NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): 2015 Updates

For 2 decades, the NCCN Guidelines® have been recognized as the standard of cancer care in the United States, combining evidence, experience, and choice, so that multidisciplinary cancer treatment teams—including patients—are empowered to make informed decisions about cancer care,” said Robert W. Carlson, MD, Chief Executive Officer of NCCN.

In 1996, the National Comprehensive Cancer Network® (NCCN®) published its first set of NCCN Guidelines®, covering eight tumor types. Today, NCCN Guidelines are published for tumor types, prevention and screening topics, supportive care considerations, and age-related recommendations. Some of the key updates were presented at NCCN’s 2015 Annual Conference and are briefly summarized here. For a more complete description of all updates, visit www.nccn.org.

“We wanted to come up with guidelines that would be clear, relevant, and something that could literally be done in the clinic in just a few minutes.”

Even after a cancer diagnosis, for any stage and prognosis, patients with cancer can reap the health benefits of smoking cessation. However, only 50% of oncologists advise their patients to quit smoking, and most of them do not provide steps on how to do it, according to Peter G. Shields, MD, Professor of Medicine at The Ohio State University and Deputy Director of The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute.

The new NCCN Guidelines for Smoking Cessation will help oncologists effectively manage these patients. The inaugural guidelines focus primarily on the 2014 Surgeon General’s Report on Smoking and Health, the adverse outcomes associated with smoking in cancer patients, and the common barriers to smoking cessation. They guide oncologists in assessment, recommend evidence-based pharmacotherapy and behavioral therapy, stress the importance of close follow-up and adequate documentation in the medical records, and present a variety of resources (quit lines, online support, and mobile apps).

The key points of the Guidelines for Smoking Cessation follow:

• Brief initial assessment can be accomplished in minutes by any member of the treatment team.
• The management algorithm is specific to current vs former smokers/recent quitters.
• Patients at high risk for relapse may need pharmacotherapy and behavioral therapy.
• Patients are assessed for willingness to quit and for level of nicotine dependence.
• Personalized quit plans are established.
• Close follow-up is critical.

“The updated Guidelines elevate PD-1 agents to the front-line setting, because we are convinced that response rates are higher and toxicity is lower than we see with ipilimumab.”

Immunotherapies along with the targeted BRAF and MEK inhibitors have dramatically improved outcomes in advanced melanoma. The availability of these novel approaches has necessitated changes to the NCCN Guidelines for Melanoma, which now feature algorithms that aid treatment selection and include antiprogrammed death protein receptor-1 (PD-1) agents among the preferred options, said John A. Thompson, MD, Co-Director of the Melanoma Clinic at the Seattle Cancer Care Alliance and Professor of Medical Oncology at the University of Washington School of Medicine.

The key updates in melanoma follow:

• The systemic therapy section was significantly revised by converting the “preferred regimens” and “other active regimens” into algorithms for the treatment of patients with BRAF-mutated vs BRAF–wild-type breast cancer.
• The systemic options for advanced or metastatic melanoma now include the following: ipilimumab ­(Yervoy, category 1 [see box below]), ­dabrafenib (Tafinlar) plus trametinib (Mekinist, category 1), nivolumab ­(Opdivo, category 1), pembrolizumab (Keytruda), high-dose interleukin 2 (in select patients), and enrollment on a clinical trial; vemurafenib ­(Zelboraf) and dabrafenib are also options as single agents for BRAF-mutant patients expected to deteriorate in < 12 weeks.
• A new “Principles of Immunotherapy and Targeted Therapy” section discusses the effectiveness of these novel treatments, with recommendations for managing their related toxicities.
• For newly diagnosed patients, the incorporation of mitotic rate in staging has been revised. Stage IA is defined as ≤ 1 mm thick, no ulceration, and a mitotic rate ≤ 1 per mm²; stage IB is ≤ 1 mm thick with ulceration or a mitotic rate ≥ 1 per mm² or 1.01–2.0 mm thick without ulceration and/or a mitotic rate ≤ 1 per mm². Sentinel lymph node biopsy is generally not recommended for lesions < 0.75 thick.

Breast Cancer Updates

“We still need lymph node staging information, at least for making decisions about adjuvant treatment, but we are not treating cancer by removing lymph nodes.”

Three breast cancer experts updated attendees on the latest advances in early-stage breast cancer, HER2-positive breast cancer, hormone-sensitive breast cancer, and triple-negative breast cancer.

