National Comprehensive Cancer Network

Clinical Recommendations

JNCCN – The Journal of the National Comprehensive Cancer Network

Table of Contents - Volume 6 Number 10: November 2008

• NCCN Clinical Practice Guidelines in Oncology™
• Acute Myeloid Leukemia
• Occult Primary
• Featured Articles
• Strategy for Incorporating Molecular and Cytogenetic Markers into Acute Myeloid Leukemia Therapy
• Optimizing Therapy for Acute Myeloid Leukemia
• Therapy for Older AML Patients: The Role of Novel Agents and Allogeneic Stem Cell Transplant
• Therapy of Adenocarcinoma of Unknown Primary: Are We Making Progress?
• Evaluation and Management of the Unknown Primary Carcinoma of the Head and Neck

NCCN Clinical Practice Guidelines in Oncology™

Acute Myeloid Leukemia

Approximately 13,290 people will be diagnosed with acute myeloid leukemia (AML) in 2008, and 8820 patients will die of the disease. As the population ages, the incidence of AML, along with myelodysplasia, appears to be rising. Equally disturbing is the increasing incidence of treatment‑related myelodysplasia and leukemia in survivors of tumors from childhood and young adulthood, such as Hodgkin disease, sarcomas, breast and testicular cancers, and lymphomas. Ionizing radiation and occupational exposure to benzene and petrochemicals are also associated with AML. Clinical trials have led to significant improvements in treatment in some areas, primarily in acute promyelocytic leukemia. However, recent large clinical trials have highlighted the need for new, innovative strategies, because outcomes for AML patients, particularly older ones, have not substantially changed in the past 3 decades. The National Comprehensive Cancer Network AML Panel has focused on outlining reasonable treatment options based on recent clinical trials and data from basic science, which may identify new risk factors and treatment approaches. These guidelines attempt to provide a rationale for including several treatment options in some categories, as divergent opinions about the relative risks and benefits of various treatment options have surfaced. Updates for 2009 include new clarifications of some treatment recommendations as well as for defining polymerase chain reaction positivity.

Occult Primary

Myelodysplastic syndromes (MDS) represent myeloid clonal hemopathies with relatively heterogeneous spectrums of presentation. The major clinical problems in these disorders are morbidities caused by patients’ cytopenias and the potential for MDS to evolve into acute myeloid leukemia (AML). In the general population, MDS occur in 5 per 100,000 people. However, among individuals older than age 70, the incidence increases between 22 and 45 per 100,000 and increases further with age. Managing MDS is complicated by the generally advanced age of patients, attendant non‑hematologic comorbidities, and older patients' relative inability to tolerate some therapies. In addition, when the illness progresses into AML, these patients experience lower response rates to standard therapy than patients with de novo AML. Important changes from the 2008 version of the guidelines include the addition of lenalidomide as a possible treatment for symptomatically anemic non-del(5q) patients whose anemia does not respond to initial therapy.

Featured Articles

Strategy for Incorporating Molecular and Cytogenetic Markers into Acute Myeloid Leukemia Therapy
Mark G. Frattini, MD, PhD, and Peter G. Maslak, MD

Acute myeloid leukemia (AML) is a heterogeneous disease that, although the focus of significant laboratory and clinical investigation, remains difficult to treat. The difficulty may be in part because of the fundamental nature of AML, which requires substantial institutional resources to adequately deal with the complications of bone marrow failure and sustain patients through periods of intensive therapy. Standard treatments may be applied to biologically distinct subgroups, resulting in different treatment outcomes. The concept of risk-adapted therapy allows for recognition of this biologic diversity by incorporating key biologic features, such as cytogenetic and molecular markers, when formulating treatment regimens and investigating emerging targeted therapies based on disease characteristics.

Optimizing Therapy for Acute Myeloid Leukemia
Holbrook E. Kohrt, MD, and Steven E. Coutre, MD

The 10-year overall survival for newly diagnosed acute myeloid leukemia has improved threefold over the past 20 years. This is largely due to advances in supportive care and efforts to optimize standard induction and consolidation therapies applied in a stratified approach based on predictors of individual patient risk. Innovations in diagnostic technologies have broadened our understanding of key prognostic factors, including cytogenetic and molecular status, which define the extensive inter-patient heterogeneity of this clonal disease. Despite this progress, only approximately 25% of patients who experience complete remission with cytotoxic chemotherapy (50%–70% of newly diagnosed patients) remain disease-free. Efforts to develop novel agents, particularly for elderly patients, and targeted therapies such as all-trans retinoic acid for acute promyelocytic leukemia are actively ongoing.

Therapy for Older AML Patients: The Role of Novel Agents and Allogeneic Stem Cell Transplant
Jeffrey E. Lancet, MD, and Sergio Giralt, MD

The development of novel therapeutics in acute myeloid leukemia (AML) is driven by the need to improve efficacy and reduce toxicity. Clearly, elderly patients with AML represent a highly heterogeneous group, based on a wide array of disease- and patient-specific characteristics. Therefore, novel treatment strategies aimed at overcoming specific biologic modifiers of disease resistance will be paramount to successful therapy for some, whereas in others, the ability to administer a low-toxicity regimen on a chronic basis to achieve disease control may prove beneficial, perhaps even in the absence of complete responses. The development of reduced-intensity preparative regimens for allogeneic transplants has allowed physicians and patients to explore the option of long-term disease control; the risk–benefit ratio will depend on the disease state, patient performance status, and comorbidities. However, current results underscore that age alone should not be a contraindication for allogeneic transplant with curative intent in these patients, and long-term disease control with good quality of life is possible. Future trials combining novel therapies described in this article and novel transplant technologies should allow more elderly patients with AML or myelodysplastic syndromes to experience long and productive lives.

Therapy of Adenocarcinoma of Unknown Primary: Are We Making Progress?
F. Anthony Greco, MD

Therapy for patients with unknown primary carcinoma is evolving and requires a detailed understanding of various clinicopathologic subsets with more favorable prognoses. For the remainder, and most patients with unfavorable prognoses, data on current empiric chemotherapy with newer drugs appears to show improved overall survival compared with historical data, including comparisons with large retrospective series and prospective phase II trial results. The survival of patients with several metastatic adenocarcinomas of known primary sites, including colon/rectum, lung, and pancreas, has been improved by the administration of chemotherapy alone or combined chemotherapy with biologic targeted drugs (bevacizumab, erlotinib). Approximately 60% of the patients with unknown primary adenocarcinoma have clinically occult primary sites of colon/rectum, lung, and pancreas, and many will benefit from therapeutic regimens now proven useful. All available data make a convincing argument that progress is being made for patients with adenocarcinoma of unknown primary site and is likely to continue as understanding of these and other neoplasms further evolves.

Evaluation and Management of the Unknown Primary Carcinoma of the Head and Neck
Chad E. Galer, MD, and Merrill S. Kies, MD

Metastatic carcinoma in the cervical lymph nodes without obvious evidence of a primary source is a common clinical entity and occurs in approximately 3% to 5% of head and neck malignancies. Most of these carcinomas arise from primary sites in the upper aerodigestive tract, but they may also arise from other sites, including the thyroid, esophagus, and lung. Histologically, squamous cell carcinoma represents up to 90% of metastatic disease to the cervical lymph nodes with unknown primary tumor and has diverse histologies, including head and neck melanoma, lymphoma, and adenocarcinoma, with rare tumors constituting the remainder. Despite advances, the unknown primary cancer remains a challenging diagnostic and therapeutic entity. This article focuses on the diagnosis, management, and outcomes of metastatic squamous cell carcinoma of the head and neck of unknown primary site.