NCCN 17th Annual Conference: Clinical Practice Guidelines & Quality Cancer Care

When seeking guidance in the application of best clinical practice standards, those in oncology healthcare routinely turn to the National Comprehensive Cancer Network (NCCN). The NCCN develops thorough, widely recognized Clinical Practice Guidelines in Oncology, and updates those guidelines each year in accordance with new insights and therapies within the field.

At this year’s annual NCCN conference, the organization presented updates in 13 areas, including specific disease states and general screening methods. Three of the guidelines, in the areas of acute lymphoblastic leukemia, adolescent and young adult oncology, and lung cancer screening, were newly introduced this year.

Renowned physicians presented the updates during the conference, which was attended by more than 1500 doctors, nurses, pharmacists, and business leaders. The meeting also focused on quality issues; business challenges; new treatments, therapies, and trends; and their application in patient care.

A roundtable discussion on the provision of cancer care to corporate employees was led by longtime NCCN moderator, ABC news reporter and cancer survivor Sam Donaldson; another roundtable, focused on balancing patient care against cost concerns, was moderated by Clifford Goodman, PhD, of the Lewin Group.

An overview of the 2012 guideline updates is provided below

Acute Lymphoblastic Leukemia

Joseph C. Alvarnas, MD

City of Hope Comprehensive Cancer Center

Dr Alvarnas: "Unlike other specialty areas, most of which were announcing updates to long-existing guidelines, the ones we announced this year were our first. It has taken many years and many trials to create anything resembling a standard of care, not only because the disease is rare, but also because there has long been controversy over what treatments work best."

• Physicians who do not specialize in acute lymphoblastic leukemia (ALL) are advised to avoid treating the condition at all. Any patients they find with the disease should be sent not just to a large hospital, but to one that specializes in treating this particular disease, and thus has both the expertise and the facilities to implement the new care guidelines.
• Genetic testing should be used before devising plans of treatment for all patients with ALL. Different variants of the disease respond to considerably different treatment protocols. If, for example, a patient has the Philadelphia chromosome, bone marrow transplants are recommended in addition to chemotherapy.
• An assessment of the risks faced by each individual patient should determine the aggressiveness of treatment. An adult at high risk of relapse should probably receive a bone marrow transplant as an initial part of therapy. A child with a less dire prognosis might only receive chemotherapy as a part of first-line therapy.
• Physicians who treat ALL are advised to recheck published guidelines frequently. Unlike the long-established guidelines for other cancers, which have been polished over the years, the ALL guidelines remain raw. In addition, given that the cure rate for adults is still under 40%, Alvarnas expects aggressive efforts to find new, and more effective, treatment protocols—particularly with targeted agents such as imatinib (Gleevec), showing that they can change response rates in this disease.

Breast Cancer

Robert W. Carlson, MD

Stanford Cancer Institute

Dr Carlson: "There was no comment previously in terms of how often staging or restaging studies should be done in patients with metastatic disease receiving systemic therapy. It was added because performing restaging studies is quite expensive, and interpretation of those studies is often difficult. We also wanted to emphasize the importance of looking not only at radiographic studies, but at symptoms, physical exams, blood tests—a series of aspects of a patient and that patient's care—to determine whether or not a therapy is helping."

• A new section titled "Principles of Monitoring Metastatic Disease" discusses how to track the progression of breast cancer and weigh the benefits of restaging studies against costs and the toxicity of ineffective treatments in patients with metastatic disease who are receiving systemic therapy. The guidelines deem positron emission tomography (PET) / computed tomography (CT) scans and tumor markers to be optional methods of restaging when disease progression is suspected.
• In invasive breast cancer, a recommendation against "routine systemic staging" has been added in stages I-IIB when asymptomatic. In stage IIIA, PETs/CTs have been added as staging studies to be considered.
• Based on the results of the ACOSOG Z11 trial, the guidelines allow for a decision against axillary lymph node dissection in patients with sentinel lymph node—positive disease who are undergoing breast conservation therapy, receiving whole-breast radiation therapy and no neoadjuvant chemotherapy, have a T1 or T2 tumor, and have no more than two positive sentinel lymph nodes.
• In patients undergoing mastectomy who have axillary lymph node involvement, the recommendation for post-mastectomy chest wall and regional lymph node radiation has been upgraded from "consider" to "strongly consider."
• Based on early results of the BOLERO-2 trial, a footnote allows the addition of everolimus (Afinitor) to exemestane (Aromasin) in the treatment of hormone receptor-positive, HER2-negative metastatic breast cancer in patients previously treated with a nonsteroidal aromatase inhibitor.