The key updates in breast cancer follow:

• NCCN now accepts the definition of a negative margin as “no ink on the tumor.”
• The use of shorter-course hypofractionated irradiation is generally preferred over standard (longer) courses of whole-breast irradiation. Some patients are also eligible for short-course accelerated partial-breast irradiation, with caveats regarding short follow-up of clinical trial patients and some concerns regarding cosmesis.
• The 21-gene recurrence score can be considered in select node-positive patients to guide the addition of combination chemotherapy to standard hormone therapy.
• Axillary surgery is no longer recommended for clinically node-negative patients meeting the criteria of ACOSOG Z0011: T1/2 tumors, one or two positive sentinel nodes only, no neoadjuvant therapy, breast-conserving therapy, and whole-breast irradiation planned. For other sentinel node–positive patients, axillary radiation may replace level I/II axillary dissection for regional control of disease.
• For hormone receptor–negative HER2-positive tumors ≤ 0.5 cm, adjuvant chemotherapy with trastuzumab (Herceptin) can be considered for node-negative patients.
• For postmenopausal patients with metastatic estrogen receptor (ER)–positive disease, the CDK4/6 inhibitor palbociclib (Ibrance) plus letrozole is a new therapeutic option; it is a recommended first-line treatment in HER2-negative patients.
• For premenopausal ER-negative patients, the Guidelines recognize that ovarian suppression with gonadotropin-releasing hormone agonists given during adjuvant chemotherapy may preserve ovarian function and diminish the likelihood of amenorrhea.

“Immunotherapies and other novel approaches will soon be coming to a clinic near you.”

The 2015 NCCN Guidelines provide new recommendations for the use of carfilzomib (Kyprolis) and pomalidomide (Pomalyst), which when given in combination with other traditional agents can yield response rates of approximately 90%, according to Kenneth C. Anderson, MD, the Kraft Family Professor of Medicine at Harvard Medical School and Director of the Lebow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute, Boston.

The key updates in multiple myeloma follow:

• Panobinostat (Farydak)/bortezomib (Velcade)/dexamethasone is a category 1 option for relapsed myeloma in patients who have received at least two prior regimens, including bortezomib and an immunomodulatory agent.
• Carfilzomib/lenalidomide (Revlimid)/dexamethasone is a category 1 option for relapsed myeloma.
• Carfilzomib/lenalidomide/dexamethasone is a category 2A primary therapy option for transplant candidates.
• Lenalidomide plus low-dose dexamethasone (recommended last year as primary therapy for nontransplant patients) should be given continuously until disease progression.

“Early molecular response is a harbinger of good things to come…. The milestone of major molecular response is a safe harbor, and very few bad things happen once you go south of that.”

The success story of the various generations of tyrosine kinase inhibitors in chronic myelogenous leukemia (CML) is well known, with many patients achieving long-term benefits from treatment. However, not every patient with CML tolerates this therapy, responds to initial treatment, or avoids disease progression or drug ­resistance.

Jerald P. Radich, MD, Director of the Molecular Oncology Lab at the Fred Hutchinson Cancer Research Center and Professor of Medicine at the University of Washington School of Medicine, Seattle, emphasized the critical role of monitoring response at 3 months, explored issues pertaining to patient adherence to therapy, discussed timing for mutational analysis, and highlighted the need to prevent evolution from chronic-phase disease into accelerated-phase/blast crisis.

The key updates in CML follow:

• The Guidelines emphasize the importance of assessing response at various “milestones,” rather than upon “failure,” with consideration of treatment switching. These assessments should be at 3, 6, 12, and 18 months.
• Nilotinib (Tasigna) and dasatinib (Sprycel) were added as treatment options for de novo accelerated-phase disease.
• Ponatinib (Iclusig) was added as a treatment option for patients with a T315I mutation or disease not responding to two prior tyrosine kinase inhibitors, in the primary treatment setting and after hematopoietic stem cell transplantation. A page has been devoted to management of ponatinib-associated toxicities, which can include vascular occlusion, heart failure, and hepatotoxicity, as well as a variety of other hematologic and nonhematologic events, for which specific interventions are given.

 “Long-term survival for patients with metastatic colorectal cancer is not based on choice of first-line therapy but on the incremental benefits that accrue over time using available agents.”

