2014 NCCN Guideline Updates: Experts Highlight New Recommendations for Clinical Practice

At the recent National Comprehensive Cancer Network (NCCN) 19th Annual Conference, experts discussed this year’s updates to the NCCN Clinical Practice Guidelines in Oncology. The meeting also included reviews of NCCN Task Force reports on issues in supportive care. We asked eleven NCCN panel members to select the most significant updates and insights presented at the conference.

Non-Hodgkin Lymphoma

Steven M. Horwitz, MD

Memorial Sloan Kettering Cancer Center

“The most significant changes are the addition of two newly approved agents for chronic lymphocytic leukemia, obinutuzumab and ibrutinib. That’s quite a lot in a single year. These drugs have the potential to make major changes in how we treat patients, particularly as we have more important non-chemotherapy options. Additionally, the brand-new guidelines for several rare lymphomas are important educational tools. Because they are for rarer diseases, they will hopefully provide useful guidance for clinicians who infrequently encounter these illnesses.”

• Obinutuzumab (Gazyva) plus chlorambucil was added as an option for previously untreated patients with chronic lymphocytic leukemia (CLL). The combination therapy is an option for those patients without an 11q or 17p deletion who are frail with significant comorbidities, and both older and younger patients either with or without comorbidities. The combination is also an option for CLL patients with either an 11q or 17p deletion.
• Ibrutinib (Imbruvica) was added as a treatment option for CLL patients with or without an 11q or 17p deletion who have received at least one prior therapy.
• For patients with diffuse large B-cell lymphoma, recommended follow-up imaging posttreatment was changed from CT scans every “6 months to 2 years” to “only as clinically needed.”
• PET-CT scan should now be considered to evaluate at presentation and following initial response to therapy in follicular lymphoma.
• Rituximab (Rituxan) plus low-dose CHOP chemotherapy (R-mini-CHOP) was added under a separate heading for patients with comorbidities aged ≥80 years with aggressive B-cell lymphoma.
• Two additional guidelines for two rare lymphomas added: Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders T-cell Large Granular Lymphocyte Leukemia “These guidelines are largely educational to define these diseases and help clinicians accurately recognize and distinguish these disorders from other types of lymphomas or even benign, reactive processes. There are also some basic therapy recommendations. Because there is little data on these disorders, these recommendations are largely based on expert experience and retrospective studies.”

Waldenström’s Macroglobulinemia, Multiple Myeloma

Kenneth C. Anderson, MD

Dana-Farber/Brigham and Women’s Cancer Center

“The updates for Waldenström’s incorporate major progress in our ability to identify a common mutation that helps determine proper treatment. As for multiple myeloma, none of the updates will radically change clinical practice, but we did add a new footnote that may indicate major changes to come. A small study has shown benefit to treating smoldering multiple myeloma rather than observing it. Further studies—which could make such treatment a standard of care—are starting up and we’re urging doctors to enroll eligible patients.”

Waldenström’s Macroglobulinemia

• Ibrutinib (Imbruvica) now appears as a non—stem cell toxic, salvage therapy option.
• MYD88 L265P AS-PCR testing of bone marrow has proven itself useful in working up certain patients.
• The intent of therapy should be based on palliation of symptoms and not necessarily levels of IgM, unless the patient is exhibiting evidence of symptomatic hyperviscosity.

Multiple Myeloma

• Bortezomib (Velcade) plus prednisone now appears, under category 2B, as an option for maintenance therapy.
• Bortezomib plus thalidomide (Thalomid) now appears, under category 2B, as an option for maintenance therapy.
• Recent studies on smoldering myeloma show that patients with certain characteristics including IgG levels >3 g/dL, IgA >2 g/dL, urinary Bence Jones protein >1 g/24 hours, or abnormal free light chain ratios, have an increased risk of progression to active myeloma.
• There is a growing consensus that the classical definition of smoldering myeloma using certain tests such as plain x-rays is outdated. Efforts to modify these criteria and reclassify some patients previously classified as “asymptomatic” to having “active disease” are under way.
• Retrospective studies suggest a 2- to 3-year minimum length of remission before caregivers consider a second autologous stem cell transplant for salvage therapy (category 2B).

