NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®): 2017 Guidelines

In 1996, the National Comprehensive Cancer Network^® (NCCN^®) published its first set of Clinical Practice Guidelines in Oncology^®, covering 8 tumor types. Guidelines are now published for more than 60 tumor types and topics. Some of the key updates for 2017 were presented at NCCN’s 22st Annual Conference and are briefly summarized here.

New NCCN Radiation Therapy Compendium™

Robert W. Carlson, MD

“NCCN is proud to introduce the NCCN Radiation Therapy Compendium™—the latest addition to the library of NCCN Guidelines derivative resources.”

—Robert W. Carlson, MD, Chief Executive Officer, NCCN

The NCCN launched its new Radiation Therapy Compendium™, which provides guidance on all radiotherapy modalities recommended within the NCCN Guidelines, including intensity-modulated radiation therapy, intraoperative radiation therapy, stereotactic radiosurgery, stereotactic body radiotherapy, stereotactic ablative radiotherapy, image-guided radiotherapy, low-dose–rate brachytherapy, high-dose–rate brachytherapy, radioisotopes, and particle therapy.

The NCCN Radiation Therapy Compendium™ includes radiotherapy recommendations for 24 cancer types. Additional cancer types will be published on a rolling basis over the coming months.

Myeloproliferative Neoplasms: Guidelines Debut

Ruben A. Mesa, MD

“Among the myeloproliferative neoplasms, treatment guidelines for myelofibrosis are the most urgently needed.”

—Ruben A. Mesa, MD

For the first time, the NCCN has published guidelines specifically geared to treating myeloproliferative neoplasms. The first set was developed for myelofibrosis. Future guidelines will be issued for polycythemia vera, essential thrombocytopenia, and atypical myeloproliferative neoplasms, according to Ruben A. Mesa, MD, Chair of the Division of Hematology and Medical Oncology at the Mayo Clinic Cancer Center in Arizona, who described the key recommendations.

For low-risk myelofibrosis, the guidelines recommend stratification according to symptom status. For asymptomatic disease, observation or a clinical trial is recommended. For symptomatic disease, the panel recommends the Janus kinase (JAK) inhibitor ruxolitinib (Jakafi) or interferon or clinical trial enrollment. In both these patient subsets, clinicians should monitor for signs or symptoms of disease progression every 3 to 6 months.

For intermediate-risk myelofibrosis, the recommended treatment is ruxolitinib, hematopoietic cell transplantation, or enrollment in a clinical trial; observation with regular assessments may also be acceptable.

For high-risk disease, treatment options depend on platelet counts. Guidelines recommend a clinical trial for patients with platelet counts ≤ 50,000/mL and ruxolitinib or a clinical trial with platelet counts ≥ 50,000/mL.

Depending on their risk score, patients with high-risk myelofibrosis may also be candidates for allogeneic transplant.

Dr. Mesa said the committee accepted and endorsed the 2016 World Health Organization diagnostic criteria, the myeloproliferative neoplasm Symptom Assessment Form for disease burden, and the International Prognostic Scoring System for patient prognoses.

Breast Cancer Update

Kilian E. Salerno, MD

“We hope to move away from the concept of standard fractionation being ‘conventional,’ because I would argue that for breast radiotherapy, hypofractionation is standard as well.”

—Kilian E. Salerno, MD

The key updates in breast cancer involved radiotherapy issues, where the new focus is on “maximal disease stage,” with various patient subgroups deemed appropriate for whole-breast radiotherapy, accelerated partial-breast irradiation, regional nodal irradiation, or omission of radiotherapy altogether, said Kilian E. Salerno, MD, Assistant Professor of Radiation Oncology and Director of Breast Radiation and Soft Tissue/Melanoma Radiation at Roswell Park Cancer Institute, Buffalo.

