NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): 2016 Guidelines

By Caroline Helwick and Alice Goodman
May 25, 2016

In 1996, the National Comprehensive Cancer Network (NCCN^®) published its first set of Clinical Practice Guidelines in Oncology^® (NCCN Guidelines^®), covering eight tumor types. The NCCN Guidelines^® are now published for more than 60 tumor types and topics. Some of the key updates for 2016 were presented at NCCN’s 21st Annual Conference and are briefly summarized here.

New Guidelines for Vulvar Cancer

“Full nodal dissection is a contentious issue in patients with clinically involved groin nodes. My preference is upfront chemoradiation and then resection of residual nodal disease later. The NCCN Guidelines give you both options.”

—Wui-Jin Koh, MD

The 2016 NCCN Guidelines for Vulvar Cancer are brand new, providing a road map for surgical, radiation, and medical oncologists for management of this rare, sometimes fatal, gynecologic cancer. Some areas of treatment remain controversial, such as the role of chemotherapy and the timing of nodal dissection.

Benjamin E. Greer, MD, Medical Director of the Seattle Cancer Care Alliance Network and Professor at the University of Washington School of Medicine, Seattle, and Wui-Jin Koh, MD, Medical Director of Radiation Oncology for the Seattle Cancer Care Alliance Network and Professor at the University of Washington, Seattle, led attendees through the thinking behind the process of development of these guidelines.

In brief, the NCCN Guidelines state:

• Early-stage cancers can be managed by surgery and postoperative surviellance.
• Lymph node status drives treatment and correlates with survival.
• Positive groin nodes often require additional therapy, including radiation with or without chemotherapy, depending on the stage.
• Sentinel lymph node biopsy is recommended in select patients.

Multiple Myeloma Updates

“Advances have expanded survival three- to fourfold, but there is still much to do.”

—Kenneth C. Anderson, MD

The 2016 NCCN Guidelines for Multiple Myeloma feature several changes in diagnosis and management. Kenneth C. Anderson, MD, Program Director, Jerome Lipper Multiple Myeloma Center and Le Bow Institute for Myeloma Therapeutics at the Dana-Farber Cancer Institute, Boston, updated attendees on optimal management.

Updates include:

• Broadened criteria for diagnosis to include asymptomatic patients, even those who lack calcium elevation, renal insufficiency, anemia, or bone abnormalities (known as CRAB). Patients who have bone marrow plasmacytosis ≥ 60%, a free light-chain ratio abnormality > 100, or bone lesions detected on sensitive imaging are eligible for treatment even if they do not have CRAB features.
• A revised International Staging System that incorporates serum albumin and beta₂ microglobulin as well as serum lactic dehydrogenase and evidence of high-risk cytogenetics on FISH (fluorescent in situ hybridization).
• Lenalidomide (Revlimid)/bortezomib (Velcade)/dexamethasone is now a category 1 preferred regimen for newly diagnosed patients, whether or not they are transplant candidates.
• The first all-oral triplet—lenalidomide/ixazomib (Ninlaro)/dexamethasone—is a category 2A recommendation for upfront treatment.
• Maintenance therapy is considered standard practice in transplanted and nontransplanted patients. Preferred, category 1 maintenance regimens include bortezomib, lenalidomide and thalidomide (category 1). Other regimens, bortezomib/prednisone, bortezomib/thalidomide, interferon, steroids, and thalidomide/prednisone, are suggested in the guidelines.
• For previously treated patients, the following regimens have category 1 ranking: bortezomib, bortezomib/liposomal doxorubicin, carlfilzomib (Kyprolis)/lenalidomide/dexamethasone, elotuzumab (Empliciti)/lenalidomide/dexamethasone, ixazomib/lenalidomide/dexamethasone, lenalidomide/dexamethasone, panobinostat (Farydak)/bortezomib/dexamethasone, and pomalidomide (Pomalyst)/dexamethasone.
• These regimens represent the first inclusion of panobinostat, a histone deacetylase (HDAC) inhibitor, as well as two recently U.S. Food and Drug Administration (FDA)-approved monoclonal antibodies: elotuzumab and daratumumab (Darzalex).
• Carlfilzomib/dexamethasone (with no lenalidomide) is another newly included combination for relapsed disease.

