Systematic assessment of clinical outcomes and toxicities of proton radiotherapy for reirradiation.

Reirradiation (reRT) for locoregional recurrences poses unique challenges and risks; re-treatment using proton beam radiotherapy (PBT) could prove advantageous. Assessing clinical outcomes and toxicity profiles, this systematic review comprehensively evaluated available evidence regarding PBT reRT. Fourteen original investigations across central nervous system (CNS) (n=6), head/neck (H&N) (n=4), lung (n=2), and gastrointestinal (n=2) malignancies were analyzed. PBT for recurrent uveal melanoma achieved 5-year eye retention of 55%; for chordomas, reRT afforded a 2-year local control and overall survival (OS) of 85% and 80%, respectively. Multiple PBT reRT studies for adult gliomas illustrate no grade ≥3 toxicities. Two pediatric CNS tumor studies demonstrated the safety and efficacy of reRT, with one total grade 3 toxicity and achievement of longer-term OS. PBT for H&N malignancies shows appropriate local/locoregional control and favorable toxicity profiles versus historical photon-based methods, including low (9-10%) rates of feeding tube placement. PBT for recurrent lung cancer can achieve favorable survival with expected toxicities/complications of reRT, especially with concurrent chemotherapy and centrally located recurrences. Lastly, PBT reRT in gastrointestinal malignancies induced very few high-grade complications. Hence, based on the limited existing data, PBT is a notably safe reRT modality for effective salvage of recurrent disease. Institutional experiences must continue to be reported: dosimetric correlations, late toxicities, and advanced PBT techniques.

Clinical and Radiologic Outcomes in Adults and Children Treated with Pencil-Beam Scanning Proton Therapy for Low-Grade Glioma.

PURPOSE: We assessed clinical and radiologic outcomes in adults and children with low-grade glioma (LGG) of the brain treated with pencil-beam scanning (PBS) proton therapy (PT). MATERIALS AND METHODS: Between 1997 and 2014, 28 patients were treated with PBS PT, 20 (71%) of whom were younger than 18 years. Median age at start of PT was 12.3 years (range, 2.2-53.0 years). Nine patients (32%) underwent at least a subtotal resection; 12 (43%) underwent biopsy; and 7 (25%) were diagnosed radiographically. Twelve patients (43%) had grade II and 9 (32%) had grade I gliomas. Eleven patients (39%) received chemotherapy before PT. A median dose of 54 Gy (relative biologic effectiveness) was administered. Radiologic response to PT was determined using the Response Evaluation Criteria in Solid Tumors (RECIST). Eight domains of quality of life (QoL) for 16 pediatric patients were assessed prospectively by patients' parents using the pediatric QoL proxy questionnaire. Progression-free survival and overall survival (OS) were estimated by the Kaplan-Meier method. Median follow-up was 42.1 months for living patients. RESULTS: Ten patients (36%) developed local, clinical failure. Three patients (11%) died, all of tumor progression. Radiographic tumor response by RECIST was evaluable in 11 patients: 9 (82%) with stable disease, 1 (9%) with partial response, and 1 (9%) with complete response to PT. Three-year OS and progression-free survival were 83.4% and 56.0%, respectively. No ≥ grade III acute toxicities were observed. Grade III, late radiation necrosis developed in 1 patient (4%). No appreciable change in pediatric QoL proxy scores in children was noted in any of the 8 domains at any time point. CONCLUSION: Treatment with PBS PT is effective for LGG, with minimal acute toxicity and, in children, no appreciable decline in QoL. More patients and longer follow-up are needed to determine the long-term efficacy and toxicity of PT for LGG.

Radiation therapy for mucosal melanoma of the head and neck.