The chief updates in breast cancer follow:

• Whole-breast radiotherapy should be delivered by hypofractionation, a shorter treatment course using larger doses per fraction.
• For the use of accelerated partial-breast irradiation, the Guidelines accept the updated definition of “suitability” by the American Society for Radiation Oncology (ASTRO). The appropriate age group has been lowered to ≥ 50 years, and ductal carcinoma in situ has moved from the “cautionary” group into the “suitable” group, provided certain criteria are met (low/intermediate nuclear grade, screen-detected tumor measuring ≤ 2.5 cm with negative margin widths of ≥ 3 mm).
• The appropriate surgical margins for lumpectomy are now defined as > 2 mm for ductal carcinoma in situ and “no tumor on ink” for invasive carcinoma.
• The use of the selective cyclin D–dependent kinase 4/6 (CDK4/6) inhibitor palbociclib (Ibrance), in conjunction with either letrozole or fulvestrant (Faslodex), has become a category 1 recommendation for the first-line treatment of recurrent or stage IV estrogen receptor–positive breast cancer.
• For women postmenopausal at diagnosis, extended use (beyond 5 years) of aromatase inhibitors can be considered.

Non–Small Cell Lung Cancer Update

Matthew A. Gubens, MD, MS

“In 2017, immunotherapy is a standard of care for patients with non–small cell lung cancer.”

—Matthew A. Gubens, MD, MS

The focus of updates for the NCCN Guidelines for non–small cell lung cancer is immunotherapy, according to Matthew A. Gubens, MD, MS, Assistant Clinical Professor of Medicine at the University of California San Francisco, who described the recommendations.

First-Line Immunotherapy:

• Pembrolizumab (Keytruda) is now a standard of care for patients with ≥ 50% expression of the programmed cell death ligand 1 (PD-L1) and no known mutations or aberrations in EGFR, ALK, or ROS1 (category 1).
• All patients should have PD-L1 testing before being prescribed pembrolizumab.
• Patients progressing on first-line pembrolizumab should be treated with subsequent chemotherapy, as per first-line recommendations for nonexpressers.
• If chemotherapy is used first, then nivolumab (Opdivo), pembrolizumab, or atezolizumab (Tecentriq) can be used in the second line.

Second-Line Immunotherapy:

• Nivolumab, pembrolizumab, and atezolizumab are category 1 recommendations.
• Nivolumab and atezolizumab are approved for all comers, regardless of level of PD-L1 expression, as second-line therapy.
• Pembrolizumab is approved second-line therapy for patients whose tumors express PD-L1 ≥ 1%.

Kidney Cancer Update

Eric Jonasch, MD

“There are ongoing trials in the adjuvant setting of immune checkpoint inhibitors, but we don’t have that data yet. My fingers are crossed. Time will tell.”

—Eric Jonasch, MD

The 2017 NCCN Guidelines for Kidney Cancer have been tweaked and refined, with reorganization and reclassification of therapies, as described by Eric Jonasch, MD, Professor in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston.

First-Line Treatment for Advanced Disease:

• Sunitinib (Sutent) and pazopanib (Votrient) are the mainstays of therapy and are considered “preferred” for good- or intermediate-risk patients (category 1).
• Bevacizumab (Avastin) plus interferon is also a category 1 recommendation for these risk groups.
• Temsirolimus (Torisel) remains an option for poor-risk patients (category 1), but its use is declining. It is a category 2D recommendation for select patients in other risk groups.

Second-Line Treatment for Advanced Disease:

• Nivolumab, cabozantinib (Cometriq), and lenvatinib (Levima) plus everolimus (Afinitor) are category 1 recommendations for the second-line treatment of advanced disease after prior treatment with a vascular endothelial growth factor (VEGF) inhibitor.
• Axitinib (Inlyta) and everolimus are also second-line options.

Soft-Tissue Sarcoma Update

Suzanne George, MD

“The current question facing all of us is not ‘What’s the best treatment for soft-tissue sarcomas?’ in a general way, but ‘What’s the best treatment for a particular patient with a particular subtype in a particular anatomic location?’”

—Suzanne George, MD

Suzanne George, MD, Co-Clinical Director of the Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School, Boston, presented updated guidelines for soft-tissue sarcoma (excluding gastrointestinal stromal tumor).

• Olaratumab (Lartruvo) plus doxorubicin is preferred over doxorubicin alone, for sarcomas deemed sensitive to an anthracycline-containing regimen.
• A new section on “Principles for Imaging” that includes recommendations for “workup” and “follow-up” was added to the Guidelines to clarify recommended modalities wherever imaging is mentioned.

