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Cyberknife Treatment of Recurrent Squamous Cell Cancers of the Head & Neck

Cyberknife Treatment of Recurrent Squamous Cell Cancers of the Head & Neck

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Published by Jacob Repko
Stereotactic body radiotherapy seems to be feasible, well-tolerated, and a potential alternative to surgery or external beam radiation. Stereotactic body radiotherapy may be a more convenient and effective form of reirradiation given the relatively short time required for delivery of the scheduled treatment fractions.
Stereotactic body radiotherapy seems to be feasible, well-tolerated, and a potential alternative to surgery or external beam radiation. Stereotactic body radiotherapy may be a more convenient and effective form of reirradiation given the relatively short time required for delivery of the scheduled treatment fractions.

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Int. J. Radiation Oncology Biol. Phys., Vol. -, No. -, pp. 1–8, 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/09/$–see front matter

doi:10.1016/j.ijrobp.2008.12.075

CLINICAL INVESTIGATION

STEREOTACTIC BODY RADIOTHERAPY FOR RECURRENT SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK: RESULTS OF A PHASE I DOSE-ESCALATION TRIAL DWIGHT E. HERON, M.D., F.A.C.R.O.,* ROBERT L. FERRIS, M.D., PH.D.,y MICHALIS KARAMOUZIS, M.D.,z REGIANE S. ANDRADE, M.D.,* ERIN L. DEEB, B.S.,x STEVEN BURTON, M.D.,* WILLIAM E. GOODING, M.S.,jj BARTON F. BRANSTETTER, M.D.,yx{ JAMES M. MOUNTZ, M.D., PH.D.,x JONAS T. JOHNSON, M.D.,y ATHANASSIOS ARGIRIS, M.D.,z JENNIFER R. GRANDIS, M.D.,y y AND STEPHEN Y. LAI, M.D., PH.D.
Departments of *Radiation Oncology, y Otolaryngology, x Radiology, jj Biostatistics, and { Biomedical Informatics, and z Division of Medical Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA Purpose: To evaluate the safety and efficacy of stereotactic body radiotherapy (SBRT) in previously irradiated patients with squamous cell carcinoma of the head and neck (SCCHN). Patients and Methods: In this Phase I dose-escalation clinical trial, 25 patients were treated in five dose tiers up to 44 Gy, administered in 5 fractions over a 2-week course. Response was assessed according to the Response Evaluation Criteria in Solid Tumors and [18F]-fluorodeoxyglucose standardized uptake value change on positron emission tomography–computed tomography (PET-CT). Results: No Grade 3/4 or dose-limiting toxicities occurred. Four patients had Grade 1/2 acute toxicities. Four objective responses were observed, for a response rate of 17% (95% confidence interval 2%–33%). The maximum duration of response was 4 months. Twelve patients had stable disease. Median time to disease progression was 4 months, and median overall survival was 6 months. Self-reported quality of life was not significantly affected by treatment. Fluorodeoxyglucose PET was a more sensitive early-measure response to treatment than CT volume changes. Conclusion: Reirradiation up to 44 Gy using SBRT is well tolerated in the acute setting and warrants further evaluation in combination with conventional and targeted therapies. Ó 2009 Elsevier Inc. Head-and-neck squamous cell carcinoma, Head-and-neck cancer, Stereotactic body radiotherapy, Reirradiation, PET-CT.

INTRODUCTION Squamous cell carcinoma of the head and neck (SSCHN) is the sixth most common malignancy worldwide, with approximately 500,000 cases annually. In the United States, 45,660 new cases and 11,210 deaths were expected in 2007 (1). The 5-year survival rate of 40% for patients with SCCHN in the United States and other developed countries is comparable to the 5-year survival rate in the 1970s, despite advances in detection, surgery, radiation, and chemotherapy (2, 3). Recurrent disease remains a significant problem: nearly 50– 60% of these patients will die because of recurrent locoregional disease (4–6). Cure rates after recurrence remain dismal at 16% with single-modality therapy (6).
Reprint requests to: Dwight E. Heron, M.D., F.A.C.R.O., University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, 5150 Centre Avenue, #545, Pittsburgh, PA 15232. Tel: (412) 623-6723; Fax: (412) 647-1161; E-mail: herond2@upmc.edu A preliminary analysis of a portion of this study was presented in poster form at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1–5, 2007, Chicago, IL.
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Chemotherapy has been commonly used for palliation in recurrent disease, with response rates of approximately 30% and a median survival of 5 to 6 months (7, 8). Reirradiation of head-and-neck cancers has posed a significant challenge in the past, given concerns of limited tissue tolerance (8, 9). Nevertheless, in the setting of recurrent SCCHN, locoregional disease predominates, and thus the opportunity for focused treatment may offer an opportunity for cure in a subset of patients. Reirradiation has been shown to produce local control rates of up to 50%, with 5-year survival of approximately 20% in highly selected cases (6, 9–13). Unfortunately, anticipated tissue complications have been reported as high as 40% with some reirradiation schedules
S. Y. Lai’s current address is: Department of Head and Neck Surgery, University of Texas M. D. Anderson Cancer Center, Houston, TX. Conflict of interest: none. Received May 19, 2008, and in revised form Dec 9, 2008. Accepted for publication Dec 24, 2008.

