National Comprehensive Cancer Network Guideline Updates From the 15th Annual Congress

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1 Continuing Education Continuing Education National Comprehensive Cancer Network Guideline Updates From the 15th Annual Congress Anthony Elias, MD Author Disclosure: Anthony Elias, MD, discloses that he has received grants for clinical trials from Pfizer and Roche, and has received honoraria for the development of this article. Planning Committee Disclosures: Independent medical writer William Yarnall, RPh, CCP, and the staff of Pharmacy Times Office of Continuing Professional education and The American Journal of Pharmacy Benefits have nothing to disclose relative to this activity. Educational Objectives After completing this activity, participants should be able to: List some of the major National Comprehensive Cancer Network (NCCN) practice guideline revisions presented at the 15th Annual Congress Identify select NCCN guideline revisions that may impact the course of treatment in a given case Discuss the use of patient characteristics to determine therapeutic management in select NCCN guideline revisions Target Audience: Pharmacy directors/administrators, clinical pharmacists practicing in managed care environments, and any other pharmacist practitioners involved in the care of patients diagnosed with cancer Type of Activity: Knowledge Overview of the National Comprehensive Cancer Network The National Comprehensive Cancer Network (NCCN) is a nonprofit affiliation consisting of 21 leading cancer centers dedicated to improving cancer patient care and disease management along the continuum of screening, diagnosis, treatment, and follow-up. This goal is facilitated through communicating decision-enhancing information to patients and all professionals in oncology. The NCCN Practice Guidelines in Oncology are recognized as the most comprehensive and most frequently updated guidelines in any therapeutic area. They are developed through an integrated review of evidence-based studies and expert judgment by multidisciplinary NCCN panel members. The NCCN oncology practice guidelines are used by professionals in more than 115 countries throughout the world. 1,2 The most recent updates to Practice Guidelines in Oncology were presented at the NCCN 15th Annual Congress held March 10 through 14 in Hollywood, Florida. Attendees of the annual congress comprised oncologists from all settings and sectors including private practice, government, industry, and academia; and oncology fellows, nurses, pharmacists, and allied oncology healthcare professionals from around the world. Featured discussions and presentations at the 15th Annual Congress included an end-oflife roundtable and a discussion about how clinical and economic issues impact cancer care delivery. A highlight was presentation of the first-ever Malignant Pleural Mesothelioma Practice Guideline and numerous guideline updates. This new guideline and major guideline revisions are summarized below. Malignant Pleural Mesothelioma Malignant pleural mesothelioma (MPM), the most common form of mesothelioma, a rare malignancy, occurs in approximately 2500 people annually in the United States. It is deadly and difficult to treat, with median overall survival of approximately 1 year. 3 Malignant pleural mesothelioma typically occurs in older men (median age, 72 years) who have been exposed to asbestos 20 to 40 years prior to disease presentation. Reports suggest, however, that MPM can also be caused by radiotherapy. 3,4 While incidence of MPM continues to increase in Western Europe and Australia, incidence has reached a plateau in the United States due to asbestos restrictions beginning in the 1970s. 3 A diagnosis of MPM can be difficult because its symptoms, which include cough, dyspnea, chest pain, tumor fevers, weight loss, chest wall mass, pleural effusion, sweats, and pneumonia, are similar to numerous conditions and Pharmacy Times Office of Continuing Professional Education is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This program is approved for 1.0 contact hours (0.10 CEUs) under the ACPE universal program number H04-P. The program is available for CE credit through June 15, The American Journal of Pharmacy Benefits June