OBJECTIVES: The aim of this study was to evaluate the long-term effectiveness and complications of radiotherapy (RT) in the treatment of patients with mucosal melanomas of the head and neck. MATERIALS AND METHODS: The medical records of 21 patients treated with definitive or postoperative (RT) between 1974 and 2011 at the University of Florida Department of Radiation Oncology in Gainesville, FL, and the University of Florida Proton Therapy Institute in Jacksonville, FL, were retrospectively reviewed under an Institutional Review Board-approved protocol. Primary sites included nasal cavity, oropharynx, and paranasal sinuses. Sixteen patients (76%) received surgery and postoperative RT and 5 patients (24%) received RT alone. Seventeen patients received photon RT alone, whereas 4 patients received combined photon-based and proton-based RT. Median follow-up for all patients was 1.05 years (range, 0.36 to 12.97 y); median follow-up for survivors was 2.2 years (range 0.9 to 13.0 y). RESULTS: The 5-year outcomes were: local control, 79%; regional control, 85%; local-regional control, 65%; distant metastasis-free survival, 20%; cause-specific survival, 22%; and overall survival, 22%. Three patients (14%) experienced severe complications including bilateral blindness and skin necrosis. CONCLUSIONS: Definitive or postoperative RT for mucosal melanoma of the head and neck yields fairly good local-regional control of disease. The prognosis for patients treated with definitive RT is less promising than for those who receive surgery and postoperative RT.

Proton therapy for skull base chordomas: an outcome study from the university of Florida proton therapy institute.

Objectives Skull base chordoma is a rare, locally aggressive tumor located adjacent to critical structures. Gross total resection is difficult to achieve, and proton therapy has the conformal advantage of delivering a high postoperative dose to the tumor bed. We present our experience using proton therapy to treat 33 patients with skull base chordomas. Design Retrospective outcomes study. Setting University of Florida Proton Therapy Institute; 2007 to 2011. Participants A total of 33 patients with skull base chordomas received postoperative three-dimensional conformal proton therapy. The patients were 79% male and 6% diabetic; 27% had received a gross total resection. Main Outcome Measures The gross tumor/tumor bed received a dose between 77.4 CGE and 79.4 CGE. Local control and overall survival were tracked, and radiation toxicity was assessed using a modified Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring Scheme. Results Median follow-up for all patients was 21 months. Local control and overall survival rates at 2 years were 86% and 92%, respectively. Grade 2 toxicity was observed in 18% of our cohort in the form of unilateral hearing loss partially corrected with a hearing aid. No grade 2 or higher optic or brainstem toxicities were observed. Conclusions Proton therapy is an effective treatment modality for skull base chordomas.

Radiotherapy for sinonasal undifferentiated carcinoma.

PURPOSE: To evaluate the long-term effectiveness of radiotherapy (RT) in the treatment of sinonasal undifferentiated carcinoma (SNUC). MATERIALS AND METHODS: The medical records of 23 patients treated with definitive or postoperative RT between 1992 and 2010 at the University of Florida were retrospectively reviewed. Fifteen patients (65%) received primary surgery and postoperative RT. Radiation doses ranged from 59.0 to 74.8 Gy (median, 70.2 Gy). The median follow-up time for all patients was 3.0 years (range, 0.9-19.9), and for living patients was 7.7 years (range, 2.5-19.9). RESULTS: The actuarial 5-year survival outcomes were as follows: progression-free survival, 42%; cause-specific survival, 43%; and overall survival, 32%. Actuarial 5-year disease control rates were as follows: local control (infield or marginal), 74%; local-regional control (excluding leptomeningeal spread), 58%, regional control 78%, freedom from leptomeningeal recurrence, 72%, and distant metastasis-free survival, 73%. Five of the 8 (62.5%) patients treated with definitive RT died with disease, and 6 of the 15 patients (40%) treated with primary surgery and postoperative RT died with disease. Three patients (13%) experienced severe complications including unilateral eye removal, osteoradionecrosis of the maxilla requiring hyperbaric oxygen and surgery, and brain necrosis. One patient died due to an infected bone graft and brain abscess. CONCLUSIONS: A multimodal approach is best when treating SNUC patients. The prognosis for patients treated with definitive RT ± chemotherapy is less promising than for those who receive surgery and postoperative RT ± chemotherapy. Severe complications occur in about 17% of patients due to the high dose of RT alone or combined with surgery required for acceptable disease control.

