Hypoxia is a characteristic feature of locally advanced solid tumors resulting from an imbalance between oxygen (O 2 ) supply and consumption. Major causative factors of tumor hypoxia are abnormal structure and function of the microvessels supplying the tumor, increased diffusion distances between the nutritive blood vessels and the tumor cells, and reduced O 2 transport capacity of the blood due to the presence of disease-or treatment-related anemia. Tumor hypoxia is a therapeutic concern since it can reduce the effectiveness of radiotherapy, some O 2 -dependent cytotoxic agents, and photodynamic therapy. Tumor hypoxia can also neg- The Oncologist 2004;9(suppl 5):4-9 www.TheOncologist.com

Adjuvant brachytherapy improves local control after complete resection of soft tissue sarcomas. This improvement in local control is limited to patients with high-grade histopathology. The reduction in local recurrence in patients with high-grade lesions is not associated with a significant reduction in distant metastasis or improvement in disease-specific survival.

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A B S T R A C T PurposeTo develop a clinical practice guideline for treatment of laryngeal cancer with the intent of preserving the larynx (either the organ itself or its function). This guideline is intended for use by oncologists in the care of patients outside of clinical trials. MethodsA multidisciplinary Expert Panel determined the clinical management questions to be addressed and reviewed the literature available through November 2005, with emphasis given to randomized controlled trials of site-specific disease. Survival, rate of larynx preservation, and toxicities were the principal outcomes assessed. The guideline underwent internal review and approval by the Panel, as well as external review by additional experts, members of the American Society of Clinical Oncology (ASCO) Health Services Committee, and the ASCO Board of Directors. ResultsEvidence supports the use of larynx-preservation approaches for appropriately selected patients without a compromise in survival; however, no larynx-preservation approach offers a survival advantage compared with total laryngectomy and adjuvant therapy with rehabilitation as indicated. RecommendationsAll patients with T1 or T2 laryngeal cancer, with rare exception, should be treated initially with intent to preserve the larynx. For most patients with T3 or T4 disease without tumor invasion through cartilage into soft tissues, a larynx-preservation approach is an appropriate, standard treatment option, and concurrent chemoradiotherapy therapy is the most widely applicable approach. To ensure an optimum outcome, special expertise and a multidisciplinary team are necessary, and the team should fully discuss with the patient the advantages and disadvantages of larynx-preservation options compared with treatments that include total laryngectomy.

To define the indications for elective neck treatment, the cases of 474 previously untreated patients were reviewed who had locally confined major salivary gland cancers treated between 1939 and 1982, Clinically positive nodes were present in 14% (67 of 474). Overall, clinically occult, pathologically positive nodes occurred in 12% (47 of 407). By univariate analysis, several factors appeared to predict the risk of occult metastases; however, multivariate analysis revealed that only size and grade were significant risk factors. Tumors 4 cm or more in size had a 20% (32 of 164) risk of occult metastases compared with a 4% (nine of 220) risk for smaller tumors [P < 0.00001). High‐grade tumors (regardless of histologic type) had a 49% (29 of 59) risk of occult metastases compared with a 7% (15 of 221) risk for intermediate‐grade or low‐grade tumors [P < 0.00001). In view of the low frequency of occult metastases in the entire group, routine elective treatment of the neck is not recommended. High‐grade tumors and larger tumors have a high rate of occult neck metastases, and treatment should be considered in this group.

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Hemithoracic radiation after complete surgical resection at a dose not previously reported is feasible. This approach dramatically reduces local recurrence and is associated with prolonged survival for early-stage tumors. Stage III disease has a high risk of early distant relapse and should be considered for trials of systemic therapy added to this regimen of resection and radiation.

Local recurrence remains a major obstacle to achieving cure of many locally advanced solid tumors treated with definitive radiation therapy. The microen-vironment of solid tumors is hypoxic compared with normal tissue, and this hypoxia is associated with decreased radiosensitivity. Recent preclinical data also suggest that intratumoral hypoxia, particularly in conjunction with an acid microenvironment, may be directly or indirectly mutagenic. Investigations of the prognostic significance of the pretreatment oxygenation status of tumors in patients with head and neck or cer-vical cancer have demonstrated that increased hypoxia, typically designated in these studies as pO 2 levels below 2.5-10 mm Hg, is associated with decreased local tumor control and lower rates of disease-free and overall survival. Hypoxia-directed therapies in the radiation oncology setting include treatment using hyperbaric oxygen, fluosol infusion, carbogen breathing, and electron-affinic and hypoxic-cell sensitizers. These interventions have shown the potential to increase the effectiveness of curative-intent radiation therapy, demonstrating that the strategy of overcoming hypoxia may be a viable and important approach. Anemia is common in the cancer population and is suspected to contribute to intratu-moral hypoxia. A review of the literature reveals that a low hemoglobin level before or during radiation therapy is an important risk factor for poor locoregional disease control and survival, implying that a strong correlation could exist between anemia and hypoxia (ulti-mately predicting for a poor outcome). While having a low hemoglobin level has been shown to be detrimental, it is unclear as to exactly what the threshold for "low" should be (studies in this area have used thresholds ranging from 9-14.5 g/dl). Optimal hemoglobin and pO 2 thresholds for improving outcomes may vary across and within tumor types, and this is an area that clearly The Oncologist 2002;7:492-508 www.TheOncologist.com The Oncologist ® LEARNING OBJECTIVES After completing this course, the reader will be able to: 1. Discuss the prognostic significance of intratumoral hypoxia and low hemoglobin levels in patients receiving curative-intent radiation for head and neck or cervical cancer. 2. Describe the potential relationship between anemia and intratumoral hypoxia in patients with solid tumors. 3. List possible interventions for improving intratumoral oxygenation and radiosensitivity in the radiation oncology setting. Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com