4% of such plans. Patients who regularly saw palliative care specialists reported less de- pression and pain and better mobility and were less likely to undergo LUNG CANCERS aggressive therapy at the end of life than individuals who received chemotherapy alone. In the study, 151 patients with the most common form of lungOver the past year, research has focused on personalizing treatment cancer were randomly assigned within eight weeks of diagnosis toapproaches on the basis of age, specific gene mutations, and the extent receive either chemotherapy with palliative care, including pain reliefof disease. These findings will help physicians refine the use of existing and other supportive measures, or chemotherapy alone. The investi-cancer treatments and offer promising new tools for groups of pa- gators found that the median survival in the palliative care group wastients. One trial found that elderly patients with lung cancer can improved by 3 months compared with that of patients who receivedtolerate the same treatment as younger patients, whereas another chemotherapy alone (11.6 v 8.9 months). Individuals whose symp-focused on the role of specific genetic mutations and the effectiveness toms were managed by palliative care specialists reported a betterof a targeted agent. A third study found that patients with lung cancer quality of life. Only 16% (v 38% of the chemotherapy group) reportedbenefitted from early palliative care given with chemotherapy. Finally, symptoms of depression over 3 months. Despite living longer, fewerresearch showed the dramatic effect of a form of radiotherapy for patients receiving palliative care (33%) chose aggressive end-of-lifepatients with early-stage inoperable disease. care (which does not improve quality of life) over those patients receiving only chemotherapy (54%).This research was supported by aMajor Advances Career Development Award from the ASCO Cancer Foundation. Chemotherapy combination increases survival of elderly patientswith advanced lung cancer. Most patients with lung cancer are olderthan age 70 years, yet there are few new clinical trials evaluating Notable Advancetherapies for this population. This year, a French study provided rare Stereotactic radiation a potential alternative for patients with inop-insight into treatment for this group.35 It showed that the same com- erable lung cancer. For patients with early-stage lung cancer whobination of chemotherapy drugs commonly used for younger patients cannot undergo surgery, conventional radiotherapy fails to controlimproved survival in elderly patients compared with the single-agent the primary lung tumor in 60% to 70% of patients, with only 20% totherapy typically used for elderly patients. 35% of patients surviving after 3 years. However, a recent study found This phase III study compared the effectiveness of carboplatin that stereotactic radiation, which involves delivering highly focusedand paclitaxel with therapy with gemcitabine or vinorelbine in 451 radiation beams to the tumor, is a good alternative for patients withpatients with advanced non–small-cell lung cancer between the ages of early-stage lung cancer whose tumors cannot be surgically removed.70 and 89 years. Researchers found that the patients treated with the A Radiation Therapy Oncology Group phase II study found thatcombination therapy had better overall survival (10.4 months) com- 48.3% of patients with inoperable stage I non–small-cell lung cancerpared with those who received a single drug (6.2 months). Those who received stereotactic body radiation therapy were alive withoutwww.jco.org © 2010 by American Society of Clinical Oncology 13 Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on November 29, 2010 from 186.137.29.43 Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
  • 14. Kris et aldisease symptoms after 3 years and, overall, 55.8% were still alive.38 Approximately 50% of melanomas harbor a mutation in theMedian disease-free survival and overall survival for all patients were cancer cell growth-promoting BRAF gene. In a phase I trial, research-34.4 and 48.1 months, respectively. Overall, patients experienced a ers initially examined optimal dosing for PLX4032 on the basis ofhigh rate of local disease control (97.6%) with moderate treatment- toxicity in a group of 55 patients with cancer, most of whom hadrelated adverse effects. The Radiation Therapy Oncology Group is part melanoma.40 After the optimal dose was established, an extensionof the NCI Cooperative Group Program, which serves as one critical cohort of 32 patients with metastatic melanoma carrying the V600Elink between scientific discoveries and improved treatment for pa- BRAF gene mutation was treated.tients with cancer nationwide. In the extension cohort, 24 patients (81%) responded to PLX4032; their tumors either completely or partially regressed, in- MELANOMA cluding metastases in the bone and liver. Cancer-related symptoms improved in as little as 1 week, and the median length of response wasThe incidence of melanoma—the deadliest form of skin cancer— has found to be greater than 7 months. Tumor shrinkage was not observedclimbed faster than that of any other cancer type in the past three in patients with tumors not carrying the BRAF mutation. These find-decades and is becoming a major public health concern. ings provide clinical validation of the V600E mutation as an important Over the past year, several studies have advanced the understand- therapeutic target in melanoma.ing and treatment of melanoma, with a particular focus on the ap-proaches that activate the immune system against the disease. In a Notable Advancesstudy that could have major implications for advanced melanoma, Indoor tanning raises melanoma risk. A study confirmed the linkresearchers found that an immune therapy extended survival in this between indoor tanning and melanoma risk. This review, comparingdifficult-to-treat disease. Another study that also focused on advanced more than 1,000 patients with melanoma with more than 1,000melanoma showed promising results for a new targeted therapy. A