Highlights from the NCCN 
15th Annual Conference

The National Comprehensive Cancer Network (NCCN) recently held its 15^th Annual Conference in Hollywood, Florida. The conference was entitled “Clinical Practice Guidelines & Quality Cancer Care” and included multiple presentations with updates to the NCCN Guidelines. Below, we cover updates to the NCCN Guidelines for breast cancer, acute myeloid leukemia, and multiple myeloma. To view the complete NCCN Guidelines, go to www.nccn.org.

NCCN Breast Cancer Guidelines Update

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At the National Comprehensive Cancer Network (NCCN) 15^th Annual Meeting, Robert W. Carlson, MD, chair of the NCCN Breast Cancer Panel Members and professor of medicine in the Division of Oncology at Stanford Comprehensive Cancer Center, reviewed changes to the NCCN Breast Cancer Guidelines for invasive breast cancer. Major changes were made to protocols regarding the initial workup and evaluation of patients, as well as the administration of local therapy, adjuvant systemic therapy, and systemic therapy for metastatic disease.

Initial Workup

NCCN’s updated guidelines now recommend offering genetic counseling to patients at high risk for hereditary breast cancer during their initial evaluation. In addition, PET/CT scanning, which combines the molecular/functional imaging of FDG-PET with the anatomical imaging of CT scanning, was added as optional study to supplement bone and CT scanning; this is a category 2B recommendation. Carlson noted that FDG PET/CT is most useful in cases where standard staging studies yield suspicious or unequivocal findings, especially in the setting of locally advanced or metastatic disease, noting it may identify unsuspected regional or distant metastasis, though biopsy in these cases may ultimately prove more useful. He also cautioned that “the use of PET or PET/CT scanning is not indicated in the staging of clinical stage I, II, or operable stage III disease.”

Local Therapy

The updated guidelines call for limiting the staging of clinically negative axilla to sentinel lymph node (SNL) biopsy, which according to the literature identifies more than 95% of SNLs accurately and has a less than 10% false-negative rate. In addition, it has a high prognostic value and low rate of complications, with less than 1% of women with negative SNLs experiencing axillary recurrence and only 7% experiencing lymph edema. One drawback to this recommendation is that SNL biopsy may not readily be available in certain parts of the United States or in some of the countries that are seeking to adopt the NCCN guidelines.

Adjuvant Systemic Therapy

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The updated guidelines divide women into biologically meaningful subsets, including hormone receptor (HR) status, and apply an algorithm using OncoDX technology to determine recurrence score (RS), which is then used to determine whether adjuvant endocrine therapy is offered in combination with chemotherapy. Women with an RS below 18 are considered low risk, 18 to 30 intermediate risk, and 31 or greater are high risk. The update was reflective of several studies, including one that found that only those women who started with high recurrence scores appeared to benefit from cytotoxic chemotherapy. Further, Carlson noted that the 21-gene RT-PCR test should be used only in patients with ER-positive, node-negative disease, as most patients with HER2-positive disease have a high RS; this finding, however, was validated only in tamoxifen-treated patients who received first-generation chemotherapy. Another significant change is that the use of AC chemotherapy followed by a course of paclitaxel every 3 weeks was removed from the adjuvant regimen options, as the regimen was found to be inferior.

Systemic Therapy for Metastatic Disease

The updated guidelines revisit the use of endocrine therapy recommendations in HER2-positive disease. In the first-line therapy setting of postmenopausal HR-positive metastatic disease, the addition of lapatinib (Tykerb) to letrozole endocrine therapy yielded no benefit in women with HER2-negative disease, and the FDA recently updated the lapatinib label to indicate it should only be used in women with HER2-positive disease. In addition, regarding HER2-targeted therapy, Carlson noted that chemotherapy plus trastuzumab (Herceptin) increases progression-free survival (PFS) and overall survival (OS), endocrine therapy plus either trastuzumab or lapatinib increases PFS, endocrine therapy plus trastuzumab does not increase survival, and use of lapatinib has not improved OS in any situation. He noted that we do not yet know whether using HER2-targeted therapy early in combination with endocrine therapy may impact the survival benefit of trastuzumab.

Future Direction

The NCCN Breast Cancer Guidelines will continue to evolve based upon scientific evidence. “My expectation is that the next version for the breast cancer guideline[s] will have substantial changes, hopefully in particular more clarity,” said Carlson. In addition, NCCN will continue to collaborate to develop international versions of the guidelines, which aim to remain respectful of resources available and specific to the populations and social settings in which they are used.

NCCN Acute Myeloid Leukemia Guidelines Updates

Every year more than 13,000 cases of acute myeloid leukemia (AML) are diagnosed and almost 9000 individuals die of this disease. At the National Comprehensive Cancer Network (NCCN) 15^th Annual Meeting, B. Douglas Smith, MD, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, presented updates to the NCCN Acute Myeloid Leukemia Guidelines, which now emphasize using risk stratification to assist in selecting treatment for patients with AML and have been expanded to distinguish the therapy options for patients with acute promyelocytic leukemia (APL). “AML is a disease of older patients, presenting a clinical challenge for physicians since advances in therapy have been limited,” noted Smith in a press release.