Proton therapy for head and neck cancer: rationale, potential indications, practical considerations, and current clinical evidence.

There is a strong rationale for potential benefits from proton therapy (PT) for selected cancers of the head and neck because of the opportunity to improve the therapeutic ratio by improving radiation dose distributions and because of the significant differences in radiation dose distribution achievable with x-ray-based radiation therapy (RT) and PT. Comparisons of dose distributions between x-ray-based and PT plans in selected cases show specific benefits in dose distribution likely to translate into improved clinical outcomes. However, the use of PT in head and neck cancers requires special considerations in the simulation and treatment planning process, and currently available PT technology may not permit realization of the maximum potential benefits of PT. To date, few clinical data are available, but early clinical experiences in sinonasal tumors in particular suggest significant improvements in both disease control and radiation-related toxicity.

Thymidylate synthase genotype-directed neoadjuvant chemoradiation for patients with rectal adenocarcinoma.

PURPOSE: Downstaging (DS) of rectal cancers is achieved in approximately 45% of patients with neoadjuvant fluorouracil (FU) -based chemoradiotherapy (CRT). Polymorphisms in the thymidylate synthase gene (TYMS) had previously defined two risk groups associated with disparate tumor DS rates (60% v 22%). We conducted a prospective single-institution phase II study using TYMS genotyping to direct neoadjuvant CRT for patients with rectal cancer. PATIENTS AND METHODS: Patients with T3/T4, N0-2, M0-1 rectal adenocarcinoma were evaluated for germline TYMS genotyping. Patients with TYMS *2/*2, *2/*3, or *2/*4 (good risk) were treated with standard chemoradiotherapy using infusional FU at 225 mg/m²/d. Patients with TYMS *3/*3 or *3/*4 (poor risk) were treated with FU/RT plus weekly intravenous irinotecan at 50 mg/m². The primary end point was pathologic DS. Secondary end points included complete tumor response (ypT0), toxicity, recurrence rates, and overall survival. RESULTS: Overall, 135 patients were enrolled, of whom 27.4% (37 of 135) were considered poor risk. The prespecified statistical goals were achieved, with DS and ypT0 rates reaching 64.4% and 20% for good-risk and 64.5% and 42% for poor-risk patients, respectively. CONCLUSION: To our knowledge, this is the first study to prospectively use TYMS genotyping to direct neoadjuvant CRT in patients with rectal cancer. High rates of DS and ypT0 were achieved among both risk groups when personalized treatment was based on TYMS genotype. These results are encouraging, and further evaluation of this genotype-based strategy using a randomized study design for locally advanced rectal cancer is warranted.

Head and neck osteosarcoma.

OBJECTIVE: The objective of the study was to discuss the optimal management and treatment outcomes for patients with head and neck osteosarcomas. STUDY DESIGN: Review article. METHODS: Review of the pertinent literature. RESULTS: Osteosarcomas account for approximately 1% or less of all head and neck cancers. The vast majority occur in the mandible and maxilla. The median age is in the fourth decade, with a wide range. They are more likely to recur locally after treatment and distant metastases are observed less often than with the more common osteosarcomas arising in the long bones. The optimal treatment is complete resection. The role of adjuvant chemotherapy is ill-defined. The vast majority of recurrences are observed within 5 years. The 5-year disease-specific and overall survival rates are approximately 60% to 70%. CONCLUSIONS: Osteosarcoma of the head and neck is a rare entity that occurs primarily in the mandible and maxilla. The optimal treatment is surgery. Adjuvant radiotherapy should be considered for those with close or positive margins. The role of adjuvant chemotherapy is ill-defined. The likelihood of cure is approximately 60% to 70%.