matched controls, found that tanning bed users were 74% more likelythird report confirmed the strong connection between tanning bed to develop melanoma than nonusers.41 This population-based case-use and melanoma. Finally, a study analyzed results from several control study overcomes some of the limitations of earlier reports andadjuvant trials and demonstrated that adding the immune-boosting provides strong support for the recent declaration by the Internationalagent interferon alfa improves survival in patients with high risk. Agency for Research on Cancer that tanning devices are carcinogenic in humans.Major Advances This study also found that frequency of indoor tanning increased Monoclonal antibody ipilimumab improves survival in advanced melanoma risk. Individuals who tanned the most—for 10 or moremelanoma. In what is to our knowledge the first-ever phase III trial to years— had more than twice the risk of melanoma compared withexhibit a survival benefit for advanced melanoma, researchers found people who never used tanning beds. Those risks did not change whenthat an immune therapy shows great promise.39 Unlike most tradi- researchers accounted for several variables, including age, sex, income,tional cancer treatments that target the cancer cell, ipilimumab is family history, education, skin and eye color, freckles, moles, sun-among the first of a new class of drugs called checkpoint inhibitors. screen use, or time in the sun. The type of tanning bed used did notIpilimumab is a fully human monoclonal immunoglobulin G1 anti- matter; the risks were the same.body that sustains activation of the immune system’s T cells, including Meta-analysis shows adding interferon alfa after surgery improvestumor-specific T cells that then seek and destroy melanoma cells. overall survival in patients with melanoma. The benefit of the immune In this phase III study, researchers compared ipilimumab with booster interferon alfa is often questioned because of its significantipilimumab plus the glycoprotein 100 kDa (gp100) vaccine (an exper- adverse effects and the lack of certainty regarding whether theimental therapeutic vaccine designed to induce tumor-specific T cells) treatment improves overall survival in patients with resected, high-and the gp100 vaccine alone among 676 patients with stage III or IV risk melanoma. Previous studies have shown that adding inter-melanoma whose disease had progressed on an earlier therapy. They feron alfa after surgery for high-risk melanoma improved disease-found that the two groups of patients who received ipilimumab lived free survival, although its effects on overall survival have been34% longer than those who received the gp100 vaccine alone (median, 10 unclear. Now, a large meta-analysis of randomized controlled clin-v 6.5 months). At 2 years, 24% of the patients who received ipilimumab ical trials conducted between 1990 and 2008 has shown that inter-and 22% of those who received the combination treatment were alive feron alfa treatment improved overall survival, supporting its usecompared with 14% of patients who received only the vaccine. in the adjuvant setting. At 6 months, the melanoma did not progress in nearly 30% of The analysis of 14 clinical trials involving 8,122 patients withthose receiving ipilimumab, compared with 11% of patients treated high-risk melanoma showed improved survival and outcomes. Inter-with the vaccine alone. About two thirds of patients developed feron alfa therapy led to improved overall survival in four of 14 trialsimmune-related adverse effects from ipilimumab such as skin rashes, and improved disease-free survival in 10 of 17 studies.42diarrhea, or endocrine imbalances. Most complications, although theywere severe in some patients, were manageable with corticosteroids. Targeted treatment shows promise for patients with advanced mel- PEDIATRIC CANCERSanoma with gene mutation. A recent study showed that the majorityof patients with advanced melanoma with a specific BRAF gene mu- An estimated 38,000 childhood cancer deaths have been averted in thetation (V600E mutant BRAF) responded to a new BRAF inhibitor, United States between 1975 and 2006. Improved treatment strategiesPLX4032, providing evidence that the targeted therapy may have a and fewer deaths from acute toxicity both contributed to this success.promising future in treating melanoma. Although long-term survival rates for childhood cancer increased14 © 2010 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on November 29, 2010 from 186.137.29.43 Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
  • 15. Clinical Cancer Advances 2010from 58% to nearly 80% during that same 30-year period, approxi- times the risk of developing cisplatin-associated hearing loss as thosemately 2,000 children still die as a result of cancer every year. without the variants. The next step for progress against pediatric cancers will be to The findings are important, because understanding genetic sus-identify more effective agents that take advantage of increased knowl- ceptibility to hearing loss may improve the ability to personalize ther-edge of individual genetic differences between tumors. Rather than a apies and better weigh treatment selection against potential adverseone-size-fits-all approach, this will mean more personalized therapies effects. They also raise the larger question of whether the geneticaimed at specific pediatric subtypes of cancer. background of the patient, not just the tumor genetics, should be A key study this year reported that adult survivors of pediatric evaluated to identify the safest drugs to use.cancers have a risk of heart disease many years after childhood treat- Effective drug combination for brain tumors in adults does not workment. Other important research described the role of genetics in in children. Brain tumors, gliomas in particular, are extremely diffi-hearing loss susceptibility, while another study evaluated a drug com- cult to treat. However, in adults, the antiangiogenesis drug bevaci-bination in pediatric brain tumors that had been found to be effective