Central Nervous System Metastases

Frank D. Vrionis, MD, MPH, PhD

H. Lee Moffitt Cancer Center & Research Institute

Dr Vrionis: "There's a lot of excitement, long term, about the potential of targeted therapies, but difficulties like crossing the blood-brain barrier mean that such treatments are not developed and tested to the point of becoming part of the guidelines yet. The main theme of our presentation this year wasn't about any changes to the guidelines, but to emphasize how best to use those treatments that are in the guidelines."

• Surgery is often the best treatment option when there is a single tumor in an accessible part of the brain, particularly in rare cases where there's no evidence of a primary tumor elsewhere in the body. More importantly, surgery can be an urgent component of a multipronged treatment strategy any time a tumor is causing swelling or otherwise creating dangerous pressure in the brain.
• Radiosurgery is the preferred treatment option when patients present with more than one tumor but fewer than five, and those tumors are less than 3 cm in size. The highly focused beams of ionizing radiation, aimed with high precision, can treat many tumors that have proven resistant to traditional radiation.
• In patients with large numbers of tumors, radiation is generally the preferred treatment option over chemotherapy, which rarely works except in cases where the primary tumor type is lymphoma or some other systemic cancer that responds particularly well to chemotherapy.
• Some targeted medications—such as BRAF inhibitors used against melanoma— continue to show promise in early trials, but larger and better trials will need to show results before such therapies become the standard of treatment.

Colorectal Cancer

Al B. Benson III, MD

Robert H. Lurie Comprehensive Cancer Center

Dr Benson: "This year's updates are what I would call fine-tuning based on the evidence that we have. Hopefully, as more clinical trials are designed and as new therapies become available, those will be reflected in future guidelines."

• Capecitabine (Xeloda) plus oxaliplatin (Eloxatin), also known as the CapOx regimen, has been changed from a category 2A treatment to a category 1 treatment in patients with locally advanced disease, meaning that based on high-level evidence the treatment is considered appropriate.
• Fluorouracil, oxaliplatin, and leucovorin calcium—also known as the FOLFOX regimen—plus cetuximab (Erbitux) was removed as a treatment option in earlier stages of colorectal cancer and as an initial treatment option in advanced and metastatic disease.
• The recommendation for cetuximab plus irinotecan (Camptosar) in patients with KRAS wild-type after progression on first-line FOLFOX with or without bevacizumab (Avastin) or CapOx with or without bevacizumab was changed from category 2B to category 2A, as more evidence suggests this is an appropriate treatment option.
• The resectability of liver metastases in colorectal cancer was redefined. Previously, a limited number of metastases (3-4) were required for resectability. In the new guidelines, a specific number of metastases is no longer a requirement.
• In testing for BRAF mutations, allele-specific polymerase chain reaction was added as another acceptable method for testing for the BRAFV600E mutation.
• In patients with advanced metastatic disease who receive capecitabine plus bevacizumab, the dose schedule of bevacizumab has been changed from 5 mg/kg IV weekly to 7.5 mg/kg IV every three weeks.

Hodgkin Lymphoma

Leo I. Gordon, MD

Robert H. Lurie Comprehensive Cancer Center

Dr Gordon: "In some ways, the changes made this year were made in a 'cost-savings' way as we learn which methods are more effective and when more or less treatment is needed."

• For early-stage classic Hodgkin lymphoma that presents unfavorably with either bulky or nonbulky disease, the primary treatment of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) has been changed from two cycles to four cycles.
• Bendamustine (Treanda) has been added as a second-line chemotherapy option prior to the patient receiving a transplant.
• For diagnosing patients, fine-needle aspiration alone should be avoided and only used if called diagnostic of Hodgkin lymphoma by a hematopathologist or a cytopathologist.
• In early-stage disease, patients with elevated erythrocyte sedimentation rate or more than three sites of the disease can be managed with the Stanford V regimen.
• Clarifications were made to treatments if a patient achieved partial response or stable disease after primary treatment. In most cases, ABVD is not used after primary treatment. Instead, the patient should receive involved-field radiation therapy.
• In patients with lymphocyte-predominant Hodgkin lymphoma who have relapsed, the treatment team should consider the addition of rituximab (Rituxan).
• The guidelines acknowledged the differences and discrepancies between various systems that define nodal sites. In this year's updates, the authors suggested the use of the German Hodgkin Study Group's definition for nodal sites, which state that the infraclavicular region is included with the ipsilateral cervical/supraclavicular, the bilateral hila are included with the mediastinum, and the abdomen is divided into two regions: upper (spleen hilum, liver hilum, celiac) and lower.