2 other malignancies. 3,5 In patients with recurrent pleural effusion/thickening, initial evaluation for suspected MPM may include chest computed tomography (CT) with contrast; cytologic assessment by thoracentesis; thoracoscopic, pleural or CT-guided biopsy; talc pleurodesis if required for pleural effusion management; and optional serum mesothelin-related peptide levels. 3 Guidelines recommend multidisciplinary team management with treatment options including surgery, radiation therapy, and chemotherapy. According to Lee M. Krug, MD, NCCN MPM panel member and guideline presenter, Surgery alone is inadequate treatment, because microscopic disease is likely residual, often requiring a trimodality approach including radiation and chemotherapy. 4 Candidates eligible for multimodal treatment include those with clinical stage I-III disease that is medically operable who have a performance status (PS) score of 0 (performance status is a measure of how well a person is able to carry on ordinary daily activities while living with cancer; a score of 0 denotes perfect health and 5 indicates death). Patient evaluation for multimodal therapy should be performed by radiation oncologists, surgeons, medical oncologists, diagnostic imaging specialists, and pulmonologists. In 1 US study, patients who completed trimodal therapy had a higher median survival (29.1 months) compared with those who did not complete trimodal therapy (16.8 months), but patient selection certainly could have contributed to this difference. 3,4 Non Small-Cell Lung Cancer Non small-cell lung cancer (NSCLC) is the leading cause of cancer deaths in the United States. In 2009, there were 219,440 newly diagnosed cases, and 159,390 deaths attributable to NSCLC. 6 Approximately 15% of patients with NSCLC are alive 5 years following diagnosis. Common symptoms include cough, dyspnea, weight loss, and chest pain. Symptomatic patients are more likely to have chronic obstructive pulmonary disease. Smoking is the primary risk factor, accounting for more than 85% of lung cancer deaths; risk increases with smoking frequency over time. Other risk factors include exposure to radon gas, asbestos, and other carcinogens; family history and lung inflammation or scarring secondary to tuberculosis also increases risk. 6 Several significant predictive and prognostic NSCLC biomarkers are recognized. For example, some epidermal growth factor receptor (EGFR) mutations are predictive of tyrosine kinase inhibitor therapeutic benefit. The 5 -endonuclease of the nucleotide excision repair complex (ERCC1) is prognostic for survival, regardless of therapeutic selection. 6 Surgery, radiation therapy, and chemotherapy comprise the most common treatment modalities, and they can be used alone or in combination, depending on individual patient status. Cure is most likely with surgery in patients with stage I or II disease. The surgical procedure employed is dependent on patient cardiopulmonary reserve. Chemotherapeutic Option Changes: Systemic Therapy in Advanced/Metastatic Disease First-line therapeutic changes for patients with a PS score of 0 to 1 include the addition of erlotinib monotherapy for those who are positive for the EGFR mutation. 6 Bevacizumab with chemotherapy can now be administered until progression (without regard to untreated metastases), but should only be used in patients with nonsquamous disease and no history of hemoptysis. 6,7 Pemetrexed is not recommended in patients with squamous histology. It should only be used in combination with chemotherapy, unless it is for maintenance therapy, where it can be used as a single agent. For patients with a PS score of 2, first-line options were reduced due to greater toxicity and lower benefit potential. Cetuximab (though not approved by the US Food and Drug Administration [FDA] for this use) plus vinorelbine and cisplatin was included as a treatment option with emphasis that full cisplatin dose should be selectively considered in these patients. 6,7 For patients with a PS score of 0 to 2, second- and third-line changes in advanced disease include the addition of platinum doublet therapy as a second-line option if erlotinib was given first line. Erlotinib was also added as a third-line option for patients positive with the EGFR mutation. Maintenance therapy for advanced disease is an entirely new NCCN guideline component. Oncologists are undecided as to whether switching from one drug used in initial therapy to another in maintenance is better than continuation. Evidence to date appears inconclusive; however, maintenance therapy demonstrated improved survival. 6,8 Continuation therapy infers the use of 1 or more first-line agents beyond 4 to 6 cycles in the absence of progression; biologic agents are recommended and chemotherapy continuation is not. Switch therapy infers switching nonprogressing patients to either pemetrexed or erlotinib. 6,7 Acute Myeloid Leukemia The incidence of acute myeloid leukemia (AML) appears to be rising as our population ages. The incidence of Vol. 2, No. 3 The American Journal of Pharmacy Benefits 237