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(10, 11). These studies have demonstrated the relationship of dose and volume of reirradiated tissue as the major predictor for treatment-related complications. There is some evidence that the soft tissues of the head and neck may tolerate reirradiation doses as high as 90% of the original dose if delivered between 6 weeks and 12 months after initial treatment (14– 16). Furthermore, reirradiation with either brachytherapy or external beam yields comparable long-term survival rates of 15–25% (9–11). Stereotactic body radiotherapy (SBRT) is a relatively new technique that can be applied to deliver high doses of radiation to tumors anywhere in the body with greater precision when compared with other, more conventional techniques. This can be accomplished by the CyberKnife Precision Radiation Delivery System (Accuray, Sunnyvale, CA), which offers an attractive alternative for the treatment of patients who have inoperable or surgically complex tumors or those who have had prior radiotherapy. The device is an image-guided stereotactic radiosurgery delivery system that does not require the application of an invasive head frame for cranial radiosurgery. Other technical specifications of this system have been previously reported (17). The integrated imaging and delivery system has been used to treat extracranial disease, such as primary and metastatic lung and spine tumors and prostate cancers, as well as head-and-neck cancers (18, 19). Stereotactic body radiotherapy also offers the ability to deliver fractionated radiosurgical treatment plans for larger lesions, minimizing the radiation of adjacent healthy tissues to potentially decrease the rate of complications. We previously reported our initial experience using this system, which resulted in local control rates (20) comparable to those with conventional techniques. On the basis of these promising retrospective findings in a cohort of patients in whom conventional external beam or intensity-modulated radiotherapy (IMRT) would have been challenging, we designed a Phase I dose-escalation trial to evaluate the safety, efficacy, and impact on quality of life of SBRT in patients with recurrent, inoperable SCCHN. PATIENTS AND METHODS
Between March 2005 and March 2007, we accrued 31 patients who had previously undergone radiation treatment for SCCHN and who re-presented with radiologically measurable, recurrent disease that was deemed to be unresectable and who had Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. In general, SBRT was selected as the choice for reirradiation when the treating radiation oncologist deemed full-dose re-treatment (i.e., >60 Gy) with either three-dimensional or IMRT as challenging because of proximity to the spinal cord or other critical structures. In some instances consideration of patient tolerance of a protracted course of treatment was important, because SBRT treatment delivered over the course of 10 days was more readily accepted by patients than a re-treatment course of 6 to 7 weeks. Patients who received at least 1 fraction of treatment were considered eligible for toxicity assessment. This Phase I clinical trial (University of Pittsburgh Cancer Institute no. 04-144) was approved by the University of Pittsburgh Institutional Review Board, and informed consent was obtained from each patient.

