anaplastic thyroid carcinoma ( atc ) is a rare but deadly tumor with a median survival of 5 - 6 months and less than 20% survival at one year [ 1 , 2 ] . atc occurs with a slight female predominance ( 1.5  :  1 ratio ) with a peak incidence in the sixth and seventh decades of life . the majority of patients ( > 75% ) develop distant metastasis either at the time of diagnosis or shortly thereafter , with the lungs being the most commonly affected organ . despite its low incidence , atc accounts for up to 39% of thyroid cancer deaths   with disease - specific mortality approaching 100% . commonly , individuals present with a rapidly enlarging neck mass causing symptoms of dysphagia , odynophagia , dyspnea , anxiety , and vocal cord paralysis . unless aggressive treatments are applied , such as surgical resection and external beam radiation therapy ( ebrt ) , patients die from uncontrolled local progression causing suffocation and massive bleeding [ 6 , 7 ] . furthermore , rapid airway obstruction remains a major cause of death even in patients undergoing tracheostomy [ 8 , 9 ] . therefore , treatment approaches should emphasize the importance of local control even in the metastatic setting . given the morbidity and poor prognosis of atc , palliative and supportive care remain an essential part in the management of these patients [ 5 , 10 ] . owing to disappointing results with current treatments strategies , there have been many attempts to improve clinical outcomes . the most promising one , in terms of local control , has been with trimodality therapy combining surgery with chemotherapy and radiation . various altered fractionation schedules have been proposed such as twice daily treatments or protracted once daily courses , but these schedules do not consider the challenges posed upon patients with limited survival . two of the main concerns with twice daily treatments are the burden of transportation and association with significant acute toxicities . furthermore , even with the use of standard fraction sizes and traditional 30-day treatment courses , treatment related side effects tend to be serious , requiring hospitalizations , parenteral nutrition , and delays in supportive care . to date , an optimal radiation approach to atc ( one that considers both outcomes and quality of life ) has not been defined . because of the significant toxicities and logistical challenges related to prolonged or twice daily treatment schedules , our institution has shifted to treat atc with maximum surgical debulking followed by short course high dose ( hypofractionated ) radiotherapy with or without chemotherapy . from our experience , shorter treatment courses minimize the challenges associated with transportation and on - treatment toxicity . in addition , shorter courses may lessen the burden of care in this population , especially when the concern for long - term radiation effects is less critical . most importantly , the quality of life in patients with limited survival should be of highest priority . here following institutional review board approval , patients with pathologically proven atc referred to the department of radiation oncology between 2004 and 2012 were retrospectively reviewed for outcomes and treatment toxicity . all patients received 2.5  gy dose per fraction ( median dose 3  gy ( range 2.54  gy ) ) . patients with metastases at the time of diagnosis were included because local control of the primary site was a major issue in this population . they were placed in a long thermoplastic mask for immobilization with their neck in maximum extension . the treatment volumes were constructed using presurgical cranial / caudal margins and the postsurgical axial margins including the entire thyroid bed . typical fields for the primary tumor extended from just below the hyoid bone to the level vi cervical and upper mediastinal lymph nodes ( figure 1 ) . only the involved and at risk nodal levels were treated . megavoltage external beam radiation was delivered using intensity modulated radiation therapy ( imrt ) and eclipse planning software . avoidance structures such as the trachea , esophagus , and spinal cord were contoured and well - defined dose constraints were applied . patients were assessed during treatment and subsequently every 24 weeks after treatment for both response and toxicity . local control and treatment response clinically , local control was defined as the absence of physical progression of disease or radiological progression . physical progression was defined as disease progression requiring any intervention after radiation to protect the airway such as tracheostomy , surgical debulking , or death from upper airway compression . radiographically , local control was defined as no increase in size greater than 25% posttreatment . at the time of this analysis , two patients had died during radiotherapy with not enough time to assess treatment response . both of these patients had unresectable disease and received two fractions of radiation before death . toxicity was measured according to the national cancer institute common toxicity criteria for adverse events version 4.0 . after completion of treatment , patients were followed up approximately every 4 weeks at vanderbilt university medical center . continuous features were described using means , medians , and ranges whereas categorical features were summarized with frequency counts and percentages . seventeen patients were diagnosed with anaplastic thyroid carcinoma and completed treatment with hypofractionated radiotherapy between 2004 and 2012 . nine patients were female and 8 were male ( m  :  f ratio , 1  :  1.1 ) . the majority of patients ( 88% ) received concurrent chemotherapy , which