Breast Cancer

William J. Gradishar, MD

Robert H. Lurie Comprehensive Cancer Center of Northwestern University

“Substantial findings in two research areas have produced widespread changes in the recent guidelines. First, trials of pertuzumab demonstrated value in a number of situations. Second, research showed that axillary lymph node dissection, while still indicated in some situations, provides no survival benefit in others.”

• A pertuzumab (Perjeta)—containing regimen may be administered preoperatively to patients with ≥T2 or ≥N1, HER2+, early-stage breast cancer.
• Patients who qualify for a neoadjuvant pertuzumab-containing regimen but do not receive it can be considered for pertuzumab after surgery on the same schedule and dosage as presurgical regimens.
• Paclitaxel + trastuzumab (Herceptin) was added to the list of therapies for patients with low-risk, stage l, HER2+ disease, particularly those not eligible for other standard adjuvant regimens due to comorbidities.
• Clinically negative axillary lymph node(s) should have axillary ultrasound; suspicious nodes should be sampled by FNA or core biopsy and clipped with image-detectable marker.
• Clinically positive axillary lymph node(s) should be sampled by FNA or core biopsy and clipped with image-detectable marker.
• Positive clipped lymph nodes must be removed if FNA or core biopsy was positive prior to neoadjuvant therapy.
• Concurrent use of trastuzumab and pertuzumab with an anthracycline should be avoided because of cardiac toxicity risks.
• For patients who have particularly favorable tumors, patients whose adjuvant systemic therapy is unlikely to be affected, the elderly, or patients with serious comorbid conditions, the performance of axillary lymph node dissection may be considered optional—except where definitive data supports it.
• In patients with HER2+ and axillary node—positive breast cancer, trastuzumab should be incorporated into adjuvant therapy (category 1).
• Trastuzumab should also be considered for patients with HER2+, node-negative tumors ≥1 cm (category 1).
• Trastuzumab should optimally be given concurrently with paclitaxel as part of the AC followed by paclitaxel regimen, and should be given for 1-year total duration.

Prostate Cancer

James Mohler, MD

Roswell Park Cancer Institute

“In this year’s NCCN prostate cancer guideline update, three definitions and clarifications have been added that more accurately assess risk and will allow patients and physicians to make better treatment decisions. Still, more data are necessary on active surveillance monitoring strategies to provide clarity on this issue. The Early Detection Panel, led by Peter Carroll, MD, and our Treatment Panel have re-emphasized strongly our interdependence and the need for patients and physicians to consider carefully the recommendations of the two guidelines to minimize the risks posed by overdetection and overtreatment of lowrisk prostate cancer. Additionally, the panel tried to place the new FDA-approved therapies for men with advanced prostate cancer in the approximate order in which they should be considered in the pre- and postchemotherapy settings. The guidelines may assist with proper choice and sequence of treatments in advanced disease, which has become more challenging due to the FDA approval of five new agents since 2010.”

• Radium Ra 223 dichloride (Xofigo) is now a category 1 option for patients who have symptomatic bone metastases after androgen deprivation therapy and a docetaxel-based chemotherapy have failed.
• A distinct clarification between active surveillance (actively monitoring the course of disease with the expectation to intervene with potentially curative therapy) and observation (monitoring the course of disease with the expectation to deliver palliative therapy for the development of symptoms or a change in exam or a PSA level that suggests symptoms are imminent) was added to the current guidelines.
• For patients with stage IIA or IIB disease who have a less than 10-year life expectancy, active surveillance was replaced with observation.
• “Recurrence group” was replaced with “risk group” to help clarify treatment discussions for different stages of prostate cancer.
• Hypofractionated intensity-modulated radiation therapy (IMRT) should now be considered carefully for localized prostate cancer, since studies have shown similar efficacy and toxicity compared with conventional fractionated IMRT.