All patients were evaluated with physical examination and crosssectional CT imaging. The majority of patients had a combined [18F]-fluorodeoxyglucose (FDG) positron emission tomography– computed tomography (PET-CT) scan no more than 4 weeks before enrollment. The Revised University of Washington Quality of Life Questionnaire (21) was administered to each patient before treatment and 1 month after treatment. This is a self-reported appraisal of quality of life in which 12 domain-specific items are scored by the patient from 0 (worst) to 100 (best). These 12 domains are averaged to yield a composite score for each patient. Patients were treated with the CyberKnife Robotic Radiosurgical System (Accuray). An individualized treatment plan was developed for each patient according to the clinical and radiographic findings. The gross target volume was defined by the radiographic and clinical areas of known gross disease, augmented by PET-CT when available. Critical structures were also contoured for exclusion from treatment. All patients were treated to the 80% isodose line, which was intended to cover >90% of the target volume. Radiation dose was administered in 5 fractions over a 2-week period. No chemotherapy was given concurrently with SBRT. The dose to all critical structures other than the spinal cord was not routinely available in most patients because many of them were initially treated at outside institutions. In general, critical structure constraints were as follows: spinal cord maximum dose: #8 Gy; larynx: # 20 Gy; mandible: #20 Gy; parotid: variable; brainstem: #8 Gy; oral cavity: variable. Dose escalation was dictated by a nonparametric adaptive plan that estimates a dose-limiting toxicity (DLT) rate of 20% for the maximally tolerated dose. Up to 10 patients were to be treated at the highest dose (44 Gy) per protocol. Acute toxicity was defined as occurring during the course of treatment and extending until 3 months after treatment. Chronic toxicity was defined as those events occurring thereafter. To assess the acute toxicity of each dose tier, a 4 -week observation period was necessary before escalation to the subsequent tier was allowed. Response assessment was conducted by the head-and-neck radiologist (B.F.B.) and a head-and-neck surgeon (J.R.G.). Response Evaluation Criteria in Solid Tumors (RECIST) were used for the assessment of response at approximately 30 days for patients with CT only (n = 4) and 45–60 days for those with PET-CT. Tumor size was based on CT measurements. Response to PET was based on standardized uptake values (SUV). The maximum SUV value (SUVmax) in the tumor region defined by the tumor target volume region of interest (ROI) was measured both before and after therapy by a radiation oncologist (R.S.A.) and nuclear medicine radiologists (E.D. and J.M.M.). In addition, owing to relatively high background SUV values in normal headand-neck regions, a background correction SUV (SUVbkg) in an adjacent but uninvolved neck region ROI was obtained. Fluorodeoxyglucose uptake attributable to tumor (SUVtum) was corrected for background by subtracting SUVbkg from SUVmax. Response was assessed by comparison between pre- and posttreatment PET scans according to the criteria proposed by the European Organization for Research and Treatment of Cancer (EORTC) PET group (22). Using this method, we obtained background corrected ratios of SUVmax in the tumor region before (SUVpre) and after (SUVpost) therapy to obtain the percentage SUV change in the tumor as the ratio defined as SUVpost/SUVpre. For PET studies, we categorized the treatment response as progressive metabolic disease (PMD), stable metabolic disease (SMD), partial metabolic response (PMR), and complete metabolic response by grouping the patient’s percentage SUV change as established by the 1999 EORTC recommendations (22). Progressive metabolic disease is defined as an SUV increase of $25% or new

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Table 1. Patient characteristics Age (y), median (range) Gender Male Female Primary site Nasopharynx Oropharynx Larynx Oral cavity Unknown Tumor volume (cm3), median (range) Prior surgery No Yes Prior chemotherapy No Yes Values are number (n) unless otherwise noted. FDG-avid areas; SMD is defined as an SUV increase of <25% or decrease of <15%; PMR is defined when the SUV is decreased by $15%, and complete metabolic response is defined when SUVtum is equivalent to background or there is complete resolution of FDG avidity. Overall survival was measured from date of on-study registration until death. Progression-free survival was measured from date of onstudy registration until documented progression or death. Survival functions were estimated with the Kaplan-Meier method. Clinical response was tested for association with dose and treatment volume by logistic regression. Quality-of-life composite scores were tested for treatment-associated changes with the signed rank test and for association with performance status with the Jonkheere-Terpstra test. For statistical purposes, the sample size was chosen to estimate the dose tier that can be classified as the maximally tolerated dose (MTD) or to choose a starting dose for an efficacy study in the absence of any DLT. Three patients were observed for at least 4 weeks (1 cycle) before further dose escalation. The following enrollment plan and decision rule was used: enroll 3 patients at each dose tier until 1 or more patients experienced a DLT. If 1 patient of 3 experienced a DLT, add 3 patients at the same dose. If 2 or more of 3 experienced a DLT, then stop the trial and declare the next-lower dose as the MTD. If 1 patient in 6 experienced a DLT, continue to escalate the dose by accruing 3 patients at the next-higher dose tier. If 2 or more of 6 patients experienced a DLT, stop the trial and declare the next-lower tier as the MTD. 63 (35–86) 24 1 1 6 10 7 1 44.8 (4.2–217) 9 16 11 14

