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  1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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.

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