Purpose We sought to improve the outcomes for loco-regionally advanced nasopharyngeal carcinoma (NPC) by testing the feasibility/safety of adding bevacizumab to chemoradiation. Patients/Methods Eligible patients with ≥T2b and/or positive node(s) were prescribed 3 cycles of bevacizumab (15 mg/kg) and cisplatin (100 mg/m2) both given on days 1, 22, and 43 of radiation (70 Gy) using IMRT delivered over 33 days on a daily basis, Monday through Friday. This is followed by 3 cycles of bevacizumab (15 mg/kg), cisplatin (80 mg/m2) both were given on days 64, 85, and 106 and fluorouracil (1000 mg/m2/d) on days 64–67, 85–88, 106–109 after radiation. The primary endpoint was to evaluate the safety of the addition of bevacizumab to chemoradiation, specifically looking at treatment-related Grade 4 hemorrhage and/or any Grade 5 adverse event in the first year. Toxicity during and after treatment were collected along with tumor control endpoints. The analysis was done per protocol. This protocol has completed its target accrual. Results There were a total of 46 patients enrolled in this study of whom 44 patients were eligible for analysis. No grade 3–4 hemorrhage or grade 5 adverse events were observed; 9 patients (20.5%) experienced grade 1–2 hemorrhage. Grade 4 adverse events were experienced by the following numbers of patients: leukopenia NOS – 6; lymphopenia – 5; neutrophil count – 5; pharyngolaryngeal pain – 2; hemoglobin – 1; infection with grade 3–4 neutrophils (blood) – 1; infection with grade 3–4 neutrophils [skin (cellulitis)] – 1; tinnitus – 1; thrombosis – 1; radiation mucositis – 1. The most common grade 3 adverse events were radiation mucositis – 33; dysphagia – 25; and mucositis/stomatitis (clinical exam) (pharynx) – 15. Two patients experienced late grade 3 xerostomia. Other late grade 3 adverse events were: dysphagia – 5; hearing impaired – 3; neuralgia NOS – 2; constitutional symptoms (other) – 1; dehydration – 1; fatigue – 1; hearing disability – 1; infection (other) – 1; muscle weakness NOS – 1; peripheral motor neuropathy – 1; peripheral sensory neuropathy – 1; radiation mucositis – 1.. With a median follow-up of 2.5 years, the estimated 2-year loco-regional progression-free, distant metastasis-free, progression-free and overall survival (OS) rates were 83.7%(95% confidence interval 72.6–94.9), 90.8% (82.2–99.5), 74.7% (61.8–87.6), and 90.9% (82.3–99.4),, respectively. Conclusion It was feasible to add bevacizumab to chemoradiation for NPC treatment. The favorable 2-year OS of 90.9% suggests that bevacizumab might delay progression of subclinical disease.
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
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