Lung Cancer Screening

Mary E. Reid, PhD

Roswell Park Cancer Institute

Dr Reid: "This is the first time the NCCN, or any American organization, has ever published recommendations for lung cancer screening. In 2010, the NCI's randomized National Lung Screening Trial demonstrated that using spiral (helical) low-dose computed tomography (LDCT) of the chest on people with a high risk of lung cancer—in comparison to chest x-ray—improved their survival by 20%. This screening will change mortality by allowing us to diagnose lung cancer at earlier stages."

• LDCT testing for "noncalcified nodules that may be suspicious for lung cancer" should be performed: On high-risk individuals, including: People aged 55 to 74 years who have smoked the equivalent of one pack of cigarettes a day for 30 years, or two packs a day for 15 years, or who smoked that heavily within the past 15 years People aged 50 years and older who have a history of smoking the equivalent of one pack of cigarettes a day for 20 years, or two packs a day for 10 years, and who have another risk factor for lung cancer, such as lung disease, asbestos or radon exposure, a history of certain cancers, or a strong family history of lung cancer Annually until age 74 in high-risk individuals in whom no lung nodules have been found, or who have ground-glass nodule or nonsolid-nodule lesions of up to 10 mm that are stable Again in three or six months if a scan reveals a solid or part-solid nodule of 4 mm to 8 mm or larger, or a ground glass-opacity, ground-glass nodule, or nonsolidnodule lesion of 5 mm to 10 mm or larger Again in one month after the finding of a solid endobronchial nodule; bronchoscopy should follow if the nodule is still there
• The guidelines also specify when treatment with antimicrobials, biopsy, or surgical excision should be considered.
• Physicians will be required to conduct more CT scans and manage a larger number of nodules, the majority of them benign.

Metastatic Melanoma

Daniel G. Coit, MD

Memorial Sloan-Kettering Cancer Center

Dr Coit: "The major changes affect oncologists and are the recognition of targeted and immunotherapies for patients with metastatic melanoma."

• Addition of novel systemic therapies for metastatic disease, vemurafenib (Zelboraf) and ipilimumab (Yervoy), as category 1 options.
• Tissue should be obtained for genotyping early on in the treatment algorithm so that patients with the BRAFV600E mutation can be considered as candidates for the new targeted therapy vemurafenib.
• Patients with wild-type BRAF gene have the option of the immunotherapy ipilimumab.
• A footnote warning states that taking vemurafenib may result in "dermatological complications" including a secondary skin cancer— cutaneous squamous cell carcinoma—and extreme photosensitivity.
• A footnote suggests that re-induction with ipilimumab can be considered for patients who have not experienced significant toxicity during initial ipilimumab therapy, and who have relapsed after initial clinical response or after more than three months of stable disease.
• The role of adjuvant radiation moved to the forefront for patients with completely resected nodal disease who are seen at high risk for nodal recurrence.
• A footnote suggests a definite wide excision. Pathology recommendations now state that either the FISH or comparative genomic hybridization (CGH) is recommended, as CGH may be more accurate at identifying specific genomic mutation.
• Routine imaging is recommended for patients, both in initial work-up and in follow-up to treatment to conserve costs and minimize radiation exposure.
• Recommendation is for a PET/CT rather than a PET scan.

Non-Hodgkin Lymphoma

Andrew D. Zelenetz, MD, PhD

Memorial Sloan-Kettering Cancer Center

Dr Zelenetz: "Historically, we followed the 5% rule, in that we didn't include guidelines for diseases that impacted less than 5% of the total population of non-Hodgkin lymphoma patients. The reality is that in these rare diseases, guidelines are even more necessary because many treating oncologists don't have a lot of experience with these diseases."