Carcinoma of the nasal cavity and paranasal sinuses.

OBJECTIVES/HYPOTHESIS: To determine the outcomes after radiotherapy (RT) alone or combined with surgery at the University of Florida for patients with carcinomas of the nasal cavity and paranasal sinuses. METHODS: Between November 1964 and June 2005, 109 patients were treated with curative intent. Patients with maxillary sinus carcinomas were excluded. Fifty-six patients were treated with definitive RT, and 53 patients received surgery and preoperative (eight patients) or postoperative (45 patients) RT. Median follow-up was 4.3 years (range, 0.2-35.9 years). Median follow-up on living patients was 9.4 years (range, 2.0-35.9 years). RESULTS: The 5-year local control rates were: T1-T3, 82%; T4, 50%; and overall, 63%. Local control at 5 years was 43% after definitive RT versus 84% after surgery and adjuvant RT (P < .0001). Multivariate analysis of local control revealed that both overall stage and treatment group (definitive RT versus surgery and adjuvant RT) significantly impacted this endpoint. Cause-specific survival rates were: stages I to III, 81%; stage IV, 54%; and overall, 62%. Multivariate analysis revealed that T-stage, N-stage, and treatment group significantly influenced this endpoint. Thirty-one (20%) of 109 patients sustained severe complications; 17 of 56 patients (16%) after definitive RT and 14 of 53 patients (25%) after surgery and adjuvant RT. CONCLUSIONS: The probability of local control and cause-specific survival is better after surgery and RT compared with definitive RT. There is a modest increase in the risk of complications after surgery and RT. Thus, the preferred treatment is surgery combined with preoperative or postoperative RT.

Hypopituitarism after radiotherapy for extracranial head and neck cancers in pediatric patients.

OBJECTIVES: To investigate the incidence of postradiation therapy (postRT) hypopituitarism (hp-pit) in pediatric patients treated for extracranial head and neck tumors. METHODS: We retrospectively reviewed 30 pediatric patients treated with RT for extracranial head and neck tumors between 1970 and 2000. RT doses to the hypothalamic-pituitary axis were estimated by re-evaluating the treatment plans. RESULTS: Clinical hp-pit was observed in 16 (53.3%) patients; the median detection latency was 3.3 years and the median dose to the pituitary was 40.7 Gy. Univariate analysis of clinical hp-pit revealed that the total dose to the pituitary was significant (P = 0.034) as was the patient's age at the time of RT (P = 0.018) showing higher susceptibility and more damage in younger patients. Though fractionation (P = 0.018) and adjuvant chemotherapy (P = 0.016) were significant in univariate analysis, the total dose received by patients in these 2 groups was higher than the median dose for all patients. A limited multivariate analysis with 3 variables indicated that the total dose to the pituitary was significant, but chemoradiation and fractionation were not. The 5- and 10-year rates of freedom from clinical hp-pit were 42% and 37%, respectively. CONCLUSIONS: Clinical manifestations of late radiation toxicity to the hypothalamic-pituitary axis were observed among the pediatric patients with hormone deficiencies. The development of hp-pit depends on the total dose received by the hypothalamic-pituitary axis and the age of the patient. Dependence on chemoradiation and fractionation were inconclusive. Relatively long latency before clinical manifestations indicates that periodic testing after RT in pediatric patients is necessary for early detection and management of hormonal deficiencies.

Re-irradiation of head and neck carcinoma.