zumab, in combination with the chemotherapy drug irinotecanfor treating adults, showing that the later-in-life effects of childhood can- (Camptosar; Pfizer, New York, NY), has shown success in delaying thecer therapies can significantly reduce life expectancy. Lastly, a report progression of gliomas.showed the benefit of adding a targeted agent to chemotherapy in treating One common biologic feature of pediatric brain tumors, includ-a rare form of leukemia in children and adolescents. ing malignant gliomas, is the overexpression of vascular endothelial growth factor, which fosters the development of tumor-feeding bloodMajor Advance vessels and which bevacizumab targets. Pediatric Brain Tumor Con- Study reveals long-term risks for cardiac problems among childhood sortium researchers evaluated the effectiveness of the drug combina-and adolescent cancer survivors. An analysis of more than 14,000 tion in a phase II trial of 31 children with either recurrent malignant5-year adult survivors of cancer from the Childhood Cancer Survivor glioma or brainstem glioma. Although the therapy was well-tolerated,Study—a study of adult survivors of childhood cancer that compiled the treatment had little effect against the tumors, with no sustainedinformation on cancer recurrence, secondary cancers, other illnesses responses observed. The reasons why childhood gliomas (in compar-and conditions, and psychosocial and other outcomes—showed ison with adult gliomas) are not responsive to this combination arehigher risks of many types of cardiovascular disease when compared not clear but may be associated with tumors in children that havewith a sibling control group. The findings are important reminders to more resistance to antiangiogenic agents in general or bevacizumabhealth care providers caring for the growing numbers of long-term in particular.45survivors of childhood cancer about the potentially life-threatening Late effects of childhood cancer substantially reduce life expectancy.late effects of cancer treatment. The growing population of long-term survivors of childhood cancer— On the basis of self-reported data from survivors and their sib- now numbering more than 300,000 —faces a higher risk of dying as alings, investigators found that survivors of cancer—all of whom were result of a subsequent cancer, heart disease, or pulmonary problemsyounger than age 21 years at diagnosis and were treated between 1970 than the general population does.and 1986 —were 6 times more likely to report congestive heart failure, By using data from the Childhood Cancer Survivor Study, inves-5 times more likely to report a myocardial infarction, and about 5times more likely to report heart valve disease than their siblings.43 tigators modeled the overall effect of the disease and its treatment The investigators also found that anthracycline drugs or radia- on life expectancy of survivors of childhood cancer. 46 They foundtion treatment to the chest increased the risk of cardiovascular prob- that the life expectancy for a group of 15-year-old 5-year survivorslems two- to six-fold among survivors compared with those who did of cancer was 50.6 years, a loss of 10.4 years of life (17.1%) com-not receive anthracyclines or chest radiation. Pediatric oncologists pared with the general population. Researchers also showed that reduc-currently attempt to limit the use of anthracyclines and chest radiation tions in life expectancy varied by diagnosis, ranging from a 4-yearand to use agents that may protect the heart from damage associated reduction for survivors of kidney tumors to more than 17.8 years forwith chemotherapy. survivors of brain and bone cancer. Additionally, the investigators re- ported that approximately one in four survivors is estimated to die as aNotable Advances result of a cancer recurrence later in life, of a new cancer that has occurred, Genetic variants linked to hearing loss in children who received or of a heart condition.cisplatin. Although the chemotherapy drug cisplatin can be effective The study also found that, after cancer recurrence, the develop-against several cancers, it comes with a caveat: the threat of permanent ment of a new, second cancer is the most important factor in reducedhearing loss, particularly in children. As many as 60% of children life expectancy. The researchers underscore the need for long-term mon-receiving the drug may be affected, and they may be at increased risk itoringof the healthof survivorsof childhoodcancerand the evaluationoffor communication and learning problems as a result. new therapies that might have fewer toxic effects later in life. Researchers studied the possibility that specific variants of pro- Adding imatinib to chemotherapy improves event-free survival inteins associated with cisplatin drug metabolism may predispose cer- high-risk acute lymphoblastic leukemia. Philadelphia chromosome–tain patients to develop hearing loss, whereas others escape this positive acute lymphoblastic leukemia (ALL) accounts for 3% to 5%adverse effect.44 By studying a large number of variations in 220 genes of childhood ALL and is extremely difficult to treat. Fewer than 40% ofthat encode these proteins, the researchers found that specific variants patients are cured through intensive chemotherapy, including bloodof two genes, TPMT and COMT, are highly associated with severe and marrow transplant. A new study showed that adding imatinib tohearing loss after cisplatin exposure. Patients with certain variants intensive chemotherapy for patients with this form of ALL may be(known as single neucleotide polymorphisms) may have up to 17 more effective than treatment with intensive chemotherapy alone.47www.jco.org © 2010 by American Society of Clinical Oncology 15 Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on November 29, 2010 from 186.137.29.43 Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