• Two rare subtypes of non-Hodgkin lymphoma were added to the guidelines this year: hairy cell leukemia and T-cell prolymphocytic leukemia.
• Immunohistochemistry and flow cytometry should be used to diagnose hairy cell leukemia and distinguish it from hairy cell leukemia variant, which is a more aggressive disease that may require different management. Purine analogs, particularly cladribine and pentostatin, are the preferred therapeutic agents for hairy cell leukemia.
• For T-cell prolymphocytic leukemia, immunophenotyping should be used to identify markers such as CD5, CD7, and CD52, which are closely associated with the disease. Treatment should be aggressive with the best responses usually achieved through the use of alemtuzumab (Campath), although enrollment in clinical trials is preferred since survival is usually less than one year.
• Standardized use of PET/CT imaging for patients with diffuse large B-cell lymphoma (DLBCL) was added to the guidelines. In general, PET/CT imaging should be used every six months to monitor patients during the first two years of treatment. Afterward, it should be used only if clinically indicated.
• After treatment is completed for a patient with DLBCL, all positive tests should be repeated. If a PET/CT scan is positive, a patient should be rebiopsied before the course of treatment is changed.
• Clarifications were made to the response to therapy for chronic lymphocytic leukemia, which previously used the qualifiers "greater than three years" for long response and "less than two years" for short response. Instead, the new recommendations state that response should be based on clinical judgment on a case-by-case basis, as different therapies might have different optimal cutoff points.

Multiple Myeloma

Kenneth C. Anderson, MD

Dana-Farber Cancer Institute

Dr Anderson: "What the guidelines are wonderful for is establishing a framework for treatment options at different stages of disease. They offer the opportunity for enrolling patients in clinical trials, especially when there are no accepted treatments."

• Initial diagnosis work-up now includes testing for the 17p13 deletion using FISH.
• After primary treatment, the serum-free light-chain assay is now recommended as part of follow-up. Lactate dehydrogenase and beta-2 microglobulin are now recommended as follow-up and surveillance at discretion of the clinician.
• For asymptomatic, smoldering multiple myeloma, clinical trials are recommended, in addition to active observation.
• Multi-parameter flow cytometry is added as a follow-up option. "This option applies primarily for transplant patients because as novel agents are now used in induction and maintenance, molecular complete responses are now being achieved," explained Anderson.
• A footnote to the active myeloma section says that autologous transplant on or off a clinical trial is an option depending on the progression of disease and the timing of the initial stem cell transplant. A post-allogeneic stem cell transplant clinical trial following maintenance therapy is an additional treatment option after an initial stem cell transplant.
• Under definitions of active myeloma, repeated infections, amyloidosis, or hyperviscosity are added to existing metrics as criteria for active myeloma.
• All previous criteria methodology has been removed in favor of uniform criteria defined by the International Myeloma Working Group.
• Bortezomib (Velcade) with liposomal doxorubicin is no longer preferred over bortezomib alone.
• For nontransplant patients, melphalan-prednisone-lenalidomide is added as a category 1 option. Bortezomib is added as a maintenance therapy option in addition to lenalidomide and thalidomide. A note of caution is attached to lenalidomide, due to increased risk for secondary cancer development, particularly following a transplant.
• Bisphosphonates are now recommended (category 1) for all patients as adjuvant therapy. Both zoledronic acid (Zometa) and pamidronate (Aredia) have shown equivalence in efficacy (reduced risk for skeletal-related events in randomized trials) according to the added footnote.
• Under salvage therapy, cyclophosphamide VAD (vincristine/doxorubicin/ dexamethasone), dexamethasone, lenalidomide, and thalidomide are no longer recommended, while bortezomib treatment is added as a combination treatment with DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide). Footnote suggestion added for single-agent thalidomide or lenalidomide for patients intolerant of steroids.

Ovarian Cancer

Robert J. Morgan, Jr, MD

City of Hope Comprehensive Cancer Center

Dr Morgan: "There were no major changes to the actual guidelines this year, but we did unveil a number of small but important tweaks, along with some major changes to the guideline wording designed to make them clearer and easier for clinicians to use."

