Gary H. Lyman

Prognostic Factors Analysis of 17,600 Melanoma Patients: Validation of the American Joint Committee on Cancer Melanoma Staging System

PURPOSE The American Joint Committee on Cancer (AJCC) recently proposed major revisions of the tumor-node-metastases (TNM) categories and stage groupings for cutaneous melanoma. Thirteen cancer centers and cancer cooperative groups contributed staging and survival data from a total of 30,450 melanoma patients from their databases in order to validate this staging proposal. PATIENTS AND METHODS There were 17,600 melanoma patients with complete clinical, pathologic, and follow-up information. Factors predicting melanoma-specific survival rates were analyzed using the Cox proportional hazards regression model. Follow-up survival data for 5 years or longer were available for 73% of the patients. RESULTS This analysis demonstrated that (1) in the T category, tumor thickness and ulceration were the most powerful predictors of survival, and the level of invasion had a significant impact only within the subgroup of thin (< or = 1 mm) melanomas; (2) in the N category, the following three independent factors were identified: the number of metastatic nodes, whether nodal metastases were clinically occult or clinically apparent, and the presence or absence of primary tumor ulceration; and (3) in the M category, nonvisceral metastases was associated with a better survival compared with visceral metastases. A marked diversity in the natural history of pathologic stage III melanoma was demonstrated by five-fold differences in 5-year survival rates for defined subgroups. This analysis also demonstrated that large and complex data sets could be used effectively to examine prognosis and survival outcome in melanoma patients. CONCLUSION The results of this evidence-based methodology were incorporated into the AJCC melanoma staging as described in the companion publication.

2006 Update of Recommendations for the Use of White Blood Cell Growth Factors: An Evidence-Based Clinical Practice Guideline

PURPOSE To update the 2000 American Society of Clinical Oncology guideline on the use of hematopoietic colony-stimulating factors (CSF). UPDATE METHODOLOGY The Update Committee completed a review and analysis of pertinent data published from 1999 through September 2005. Guided by the 1996 ASCO clinical outcomes criteria, the Update Committee formulated recommendations based on improvements in survival, quality of life, toxicity reduction and cost-effectiveness. RECOMMENDATIONS The 2005 Update Committee agreed unanimously that reduction in febrile neutropenia (FN) is an important clinical outcome that justifies the use of CSFs, regardless of impact on other factors, when the risk of FN is approximately 20% and no other equally effective regimen that does not require CSFs is available. Primary prophylaxis is recommended for the prevention of FN in patients who are at high risk based on age, medical history, disease characteristics, and myelotoxicity of the chemotherapy regimen. CSF use allows a modest to moderate increase in dose-density and/or dose-intensity of chemotherapy regimens. Dose-dense regimens should only be used within an appropriately designed clinical trial or if supported by convincing efficacy data. Prophylactic CSF for patients with diffuse aggressive lymphoma aged 65 years and older treated with curative chemotherapy (CHOP or more aggressive regimens) should be given to reduce the incidence of FN and infections. Current recommendations for the management of patients exposed to lethal doses of total body radiotherapy, but not doses high enough to lead to certain death due to injury to other organs, includes the prompt administration of CSF or pegylated G-CSF.

American Society of Clinical Oncology Guideline Recommendations for Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer

PURPOSE To develop a guideline for the use of sentinel node biopsy (SNB) in early stage breast cancer. METHODS An American Society of Clinical Oncology (ASCO) Expert Panel conducted a systematic review of the literature available through February 2004 on the use of SNB in early-stage breast cancer. The panel developed a guideline for clinicians and patients regarding the appropriate use of a sentinel lymph node identification and sampling procedure from hereon referred to as SNB. The guideline was reviewed by selected experts in the field and the ASCO Health Services Committee and was approved by the ASCO Board of Directors. RESULTS The literature review identified one published prospective randomized controlled trial in which SNB was compared with axillary lymph node dissection (ALND), four limited meta-analyses, and 69 published single-institution and multicenter trials in which the test performance of SNB was evaluated with respect to the results of ALND (completion axillary dissection). There are currently no data on the effect of SLN biopsy on long-term survival of patients with breast cancer. However, a review of the available evidence demonstrates that, when performed by experienced clinicians, SNB appears to be a safe and acceptably accurate method for identifying early-stage breast cancer without involvement of the axillary lymph nodes. CONCLUSION SNB is an appropriate initial alternative to routine staging ALND for patients with early-stage breast cancer with clinically negative axillary nodes. Completion ALND remains standard treatment for patients with axillary metastases identified on SNB. Appropriately identified patients with negative results of SNB, when done under the direction of an experienced surgeon, need not have completion ALND. Isolated cancer cells detected by pathologic examination of the SLN with use of specialized techniques are currently of unknown clinical significance. Although such specialized techniques are often used, they are not a required part of SLN evaluation for breast cancer at this time. Data suggest that SNB is associated with less morbidity than ALND, but the comparative effects of these two approaches on tumor recurrence or patient survival are unknown.

Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer

Abstract Background. Neutropenia and infection are major dose-limiting side effects of chemotherapy. Previous studies have suggested that recombinant methionyl granulocyte colony-stimulating factor (G-CSF) can reduce chemotherapy-related neutropenia in patients with cancer. We conducted a randomized clinical trial to test this hypothesis and the clinical implications. Methods. Patients with small-cell lung cancer were enrolled in a multicenter, randomized, double-blind, placebo-controlled trial of recombinant methionyl G-CSF to study the incidence of infection as manifested by fever with neutropenia (absolute neutrophil count, <1.0×l09 per liter, with a temperature ≥38.2°C) resulting from up to six cycles of chemotherapy with cyclophosphamide, doxorubicin, and etoposide. The patients were randomly assigned to receive either placebo or G-CSF, with treatment beginning on day 4 and continuing through day 17 of a 21 -day cycle. Results. The safety of the study treatment could be evaluated in 207 of the 211 pa...

Comorbidity and functional status are independent in older cancer patients.

PURPOSE Comorbidity is a frequent and often therapeutically limiting problem in older cancer patients. However, to date, there is no standard measure of the comorbidity burden available for these patients. We tested the performance of two comorbidity scales and their relationship with functional status. PATIENTS AND METHODS The Cumulative Illness Rating Scale-Geriatric (CIRS-G) was compared with the Charlson scale in 203 patients who received a comprehensive geriatric assessment (CGA) in our Senior Adult Oncology Program (SAOP). Study end points were variability, reliability, correlation with Eastern Cooperative Oncology Group (ECOG) performance status (PS), Activities of Daily Living (ADL), and Instrumental Activities of Daily Living (IADL). The relative weight of comorbidity versus tumor stage in the correlations with functional status was assessed. RESULTS Median age was 75 years (range, 63 to 91). Sixty-four percent of patients scored 0 on the Charlson scale versus 6% on the CIRS-G. The correlation between the Charlson and CIRS-G was fair (p = 0.25 to 0.39). CIRS-G grade 3/4 had a fair correlation with ADL (p = 0.27). Otherwise, there was low or no correlation between comorbidity and functional status across the measures. Tumor stage was not correlated with functional status either. Correlation of ECOG PS with ADL (p = 0.51)c and IADL (p = 0.61) was moderate. Interrater and test-retest correlations were good or very good for both the Charlson and CIRS-G. CONCLUSION Comorbidity needs to be assessed independently from functional status. Both the Charlson and CIRS-G scales are reliable tools for use in trials of older cancer patients. Both can be tested in further studies as predictors of outcomes such as toxicity of treatment, changes in functional status, or survival.

American Society of Clinical Oncology Guideline: Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer

PURPOSE To develop guideline recommendations for the use of anticoagulation in the prevention and treatment of venous thromboembolism (VTE) in patients with cancer. METHODS A comprehensive systematic review of the medical literature on the prevention and treatment of VTE in cancer patients was conducted and reviewed by a panel of content and methodology experts. Following discussion of the results, the panel drafted recommendations for the use of anticoagulation in patients with malignant disease. RESULTS The results of randomized controlled trials of primary and secondary VTE medical prophylaxis, surgical prophylaxis, VTE treatment, and the impact of anticoagulation on survival of patients with cancer were reviewed. Recommendations were developed on the prevention of VTE in hospitalized, ambulatory, and surgical cancer patients as well as patients with established VTE, and for use of anticoagulants in cancer patients without VTE to improve survival. CONCLUSION Recommendations of the American Society of Clinical Oncology VTE Guideline Panel include (1) all hospitalized cancer patients should be considered for VTE prophylaxis with anticoagulants in the absence of bleeding or other contraindications; (2) routine prophylaxis of ambulatory cancer patients with anticoagulation is not recommended, with the exception of patients receiving thalidomide or lenalidomide; (3) patients undergoing major surgery for malignant disease should be considered for pharmacologic thromboprophylaxis; (4) low molecular weight heparin represents the preferred agent for both the initial and continuing treatment of cancer patients with established VTE; and (5) the impact of anticoagulants on cancer patient survival requires additional study and cannot be recommended at present.

Development and validation of a predictive model for chemotherapy-associated thrombosis

Risk of venous thromboembolism (VTE) is elevated in cancer, but individual risk factors cannot identify a sufficiently high-risk group of outpatients for thromboprophylaxis. We developed a simple model for predicting chemotherapy-associated VTE using baseline clinical and laboratory variables. The association of VTE with multiple variables was characterized in a derivation cohort of 2701 cancer outpatients from a prospective observational study. A risk model was derived and validated in an independent cohort of 1365 patients from the same study. Five predictive variables were identified in a multivariate model: site of cancer (2 points for very high-risk site, 1 point for high-risk site), platelet count of 350 x 10(9)/L or more, hemoglobin less than 100 g/L (10 g/dL) and/or use of erythropoiesis-stimulating agents, leukocyte count more than 11 x 10(9)/L, and body mass index of 35 kg/m(2) or more (1 point each). Rates of VTE in the derivation and validation cohorts, respectively, were 0.8% and 0.3% in low-risk (score = 0), 1.8% and 2% in intermediate-risk (score = 1-2), and 7.1% and 6.7% in high-risk (score >/= 3) category over a median of 2.5 months (C-statistic = 0.7 for both cohorts). This model can identify patients with a nearly 7% short-term risk of symptomatic VTE and may be used to select cancer outpatients for studies of thromboprophylaxis.

Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update 2014

PURPOSE To provide current recommendations about the prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer. METHODS PubMed and the Cochrane Library were searched for randomized controlled trials, systematic reviews, meta-analyses, and clinical practice guidelines from November 2012 through July 2014. An update committee reviewed the identified abstracts. RESULTS Of the 53 publications identified and reviewed, none prompted a change in the 2013 recommendations. RECOMMENDATIONS Most hospitalized patients with active cancer require thromboprophylaxis throughout hospitalization. Routine thromboprophylaxis is not recommended for patients with cancer in the outpatient setting. It may be considered for selected high-risk patients. Patients with multiple myeloma receiving antiangiogenesis agents with chemotherapy and/or dexamethasone should receive prophylaxis with either low-molecular weight heparin (LMWH) or low-dose aspirin. Patients undergoing major surgery should receive prophylaxis starting before surgery and continuing for at least 7 to 10 days. Extending prophylaxis up to 4 weeks should be considered in those undergoing major abdominal or pelvic surgery with high-risk features. LMWH is recommended for the initial 5 to 10 days of treatment for deep vein thrombosis and pulmonary embolism as well as for long-term secondary prophylaxis (at least 6 months). Use of novel oral anticoagulants is not currently recommended for patients with malignancy and VTE because of limited data in patients with cancer. Anticoagulation should not be used to extend survival of patients with cancer in the absence of other indications. Patients with cancer should be periodically assessed for VTE risk. Oncology professionals should educate patients about the signs and symptoms of VTE.

The orderly progression of melanoma nodal metastases

ObjectiveThe aim of this study was to determine the order of melanoma nodal metastases. Summary Background DataMost solid tumors are thought to demonstrate a random nodal metastatic pattern. The incidence of skip nodal metastases precluded the use of sampling procedures of first station nodal basins to achieve adequate pathological staging. Malignant melanoma may be different from other malignancies in that the cutaneous lymphatic flow is better defined and can be mapped accurately. The concept of an orderly progression of nodal metastases is radically different than what is thought to occur in the natural history of metastases from most other solid malignancies. MethodsThe investigators performed preoperative and intraoperative mapping of the cutaneous lymphatics from the primary melanoma in an attempt to identify the “sentinel” lymph node in the regional basin. All patients had primary melanomas with tumor thicknesses > 0.76 mm and were considered candidates for elective lymph node dissection. The sentinel lymph node was defined as the first node in the basin from which the primary site drained. The sentinel lymph node was harvested and submitted separately to pathology, followed by a complete node dissection. The null hypothesis tested was whether nodal metastases from malignant melanoma occurred in equal proportions among sentinel and nonsentinel nodes. ResultsForty-two patients met the criteria of the protocol based on prognostic factors of their primary melanoma. Thirty-four patients had histologically negative sentinel nodes, with the rest of the nodes in the basin also being negative. Thus, there were no skip metastases documented. Eight patients had positive sentinel nodes, with seven of the eight having the sentinel node as the only site of disease. In these seven patients, the frequency of sentinel nodal metastases was 92%, whereas none of the higher nodes had documented metastatic disease. Nodal involvement was compared between the sentinel and nonsentinel nodal groups, based on the binomial distribution. Under the null hypothesis of equality in distribution of nodal metastases, the probability that all seven unpaired observations would demonstrate that involvement of the sentinel node is 0.008.

Recommendations on the Use of 18F-FDG PET in Oncology

The rationale was to develop recommendations on the use of 18F-FDG PET in breast, colorectal, esophageal, head and neck, lung, pancreatic, and thyroid cancer; lymphoma, melanoma, and sarcoma; and unknown primary tumor. Outcomes of interest included the use of 18F-FDG PET for diagnosing, staging, and detecting the recurrence or progression of cancer. Methods: A search was performed to identify all published randomized controlled trials and systematic reviews in the literature. An additional search was performed to identify relevant unpublished systematic reviews. These publications comprised both retrospective and prospective studies of varied methodologic quality. The anticipated consequences of false-positive and false-negative tests when evaluating clinical usefulness, and the impact of 18F-FDG PET on the management of cancer patients, were also reviewed. Results and Conclusion: 18F-FDG PET should be used as an imaging tool additional to conventional radiologic methods such as CT or MRI; any positive finding that could lead to a clinically significant change in patient management should be confirmed by subsequent histopathologic examination because of the risk of false-positive results. 18F-FDG PET should be used in the appropriate clinical setting for the diagnosis of head and neck, lung, or pancreatic cancer and for unknown primary tumor. PET is also indicated for staging of breast, colon, esophageal, head and neck, and lung cancer and of lymphoma and melanoma. In addition, 18F-FDG PET should be used to detect recurrence of breast, colorectal, head and neck, or thyroid cancer and of lymphoma.