  • 16. Kris et alThe current standard of care for patients with Philadelphia chromo- clined significantly in recent years for men and women overall and forsome–positive ALL is blood and marrow transplant, which can be an most racial and ethnic populations in the United States.48invasive and more toxic therapy. The results of this study suggest that The report, issued by the NCI, the US Centers for Disease Controlpatients receiving chemotherapy plus continuous imatinib do just as and Prevention, the American Cancer Society, and the North Ameri-well as those patients receiving blood and marrow transplant. can Association of Central Cancer Registries, showed that the number In this Children’s Oncology Group study, researchers examined of new cancer cases declined, on average, by nearly 1% per yeartreatment with imatinib added to intensive chemotherapy in 92 chil- between 1999 and 2006. In addition, death rates dropped 1.6% annu-dren and adolescents with newly diagnosed, high-risk Philadelphia ally from 2001 to 2006, which was primarily attributed to reductions inchromosome–positive ALL. All patients received two cycles of chem- new cases and death rates for the three most common cancers in menotherapy, after which those patients with blood and marrow donor (lung, prostate, and colorectal cancers) and for two of the three leadingmatches received transplants, whereas the remaining patients were cancers in women (breast and colorectal cancers).divided into five groups and doses and length of treatment with The report also created a model suggesting that there could be animatinib were progressively increased. overall reduction in colorectal cancer mortality by 50% in 2020, citing Investigators found that the 3-year event-free survival rate was improvements in treatment and early detection for the progress.80% in the group of patients who received chemotherapy and contin- One-time sigmoidoscopy screening reduces colon cancer incidence,uous imatinib compared with 35% for historical control patients who death. A large trial involving more than 170,000 individuals in thehad been treated with chemotherapy alone. Chemotherapy and United Kingdom found that one-time screening by flexible sigmoid-continuous imatinib also resulted in an event-free survival at 3 oscopy reduced colorectal cancer incidence by one third and relatedyears that was similar to (or slightly better than) that seen in deaths by more than 40%. Flexible sigmoidoscopy examines only thepatients who received sibling donor transplants along with stan- lower half of the colon as opposed to a colonoscopy, which examinesdard chemotherapy. Further long-term follow-up is necessary, but the full length of a patient’s colon. The purpose of these tests is tothese results are encouraging, particularly for patients without identify patients with precancerous polyps and/or early-stage cancersbone marrow transplant donors. before the polyps or cancers grow and spread. Although colonoscopy may be superior to flexible sigmoidoscopy in detecting cancer, the latter requires less preparation and discomfort, which may result in PREVENTION AND SCREENING better compliance. In the study, a group of 170,432 patients between 55 and 64Although screening for breast, colon, and cervical cancers has been years old were randomly assigned to either the intervention groupextremely successful in reducing the risk of cancer-related death (n 40,674), which received a single flexible sigmoidoscopy, or tothrough early detection, there are no effective screening tools for the a control group (n 113,195), which received no intervention.49early detection of major cancer killers such as lung, pancreatic, and After a median follow-up of 11.2 years, the incidence of colorectalovarian cancers, which are often found in advanced stages. cancer was reduced by 33% in the intervention group compared A major report published this year found reductions in cancer with the control group. Sigmoidoscopy also cut cancer death rates byincidence and death rates, in part as a result of improvements in 43% compared with controls. In all, the incidence of colorectal cancerprevention and early detection. In an important advance for cancer in the rectum and sigmoid colon—the area directly examined by theprevention and screening, another study showed that one-time sigmoidoscope—was reduced by 50%.screening with flexible sigmoidoscopy reduces colon cancer incidence Federal task force provides recommendations on routine breastand death and may offer a lower-cost, less invasive alternative to screening mammography for women between 40 and 49 years old. Acolonoscopy. Lastly, a significant report on screening, issued by the US report by the US Preventive Services Task Force, a group of indepen-Preventive Services Task Force, questioned the value of routine dent health experts convened by the Department of Health and Hu-screening for breast cancer in women under the age of 50 years, raising man Services, recommended against routine mammographysubstantial controversy. screening for women under the age of 50, saying that the risks of mammography—including unnecessary follow-up tests and treat-Notable Advances ment and related anxiety— outweighed the potential benefits for this National Lung Screening Trial shows 20% decrease in lung cancer age group.50 The report instead urged women ages 40 to 49 years todeaths. On November 4, 2010, the NCI released initial results (pub- talk with their doctors about the risks and benefits of the test, beforelication pending) from the National Lung Screening Trial (NLST), deciding whether they want to be screened.which found 20% fewer lung cancer deaths among trial participants For women ages 50 to 74 years, the task force recommendedscreened with low-dose chest computed tomography than those routine mammography screenings every 2 years. Risks and benefits forscreened with a chest x-ray. The NLST is a national trial involving women age 75 years and older are unknown, it said. The group’smore than 53,000 Americans, age 55 to 74 years, who had smoked previous recommendation was for routine screenings every year orthe equivalent of a pack of cigarettes per day for 30 years. This is the two for women age 40 years and older.first study, to our knowledge, to provide clear evidence of a signif- Overall, the report says the modest benefit of mammograms—icant reduction in lung cancer deaths with a screening chest com- reducing the breast cancer death rate by 15%—must be weighedputed tomography in a randomized controlled trial. against the risk of harm. The task force concluded that 1 cancer-related Report describes declines in cancer incidence, death rates in United death is prevented for every 1,904 women age 40 to 49 years who areStates. A report issued in December 2009 found that rates of new screened for 10 years compared with 1 death for every 1,339 womendiagnoses and rates of death as a result of all cancers combined de- age 50 to 59 years, and 1 death for every 377 women age 60 to 69 years.16 © 2010 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on November 29, 2010 from 186.137.29.43 Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