• The recommendation that physicians consider neoadjuvant chemotherapy with carboplatin and paclitaxel, rather than immediate surgery, has been upgraded from 2a (general consensus of good treatment option) to 1 (supported by strong clinical data).These recommendations are based on studies indicating that neoadjuvant chemotherapy—in selected patients and following consultation with a gynecologic oncologist—leads to decreased surgical morbidity with equivalent survival times.
• The published instructions for managing drug interactions have been completely redesigned. Treatment strategies remain largely unchanged, but old text summaries have given way to guidelines written in an algorithmic structure—much like the published primary treatment algorithms—which should make compliance easier.
• Physicians are now advised to confer with patients on routine monitoring CA- 125 levels and using this information to help time chemotherapy. A British study involving 1500 patients found that initiating treatment based on CA-125 levels exposed patients to an extra five months of chemotherapy without extending survival times. There were some limitations in the study, however, so the guidelines encourage physicians and patients to discuss the pros and cons associated with the routine monitoring of CA-125 levels.
• New data have not overturned previous recommendations that minimallyinvasive surgery may be an appropriate treatment option for physicians expert in its use, but not as a general standard of care. Currently available case studies do suggest equal efficacy, particularly when the minimally invasive surgery is performed with robot assistance, but more evidence is still needed before the approach can be recommended for primary surgical staging.

Non—Small Cell Lung Cancer

Ramaswamy Govindan, MD

Siteman Cancer Center

Dr Govindan: "Crizotinib (Xalkori) for patients with advanced or metastasized non—small cell lung cancer (NSCLC) who are ALKpositive is the ultimate story of personalized therapy. It works in 60% to 65% of these patients, even those who have cancer in their brains, to cause dramatic shrinkage of tumors. This produces results two to three times better than chemotherapy. It's one of the big breakthroughs in cancer treatment."

• Crizotinib was added as a recommended first-line therapy for patients with advanced or metastatic ALK-positive NSCLC.
• A recommendation was added to test for ALK mutations in patients with advanced or metastatic adenocarcinoma, large cell lung cancer, or NSCLC not otherwise specified.
• The guidelines, which list fluorescence in situ hybridization (FISH) as the current standard for ALK testing, note that the FDA recently approved a molecular diagnostic test that uses FISH to detect ALK mutations in patients with advanced or metastatic NSCLC.
• Screening with low-dose CT scans decreases mortality in people at high risk for developing lung cancer—those over age 55 who have smoked the equivalent of one pack of cigarettes a day for 30 years, or two packs a day for 15 years.
• For patients with recurrent or metastatic disease whose EGFR mutation is discovered prior to first-line therapy, the NCCN has upgraded—from category 2A to category 1—its recommendation to treat with erlotinib (Tarceva).

Prostate Cancer

Sandy Srinivas, MD

Stanford Cancer Center

Dr Srinivas: "We made very few changes to guidelines over the past year, so we used our presentation to highlight guideline changes that physicians will need to watch for and potential guideline changes related to new drugs—or existing drugs being used in new ways—that may well be adopted before the end of the year."

• Current guidelines still put a Level 2B rating on the evidence in favor of using abiraterone acetate (Zytiga) plus prednisone for the treatment of asymptomatic or mildly symptomatic patients with metastatic castrationresistant prostate cancer (mCRPC) before chemotherapy. But a new study announced by Janssen Research & Development has found unspecified clinical benefits that many expect to boost guidelines for pre-chemotherapy abiraterone use to a Level 1 recommendation.
• The FDA is likely to approve—and guidelines are likely to embrace—the use of the AR antagonist MDV3100 after docetaxel-based chemotherapy following a study of 1199 mCRPC patients that found MDV3100 extended survival from 13.6 months to 18.4 months while raising the mean time to prostate-specific antigen (PSA) progression from three months to eight months. Fifty-four percent of those who received MDV3100 saw PSA fall by half compared with 1.5% of those who received the placebo.
• Guideline changes will likely follow tests that showed radium-223 chloride (Alpharadin) improved overall survival in patients with mCRPC and symptomatic bone metastases. Those who received the treatment in a phase III trial had a median survival of 14 months versus 11.2 months for placebo.
• Expected guideline changes embracing the use of denosumab (Xgeva) for the treatment of patients with mCRPC but no bone metastases suffered a major setback after the FDA rejected such usage, following one study that found the bone-modifying agent only delayed bone metastases by four months.

This article is based on writing and reporting by Anna Azvolinsky, PhD, Beth Fand Incollingo, Ben Leach, and Andrew D. Smith.