To determine the efficacy of re-irradiation of patients with head and neck carcinoma we reviewed the pertinent literature. Depending on the location and extent of the tumor, re-irradiation may be accomplished with external beam radiotherapy (RT), brachytherapy, intraoperative RT, and/or radiosurgery. The likelihood of cure is impacted by the interval between the initial course of RT and re-irradiation, whether the carcinoma is a recurrence or a second primary tumor, initial T-stage, and recurrent T-stage (rT-stage), whether the gross disease is isolated or local-regional, and histology. Patients with T1-T2 N0 second primary tumors have a relatively high likelihood of cure, whereas those with recurrent T3-T4 cancers, a short disease-free interval, and/or associated with a regional recurrence have a very low probability of cure. The likelihood of severe late complications is relatively high and is related to prior RT dose, primary site, retreatment RT dose, treatment volume, and technique. Previously irradiated patients with T1-T2 N0 carcinomas who are not surgical candidates may benefit from re-irradiation, albeit with an elevated risk of late complications. Those with advanced recurrences are unlikely to benefit from re-irradiation and should be considered for either a prospective clinical trial or for palliative chemotherapy or supportive care.

Tumor hypoxia detected by positron emission tomography with 60Cu-ATSM as a predictor of response and survival in patients undergoing Neoadjuvant chemoradiotherapy for rectal carcinoma: a pilot study.

PURPOSE: The response of rectal cancers to neoadjuvant chemoradiotherapy is variable. Tumor hypoxia reduces the effectiveness of both radiation therapy and chemotherapy and is a well-known risk factor for tumor radioresistence. We hypothesized that imaging with the novel hypoxia-detecting agent, (60)Cu-diacetyl-bis (N(4)-methylthiosemicarbazone) ((60)Cu-ATSM), previously validated in cervical and lung cancers, would predict the response of rectal cancers to neoadjuvant chemoradiotherapy and prognosis. METHODS: Patients with locally invasive (T2-4) primary or node-positive rectal cancer located <12 cm from the anal verge were recruited for this pilot study. Pretreatment tumor size and stage were determined by endorectal ultrasonography, CT, and magnetic resonance imaging. Eleven patients also underwent clinical positron emission tomography with (18)F-fluorodeoxyglucose at the discretion of the treating clinician. The primary tumor was imaged by positron emission tomography with (60)Cu-ATSM, and accumulation of the tracer was measured semiquantitatively by determining the tumor-to-muscle activity ratio. Neoadjuvant chemoradiotherapy was then administered (within 2 weeks of (60)Cu-ATSM-positron emission tomography) and consisted of 45 Gy given in 25 fractions to the pelvis with continuous intravenous infusion of 5-fluorouracil (225 mg/m(2)/day). Proctectomy was performed six to eight weeks after neoadjuvant chemoradiotherapy and the tumor submitted to pathology for size measurement and staging. Tumor-to-muscle activity ratios were compared with tumor (18)F-fluorodeoxyglucose uptake, tumor response to neoadjuvant chemoradiotherapy, and with patient survival. RESULTS: Nineteen patients were enrolled in the study, two of whom were excluded from final analysis (1 death during neoadjuvant chemoradiotherapy and 1 tumor perforation during neoadjuvant chemoradiotherapy requiring emergent surgery). Of the 17 remaining patients, 14 had a reduction in tumor size and 13 were downstaged. The median tumor-to-muscle activity ratio of 2.6 discriminated those with worse prognosis from those with better prognosis. Both overall and progression-free survivals were worse with hypoxic tumors (tumor-to-muscle activity ratio >2.6) than with nonhypoxic tumors (tumor-to-muscle activity ratio 2.6 (positive predictive value 66 percent), whereas 6 of 14 with decreased size had tumor-to-muscle activity ratios >2.6 (negative predictive value 57 percent). Three of the 4 tumors not downstaged had tumor-to-muscle activity ratios >2.6 (positive predictive value 75 percent), whereas 5 of 13 downstaged tumors had tumor-to-muscle activity ratios >2.6 (negative predictive value 62 percent). The mean tumor-to-muscle activity ratio for downstaged tumors (2.2) was significantly lower than that of nondownstaged tumors (3.3) (P = 0.03). The difference in mean tumor-to-muscle activity ratio between downsized (2.3) and nondownsized (2.9) tumors did not reach statistical significance (P = 0.36). Tumor (18)F-fluorodeoxyglucose uptake (n = 11) did not correlate with (60)Cu-ATSM uptake (r = 0.4; P = 0.9) and there was no significant difference in mean tumor (18)F-fluorodeoxyglucose uptake between patients with hypoxic tumors and those with normoxic tumors (P = 0.3). CONCLUSIONS: The results of this small pilot study suggest that (60)Cu-ATSM-PET may be predictive of survival and, possibly, tumor response to neoadjuvant chemoradiotherapy in patients with rectal cancer. A larger Phase II study is warranted to validate these results.