Thinking about the future, Dr. Anderson said that immune approaches, including programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) checkpoint inhibitors, vaccines, and CAR-T (chimeric antigen receptor T cells) may hold promise for myeloma. Early studies are exploring these immune approaches.

Melanoma Updates

“This has been encouraging for all of us in melanoma to look at the possibility of a flattening of the plateau of the overall survival curve…. And we are now talking of response rates in the 60% to 75% range, which was almost unheard of from where we were a few years ago.”

—John Thompson, MD

Multiple new agents have radically changed the therapeutic landscape in advanced melanoma and substantially moved the survival curve. John A. Thompson, MD, Medical Director of the Phase I Clinical Trials Program; Co-Director of the Melanoma Clinic at the Seattle Cancer Care Alliance; and Professor in the Medical Oncology Division at the University of Washington School of Medicine, Seattle, described how the 2016 NCCN Guidelines for Melanoma reflect these advances, with these important new recommendations:

• Anti–PD-1 monotherapy with either pembrolizumb (Keytruda) or nivolumab (Opdivo) has become a category 1 recommendation, based on improvements in overall survival in both untreated and previously treated patients.
• Based on impressive outcomes when combined with nivolumab, ipilimumab (Yervoy) is part of second-line (and beyond) treatment recommendations.
• Adjuvant treatment with high-dose ipilimumab is a new treatment option, with a category 2B ranking, for patients with resected, high-risk grade III disease who have shown an improvement in recurrence-free survival. High-dose therapy requires close patient monitoring, as treatment-related deaths have been reported.
• Intralesional injection of the talimogene laherparepvec (T-VEC) is a new category 1 option for patients with stage III melanoma in transit; a footnote mentions its efficacy as well in stages IIIB, IIIC, and IV M1a disease, especially in treatment-naive patients.
• The BRAF inhibitors vemurafenib (Zelboraf) and dabrafenib (Tafinlar) remain category 1 options, but the new focus is on combining them with MEK inhibitors in the first-line setting. Preferred combinations include dabrafenib/trametinib (Mekinist) and vemurafenib/cobimetinib (Cotellic)—both of which are now category 1 recommendations for BRAF-mutated disease.

“The field has now moved beyond BRAF monotherapy to combination BRAF and MEK inhibitor therapy,” said Dr. Thompson.

Pancreatic Cancer Updates

“We need a standardized template for radiology reporting using universally accepted and agreed-on terminology. If you don’t understand the language, the report is useless.”

—Mahmoud Al-Hawary, MD

Imaging is a key component of diagnosis and staging of pancreatic cancer. Computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasound are recommended imaging modalities. Mahmoud Al-Hawary, MD, Associate Professor of Radiology; Director, Gastrointestinal Radiology Service, Abdominal Radiology Division of the Michigan Comprehensive Cancer Center, Ann Arbor, discussed the role of these three imaging modalities.

The major update to the 2016 NCCN Guidelines is a recently published standardized Pancreatic Cancer Radiology Reporting Template endorsed by two major societies, the Society of Abdominal Radiologists and the American Pancreatic Association, which will standardize reporting and facilitate communication among the various members of the team treating patients with pancreatic cancer, leading to appropriate management, according to Dr. Al-Hawary.

Other updates include:

• Intraoperative ultrasound as a diagnostic adjunct during staging laparoscopy.
• Serial CT for locally advanced/metastatic disease or MRI of known sites of disease to determine therapeutic benefit.
• Recognition that clinically progressive disease may not be evident on imaging.