consisted of weekly paclitaxel ( 135  mg / m ) or weekly carboplatin ( auc 1 - 2 ) and paclitaxel ( 135  mg / m ) . fourteen patients underwent surgical resection prior to radiation ( 82.3% ) : ten patients underwent a total thyroidectomy and 4 patients underwent a partial thyroidectomy . three patients were deemed inoperable at the time of diagnosis : 1 patient due to medical comorbidities and 2 patients due to unresectable disease . the most frequently used fraction size was 3.0  gy , and the most frequently prescribed dose was 54  gy in 18 daily fractions ( 35.3% ) with a range of 4062.5  gy ( table 3 ) . for those with metastatic disease at diagnosis , the median survival was 6.4 months ; for those without initial metastases , median survival was 14.2 months . seven of the 17 patients ( 41% ) were alive one year after initial diagnosis . two of the 8 patients with metastatic disease at diagnosis were alive after one year , while 5 of the 9 patients ( 56% ) without initial metastases were alive after one year . the median time from diagnosis to metastasis was 2.1 months , and 88% of irradiated patients developed metastatic disease . these patients were assumed dead with survival calculated from the last date of follow - up . fourteen of the 17 patients ( 82% ) maintained local control of disease at the time of death . two patients required palliative tracheostomies and one patient required surgical debulking after irradiation . in the patients who experienced local progression , 2 had unresectable disease at diagnosis and 1 received a partial thyroidectomy . radiation induced esophagitis was the reason for gastrostomy tube placement in 2 of 4 patients . treatment related toxicities were graded using the national cancer institute common toxicity criteria for adverse events version 4.0 . specifically , dysphagia , esophagitis , and radiation dermatitis were analyzed as documented in the medical record . there were no grade 4 toxicities . however , 7 out of 17 patients ( 41% ) experienced at least one grade 3 toxicity . moreover , patients with grade 3 toxicity in one category were more likely to have grade 3 toxicity in another category ( hr = 1.33 ) . frequently , this was the result of symptomatic overlap between esophagitis and dysphagia . patients who were deemed unresectable at diagnosis or underwent a partial resection prior to radiation were more likely to develop grade 3 dysphagia during treatment . this appeared to be related to local tumor progression resulting in mechanical obstruction as opposed to radiation induced esophagitis . patients who underwent a complete resection prior to the start of radiation experienced the fewest toxicities and treatment delays . a treatment delay was defined as an interruption between two radiation fractions greater than 5 days or a total treatment time 10 days greater than expected . reasons for a treatment delay were local progression requiring tracheostomy or poor nutritional intake requiring gastrostomy tube placement . given the poor prognosis and rapid progression of this disease , early integration of palliative and supportive care is essential when managing these patients . knowing when and what type of radiation treatment to deliver can be a clinical challenge and requires a comprehensive understanding of the disease 's natural history , sequelae of symptoms , treatment effectiveness , and goals of care . unfortunately , patients with atc are confronted with an aggressive disease that affects critical respiratory organs and local control remains a primary determinant of quality of life even in the metastatic setting . results from the present study appear similar to prior studies with regard to local control and survival ( table 5 ) . similar to other reports , our data underline the importance of surgical debulking in the management of atc . reported that patients who underwent a total or partial thyroidectomy had prolonged survival times compared with patients for whom only a biopsy was feasible . surgical debulking can prevent distressing symptoms such as airway compression and it is recommended even in the presence of metastasis [ 16 , 17 ] . furthermore , reducing the burden of local disease may improve the efficacy of adjuvant therapy . the combination of surgery and radiotherapy is an independent predictor of reduced cause - specific mortality in patients with atc , though the ideal adjuvant radiation regimen remains unclear . the low incidence and poor survival rates of patients with atc limit the ability to conduct large phase iii trials . wang et al . reported on 47 patients with atc who received radiotherapy as either once or twice daily fractionation escalating up to 66  gy . median survival was 5.6 months , but patients receiving higher doses of radiation ( 4566  gy ) had significantly longer survival times compared to those receiving doses less than 40  gy ( 11.1 versus 3.2 months ; p < 0.001 ) . in our series , delivering larger doses in a shorter period of time maintained the concept of dose escalation , yielding an average biologically equivalent dose of 70.2  gy . several common treatment schedules are used in radiation oncology including once daily treatments for ~2535 days , twice daily treatments for ~1525 days , and hypofractionated treatments for ~120 days . typically , radiation oncologists attempt to achieve the same total effective dose ; therefore , if the number of treatments decreases , the total dose per treatment must increase or the dose is delivered twice daily . one of the major challenges with twice daily treatments is the 6-hour break between fractions . the patient spends most of the day in the clinic or arranging transportation to and from it . the second challenge is