Adjuvant interferon-based chemoradiation followed by gemcitabine for resected pancreatic adenocarcinoma: a single-institution phase II study.

PURPOSE: This is a phase II, single-center, single-arm study of patients with resectable adenocarcinoma of the pancreas who were treated with adjuvant interferon-based chemoradiation followed by gemcitabine. The primary end point was 2-year overall survival, with secondary endpoints being 2-year disease-free survival, and the frequency of grade 3 or 4 toxicity. PATIENTS AND METHODS: From April 2002 to September 2005, 53 patients with adenocarcinoma of the pancreas underwent curative resection at a single institution, and subsequently received interferon- and gemcitabine-based adjuvant therapy consisting of external-beam irradiation at a dose of 5040 cGy (25 fractions per 5 weeks) and simultaneous 3-drug chemotherapy consisting of (1) continuous infusion 5-fluorouracil (175 mg/m2); (2) weekly intravenous bolus cisplatin (25 mg/m2); and (3) interferon-alpha (3 million units subcutaneously 3 times per week) during the 6 weeks of radiation. This was followed by two 4-week courses of weekly intravenous infusion of gemcitabine (1000 mg/m2, 3 of 4 weeks). RESULTS: Median follow-up is 38 months. Seventy-seven percent of patients had node-positive disease. Sixteen patients (30%) failed to complete adjuvant therapy, due to disease progression (7 patients), toxicity (7 patients), and consent withdrawal (2 patients). No patients completed planned therapy without dose modification. Median overall survival was 25 months (confidence interval [CI] = 21.5-48.5 months). Actuarial overall survival for the 1-, 2- and 3-year periods were 75% (CI = 61-85%), 56% (CI = 41-69%), and 41% (26-55%), respectively. CONCLUSIONS: This phase II trial demonstrated increased patient survival compared with historical controls, and equivalent survival compared with the regimen combining interferon-alpha with 5-fluorouracil-based chemoradiation. Despite these encouraging results, significant concerns regarding dose- and treatment-limiting toxicities remain.

Hypopituitarism after radiotherapy for extracranial head and neck cancers.

BACKGROUND: The purpose of this study was to investigate the incidence of radiotherapy-induced primary and secondary hypopituitarism. METHODS: Three hundred twelve patients treated with radiotherapy for extracranial head and neck tumors between 1964 and 2000 were evaluated. Radiotherapy doses to the hypothalamus and pituitary were estimated by reconstructing treatment plans. RESULTS: Clinical hypopituitarism was observed in 44 (14.1%) patients after a median interval of 5.6 years. Hypothalamic dysfunction was reported in 14 patients after a median interval of 4.4 years. Neither fractionation nor adjuvant chemotherapy significantly impacted clinical hypopituitarism on multivariate analysis, but total dose to the pituitary was significant (p = .0228). Twenty-three of 68 (33.8%) patients tested for hypopituitarism demonstrated subclinical hypopituitarism. The 5- and 10-year rates of freedom from clinical hypopituitarism were 93% and 72%. The 5- and 10-year rates of freedom from subclinical hypopituitarism were 85% and 65%. CONCLUSION: Clinical and subclinical manifestations of late radiation toxicity were observed in the hypothalamic-pituitary axis.

Salivary gland pleomorphic adenoma.