RESULTS Patient characteristics Patient characteristics are outlined in Table 1. Of the 31 (30 male, 1 female) enrolled patients, 25 (81%) completed their prescribed treatment in 5 equal fractions over a 2-week period and were evaluable for response or toxicity. Two patients died before disease response assessment (one myocardial infarction and one decline in performance status). Six patients were not evaluable for response for the following reasons: inability to lay supine for duration of treatment (n = 2), patient refusal (n = 2), and unrelated comorbidity (n = 2). All results reported herein apply to the 25 evaluable patients. The median age was 63 years (range, 35–86 years); ECOG performance score was 0 in 6 patients, 1 in 15 patients, and 2 in 4 patients. Primary tumors involved the oropharynx (n = 6), oral cavity (n = 7), larynx (n = 10), nasopharynx (n = 1), and unknown primary site (n = 1). All patients had received prior radiotherapy (median dose, 64.7 Gy); 16 patients had surgery as a component of their initial therapy. Fifty-six percent of patients (n = 14) received chemotherapy during their primary treatment. The median volume treated with SBRT was 44.8 mm3 (range, 4.2–216.6 mm3). Recurrent disease involving the primary site was treated in 13 patients, with 12 requiring irradiation of the neck or base of skull. Median time to failure from completion of prior radiotherapy was 13 months (range, 5–94 months).

Dose escalation and toxicity assessment Patients treated by dose tier are reported in Table 2. Acute and chronic toxicity was assessable in the 25 patients completing their radiotherapy. There were 2 patients with Grade 1 mucositis, 1 patient with Grade 2 dysphagia, and 1 patient with Grade 1 hyperpigmentation. No Grade 3 or 4 toxicities or DLTs were observed. During the follow-up period, no patient experienced soft-tissue or bone necrosis. Because of the small number of toxicities, the association between dose and toxicity could not be assessed. Therefore, a maximum tolerated dose (MTD) could not be determined, and the highest dose administered was selected as suitable for a Phase II trial. The top-tier dose of 44 Gy was selected as a reasonable estimate of acceptable normal tissue tolerance with reirradiation.

Table 2. Patient enrollment and prior radiotherapy dose by dose tier Dose tier 1 2 3 4 5 Subjects (n) 3 3 3 6 10 Prior RT dose (mean Gy/no. of fx) 69.2/36 69.6/35 66/30 68.5/36 66.8/35 Prior spinal cord dose (mean Gy) 45.5 45.2 40.7 44.6 45.1 Dose/fx (Gy) 5 6.4 7.2 8.0 8.8 No. of fx 5 5 5 5 5 Total dose (Gy) 25 32 36 40 44 Mean volume of GTV receiving PD (%) 98.4 96.7 95 92 94

Abbreviations: RT = radiotherapy; fx = fraction; GTV = gross tumor volume; PD = prescription dose.

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Table 3. Patient responses by dose tier Dose (Gy) Response Complete response Partial response Stable disease Progressive disease Not evaluable 25 1 1* 0 0 1 32 0 0 3 0 0 36 1* 1* 0 0 1 40 0 1 3 2 0 44 0 2 6 2 0 Total 2 5 12 4 2

* Responses not confirmed.

Objective response Of the 25 patients completing their therapy, 2 died before radiographic staging, and the remaining 23 were assessed for clinical response (Table 3). Among the 23 patients who were evaluable for response, 1 had a complete response (CR) and 3 had partial response (PR) meeting RECIST definitions, for a response rate of 17.4% (95% confidence interval [CI] 2%–33%). Twelve patients had stable disease (SD), and 4 had progressive disease (PD). Two patients with objective responses (1 CR, 1 PR) died before a confirmatory scan could be obtained and therefore did not qualify as response by RECIST. Response rate was independent of dose (p = 0.209) and initial treated volume (p = 0.306) (Table 2). Median duration of response, including the unconfirmed responses, was 3 months with a maximum of 4 months.