Non–Small Cell Lung Cancer Updates

“Genotyping should be performed for every patient with nonsquamous NSCLC. Testing should not be limited to patients with a high probability of EGFR mutations.”

—Rogerio Lilenbaum, MD

Rogerio Lilenbaum, MD, Professor of Medicine and Chief Medical Officer of Smilow Cancer Hospital at Yale-New Haven, New Haven, Connecticut, and Leora Horn, MD, Associate Professor of Medicine, Clinical Director of the Thoracic Oncology Program, and Associate Vice-Chancellor for Faculty Development at Vanderbilt-Ingram Cancer Center, Nashville, discussed molecular testing and acquired resistance as part of management of EGFR-positive metastatic non–small cell lung cancer (NSCLC).

Updates include the following:

• Broad molecular testing is now recommended for all patients with nonsquamous NSCLC.
• Three different EGFR tyrosine kinase inhibitor agents are recommended as first-line treatment of EGFR mutation-positive NSCLC: gefinitib (Iressa), erlotinib, and afatinib (Gilotrif).
• The majority of responding patients will progress, and the type of disease progression drives management. Systemic disease progression requires switching tyrosine kinase inhibitor treatments, whereas patients with oligoprogression and central nervous system progression only should have their new lesions treated but continue on their tyrosine kinase inhibitor.
• Afatinib plus cetuximab (Erbitux) may be considered in patients who progress on EGFR tyrosine kinase inhibitor treatment, particularly in T790M-negative patients.
• Osimertinib (Tagrisso) is a treatment option as a category 2A recommendation. This drug is approved for EGFR T790M mutation–positive tumors.

Early Breast Cancer Updates

“There is no excuse for the radiation oncologist not to adopt hypofractionation.”

—Kilian E. Salerno, MD

The updates to the management of early invasive breast cancer were relatively minor, primarily refinements, but they have important treatment implications for patients.

William Gradishar, MD, the Betsy Bramsen Professor of Breast Oncology at the Feinberg School of Medicine, Northwestern University, Chicago, presented the new recommendations for systemic treatment, and Kilian E. Salerno, MD, Assistant Professor of Radiation Oncology and Director of Breast Radiation and Soft Tissue/Melanoma Radiation at Roswell Park Cancer Institute, gave an update on radiotherapy.

The key changes are as follows:

• Endocrine therapy was added as a neoadjuvant treatment for patients with estrogen receptor–rich ­tumors.
• As adjuvant treatment of women with estrogen receptor–positive tumors who are premenopausal at diagnosis, the NCCN Guidelines suggest tamoxifen 5 to 10 years without ovarian suppression, and 5 years with ovarian suppression, or an aromatase inhibitor for 5 years combined with ovarian suppression or ablation.
• For HER2-positive patients, neoadjuvant treatment with a combination of anti-HER2 agents (trastuzumab [Herceptin], pertuzumab [Perjeta]) can be considered.
• For women with advanced estrogen receptor–positive disease, palbociclib (Ibrance) has been added as a drug that can be used with an endocrine agent.
• Hypofractionated whole-breast irradiation has become the preferred approach to adjuvant radiation therapy following breast-conserving surgery.
• Accelerated partial-breast irradiation is acceptable for women considered suitable by ASTRO (American Society for Radiation Oncology) criteria, and radiotherapy can be omitted in select patients, ie, those considered at low risk for recurrence.
• Regional nodal irradiation—either in the setting of breast-conserving surgery or post mastectomy—should be strongly considered for women with one to three lymph nodes and is indicated for women with four or more lymph nodes. The NCCN Guidelines include new “language” regarding the treatment of nodal regions.

Prostate Cancer

“Localized prostate cancer is characterized by extraordinary genomic complexity, with copy number alterations, chromosomal rearrangements, and point mutations.”