Bladder Cancer Update

Elizabeth R. Plimack, MD, MS

“Overall, PD-1 checkpoint inhibitors perform similarly in the postplatinum setting.”

—Elizabeth R. Plimack, MD, MS

Two antibodies targeting the programmed cell death protein or its ligand (PD-1/PD-L1) have been added to the advanced bladder cancer treatment Guidelines, according to Elizabeth R. Plimack, MD, MS, Chief of Genitourinary Medical Oncology at Fox Chase Cancer Center, Philadelphia. She noted:

• Nivolumab and atezolizumab are now listed as second-line therapies in patients with locally advanced or metastatic cancer. The two checkpoint inhibitors were given a category 2A designation, meaning there was substantial concurrence by the NCCN Panel on their inclusion, but evidence from randomized phase III clinical trials was still lacking.
• Pembrolizumab is not yet listed in the Guidelines, but its future inclusion is expected, based on findings from the phase III Keynote 045 study, in which the drug significantly improved overall survival.

Colon Cancer Update

Wells Messersmith, MD

“Resected tumors should be tested for microsatellite instability. In my own clinic, some patients with mismatch repair–deficient tumors, on clinical trials, have been responding to immune checkpoint -inhibitors for years.”

—Wells Messersmith, MD

Several impactful updates to the 2017 NCCN Guidelines for colon cancer were presented by Wells Messersmith, MD, Professor of Medicine; Director of the Gastrointestinal Medical Oncology Program, at the University of Colorado School of Medicine, Aurora; and Co-Director of the Developmental Therapeutics Program at the University of Colorado Cancer Center.

• FOLFOX (leucovorin, fluorouracil, oxaliplatin) plus cetuximab (Erbitux) or panitumumab (Vectibix) are recommended only for KRAS/NRAS wild-type disease and left-sided tumors. This is based on findings from the CALGB/SWOG 80405 trial, showing that patients with tumors originating on the right side of the colon are unlikely to respond to cetuximab and panitumumab as first-line therapy for metastatic disease (data are lacking for the transverse colon).
• The panel defines the right side of the colon as hepatic flexure through cecum, and the left side of the colon is defined as splenic flexure to rectum.
• After resection for metastatic disease, FOLFOX and CAPEOX (capecitabine and oxaliplatin) are category 1 recommendations and preferred options as adjuvant therapy. Bevacizumab and cetuximab are not recommended.
• FOLFOX and CAPEOX have become preferred neoadjuvant chemotherapy options as well.
• Under adjuvant treatment, the wording “systemic chemotherapy” has been revised to “systemic therapy with or without biologic therapy.”
• For patients with deficient mismatch–repair or microsatellite instability–high tumors, nivolumab or pembrolizumab have been added as treatment options in the advanced/metastatic setting.
• Multigene assay panels are not yet recommended for predicting benefit from adjuvant chemotherapy.

Multiple Myeloma

Shaji K. Kumar, MD

“Identifying the time point for therapy [in multiple myeloma] is critical. Most patients will eventually relapse. Hopefully, we can offer patients an extended treatment-free interval.”

—Shaji K. Kumar, MD

Updates and key components of the 2017 NCCN Guidelines for multiple myeloma were presented by Shaji K. Kumar, MD, Professor of Medicine at Mayo Clinic Cancer Center, Rochester.

Diagnosis:

• The 2017 NCCN Guidelines incorporate an expanded definition of the diagnosis of active myeloma that includes the introduction of markers. The old definition relied on hypercalcemia, renal insufficiency, anemia, and bone disease. The expanded definition now includes bone marrow plasma cell involvement ≥ 6%, at least one positron-emission tomography/magnetic resonance imaging lesions, and free light chain ratio > 100.
• The new Guidelines also incorporate high-risk factors.
• The International Staging System [ISS] groups patients into three stages for prognostication based only on the serum beta-2 microglobulin and serum albumin levels.

Newly Diagnosed Transplant Candidates:

• Bortezomib (Velcade)/lenalidomide (Revlimid)/dexamethasone remains the preferred regimen for all newly diagnosed patients (both transplant and nontransplant candidates).
• “Preferred” regimens for primary therapy listed in the 2017 Guidelines include bortezomib/doxorubicin/dexamethasone and bortezomib/thalidomide (Thalomide)/dexamethasone (both category 1). Newer regimens incorporating carfilzomib (Kyprolis) and ixazomib (Ninlaro) are listed as “other” treatment options.