  • 17. Clinical Cancer Advances 2010The guidelines are not meant for women considered at increased risk experience problems after therapy ends. Few effective treatments arefor breast cancer such as those who have a BRCA1 or BRCA2 gene available. In a randomized, multicenter phase II/III trial, the benefitsmutations or who have had extensive chest radiation. of yoga were assessed in 410 survivors of early-stage cancers (96% women; 75% patients with breast cancer) who reported sleeping prob- lems between 2 and 24 months after completing adjuvant therapy for QUALITY OF LIFE AND QUALITY OF CANCER CARE cancer. Participants received either usual care and standard monitor- ing or standard monitoring plus a two times per week, 4-week Yoga forWhereas scientists attempt to better understand the behavior and Cancer Survivors (YOCAS) program, consisting of mindfulness exer-underpinnings of cancer in developing new treatments, other research cises such as breathing, meditation, visualization, and poses in stand-focuses on ways to improve patient care and quality of life. ing, seated, and lying down positions. This year, research provided new insights into the prevalence of Patients in the yoga group reported greater improvement insleep disorders among patients with cancer and the benefits of adding sleep quality (22% v 12%), reduced incidence of clinically impairedpalliative care to chemotherapy after a diagnosis of advanced lung sleep (31% v 16%), greater reduction in sleep medication use (21%cancer. Other studies focused on the use of yoga in improving sleep v 5%), and less daytime sleepiness (29% v 5%) compared withand quality of life for cancer survivors, techniques to remotely patients in the control group. Yoga participants reported a 42%manage a patient’s depression and pain, and factors affecting the reduction in fatigue, whereas the control group reported only adecision to undergo surgery for early-stage lung cancer. 12% reduction in fatigue. The former also reported an improved quality of life (6%), whereas the control group reported no changeMajor Advance in quality of life. Sleep problems affect most patients with cancer taking chemotherapy. Telephone-based patient management improves cancer depression,In what is to our knowledge the first large study to evaluate the pain. A recent trial found that a telephone-based care managementprevalence of insomnia in patients undergoing chemotherapy, re- program delivered by a nurse with physician-psychiatrist consulta-searchers found that more than three quarters of such patients have tion, coupled with an automated symptom monitoring system, im-insomnia and other sleep disorders—nearly 3 times the rate found in proved pain and depression outcomes in patients with cancerthe general population. receiving care in geographically dispersed oncology practices.53 In the study, 823 persons with cancer completed questionnaires In the study, 405 patients with depression and/or pain whoafter two rounds of chemotherapy.51 The investigators found that 301 were receiving treatment from one of 16 urban and rural oncologypatients (nearly 37%) had insomnia symptoms and another 362 pa- practices were randomly assigned to intervention or usual caretients (43%) had difficulty falling asleep and staying asleep for at least (regular care delivered by their own physicians and no special callsthree nights in a week. The researchers showed that sleep problems were more prev- or monitoring). Patients in the intervention group received peri-alent in younger patients, with 85.6% younger than age 58 years odic telephone calls from a nurse care manager trained in assessingreporting symptoms compared with 75.5% for patients age 58 symptoms and in providing pain and depression education. Theseyears or older. Insomnia also differed by cancer diagnosis: patients patients were also regularly monitored for depression and/or painwith breast cancer reported the highest number of overall insom- via an automated system that involved interactive phone calls ornia complaints, and those with lung cancer were most likely to Internet-based surveys.report insomnia of any group. Patients reporting insomnia were Of the 405 participants, 131 had depression only, 96 had onlyalso significantly more likely to report depression and fatigue than pain, and 178 had both. Of the 274 with pain, those in the inter-those who did not report insomnia. vention group had greater improvements in pain severity after 1 year compared with patients in the usual care group. Similarly, ofNotable Advances the 309 with depression, patients in the intervention arm reported Adding palliative care to chemotherapy improves survival, quality of improvements in depression compared with the usual care group.life in patients with lung cancer. A randomized clinical trial found In addition to improving pain and depression among participants,that patients with advanced lung cancer who received standard the study proved the feasibility of a telephone-based care manage-chemotherapy coupled with palliative care immediately after diag- ment system.nosis lived significantly longer and had a better quality of life than Poor communication, other medical conditions affect decision mak-those