Multiple effective agents can, and should, be incorporated into the continuum of treatment for colorectal cancer, and treatment targeting the vascular endothelial growth factor (VEGF) should be extended. NCCN now emphasizes the importance of identifying patients with any mutation in the RAS pathway, and for RAS–wild-type patients, chemotherapy plus bevacizumab (Avastin) or antibodies targeting the epidermal growth factor receptor (EGFR) are viable first-line options, according to Axel Grothey, MD, Professor of Oncology at the Mayo Clinic, Rochester, Minnesota, who emphasized individualization of treatment.

The key updates in colorectal cancer follow:

• The NCCN panel strengthened its recommendations for testing for all RAS and BRAF mutations in patients with metastatic disease.
• For patients with resectable synchronous liver and or lung metastases, after colectomy, FOLFOX (folinic acid, fluorouracil [5-FU], oxaliplatin) plus cetuximab was added as a treatment option.
• For patients with unresectable metastases, systemic therapy with ­FOLFOXIRI (FOLFOX and irinotecan) with or without bevacizumab is now a category 2A option (not 2B).
• For rectal cancer, FOLFOX and CapeOx (capecitabine and oxaliplatin) are noted as “preferred” adjuvant treatments.
• For rectal cancer, treatment options prior to resection are FOLFOX or CapeOx (preferred) or 5-FU/leucovorin or capecitabine, followed by chemoradiation (capecitabine/radiotherapy preferred) or infusional 5-FU/radiotherapy (preferred) or bolus 5-FU/leucovorin and radiotherapy.

“We are now facing multiple lines of effective systemic therapies, but the appropriate sequence of these agents is not well known.”

Most men with metastatic prostate cancer progress through local disease, rising prostate-specific antigen (PSA) levels, and local therapy and then to nonmetastatic castration-resistant disease before the onset of metastases. About 3% to 5% of men, however, will present at diagnosis with metastatic disease. Patients with prostate cancer typically move through first, second, and third lines of therapies, often sequencing through secondary hormonal strategies such as the antiandrogens (eg, enzalutamide ­[Xtandi], androgen synthesis inhibitors (eg, abiraterone [Zytiga]), immunotherapy (eg, sipuleucel-T [Provenge]), and maybe even an alpha emitter (radium-223 [Xofigo]). As their disease transitions to treatment-refractory metastatic castration-resistant prostate cancer, they often face fourth-line options.

Most of the updates in the 2015 NCCN Guidelines centered on the context in which to use the host of new systemic agents, as described by Andrew J. Armstrong, MD, ScM, Associate Professor of Medicine and Co-Director of the Clinical Research Program at Duke Cancer Institute, Durham, North Carolina.

The key updates in prostate cancer follow:

• For men with clinically localized disease, a tumor-based molecular assay could be considered for stratifying risk.
• The algorithm for systemic therapy for advanced disease was divided into M0 or low-volume M1 disease, vs high-volume M1 disease; high-volume disease is differentiated from low-volume disease by visceral metastases and/or four or more bone metastases, with at least one metastasis beyond the pelvic vertebral column.
• For high-volume disease in castration-sensitive men, continuous androgen deprivation therapy and docetaxel without prednisone for six cycles is an option.
• For castration-resistant prostate cancer without visceral metastases, the following category 1 options were added: enzalutamide; abiraterone with prednisone; docetaxel with prednisone; radium-223 for men with symptomatic bone metastases.
• For first-line therapy in castration-resistant prostate cancer with visceral metastasis, enzalutamide was added as a category 1 option.
• For second-line therapy in advanced castration-resistant prostate cancer, recommendations for patients with and without visceral metastases were stratified based on prior therapy with enzalutamide/abiraterone vs docetaxel.
• Several new points were made in the imaging section: (1) as compared to plain radiography, CT or MRI may be more useful for assessing fracture risk; (2) with bone scans, newer technology using 18F-NaF (18F sodium fluoride) as the tracer for a PET scan can be used as a diagnostic study; (3) PET and hybrid imaging may be more sensitive than conventional 99-technetium bone scans; (4) multiparametric MRI can be used for staging and characterizing disease, to risk-stratify men for active surveillance, and to detect large and poorly differentiated tumors and extracapsular extension.
• For brachytherapy, low-dose-rate brachytherapy as monotherapy is indicated for patients with low-risk cancers and selected patients with low-volume intermediate-risk cancers.