We discuss the optimal treatment and outcomes for pleomorphic adenoma of the salivary glands by reviewing the pertinent literature. Pleomorphic adenoma is the most common benign salivary gland neoplasm. It is found mostly in the parotid gland in middle-aged women. It progresses slowly and, left untreated, can produce significant morbidity and, rarely, death. The optimal treatment is superficial or total parotidectomy with facial nerve preservation, which results in local control rates of 95% or higher. Radiotherapy (RT) is useful to obtain local control in patients with positive margins, unresectable tumors, and multifocal recurrences after prior resection. Local control rates after RT for microscopic and gross residual tumor are approximately 80% to 85% and 40% to 60%, respectively. The main complication is surgically induced 7th nerve injury. Surgery is the mainstay of treatment and results in a very high cure rate. RT increases the likelihood of local control in the small subset of patients with incompletely resectable tumors and/or multifocal recurrences.

Ameloblastoma.

The purpose of this article is to review the pertinent literature and discuss the optimal treatment and outcomes for patients with ameloblastoma. Ameloblastoma is an uncommon benign, locally aggressive odontogenic neoplasm that usually occurs in the vicinity of the mandibular molars or ramus. Uncontrolled, ameloblastoma may cause significant morbidity and occasionally death. The median age is approximately 35 years and males and females are equally affected. The majority of ameloblastomas are multicystic, which are more difficult to eradicate than the unicystic and peripheral varieties. Although surgery is the mainstay of treatment, the extent of resection is controversial. Radical resections, including marginal and segmental mandibulectomy, result in local control rates exceeding 90%. In contrast, conservative procedures such as enucleation and/or curettage result in local control rates of approximately 80% and 50% for unicystic and multicystic ameloblastomas, respectively. Limited experience with radiotherapy indicates that it may reduce the risk of progression and result in long-term local control in the occasional patient with incompletely resectable disease. The optimal treatment for ameloblastoma is wide en bloc resection. Radiotherapy may improve the likelihood of local control in the occasional patient with incompletely resectable tumor.

Inverted papilloma of the nasal cavity and paranasal sinuses.

PURPOSE: To discuss the treatment and outcomes of inverted papilloma of the nasal cavity and paranasal sinuses. METHODS: Review of the pertinent literature. RESULTS: Inverted papilloma is a benign, locally aggressive neoplasm that arises in the nasal cavity and is associated with squamous cell carcinoma in approximately 5% of patients. Squamous cell carcinoma may be present with inverted papilloma at the initial diagnosis or it may occur metachronously after prior treatment. Surgery is the primary treatment of inverted papilloma. The likelihood of local recurrence varies from less than 5% to over 50%, depending on the extent of resection. There is likely no significant difference in the risk of local recurrence after open compared with endoscopic resection. The probability of local recurrence and/or death from tumor is increased if inverted papilloma is associated with squamous cell carcinoma. The likelihood of cure is approximately 50% when malignancy is present and postoperative radiotherapy should be considered for the majority of patients. A small subset of patients with inverted papilloma present with incompletely resectable disease. Definitive radiotherapy using doses between 65 and 70 Gy will locally control gross disease in the majority of patients. CONCLUSION: The preferred treatment of inverted papilloma is surgery; postoperative radiotherapy is added if it is associated with squamous cell carcinoma. The likelihood of local recurrence after surgery for inverted papilloma may be substantial and varies with the extent of resection. Definitive radiotherapy may be used to successfully treat patients with incompletely resectable inverted papilloma.

Multidisciplinary management of laryngeal carcinoma.

The management of head and neck cancer has evolved into a multidisciplinary approach in which patients are evaluated before treatment and decisions depend on prospective multi-institutional trials, as well as retrospective outcome studies. The choice of one or more modalities to use in a given case varies with the tumor site and extent, as exemplified in the treatment of laryngeal squamous cell carcinomas. The goals of treatment include cure, laryngeal voice preservation, voice quality, optimal swallowing, and minimal xerostomia. Treatment options include transoral laser excision, radiotherapy (both definitive and postoperative), open partial laryngectomy, total laryngectomy, and neck dissection. The likelihood of local control and preservation of laryngeal function is related to tumor volume. Patients who have a relatively high risk of local recurrence undergo follow-up computed tomography scans every 3-4 months for the first 2 years after radiotherapy. Patients with suspicious findings on computed tomography might benefit from fluorodeoxyglucose positron emission tomography to differentiate post-radiotherapy changes from tumor.