who received only chemotherapy. Patients who regularly saw pallia- ing about surgery for early-stage lung cancer. Surgery for early-stagetive care specialists reported less depression and pain and better mobility lung cancer is the most effective treatment for this type of cancer, andand were less likely to have aggressive therapy at the end of life than those those who do not have surgery generally live less than 1 year afterwho had chemotherapy alone (see Lung Cancer). diagnosis. Historically, African Americans have particularly low sur- Yoga improves sleep and quality of life, lessens fatigue for survivors of gical rates, but the reasons why they and other patients forgo surgerycancer. The largest study to date examining the value of yoga de- have been unclear.signed specifically for survivors of cancer, to our knowledge, found In an attempt to find out, investigators surveyed 437 patientsthat a 4-week yoga program helped survivors sleep better and experi- diagnosed with early-stage lung cancer who had not yet decided on aence less fatigue and improved quality of life.52 course of treatment.54 Patients were asked questions about trust in Sleep problems and fatigue are among the most prevalent adverse their physician, patient-physician communication, attitudes towardeffects experienced by survivors of cancer. Approximately 80% of cancer, and their ability to function in daily physical activities. Thepatients report sleep problems during treatment and as many as 65% survey identified several factors associated with a patient’s decision notwww.jco.org © 2010 by American Society of Clinical Oncology 17 Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on November 29, 2010 from 186.137.29.43 Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
  • 18. Kris et alto have surgery, including poor communication with health profes- prevention, treatment, and quality of life (Table 4). As NCI continuessionals, distrust about their diagnosis and the value of surgery, other to lead the way in our growing understanding of the cancer genome,concurrent medical conditions, and a lack of a consistent source of the NCI Cooperative Group Program will be the critical link to trans-medical care. late laboratory discoveries into improved treatments for patients with Surgery rates were higher among white patients. Of 386 patients cancer. Unfortunately, this program is not currently positioned toeligible for surgery, 66% of whites (179 of 273) and 55% of African serve in this crucial role. Funding for Cooperative Clinical ResearchAmericans (62 of 113) underwent surgery. This gap occurred despite has been virtually flat since 2002, which means that total funding inthe lower age of the African American patients. Researchers found real dollars is less today than it was a decade ago. In addition, numer-that surgery rates among African Americans were particularly low ous administrative and oversight challenges threaten the program’s(13%) for patients who had two or more concurrent illnesses ability to continue conducting innovative clinical trials that are neededversus 62% for those with one or no other medical conditions, to demonstrate the effectiveness of new cancer treatments.compared with 39% and 70% for white patients, respectively. Thenumber of surgeries among African Americans who did not see a Double Funding for Cooperative Clinical Researchdoctor regularly for care was 42% compared with 57% for those The first step toward reinvigorating NCI’s Cooperative Groupwho received regular care. Program comes in increased funding. Administrative changes alone will not sustain this vital research system. Currently, NCI devotes $250 POLICY RECOMMENDATIONS million to cooperative group trials in the academic and community settings and provides approximately $2,000 to sites to enroll a patient onto a cooperative group trial. However, a 2003 Journal of ClinicalOn April 15, 2010, the IoM released a report that provides compre-hensive recommendations to strengthen NCI’s Cooperative Group Oncology study55 and a 2005 C-Change study56 determined that theProgram.1 On that same day, ASCO called on NCI to implement the actual cost of conducting NCI trials was $5,000 to $6,000 per case.recommendations and double its funding for Cooperative Clini- Since these studies were completed, the cost and complexity of coop-cal Research. erative group trials have increased. This year, ASCO’s public policy recommendations are focused These payments are insufficient to cover research costs, whichsquarely on two goals that call for NCI to double its funding for forces cooperative group research sites to limit patient enrollmentCooperative Clinical Research and for the full implementation of the onto clinical trials. An ASCO survey of cooperative group partici-recommendations of the IoM report. pants published in the April 2010 issue of Journal of Oncology Practice found that one third of participating sites plan to limit participation in federally funded clinical trials as a result of inade-State of the NCI Cooperative Group Program quate patient reimbursement.57 If our expectations are fulfilled, the stimulus provided by the To cover the true costs of conducting research without decreas- Congress may result in a truly national effort toward a co- ing the number of trials or patients enrolled, ASCO has called on the operative and integrated search for agents useful in the treat- NCI to double funding for Cooperative Clinical Research from its ment of cancer in humans. current level of $250 million to $500 million by 2015. —W.H. Sebrell Jr, MD, Director, National Institutes of Health, on the formation of the NCI Cooperative Group Program, May The IoM Report Recommendations 4, 1954 ASCO also supports the IoM report’s recommendations, which The NCI Cooperative Group Program is designed for the pur- are consolidated into four goals. The society urges all stakeholderspose of developing and conducting clinical trials in academic and affected by these recommendations to immediately take the necessarycommunity settings across the country and around the world. It