The best indicator of response is cytogenetics, as certain cytogenetic abnormalities are associated with very good outcomes, whereas others are associated with a poor prognosis and a high risk of relapse following treatment. According to Smith, however, approximately 50% of all AML patients have “normal” cytogenetics and fall into an intermediate-risk group. In these patients, the use of molecular markers may be especially important, as traditional testing does not provide insight into their disease and prognosis. One of the molecular markers he discussed was the FLT3-ITD mutation, which has a poor prognosis, unless it is the wild type, whereas another mutation, NPM1, carries a better prognosis unless it is the wild type. Smith noted that sometimes the FLT3-ITD and NPM1 mutations may be found in combination, and while targeting mutations such as these (most notably, FLT3-ITD) has not been successful as of yet, there is promise for the future, and for the time being, their presence can give an indication of a patient’s prognosis.

One important prognostic indicator that Smith discussed was white blood cell (WBC) count at presentation. He noted that these counts, which may assist with treatment selection, may be especially important for patients found to have APL, which is the most curable subtype of AML. “If physicians can better define the prognosis of an individual patient’s APL, they can more accurately develop a tailored treatment plan for the patient,” said Smith. “This may even allow physicians to decrease the total amount of treatment a patient receives while maintaining positive outcomes,” he continued, stressing that “lower-risk disease can have good outcomes with less treatment, resulting in better long-term outcomes.”

The NCCN Guidelines now distinguish the therapy options for APL patients with low-risk or high-risk disease using their WBC count status, recommending assessing WBC count prior to therapy in those who can tolerate anthracycline therapy. Those found to have a WBC count ≥10,000 are considered to be low/intermediate risk, whereas those with a count <10,000 are considered high risk. A platelet count <40,000 at presentation is another poor risk feature. A strong recommendation in the NCCN Guidelines is that APL should be treated according to one of the regimens established from clinical trials. “The panel strongly emphasizes the importance of using these regimens consistently and not mixing induction from one with consolidation from the other,” Smith said, and then told the audience to “pick one protocol and stick to it.”

Smith also noted that the treatment of AML in individuals aged ≥60 years continues to be challenging, stating that “many will die [of] their leukemia.” Because the long-term survival rates of these patients have not improved, the updated NCCN Guidelines recommend that patient performance status, adverse features, comorbid conditions, and chronological age must be considered when selecting treatment, which has received some additions. The NCCN updates now include 5-azacytidine (Vidaza) and decitabine (Dacogen) as low-intensity treatment options and clofarabine (Clolar) as an intermediate-intensity treatment option in patients aged ≥60 years; these agents have a category 2B designation. He also noted that “some patients will have a good response [to treatment], and if they respond, they will do OK regardless of age.”

Smith concluded the presentation by emphasizing the importance of ongoing clinical trials in improving AML outcomes and noted that there are several areas in the NCCN Guidelines where referral to a clinical trial is recommended.

NCCN Multiple Myeloma Guidelines Updates

At the National Comprehensive Cancer Network (NCCN) 15^th Annual Conference, George Somlo, MD, City of Hope Comprehensive Cancer Center, presented the updates to the NCCN Multiple Myeloma Guidelines. Solmo started the session by providing an overview of multiple myeloma, noting that approximately 20,580 new cases would be diagnosed this year. This disease, which occurs more frequently in African Americans than in whites and primarily affects older individuals (median age, 66 y), generally presents with bone pain, with loss of height often being the first sign. Patients may also experience constitutional weakness, anemia, and renal compromise when the disease becomes more aggressive.

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According to Somlo, it is important to perform cytogenetic analysis to determine prognosis, noting that certain chromosomal abnormalities documented by FISH (fluorescence hybridization) carry a worse prognosis, such as t(4;14) or t(14;16). Unilateral bone marrow aspirate plus biopsy, including bone marrow immunohistochemistry and bone marrow flow cytometry, were added to the initial diagnostic workup, whereas use of C-reactive protein was removed as a potentially useful diagnostic for some patients.

The Guidelines indicate that patients who have smoldering myeloma may be observed at 3- to 6-month intervals; this is a class 1 indication. For those requiring treatment, VAD (vincristine [Oncovin], Adriamycin [doxorubicin], and dexamethasone), melphalan (Alkeran), prednisone, or dexamethasone alone are not acceptable frontline treatment options in 2010, noted Solmo. “First of all, one has to decide whether any particular patient with active multiple myeloma is a candidate for stem cell transplantation,” he said. “The goal still is to get a patient into as close to a complete response as possible, or at least a very good partial response, and then proceed to a stem cell transplant” and consider whether an adjuvant regimen may be necessary. The Guidelines classify a complete response as negative immunofixation on the serum and urine, disappearance of soft tissue plasmacytomas, and ≤5% plasma cells in bone marrow. “Almost as good is very good partial response [VGPR],” noted Somlo. VGPR is considered a ≥90% decrease in serum M-protein and a urine M-protein level <100 mg per 24 hours. “Anything less than that is considered a partial response and it’s not good enough,” said Somlo.

For patients with ISS stage II or DS stage III disease, the guidelines recommend induction with thalidomide/dexamethasone, bortezomib (Velcade)/dexamethasone, lenalidomide (Revlimid)/dexamethasone, or a combination of 3 agents. For patients with active (symptomatic) myeloma who are in response after induction therapy, there are also options, noted Somlo. These include autologous stem cell transplantation, continuation of the induction regimen until there is a plateau, or possible stem cell transplantation. Somlo noted that melphalan should be avoided because of the risk for significant toxicity, particularly in older patients.

Single agent lenalidomide was also added as an option for maintenance therapy. This recommendation is a category 2A because although lenalidomide has been evaluated in three independent clinical trials, and results of each showed improvements in time to progression, the results of these studies have not yet undergone full peer review and their safety and efficacy data are still preliminary.