Colorectal Cancer

Al B. Benson III, MD

Robert H. Lurie Comprehensive Cancer Center of Northwestern University

“This year’s updates contain small but significant changes on several fronts—everything from the use of chemotherapy regimens to the consistency of guideline wording—but the most substantial change, by far, is the call for additional testing of tumor genetics and the increased contraindication of two targeted therapies.”

• All patients with metastatic colorectal cancer should have tumor tissue genotyped for KRAS and NRAS mutations. Whenever possible, non-exon 2 KRAS and NRAS mutation status should also be determined. Patients with any KRAS mutation (exon 2 or non-exon 2) or any NRAS mutation (exon 2 or non-exon 2) should not be treated with either cetuximab (Erbitux) or panitumumab (Vectibix).
• Lynch syndrome tumor screening such as IHC or MSI should be considered for all colorectal cancer patients diagnosed when they are aged ≤70 years or, for patients who are diagnosed later in life, when they meet the Bethesda Guidelines.
• Bevacizumab (Avastin) has been added as an option, in combination with FOLFOXIRI, as an initial therapy for advanced or metastatic disease or for unresectable synchronous liver and/or lung metastases.
• Regorafenib (Stivarga), which had been recommended only for KRAS mutant tumors, is now a treatment option for all patients who have progressed through all available regimens (eg, KRAS mutant or KRAS wild-type with previous exposure to an anti-EGFR inhibitor).
• For untreated, resectable metachronous metastases, the preferred adjuvant and neoadjuvant chemotherapy regimens are FOLFOX or CapeOx. Other indicated—though less preferred—regimens are FLOX or capecitabine or 5-FU/leucovorin.
• The indication for laparoscopic-assisted colectomy has been expanded to cases where there is some indication of disease in the rectum or significant abdominal adhesions.
• Recommendations for serial CEA evaluation no longer include that physicians consider a PET scan or CT scan when performing their work-ups on patients.

Melanoma

Daniel G. Coit, MD

Memorial Sloan Kettering Cancer Center

“The NCCN melanoma guidelines are mature and quite up-to-date. The recent update on systemic therapies includes the addition of the combination of dabrafenib plus trametinib as a treatment option for patients with advanced BRAF-mutated disease. The ultimate impact of this combination, in terms of improvement in overall survival, still needs to be demonstrated. This is the focus of two ongoing phase III clinical trials that will soon be reported. The long-term efficacy of this combination remains to be demonstrated.”

• The combination of the BRAF inhibitor dabrafenib (Tafinlar) and MEK inhibitor trametinib (Mekinist) has been added as a preferred systemic therapy option for advanced melanoma that is BRAF-mutation positive. The combination was approved by the FDA based on a phase I/II clinical trial demonstrating improvement in progression-free survival.
• Single-agent trametinib is not indicated for patients with BRAFmutated melanoma who have experienced progression following monotherapy with an oral BRAF inhibitor (either dabrafenib or vemurafenib [Zelboraf]).
• A nodal basin ultrasound prior to a sentinel lymph node biopsy (SLNB) should be considered for patients who have an equivocal regional lymph node physical exam.
• Results of the international MSLT-1 trial confirm the important role of SLNB in staging patients with localized disease, but confirmed no survival advantage in patients who have had SLNB.

Hepatobiliary Cancers

Chandrakanth Are, MBBS

Fred & Pamela Buffett Cancer Center at The Nebraska Medical Center

“The main thing for general oncologists to know, when it comes to gallbladder cancer, as well as intrahepatic and extrahepatic cholangiocarcinoma, is that they should probably refer any cases they see to specialists. The rarity of these cancers makes it nearly impossible for general practitioners to develop expertise. It also slows the pace of guideline updates. Hepatocellular carcinoma, on the other hand, is far more common and more studied, so there are more updates.”