con- steps to implement them.sists of 10 groups and involves more than 3,100 institutions and 14,000 Goal I: Improve the speed and efficiency of the design, launch, andinvestigators, who enroll more than 25,000 patients each year. Each of conduct of clinical trials.1the groups differs in disease focus, geographic setting, and types of ● NCI should facilitate some consolidation of the Cooperativetreatment. For example, the Children’s Oncology Group focuses on Group Program’s front office operations by reviewing andthe medical specialty of pediatric cancers, whereas other groups ranking the groups with defined metrics on a similar timetablefocus on specific cancers or therapeutic approaches. All of the and by linking funding to review scores.groups’ research largely centers on areas that the private sector has ● NCI should require and facilitate the consolidation of admin-little incentive to investigate, such as comparative effectiveness of istration and data management operations across all of thetreatments made by different companies, cancers that affect a small cooperative groups (the back office operations) and, workingpatient population, and quality of life after treatment. These fed- with the extramural community, make process improvementerally funded trials build on industry breakthroughs to discover in the operational and organizational management of clinicalnew uses for cancer treatments and are crucial to our long-term trials a priority.progress against cancer. ● The US Department of Health and Human Services should Since the program was established in the 1950s when Congress lead a transagency effort to streamline and harmonize govern-provided $5 million and directed NCI to expand the research of ment oversight and regulation of cancer clinical trials.chemotherapy in cancer, cooperative group trials have provided or ● NCI should take steps to facilitate more collaboration amongenabled virtually all of the important scientific advances in cancer the various stakeholders in cancer clinical trials.18 © 2010 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on November 29, 2010 from 186.137.29.43 Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
  • 19. Clinical Cancer Advances 2010 A clinical trial must be developed and launched as efficiently ● NCI, the Cooperative Groups Program, and physiciansas possible to ensure that it keeps pace with scientific findings, but should take steps to increase the speed, volume, and diversityrecent studies have indicated that the average time to develop and of patient accrual and to ensure high-quality performance atlaunch a phase III cooperative group trial often exceeds two years. all sites participating in cooperative group trials.For patients diagnosed with or battling cancer, this is unacceptable. ● NCI should allocate a larger portion of its research portfo-Redundancy among the groups, iterative oversight by agencies lio to the clinical trial Cooperative Group Program towithin the US Department of Health and Human Services, and ensure that the program has sufficient resources to achievebureaucratic challenges create inefficiencies that can cause signifi- its unique mission.cant delays. To further combat the delays that cooperative group trials face, Although the methods of vetting concepts and statistical designs NCI must reevaluate its role in the clinical trials process. Since 1980,for trial and data management duties may vary among the groups, a NCI has conducted oversight of every aspect of the Cooperativeconsolidated effort on the basis of merit and efficiency will help to Groups Program’s clinical trials process, which can become repetitivespeed the launch of clinical trials. In addition, parallel, concurrent, if the additional layers of oversight are considered. There are instancesor—ideally—joint reviews conducted by the various US Department in which this oversight is necessary—such as trials for which NCI hasof Health and Human Services agencies that oversee clinical trials, filed an investigational new drug application for a group. In contrast,including NCI, the US Food and Drug Administration, the Office of when NCI has not filed an investigational new drug application for aHuman Research Protections, and the Office for Civil Rights, will help trial, NCI and the group would be better served if NCI uses its limitedreduce the number of repetitive reviews. Finally, steps like developing resources to support the group.standard forms for data collection and contract templates for intellec- In addition to doubling the funding for cooperative clinical re-tual property ownership and more closely aligning the regulatory search, NCI, the Cooperative Groups Program, and physicians canrequirements of the National Institutes of Health, US Food and Drug make an across-the-board push to improve patient accrual for clinicalAdministration, the Office of Human Research Protections, and the trials. Methods for doing this include encouraging patient eligibilityOffice for Civil Rights can lead to improved efficiency in the develop- criteria that ensure the broadest participation possible, partneringment and launch of trials. with patient advocacy organizations, and working with private and Goal II: Incorporate innovative science and trial design into cancer federal payers to promote clinical trial participation.clinical trials.1 Goal IV: Incentivize the participation of patients and physicians in ● NCI should mandate the submission of annotated biospeci- clinical trials.1 mens to high-quality, standardized central biorepositories ● All stakeholders—including academic medical centers, com- when samples are collected from patients in the course of munity practices, professional societies, and NCI—should cooperative group trials and should implement new funding work to ensure that clinical investigators have adequate train- mechanisms and policies to support the management and use ing and mentoring, paid protected research time, the neces- of those resources for retrospective correlative science. sary resources, and recognition. ● Cooperative groups should lead