Nontransplant Candidates:

• The following are preferred regimens for nontransplant candidates: bortezomib/cyclophosphamide/dexamethasone, bortezomib/doxorubicin/dexamethasone, and bortezomib/lenalidomide/dexamethasone, with the caveat that response should be assessed after two cycles of therapy. There are a number of “other” options containing newer agents.
• Maintenance therapy regimens include bortezomib and lenalidomide.
• The listing of carlfilzomib/lenalidomide/dexamethasone as an option carries a caveat that this regimen may be associated with cardiac and pulmonary toxicity, especially in older patients.
• A footnote has been added: “Triplet regimens should be used as the standard therapy for patients with multiple myeloma; however, elderly or frail patients may be treated with doublet regimens.”

Previously Treated Myeloma:

• Daratumumab (Darzalex)/lenalidomide/dexamethasone has been added as a category 1 recommendation.

Multigene Testing

Kenneth Offit, MD

“Someday, we’ll be able to spit into our iPhones and get a genetic readout, but we are not there yet.”

—Kenneth Offit, MD

The 2017 NCCN Guidelines do not currently recommend routine multiplex testing in the clinical setting. Kenneth Offit, MD, Chief of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center, New York, presented the updates regarding gene testing.

• At present, the NCCN does not endorse routine multiplex testing outside of a research setting and/or intensive genetic counseling regarding risks/benefits. The Guidelines do, however, provide suggestions for mutation carriers identified by panel tests.
• The 2017 NCCN Guidelines for Genetic/Familial High-Risk Assessment for Breast and Ovarian Cancers are greatly expanded from the 2016 version. To replace one page, there are now six pages listing a number of genes that can be identified by multiplex testing and suggestions for management when those genes are present. Some of the genes pose no increased risk of breast cancer, others pose no increased risk of ovarian cancer, and still others put patients at increased risk of one or the other or both cancers.
• The genes included in the new recommendations are ATM, BRCA1, BRCA2, BRIP1, CON1, CHEK2 NBN, NF1, PALB1, PTEN, RAD 61C, RAD 61D, STK11, and TP53. The panel has grouped together MSH2, MLH1, MSH8, PMS2, and EPCAM; these genes do not increase the risk of breast cancer but are associated with an increased risk of ovarian cancer.

Smoking Cessation

Paul M. Cinciripini, PhD

“Follow-up is important for patients to maintain high levels of motivation. At each juncture point, for a quitter or relapse prevention or switching to another therapy, continue to engage with your patient.”

—Paul M. Cinciripini, PhD

Paul M. Cinciripini, PhD, Professor and Chair for the Department of Behavioral Science, The University of Texas MD Anderson Cancer Center, Houston, led attendees through the difficulties involved in getting patients to quit smoking and explained it can take as many as 12 or 14 different attempts. The 2017 NCCN Guidelines on Smoking Cessation provide a roadmap for oncologists as they engage in this important effort, with a renewed emphasis on motivational counseling.

• Clinicians should assess past quit attempts and ascertain whether the person is ready to quit. If he or she indicates a readiness to quit in the next 4 weeks, establish a treatment plan. If not, assess the barriers and concerns of patients.
• Guideline-recommended therapy includes combination nicotine replacement therapy or varenicline (Chantix), plus behavioral therapy, for 12 weeks.
• The standard dose information has been revised as follows: begin with a 21-mg patch plus a short-acting nicotine replacement therapy; if this is not effective, consider using more than one patch to increase the dose to 35 or 42 mg. Use short-acting nicotine replacement therapy as needed, every 1 to 2 hours for cravings.
• Persons who become smoke-free should be provided motivational strategies for continued abstinence and extended duration of pharmacotherapy if needed.
• Clinicians should continue to reassess smoking status 6 and 12 months after treatment. If the patient has relapsed or is still smoking, continue the attempts at pharmacotherapy and counseling and consider intensifying behavioral therapy. 

Disclosure: For full disclosures of all speakers, visit https://www.nccn.org/disclosures/guidelinepanellisting.aspx.