increased acute toxicity , which is an important consideration when treating the head and neck region . toxicity is divided into acute and late - responding effects depending on whether the tissue is more likely to manifest radiation damage around the time of treatment or in the future . larger radiation doses per day correspond to greater risk of damage in late - responding tissues ( such as the spinal cord ) as compared to smaller doses given over a protracted course . however , in patients with limited survival , shorter treatment courses are practical because the patient will not live long enough to face the increased risk of long - term side effects , which classically occur many months to years later . in the pursuit of better outcomes , several studies have examined the use of twice daily accelerated radiotherapy . de crevoisier demonstrated treatment effectiveness , but 33% of their patients experienced grade iii or iv acute mucositis with a significant amount of chemotherapy induced hematologic toxicity . dandekar et al . reported that greater than 70% of their patients experienced grade iii or iv acute dysphagia and esophagitis and many of these patients discontinued treatment , with less than 10% survival at one year . in our series , toxicity with hypofractionated radiotherapy continued to be an issue with 41% of patients experiencing grade 3 toxicities , but no grade 4 toxicities . the important difference between this regimen and others was that acute toxicities were seen near the end of treatment or after the patient had finished their radiation , thereby limiting the number of treatment related breaks and total treatment time . this allowed patients to continue forward with adjuvant systemic therapy or palliative and supportive care as needed . from the perspective of patient comfort , shorter treatment courses are preferable to longer courses , especially in the setting of limited survival . local recurrence in this disease can have devastating consequences and patients have a median survival of 66 days after local progression ( mciver et al . this study also demonstrated that radiation after complete or near complete resection did not improve local control but did delay the time to local progression ( 5 versus 3 months ) . these studies used twice daily treatment schedules of varying doses and chemotherapy regimens [ 11 , 21 ] . in our study , death attributed to local failure was seen in 18% of patients , though the patients who developed local failure were inoperable at the time of diagnosis or only received a partial resection or biopsy . similarly , foote et al . achieved local control in 30% of patients with variable radiation schedules and dual chemotherapy ; however , patients with metastatic disease at diagnosis were excluded from their study . these patients account for a significant portion of patients with atc and were included in our series . results from the present study suggest that a hypofractionated regimen is as effective as hyperfractionated regimens and while treatment courses were slightly longer , patients were only treated once per day . there were multiple limitations in this study including the single institutional retrospective nature , small patient numbers , and variable radiation doses . therefore , selection bias may have influenced the overall survival . despite these issues , this treatment approach is unreported in the literature . results from the present study suggest that a hypofractionated regimen with concurrent chemotherapy is well tolerated with a favorable toxicity profile and rates of local control when compared with previously used fractionation schemes . while there was no formal assessment of quality of life , given the favorable toxicity as well as the convenience of a shorter , once a day treatment regimen , we believe that this regimen may improve the quality of life in these patients with a generally poor outcome . based on our results , short course hypofractionated radiation therapy appears to be a viable and safe option in the treatment of atc and remains a sensible approach given the poor prognosis and symptomatic needs of this patient population . specifically , this protocol may be useful in patients who have difficulty with a twice daily regimen due to either travel or concerns about their ability to tolerate the acute effects of a twice daily regimen .
purpose . anaplastic thyroid carcinoma ( atc ) is a rare but aggressive tumor with limited survival . to date , the ideal radiation treatment schedule , one that balances limited survival with treatment efficacy , remains undefined . in this retrospective series 
 we investigate the effectiveness and tolerability of hypofractionated radiation therapy in the treatment of atc . 
 methods . 
 17 patients with biopsy proven atc treated between 2004 and 2012 were reviewed for outcomes and toxicity . 
 all patients received short course radiation . results . 
 the most commonly prescribed dose was 54  gy in 18 fractions . 
 median survival was 9.3 months . 
 47% of patients were metastatic at diagnosis and the majority of patients ( 88% ) went on to develop metastasis . 
 death from local progression was seen in 3 patients ( 18% ) , 41% experienced grade 3 toxicity , and there were no grade 4 toxicities . conclusions . 
 here we demonstrated the safety and feasibility of hypofractionated radiotherapy in the treatment of atc . 
 this approach offers shorter treatment courses ( 3 - 4 weeks ) compared to traditional fractionation schedules ( 6 - 7 weeks ) , comparable toxicity , local control , and the ability to transition to palliative care sooner . local control was dependent on the degree of surgical debulking , even in the metastatic setting .