—Ashley Ross, MD, PhD

For the first time, the 2016 NCCN Guidelines for Prostate Cancer include wording suggesting that tissue-based molecular testing be considered for localized prostate cancer. Ashley Ross, MD, PhD, Assistant Professor in the Departments of Urology, Oncology, and Pathology at Johns Hopkins School of Medicine, Baltimore, reviewed the six tissue-based tests (four of them multigene tests) available for determining prognosis in localized prostate cancer.

The molecular testing recommendation is based on retrospective case cohort studies showing that molecular assays performed on prostate or prostatectomy specimens provide prognostic information independent of NCCN risk groups regarding—but not limited to—the likelihood of death with conservative management, biochemical progression after radical prostatectomy or radiation therapy, and development of metastasis after primary surgery or radiation therapy.

Survivorship Updates: Sexual Dysfunction

“As a breast cancer specialist, I did not know how common these [sexual dysfunction] problems were in other areas of cancer.”

—Michelle Melisko, MD

Michelle Melisko, MD, Associate Clinical Professor of Hematology/Oncology, Department of Medicine, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, told attendees that the 2016 NCCN Guidelines for Survivorship contain a substantially updated algorithm for assessing women with concerns/issues regarding sexual function. The types of symptoms lead to the appropriate treatment options and follow-up recommendations.

For women, the first category of symptoms focuses on those of menopause, vaginal dryness, or other issues related to vaginal health (eg, discomfort, discharge, or pain). In the 2016 NCCN Guidelines, for patients with problems with orgasm, referral to an appropriate specialist for a discussion of options, including a vibrator or clitoral stimulatory device, should be considered. As for libido and desire issues, a discussion of available drugs, such as androgens and flibanserin (Addyi; which was approved in August 2015), is warranted. Flibanserin is not contraindicated in patients with breast cancer, although there are no clear data for efficacy in this population, and it is currently only FDA approved in premenopausal women.

The assessment should begin with two questions: Do you have any concerns regarding your sexual function, sexual activity, sexual relationship, or sex life? And are these concerns causing you distress? Further assessment depends on the patient’s concerns and desire to discuss them with the physician. ■

Disclosure: Drs. Al-Hawary, Greer, and Salerno reported no potential conflicts of interest. Dr. Anderson reported serving on advisory boards for Celgene, Millennium, and Gilead, and he is scientific founder of Acetylon, Oncopep, and C4 Therapeutics. Dr. Gradishar reported receiving clinical research support and/or participating on a data safety monitoring board for Genentech and Pfizer; he reported serving on a scientific advisory board, as a consultant, or expert witness for Eisai and Genentech. Dr. Horn reported receiving clinical research support and/or participating on a data safety monitoring board for Bristol-Myers Squibb, Genentech, and Xcovery; she reported serving on a scientific advisory board, as a consultant, or expert witness for Bayer HealthCare, Bristol-Myers Squibb, Lilly, Genentech, Merck, and Xcovery. Dr. Koh reported receiving clinical research support and/or participating on a data safety monitoring board for NRG Oncology. Dr. Lilenbaum reported receiving clinical research support and/or participating on a data safety monitoring board for Celgene and participating in scientific advisory boards, or as a consultant or expert witness, for Boehringer Ingelheim GmbH, Celgene, and Genentech, Inc. Dr. Melisko reported receiving clinical research support and/or serving on a data safety monitoring board for Celidex, Galena, and Puma; she reported serving on a scientific advisory board, as a consultant, or expert witness for Nektar; as a participant on promotional advisory boards, consultant, or speakers&rsquo; bureau for Agendia BV. Dr. Melisko reported spouse/domestic partner/dependent potential conflict with Merrimak. Dr. Ross has ownership interest in GenomeDX Biosciences (stock options), Collaborative Research, and has received unrestricted research funding from Metamark. Dr. Thompson reported receiving clinical research support and/or serving on a data safety monitoring board for Bristol-Myers Squibb Company, Merck, Pfizer, Roche, and Seattle Genetics; he reported serving on an advisory board, as a consultant, or expert witness, for Celldex, Eisai, and Genentech.</p>

---