3 n Elias myelodysplasia and leukemia in survivors of child and youngchildhood Hodgkin s disease, sarcomas, breast and testicular cancers, and lymphomas has also increased. AML is also associated with exposure to ionizing radiation, benzene, and petrochemicals. In 2009, approximately 12,810 people were diagnosed with AML and 9000 deaths were attributable to the disease. 9 Outcomes, particularly in older people, remain unchanged in the past 30 years. The median age of patients with AML is 70 years; patients of this age are 10 times more likely to be diagnosed with AML than those who are 50 years of age. 10 Older patients with AML have increased DNA damage and toxin exposure, coupled with decreased immunity and reduced detoxifying enzyme activity. Determining the molecular marker status of specifically known entities can provide insight into survival and relapse risk, and the molecular characterization of AML is steadily improving and contributing toward informed therapeutic decisions. Induction and postremission therapy comprise current treatment principles. Achieving remission is the first and primary goal; however, the patient must emerge from induction with sufficient health to undergo consolidation therapy to obtain lasting control. 9 Major Therapeutic Option Changes Risk stratification in therapeutic selection is emphasized in the revised guidelines, which have been expanded to distinguish therapeutic options for acute promyelocytic leukemia (APL). Acute promyelocytic leukemia is the most curable AML subtype. 11 It is now recommended to assess white blood cell (WBC) count in anthracycline-tolerant patients prior to therapy. Those with a WBC of at least 10,000/µL are considered high risk, while those with a WBC less than 10,000/µL are considered low/intermediate risk. 9 In patients at high risk at presentation, or with WBC of at least 30,000/µL later in therapy, the addition of gemtuzumab 9 mg/m 2 should be considered. The guidelines strongly recommended the use of an acceptable therapeutic protocol for APL that has been established in clinical trials, and that once implemented, adherence to the selected protocol should remain consistent. Lowintensity treatment options added in the revisions include 5-azacytidine and decitabine. For patients at least 60 years of age, clofarabine has been added as an intermediateintensity option. Breast Cancer Among women in the United States, breast cancer is the most common malignancy, and it is the second leading cause of cancer-related deaths. In 2009, there were 194,280 new cases of invasive breast cancer and 40,610 deaths attributable to the disease. The incidence of breast cancer has increased over the past few decades, although mortality is decreasing somewhat. The 2 most significant risk factors for breast cancer are female sex and increasing age; other risk factors are associated with a minority of cases. Approaches to treatment must take into account the molecular subtype of breast cancer (currently defined by estrogen receptor and human epidermal growth factor receptor 2 [HER2] status) and include surgery and/or radiation for local disease, and cytotoxic chemotherapy, endocrine, biologic therapies, or combinations of these for systemic disease. 12 Updates in Initial Workup and Patient Evaluation As part of the general workup, the revised guidelines now recommend that genetic counseling be offered to patients with high-risk hereditary breast cancer as a standard component of their initial evaluation. 12 The use of positron emission tomography (PET)/CT to supplement bone and CT scanning was also added as an optional study (category 2B recommendation). Position emission tomography/ct is most useful in locally advanced or metastatic disease in situations where standard studies are inconclusive, though biopsy is likely to prove more useful. 13 However, the use of PET or PET/CT is not clearly indicated in stage I, II, or operable stage III disease. Updates in Administration of Local Therapy Sentinel lymph node (SLN) biopsy identifies more than 95% of these nodes accurately with false-negative rates of less than 10%. 13 Based on this, the updated guideline suggests limiting clinically negative axilla staging to SLN biopsy. 12 Sentinel lymph node biopsy has high prognostic value and a low complication rate; less than 1% of patients with negative SLNs have axillary recurrence and just 7% experience lymph edema. 13 Updates in Adjuvant Systemic Therapy Women are divided biologically in the revised guideline into therapeutically relevant characteristic subsets such as hormone receptor (HER2) status. The application of an algorithm determines recurrence score, which in turn plays a role in deciding whether adjuvant endocrine therapy is administered in combination with chemotherapy (based on estimated risk of relapse or death and benefits of systemic therapy). Several molecular assays are available for clinical decision making. These tools help objectively estimate outcomes of local versus systemic therapy, as well as the absolute benefits from systemic adjuvant endocrine therapy and chemotherapy. 12,13 Regimens including paclitaxel 238 The American Journal of Pharmacy Benefits June

