Long-term outcome and morbidity after treatment with accelerated radiotherapy and weekly cisplatin for locally advanced head-and-neck cancer: results of a multidisciplinary late morbidity clinic.

PURPOSE: To evaluate the long-term outcome and morbidity after intensified treatment for locally advanced head-and-neck cancer. METHODS AND MATERIALS: Between May 2003 and December 2007, 77 patients with Stage III to IV head-and-neck cancer were treated with curative intent. Treatment consisted of accelerated radiotherapy to a dose of 68 Gy and concurrent cisplatin. Long-term survivors were invited to a multidisciplinary outpatient clinic for a comprehensive assessment of late morbidity with special emphasis on dysphagia, including radiological evaluation of swallowing function in all patients. RESULTS: Compliance with the treatment protocol was high, with 87% of the patients receiving at least five cycles of cisplatin and all but 1 patient completing the radiotherapy as planned. The 5-year actuarial disease-free survival and overall survival rates were 40% and 47%, respectively. Locoregional recurrence-free survival at 5 years was 61%. The 5-year actuarial rates of overall late Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) Grade 3 and Grade 4 toxicity were 52% and 25% respectively. Radiologic evaluation after a median follow-up of 44 months demonstrated impaired swallowing in 57% of the patients, including 23% with silent aspiration. Subjective assessment using a systematic scoring system indicated normalcy of diet in only 15.6% of the patients. CONCLUSION: This regimen of accelerated radiotherapy with weekly cisplatin produced favorable tumor control rates and survival rates while compliance was high. However, comprehensive assessment by a multidisciplinary team of medical and paramedical specialists revealed significant long-term morbidity in the majority of the patients, with dysphagia being a major concern.

External beam radiotherapy with endocavitary boost for nasopharyngeal cancer: treatment results and late toxicity after extended follow-up.

PURPOSE: To evaluate the long-term outcome after treatment of nasopharyngeal carcinoma and assess late toxicity in a multidisciplinary clinic. METHODS AND MATERIALS: A retrospective analysis of 117 patients treated for nasopharyngeal cancer in a single institute between 1985 and 2002 was performed. Fifty-one long-term survivors were evaluated for late toxicity by a multidisciplinary team comprising a radiation oncologist, otolaryngologist, neurologist, and oral and maxillofacial surgeon. RESULTS: The 5-year local control rate for T1 to T2 and T3 to T4 tumors was 97% and 76%, respectively. Five-year disease-free survival and overall survival were 82% and 88% for Stage I to IIb disease and 46% and 52% for Stage III to IVb, respectively. Late morbidity evaluation revealed Radiation Therapy Oncology Group (RTOG) Grade III to IV toxicity in 71% of patients. A high incidence of cranial nerve palsies (47%) and mandibular osteolysis (82%) was found, although these complications had limited clinical impact. CONCLUSIONS: The multidisciplinary late morbidity clinic revealed an unexpected high incidence of cranial nerve palsies and mandibular osteolysis and overall an RTOG Grade III to IV toxicity in 71% of patients treated for nasopharyngeal cancer. External beam radiotherapy with endocavitary brachytherapy produces excellent rates of local control for T1 to T2 tumors, but the high incidence of late toxicity suggests an overtreatment.

Bath and shower effect in spinal cord: the effect of time interval.

PURPOSE: To evaluate the time dependency of the sensitizing effect of a large low-dose field on a small high-dose field in the rat cervical spinal cord. METHODS AND MATERIALS: Irradiation experiments with a relatively low dose to a large volume (bath, 2 cm, 4 Gy) were combined with high doses to a small volume (shower, 4.7 mm, 26-43 Gy) at intervals of 8 minutes and 3, 12, and 24 hours. Both a functional score defined as motor impairment and a histologic score characterized as white matter necrosis were used as end points. RESULTS: Application of the 4-Gy bath dose resulted in a significant decrease in 50% isoeffective dose (ED(50)) from 48.7 Gy (small field) to 40.8 Gy. If the interval was extended, the ED(50) increased to 44.4 (3 hours) and 44.8 Gy (12 hours), whereas a 24-hour interval resulted in a significant increase to 51.9 Gy. If the histologic end point was considered, the ED(50) for all dose-response curves decreased slightly with 0.2 to 2.6 Gy without significantly changing the kinetics. CONCLUSIONS: The bath effect as applied in the bath-and-shower experiment lasted for at least 12 hours and disappeared in the 24-hour interval. This time scale clearly deviates from the repair kinetics in spinal cord derived from low-dose-rate and fractionated irradiations.