the development and assess- ● Health care payment policies should value the care provided ment of innovative designs for clinical trials that evaluate cancer therapeutics and biomarkers (including combinations to patients in clinical trials and adequately compensate of therapies). that care. ● In cooperation with other agencies, NCI should establish a Participation in clinical trials exists because investigators, re- consistent, dynamic process to oversee the development of search staff, and patients believe in and have personal pride in the national unified standards as needed for oncology research. contributions they are making toward advancing the science of treat- An effective cooperative group trial must be able to incorpo- ment. For investigators, the most important factors that would pre-rate emerging discoveries, such as biomarkers and alternative trial serve and enhance volunteerism are having an impact on the trialdesigns. However, few standards and resources are in place to development process and getting credit for participation. The Coop-ensure that this happens in a consistent manner and in accordance erative Groups Program plays an important role in providing investi-with regulatory requirements. For example, biospecimens from gators the opportunity to participate in the development andpatients who participate in clinical trials have proven invaluable to leadership of nationally conducted trials. The Cooperative Groupsdeveloping molecularly based testing for appropriate cancer ther- Program also provides important mentorship, training, and careerapies. Yet, it can be difficult for investigators in one cooperative opportunities for the next generation of clinical investigators. Thegroup to access biospecimens taken from patients participating in credit for participation comes in the form of protected time to con-another cooperative group trial without having to seek additional ceive, design, and conduct clinical trials. For patients, it means ensur-funds. NCI and the groups can address this by promoting stan- ing that their costs for participating in a clinical trial, excluding thosedardization of collection and maintenance techniques and by pro- covered by a drug manufacturer, will be covered. The Patient Protec-viding adequate resources. NCI, the US Food and Drug tion and Affordable Care Act, which passed after completion of theAdministration, the Office of Human Research Protections, and IoM report, now guarantees insurance coverage for individuals par-the Office for Civil Rights should also promote common ap- ticipating in clinical trials. However, additional measures, such asproaches to deal with privacy, access, and ownership concerns. collaboration with insurance providers to encourage trial participa- Goal III: Improve the means of prioritization, selection, support and tion, must be taken.1completion of cancer clinical trials.1 For more information about ASCO’s policy priorities, visit ● NCI should reevaluate its role in the clinical trials system. www.asco.org/ascoaction.www.jco.org © 2010 by American Society of Clinical Oncology 19 Downloaded from jco.ascopubs.org by HENK-JAN GUCHELAAR on November 29, 2010 from 186.137.29.43 Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
  • 20. Kris et al sanofi-aventis; Quynh-Thu Le, GlaxoSmithKline, Amgen; Maurie AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS Markman, Eli Lilly, Amgen; Nicholas J. Vogelzang, Cougar OF INTEREST Biotechnology, Pfizer, Bayer, Eli Lilly, Clinical Care Options, Imedex, Onyx, Amgen, Genentech, ArQule, Novartis, Aveo Research Funding:Although all authors completed the disclosure declaration, the following Quynh-Thu Le, Amgen, GlaxoSmithKline; Nicholas J. Vogelzang,author(s) indicated a financial or other interest that is relevant to the subject Cougar Biotechnology, Tokai Pharmaceuticals, Algeta Expertmatter under consideration in this article. Certain relationships marked Testimony: None Other Remuneration: Nonewith a “U” are those for which no compensation was received; thoserelationships marked with a “C” were compensated. For a detaileddescription of the disclosure categories, or for more information about AUTHOR CONTRIBUTIONSASCO’s conflict of interest policy, please refer to the Author DisclosureDeclaration and the Disclosures of Potential Conflicts of Interest section in Conception and design: Mark G. Kris, Steven I. Benowitz, Lisa Diller,Information for Contributors. Quynh-Thu Le, Maurie Markman, Gregory A. Masters, Lisa Newman,Employment or Leadership Position: Nicholas J. Vogelzang, Southwest Jennifer C. Obel, Nicholas J. PetrelliOncology Group (C), US Oncology (C) Consultant or Advisory Role: Provision of study materials or patients: Patricia Ganz, Lisa NewmanMark G. Kris, Pfizer (C), Boehringer Ingelheim (C), sanofi-aventis (C), Collection and assembly of data: Mark G. Kris, Steven I. Benowitz,GlaxoSmithKline (C), Novartis (C), AstraZeneca (C); Maurie Markman, Sylvia Adams, Patricia Ganz, Quynh-Thu Le, Gregory A. Masters, LisaGenentech (C), Boehringer Ingelheim (C), Celgene (C); Sonali M. Smith, NewmanGenentech (C), GlaxoSmithKline (C), Eli Lilly (C), Spectrum (C), Data analysis and interpretation: Mark G. Kris, Steven I. Benowitz,Pharmacyclics (C), Celgene (C), Cephalon (C), Biogen Idec (C); Sylvia Adams, Lisa Diller, Patricia Ganz, Morton S. Kahlenberg,Nicholas J. Vogelzang, Bayer (C), Amgen (C), Wilex (C), Pfizer (C), Eisai Quynh-Thu Le, Gregory A. Masters, Lisa Newman, Andrew D. Seidman,(C), Novartis (C), Celgene (C), Genentech (C), Medscape (C), Sonali M. Smith, Nicholas J. VogelzangGlaxoSmithKline (C), Dendreon (C), sanofi-aventis (C) Stock Manuscript writing: All authorsOwnership: None Honoraria: Morton S. Kahlenberg, Genentech, Final approval of manuscript: All authors apy for breast cancer. N Engl J Med 362:513-520, 19. Conroy T, Desseigne F, Ychou M, et al: Ran- REFERENCES 2010 domized phase III trial comparing FOLFIRINOX (F: 10. Giuliano AE, McCall LM, Beitsch PD, et al: 5FU/leucovorin [LV], irinotecan [I], and oxaliplatin 1. 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