Hepatocellular Carcinoma

• When masses <1 cm are found to be stable, continue imaging every 3 to 6 months for 2 years using the technique that first identified nodule(s). Return to baseline surveillance schedule after 2 years of stability.
• Continual monitoring, including multidisciplinary review, is recommended for a growing mass, even if a biopsy has come back negative.
• New studies indicate that for some well-selected, transplant-ineligible patients with small, well-located tumors, ablation should be considered the definitive therapy.
• For some transplant-ineligible patients, case series and single-arm studies suggest safety and possible efficacy of radiation.
• In cases of unresectable tumors, there are limited data supporting the use of systemic chemotherapy, but its use should generally be limited to clinical trials.
• Palliative EBRT is appropriate for symptom control and/or prevention of complications from metastatic hepatocellular carcinoma lesions.

Gallbladder Cancer and Extrahepatic Cholangiocarcinoma

• Adjuvant chemotherapy or chemoradiation has been associated with a survival benefit in patients with biliary tract cancer, especially those with lymph node—positive disease.

Intrahepatic Cholangiocarcinoma

• Only experienced centers (or clinical trials) should use systemic or intraarterial chemotherapy.
• Fluoropyrimidine chemoradiation was removed as a treatment option for cases with no residual local disease (R0 resection).
• Adjuvant chemotherapy or chemoradiation for patients with biliary tract cancer should only be done as part of clinical trials.

Survivorship

Elizabeth Kvale, MD

University of Alabama at Birmingham Comprehensive Cancer Center

“Every day brings new evidence that cancer survivors have unique and often unexpected healthcare needs. These initial survivorship guidelines are an effort to improve that by laying out some minimum standards for good care, but they are, in many ways, very preliminary. We really hope the people who read these will give us feedback which, along with new research, should lead to significant changes as we fine-tune these recommendations in the years to come.”

• Caregivers should systematically assess cancer survivors’ overall well-being with screening for common post-treatment problems: anxiety, depression, pain, fatigue, weakness, cognitive impairment, sexual dysfunction, and others. Prewritten surveys are available in many guidelines to insure consistent and thorough follow-up.
• Good preventive health programs can stop survivors from ever developing many common problems. Caregivers should work with patients from the beginning of treatment on issues such as diet, exercise, blood pressure, and others.
• Cancer specialists should understand the most common causes and treatment strategies for the problems that cancer survivors most frequently incur. When a chemotherapy patient complains of cognitive impairment, for example, symptoms may arise from depression or sleep disturbance rather than chemotherapy itself. The appropriate treatment, therefore, can range from antidepressants to psychostimulants to exercise.
• Specialist care ranging from psychiatry to physical therapy is often indicated for survivors with serious ongoing problems. Cancer therapists should know when to recommend specialists and know specialists who are experienced in dealing with cancer survivors. They should also take steps to coordinate care among several medical practitioners.
• The secondary problems that survivors face tend to occur relatively soon after treatment, but they can unexpectedly arise long thereafter. Follow-up checks for such issues should continue with the same sort of ongoing vigilance as follow-up checks for new signs of cancer.

Ovarian Cancer

Robert J. Morgan, MD

City of Hope Comprehensive Cancer Center

“There were no major changes to the guidelines this year, but there have been some substantive clarifications, particularly on a genetic risk evaluation. I think that the major recommendation for changes this year should be that virtually all ovarian cancer patients should be referred for genetics risk evaluation. This recommendation will help patients, families, and future families. No new treatments were added to the guidelines this year.”

• A strong emphasis on a genetic risk evaluation is in the newly updated guidelines, including stressing both obtaining family history and referring the patient for a genetic risk evaluation. The guidelines for genetic/familial risk assessment now consider the diagnosis of epithelial ovarian cancer to be an adequate indication to refer the patient to a clinical cancer genetics specialist for evaluation for the possibility of a familial inheritance.
• The principles of surgery section has been revised and updated, with an increased emphasis on the goal of surgical resection of all gross disease, rather than just optimal cytoreduction to <1 cm residual disease. This emphasis is based on published data showing that gross disease resection results in superior survival outcomes.
• In both the guideline and the surgical section, fertility-sparing surgical principles are outlined for those patients desiring fertility.