Dose-volume effects in rat thoracolumbar spinal cord: the effects of nonuniform dose distribution.

PURPOSE: To investigate dose-volume effects in rat spinal cord irradiated with nonuniform dose distributions and to assess regional differences in radiosensitivity. METHODS AND MATERIALS: A total of 106 rats divided into three groups were irradiated with (192)Ir gamma-rays at a high dose rate. The groups were irradiated with one, two, or six catheters distributed around the thoracolumbar spinal cord to create different dose distributions. After irradiation, the animals were tested for motor function for 9 months. The response was defined as motor dysfunction and WM or nerve root necrosis. Dose-response data were analyzed with a probit analysis as function of the dose level at a percentage of the volume (D(%)) and with different normal tissue complication probability models. Additionally, the histologic responses of the individual dose voxels were analyzed after registration with the histologic sections. RESULTS: The probit analysis at D(24) (24% of the volume) gave the best fit results. In addition, the Lyman Kutcher Burman model and the relative seriality model showed acceptable fits, with volume parameters of 0.17 and 0.53, respectively. The histology-based analysis revealed a lower radiosensitivity for the dorsal (50% isoeffective dose [ED(50)] = 32.3) and lateral WM (ED(50) = 33.7 Gy) compared with the dorsal (ED(50) = 25.9 Gy) and ventral nerve roots (ED(50) = 24.1 Gy). CONCLUSIONS: For this nonuniform irradiation, the spinal cord did not show typical serial behavior. No migration terms were needed for an acceptable fit of the dose-response curves. A higher radiosensitivity for the lumbar nerve roots than for the thoracic WM was found.

Oxygen-modifying treatment with ARCON reduces the prognostic significance of hemoglobin in squamous cell carcinoma of the head and neck.

PURPOSE: To evaluate the prognostic significance of hemoglobin (Hb) levels measured before and during treatment with accelerated radiotherapy with carbogen and nicotinamide (ARCON). METHODS AND MATERIALS: Two hundred fifteen patients with locally advanced tumors of the head and neck were included in a phase II trial of ARCON. This treatment regimen combines accelerated radiotherapy for reduction of repopulation with carbogen breathing and nicotinamide to reduce hypoxia. In these patients, Hb levels were measured before, during, and after radiotherapy. RESULTS: Preirradiation and postirradiation Hb levels were available for 206 and 195 patients respectively. Hb levels below normal were most frequently seen among patients with T4 (p < 0.001) and N2 (p < 0.01) disease. Patients with a larynx tumor had significantly higher Hb levels (p < 0.01) than other tumor sites. During radiotherapy, 69 patients experienced a decrease in Hb level. In a multivariate analysis there was no prognostic impact of Hb level on locoregional control, disease-free survival, and overall survival. Primary tumor site was independently prognostic for locoregional control (p = 0.018), and gender was the only prognostic factor for disease-free and overall survival (p < 0.05). High locoregional control rates were obtained for tumors of the larynx (77%) and oropharynx (72%). CONCLUSION: Hemoglobin level was not found to be of prognostic significance for outcome in patients with squamous cell carcinoma of the head and neck after oxygen-modifying treatment with ARCON.

Dose-volume effects in rat thoracolumbar spinal cord: an evaluation of NTCP models.

PURPOSE: To evaluate models for normal-tissue-complication probability (NTCP) on describing the dose-volume effect in rat thoracolumbar spinal cord. METHODS AND MATERIALS: Single-dose irradiation of four field lengths (4, 1.5, 1.0, and 0.5 cm) was evaluated by the endpoints paresis and white-matter necrosis. The resulting dose-response data were used to rank phenomenological and tissue architecture NTCP models. RESULTS: The 0.5-cm field length showed a steep increase in radiation tolerance. Statistical analysis of the model fits, which included evaluation of goodness of fit (GOF) and confidence intervals, resulted in the rejection of all the models considered. Excluding the smallest field length, the Schultheiss (D(50) = 21.5 Gy, k = 26.5), the relative seriality (D(50) = 21.4 Gy, s = 1.6, gamma(50) = 6.3), and the critical element (D(50,FSU) = 26.6 Gy, gamma(50,FSU) = 2.3, n = 1.3) model gave the best fit. CONCLUSION: A thorough statistical analysis resulted in a serial or critical-element behavior for the field lengths of 1.0 cm and greater. Including the 0.5-cm field length, the radiation response markedly diverged from serial properties, but none of the models applied acceptably described this dose-response relationship. This study suggests that the commonly assumed serial behavior of the spinal cord might be valid for daily use in external- beam irradiation.

Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer.

Hypoxia is associated with tumor aggressiveness and is an important cause of resistance to radiation treatment. Assays of tumor hypoxia could provide selection tools for hypoxia-modifying treatments. This study correlated the exogenous 2-nitroimidazole hypoxia marker 1-[(2-hydroxy-3-piperidinyl)propyl]-2-nitroimidazole hydrochloride (pimonidazole) with the endogenous hypoxia-related marker carbonic anhydrase 9 (CA9) and with vascular parameters using immunohistochemical techniques and a computerized image analysis system. Tumor biopsies were obtained from patients with head and neck carcinomas that were potential candidates for a Phase II trial with accelerated radiotherapy combined with carbogen and nicotinamide (ARCON). If, after completion of the diagnostic workup, the eligibility criteria were met and informed consent was obtained, patients were treated with ARCON. Those patients that were not eligible or refused ARCON were treated with radiotherapy, surgery, or a combined modality. Forty-three biopsies were analyzed, and the results were related with treatment outcome. The distribution patterns of pimonidazole and CA9 were similar, although the CA9 signal was generally observed already at shorter distances from blood vessels. There was a weak but significant correlation between the relative tumor areas positive for pimonidazole binding and areas with CA9 expression. Locoregional tumor control was significantly lower for patients who had hypoxic tumors or tumors with low vascular density. The 2-year control rates were 48 versus 87% for tumors with high and low pimonidazole binding levels (stratified by median, P = 0.01) and 48 and 88% for tumors with low and high vascular density (stratified by median, P = 0.01). These associations disappeared in the subgroup of patients treated with ARCON. There was no relationship between the level of CA9 expression and treatment outcome. It is concluded that pimonidazole binding and vascular density can predict treatment outcome in head and neck cancer and may be useful as selection tools for hypoxia-modifying treatments. Pimonidazole and CA9 demonstrate concordant staining patterns, but the latter is a less specific marker for hypoxia.

ARCON: experience in 215 patients with advanced head-and-neck cancer.

PURPOSE: "ARCON" combines accelerated radiotherapy to counteract tumor repopulation with carbogen breathing and nicotinamide to reduce chronic and acute hypoxia. The aim of this Phase II study was to assess the feasibility, toxicity, and potential effectiveness of ARCON for advanced head-and-neck cancer. METHODS AND MATERIALS: The study included 215 patients with head-and-neck carcinoma distributed as follows: larynx, n = 100; hypopharynx, n = 50; oropharynx, n = 52; oral cavity, n = 13; Stage II, n = 8, Stage III, n = 71, and Stage IV, n = 136. Accelerated radiotherapy was given to a total dose of 64-68 Gy in 2-Gy fractions within 36-38 days. This was combined with carbogen breathing during irradiation and administration of nicotinamide (60-80 mg/kg) 1-1.5 h before irradiation. RESULTS: There was full compliance with carbogen breathing in 88% of the patients. A nicotinamide dose of 80 mg/kg produced severe nausea and vomiting, necessitating discontinuation of the drug, in 31% of the patients. Adjustment of the dose to 60 mg/kg and antiemesis prophylaxis reduced the discontinuation rate to 10%. Confluent mucositis was observed in 91% of the patients with a median duration of 6 weeks. Grade 4 late complications occurred in 5% of the patients. The actuarial 3-year local control rates were 80% for larynx, 69% for hypopharynx, 88% for oropharynx, and 37% for oral cavity tumors. For T3-4 tumors, the local control rates were 80% for larynx, 60% for hypopharynx, 87% for oropharynx, and 29% for oral cavity. Regional control rates were 100% for N0, 93% for N1, and 74% for N2 disease. CONCLUSION: ARCON yields high local and regional control rates in advanced head-and-neck carcinomas, and compliance is satisfactory and morbidity acceptable. The local control rate of 80% for T3 and T4 larynx carcinomas offers excellent possibilities for organ preservation.