4 Continuing Education every 3 weeks were removed from the guidelines in favor of dose-dense weekly or biweekly schedules. Updates in Systemic Therapy for Metastatic Disease For first-line postmenopausal metastatic disease, the FDA updated the lapatinib label to indicate its use in HER2-positive disease only. 12,13 Further affecting HER2- targeted therapy, it was noted that trastuzumab plus chemotherapy increased progression-free survival (PFS) and overall survival. Also noted was that endocrine therapy plus trastuzumab increased PFS. On the other hand, endocrine therapy plus trastuzumab did not increase survival, and lapatinib, regardless of application, has not demonstrated overall survival improvement Colon and Rectal Cancer Although there are separate NCCN guidelines for colon and rectal cancer, NCCN duly notes considerable overlap exists between the 2 guidelines. 14 Colorectal cancer is the fourth most frequently diagnosed cancer and second leading cause of cancer deaths in the United States. In 2009, there were 106,100 cases of colon cancer and 40,870 cases of rectal cancer, and 49,920 patients in total died. 15 Mortality decreased over the past 3 decades, perhaps due to screening, early diagnosis, and better treatment. Patients should be counseled concerning family history because first-degree relatives of those with colorectal cancer are at increased risk. A multidisciplinary professional team, representing gastroenterology, surgery, medical and radiation oncology, and radiology, is best equipped to address issues regarding colorectal cancer. Treatment modalities include surgery, radiation, chemotherapy, and targeted therapy alone and/or in combination. Updates in Colon and Rectal Cancer Panitumumab was added as an alternative to cetuximab in combination with FOLFOX (folinic acid, fluorouracil, and oxaliplatin) and FOLFIRI (folinic acid, fluorouracil, and irinotecan) for patients with metastatic colorectal cancer (mcrc) with wild-type KRAS tumors. 14,15 As secondline therapy, panitumumab can be used in combination with FOLFIRI for patients progressing on FOLFOX and bevacizumab. Panitumumab can be used (1) with these chemotherapies following colectomy to treat resectable synchronous liver and/or lung metastases; (2) as primary therapy in advanced mcrc if adjuvant FOLFOX was given in the year prior; and (3) as initial therapy or therapy post first progression in patients with advanced mcrc who are candidates for intensive therapy. Cetuximab is no longer recommended in combination chemotherapy regimens including capecitabine and oxaliplatin. 14,15 Bevacizumab can be administered safely at 0.5 mg/kg over 10 minutes and 7.5 mg/kg over 15 minutes, and FOLFOX is noted as superior to fluoropyrimidine alone in stage III disease. 15 Regarding adjuvant therapy, NCCN advises against treating stage II or III disease with bevacizumab, cetuximab, panitumumab, or irinotecan outside clinical trials. Also noted, patients with stage II disease exhibiting low-frequency microsatellite instability may have good prognosis and will not benefit from treatment with fluorouracil. 16,17 Conclusion The 15th Annual Congress featured an entirely new guideline for mesothelioma, the first NCCN Acute Myeloid Leukemia Practice Guideline, and also introduced maintenance therapy guidelines in the management of NSCLC. The NCCN Practice Guidelines in Oncology are updated at least annually and are also revised whenever significant data become available and are evaluated by NCCN panel members. Throughout the world, these guidelines are recognized as the foremost authority in the clinical management of oncology. This article contains only highlights of the most recent oncology guideline revisions. Acknowledgment Dr Elias was assisted by an independent medical writer, William Yarnall, RPh, CCP, who received payment for his work in the development of this article. Author Affiliation: From the University of Colorado Cancer Center, Aurora, CO. Funding Source: There was no financial support for this work. Author Disclosure: Dr Elias reports receiving grants for clinical trials from Pfizer and Roche, and has received honoraria for the development of this article. Authorship Information: Analysis and interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content. Address correspondence to: Anthony Elias, MD, Professor of Medicine, University of Colorado Cancer Center, MS 8117, Rm 8111, E 17th Ave, Aurora, CO anthony.elias@ucdenver.edu. References 1. NCCN. National Comprehensive Cancer Network 2010 Fact Sheet. Accessed May 13, 2. NCCN. National Comprehensive Cancer Network Overview. Accessed May 11, 3. NCCN Malignant Pleural Mesothelioma Panel Mambers. Practice Guidelines in Oncology Malignant Pleural Mesothelioma. Published January 26, Accessed May 5, 4. Mulcahy N. First-Ever Guideline on Mesothelioma Issued by NCCN. Published March 17, Accessed May 10, Vol. 2, No. 3 The American Journal of Pharmacy Benefits 239

5 n Elias 5. Loguidice C. New NCCN Guidelines for Malignant Pleural Mesothelioma. nant_pleural_mesothelioma. Published March 16, Accessed May 11, 6. NCCN Non-Small Cell Lung Cancer Panel Members. Practice Guidelines in Oncology Non-Small Cell Lung Cancer. nccn.org/professionals/physician_gls/pdf/nscl.pdf. Published March 5, Accessed May 5, 7. Mulcahy N. Many Changes in NSCLC Guideline Update From NCCN. Published March 23, Accessed May 10, 8. Melton C. Reviewing Initial Therapy and Maintenance in NSCLC. maintenance. Published March 15, Accessed May 11, 9. NCCN Acute Myeloid Leukemia Panel Members. Practice Guidelines in Oncology Acute Myeloid Leukemia. org/professionals/physician_gls/pdf/aml.pdf. Published December 4, Accessed May 5, 10. Brauser D. NCCN AML Guidelines Updated: Cytogenetic Analysis, Expanded Treatment for Those Over 60 Recommended. Published March 15, Accessed May 10, 11. Loguidice C. NCCN Acute Myeloid Leukemia Updates. Published March 15, Accessed May 11, 12. NCCN Breast Caner Panel Members. Practice Guidelines in Oncology Breast Cancer. cian_gls/pdf/breast.pdf. Published March 16, Accessed May 5, 13. Loguidice C. NCCN Breast Cancer Updates. com/oncology/nccn_2010/nccn_breastcancer_updates. Published March 12, Accessed May 11, 14. NCCN Rectal Cancer Panel Members. Practice Guidelines in Oncology Rectal Cancer. cian_gls/pdf/rectal.pdf. Published February 8, Accessed May 5, 15. NCCN Colon Cancer Panel Members. Practice Guidelines in Oncology Colon Cancer. cian_gls/pdf/colon.pdf. Published February 8, Accessed May 5, 16. Melton C. Overview of NCCN Colon and Rectal Guideline Updates. rectal_guidelines. Published March 15, Accessed May 11, 17. Mulcahy N. NCCN Colon Cancer Guideline Update Includes BRAF Testing, Adjuvant Chemotherapy. viewarticle/ Published March 15, Accessed May 10, INSTRUCTIONS FOR CREDIT There is no fee for this activity. To receive credit, participant must read the CE activity in its entirety and complete the post-test and evaluation form. Each participant achieving a passing grade of 70% or better will receive a statement of credit giving the number of CE credits earned. If you do not achieve a score of 70% or better on the post-test, you will have the opportunity take the post-test one more time at no cost. The post-test and evaluation can be completed online. Please visit where you will be provided with a link to the lesson, post-test, and evaluation. You will have the opportunity to print the post-test questions and evaluation and manually complete ahead of time and submit answers online at your convenience. Please retain a copy of the certificate for your records. For questions, please ceinfo@pharmacytimes.com. Educational Disclaimer: Continuing professional education (CPE) activities sponsored by Pharmacy Times Office of CPE are offered solely for educational purposes and do not constitute any form of professional advice or referral. Discussions concerning drugs, dosages, and procedures may reflect the clinical experience of the author(s) or they may be derived from the professional literature or other sources and may suggest uses that are investigational in nature and not approved labeling or indications. Participants are encouraged to refer to primary references or full prescribing information resources. The author(s), reviewer(s), and editor(s) have made extensive efforts to ensure that the information including treatments, drugs, and dosage regimens are accurate and conform to the standards accepted at the time of publication. However, health care professionals should always consult additional sources of information and exercise their best professional judgment before making clinical decisions of any kind. In particular, the reader is advised to check the product information provided by the manufacturer of a drug product before prescribing or administering it, especially if the drug is unfamiliar or is used infrequently. 240 The American Journal of Pharmacy Benefits June