NCCN Bone Health Task Force: Key Recommendations

Azeez Farooki, MD

Memorial Sloan Kettering Cancer Center

“The 5 years that have passed since our last report have seen the introduction of several new medications that can lessen the toll that cancer treatment can take on bone health, but they have also raised some concerns about rare complications from long-term use of certain medications.”

• Cancer patients who are at risk of bone loss either from age or from therapy that will suppress sex hormones, induce early menopause, or include glucocorticoids should undergo a baseline test of bone health and periodic follow-ups.
• Dual-energy x-ray absorption, despite several limitations, is the preferred test because of its rich diagnostic information, intermediate cost, and low radiation exposure.
• Patients at risk for bone loss should avoid tobacco, limit alcohol, ensure adequate calcium and vitamin D from food and supplements, and perform load-bearing exercises.
• Pharmaceutical treatment should be used when lifestyle modifications fail to protect against loss of bone mineral density or when fracture risk increases to high levels: T score ≤-2.0 at lumbar spine, femoral neck, or total hip sites, or 10-year absolute FRAX risk greater than 20% for any major fracture or 3% for hip fracture.
• There are a variety of pharmaceutical options available to reduce the risk of osteoporotic fracture: bisphosphonates, denosumab, estrogen/hormone therapy, selective estrogen receptor modulators, recombinant parathyroid hormone (1-34). Intravenous bisphosphonates and denosumab are also approved for patients with cancer that is metastatic to bone. There are rare cases of atypical femur fractures associated with use of such potent antiresorptive therapy, so the FDA has suggested in the osteoporosis context that doctors reevaluate use after 3 to 5 years.
• Recombinant parathyroid hormone should be used with extreme caution in patients with a history of malignancy.

Management of Dermatologic Toxicities Associated With Targeted Agents

Barbara Ann Burtness, MD

Yale Cancer Center

In 2009, the NCCN convened a task force that published a report on the management of dermatologic and other toxicities associated with EGFR inhibition therapy for cancer patients. At this year’s NCCN 19th Annual Conference, Barbara Ann Burtness, MD, provided an update, covering the 2009 report and providing an update on dermatological toxicities associated with recently approved targeted agents in oncology. “There are not a lot of formally conducted randomized trials for managing dermatological toxicities associated with targeted agents for cancer treatment. The task force consisted of experts, including dermatologists, with a long track record of working with these targeted agents. Most of the recommendations are [based on] expert experience. The body of literature on management of these toxicities has not really grown in the last 5 years, although clinicians are now much more comfortable managing the toxicities. Particularly, topical steroids have become a mainstay for a lot of practices to manage dermatological adverse events in patients [receiving] targeted agents. “There is some evidence to show that preemptive therapy can reduce the number of skin lesions in patients, but most clinicians are still content to treat rashes and skin toxicities as they emerge.”

Novel oral agents and their associated dermatological toxicities:

• RAF kinase inhibitors: squamous cell cancers of the skin
• EGFR inhibitors (monoclonal antibodies and oral kinase inhibitors): skin rash, paronychia, xerosis, dry mucus membranes, pruritus, urticaria, infections of the skin, trichomegaly, facial hirsutism, and alopecia
• mTOR inhibitors: mucositis
• Regorafenib (Stivarga): hand-foot syndrome
• Lenalidomide (Revlimid): skin rash
• Pan-HER inhibitors: hair, nail, and skin changes
• Trastuzumab (Herceptin): alopecia
• MEK inhibitors: papulopustular rash, xerosis, pruritus, telangiectasias, hyperpigmentation, and alopecia