“If you are thinking about giving patients with locally advanced disease gemcitabine monotherapy, and they do well on it, you cannot justify following this with radiation.”

Pancreatic cancer remains a vexing treatment challenge, as the cure rate remains just 7%. Two effective regimens—gemcitabine/nab-paclitaxel (Abraxane) and FOLFIRINOX (folinic acid, 5-FU, irinotecan, oxaliplatin)—have improved outcomes and are being used earlier in the disease, but meaningful differences in outcomes may not be realized without novel strategies. Targeting of the immune system is an active area of research.

The key updates in pancreatic cancer follow:

• For imaging as part of the initial assessment, MRI was removed, and a pancreatic protocol CT is now recommended. If imaging shows no mass in the pancreas and no metastatic disease, endoscopic ultrasonography is the preferred next step.
• Adjuvant therapy should be initiated within 12 weeks (not within 4–12 weeks).
• The Guidelines state there is no clear benefit for the addition of conventional chemoradiation after gemcitabine monotherapy.
• For patients with a good performance status, treatment options are separated into “preferred” and “other.” The preferred options are a clinical trial, FOLFIRINOX (category 1), or gemcitabine plus nab-paclitaxel (category 1). ■

NCCN Panel Members

Peter G. Shields, MD, Chair, NCCN Guidelines Panel for Smoking Cessation
John A. Thompson, MD, Vice-Chair, NCCN Guidelines Panel for Melanoma
Amy Cyr, MD, NCCN Guidelines Panel for Breast Cancer
Kenneth C. Anderson, MD, Chair, NCCN Guidelines Panel for Multiple Myeloma
Jerald P. Radich, MD, Vice-Chair, NCCN Guidelines Panel for Chronic Myelogenous Leukemia
Axel Grothey, MD, Member, NCCN Guidelines Panel for Colon and Rectal Cancers
Andrew J. Armstrong, MD, ScM, Vice-Chair, NCCN Guidelines Panel for Prostate Cancer
Margaret Tempero, MD, Chair, NCCN Guidelines Panel for Pancreatic Adenocarcinoma

Disclosure Information

Dr. Cyr reported no conflicts of interest. Dr. Shields on scientific advisory boards, promotional advisory boards, and speakers bureaus for various law firms involved in chemical exposure cases and as a consultant or expert witness for the National Cancer Institute. Dr. Thompson has received or participated in clinical research support/data safety monitoring board for Bristol-Myers Squibb Company, Genentech, GlaxoSmithKline, Merck & Co, Novartis Pharmaceuticals Corportation, Agensys, Altor Biosciences, and Seattle Genetics, and has served on scientific advisory boards and as a consultant or expert witness for Amgen Inc, Bristol-Myers Squibb, and Celldex. Dr. Anderson has served on scientific advisory boards and as a consultant or expert witness for Bristol-Myers, Celgene Corporation, Millennium Pharmaceuticals, Gilead Sciences, and sanofi-aventis U.S. Dr. Anderson also reported potential conflicts of interents with Acetylon and Oncopep. Dr. Radich has received or participated in clinical research support/data safety monitoring board for Novartis, and has served on scientific/promotional advisory boards, speakers bureaus, or as an expert witness or consultant for Novartis, Pfizer, Inc, ARIAD Pharmaceuticals, and Incyte. Dr. Grothey has received or participated in clinical research support/data safety monitoring board for Bayer Healthcare, Eisai, Eli Lilly and Company, Genentech, ImClone Sytems Incorporated, and Pfizer, and has served on scientific advisory boards and as a consultant or expert witness for Bayer, Bristol-Myers Squibb, and Genentech. Dr. Armstrong has received or participated in clinical research support/data safety monitoring board for Active Biotech AB, Bristol-Myers Squibb, Dendreon Corporation, ImClone, Johnson & Johnson, Novartis, Kanglaite, Medivation, Pfizer, and sanofi-aventis U.S., and has served on scientific advisory boards, promotional advisory boards, and speakers bureaus and a consultant or expert witness for Johnson & Johnson, Astellas, and Dendreon. Dr. Tempero has received or participated in clinical research support/data safety monitoring board for Celgene; and has served on scientific advisory boards, promotional advisory boards, and speakers bureaus and as a consultant or expert witness for Celgene, Genentech, Myriad Genetic Laboratories, Inc, and Targovox.

For more information visit http://www.nccn.org/disclosures/default.asp.