Primary and central hypothyroidism after radiotherapy for head-and-neck tumors.

PURPOSE: To investigate the incidence of radiotherapy (RT)-induced central and primary hypothyroidism regarding total dose, fractionation, and adjuvant chemotherapy. METHODS AND MATERIALS: We retrospectively reviewed the data from 312 patients treated with RT for extracranial head-and-neck tumors between 1964 and 2000. The cervical lymph nodes were irradiated in 197 patients. The radiation doses to the thyroid gland and hypothalamic-pituitary axis were estimated by reconstructing the treatment plans. RESULTS: Clinical central hypothyroidism (CH) was observed in 17 patients (5.4%); the median clinical latency was 4.8 years. Clinical primary hypothyroidism (PH) was observed in 40 patients (20.3%); the median clinical latency was 3.1 years. Multivariate analysis of clinical CH revealed that fractionation, adjuvant chemotherapy, and total dose to the pituitary were not significant. Multivariate analysis of clinical PH revealed that the total dose to the thyroid (p = 0.043) was significant, but adjuvant chemotherapy, age, and gender were not. Of the patients tested for hypopituitarism, 14 (20.3%) of 69 demonstrated subclinical CH and 17 (27.4%) of 62 demonstrated subclinical PH. The 5-year and 10-year rates of freedom from clinical CH and PH were 97% and 87% and 68% and 67%, respectively. Of the patients tested, the 5-year and 10-year rates of freedom from subclinical CH and PH were 91% and 78% and 71% and 71%, respectively. CONCLUSION: Clinical and subclinical manifestations of late radiation toxicity were observed in the thyroid and hypothalamic-pituitary axis. Although CH did not indicate a dependence on fractionation, adjuvant chemotherapy, or total dose to the pituitary, PH showed a dependence on the total dose to the thyroid gland.

Comparison of molecular markers of hypoxia and imaging with (60)Cu-ATSM in cancer of the uterine cervix.

PURPOSE: To determine if hypoxia-related molecular markers are associated with (60)Cu labeled diacetyl-bis (N4 -methylthiosemicarbazone); ((60)Cu-ATSM) imaging of tumor hypoxia in cervical cancer. PROCEDURES: Fifteen patients were enrolled in a prospective study and underwent evaluation of tumor hypoxia with positron emission tomography (PET) using (60)Cu-ATSM. (60)Cu-ATSM-PET imaging was compared with the expression of tissue molecular markers, which included vascular endothelial growth factor (VEGF), cyclo-oxygenase-2 (COX-2), epidermal growth factor receptor (EGFR), carbonic anyhdrase IX (CA-9), and apoptotic index. RESULTS: Six patients had hypoxic tumors determined by (60)Cu-ATSM, and nine had non-hypoxic tumors. The 4-year overall survival estimates were 75% for patients with non-hypoxic tumors and 33% for those with hypoxic tumors (p = 0.04). Overexpression of VEGF (p = 0.13), EGFR (p = 0.05), CA-9 (p = 0.02), COX-2 (p = 0.08), and the presence of apoptosis (p = 0.005) occurred in patients with hypoxic tumors. Cox proportional hazards modeling demonstrated hypoxia as determined by (60)Cu-ATSM to be a significant independent predictor of tumor recurrence (p = 0.0287). CONCLUSIONS: (60)Cu-ATSM hypoxia was correlated with overexpression of VEGF, EGFR, COX-2, CA-9, an increase in apoptosis, and a poor outcome.