the tumor size, PET demonstrated an increase in FDG uptake suggesting PMD, but these patients ultimately were confirmed as PD on subsequent follow-up. Another case considered PR by CT but SMD by PET with a mild FDG response (3%) ultimately was confirmed to have persistent disease with a modest FDG change (38%) on a later PET-CT study. Additionally, in 2 cases considered PD by CT, a decrease was observed in the FDG uptake. One patient had a 45% reduction in FDG avidity, and the subsequent PET-CT study showed a substantial increase, confirming progression (PMD). In the other case, a 64% decrease in the FDG was seen, but this patient developed a new primary lung cancer and died during treatment without confirmation of disease response in the neck. Quality of life The Revised University of Washington Quality of Life Questionnaire was administered to 24 patients before SBRT, of whom 16 completed the survey after treatment. Among those completing the questionnaire at both times, overall quality of life declined. The median decrease in the composite score was 10 (two-tailed signed rank test, p = 0.0831). Quality of life at baseline and quality-of-life change with treatment were unrelated to performance status (Kruskal-Wallis p = 0.604 and 0.648, respectively). Major selfreported issues affecting 30–50% of patients at baseline were speech, swallowing, pain, and saliva. These issues persisted after treatment. Patterns of failure Patterns of failure are important criteria in assessing the efficacy of treatment, given the highly conformal nature of SBRT and the concern about marginal misses. Treatment volumes were created without additional dosimetric margins (i.e., no planning target volume). Nonetheless, much like our retrospective experience (20), patients rarely failed exclusively at the boundary of the SBRT field. Rather, all failures were either entirely within the radiation portal, outside the field, or a combination of both. Although the prognosis is often poor in patients with recurrent disease, focused therapy can offer significant local control and palliation. On the basis of the tumor treated with SBRT, the observed treatment response (radiologic and metabolic: CR + PR + SD) was 76% (19 of 25). However, we were unable to establish a relationship between dose, tumor size, and probability of local control in this patient cohort. Survival Of the 23 patients with known disease status, 12 patients had documented progression, 9 patients died without documented disease progression, and 2 patients are alive without progression. The median time to progression was 4 months (95% CI 4–6 months; Fig. 2A). The probability of 6-month disease-free survival was 0.31 (95% CI 0.13–0.51). Twenty-three of 25 patients have died. The median overall survival was 6 months (95% CI 5–8 months). Two patients with SD remain alive at 14 and 18.5 months after treatment

Tumor size changes and metabolic response to SBRT Patient SBRT responses were classified by CT volume changes according to RECIST and by PET metabolic change according to the EORTC recommendations (Table 4). Twelve patients had SD by RECIST, but 7 of these patients showed improvement on PET (PMR), with 2 cases having had a complete (100%) or near-complete (>90%) resolution of FDG uptake. However, 2 patients with SD by RECIST showed PMD on PET. Five patients with PD by RECIST also showed PMD on PET. Figure 1A–D depicts an example of PET and PET-CT response to SBRT. In cases of PR, agreement between CT and PET were mixed. In 2 patients with PR showing a modest decrease in

Table 4. Tumor response to SBRT by RECIST and PET Response CR/CMR PR/PMR SD/SMD PD/PMD Total RECIST 2 5 9 5 23 PET 2 10 1 6 19

Abbreviations: SBRT = stereotactic body radiotherapy; RECIST = Response Evaluation Criteria in Solid Tumors; PET = positron emission tomography; CR = complete response; CMR = complete metabolic response; PR = partial response; PMR = partial metabolic response; SD = stable disease; SMD = stable metabolic disease; PD = progression of disease; PMD = partial metabolic disease.

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Fig. 1. Positron emission tomography–computed tomography (PET-CT) scans of recurrent squamous cell carcinoma of the head and neck: primary (A, C) and cervical (B, D) metastatic disease before (A, B) and after (C, D) stereotactic body radiotherapy.

and were treated on dose tier 5 (44 Gy). Figure 2B shows a Kaplan-Meier plot of overall survival with confidence bands. Figure 3 shows the SBRT plan for the patient depicted in Fig. 1. Note the steep dose gradient between the gross target volume and the adjacent spinal cord. DISCUSSION Despite major advances in the treatment of head-and-neck cancers, locoregional recurrences remain a significant problem in 50–60% of patients. Many of those patients dying from disease have local or regional disease as the sole site of failure (23–25). Although salvage surgery remains the mainstay of therapy for the majority of patients with recurrent disease, some are poor surgical candidates or have unresectable disease. For the vast majority of patients with recurrent head-and-neck cancer, surgical resection remains the single most important factor in effecting durable salvage. However,

in patients deemed to be unresectable or medically inoperable, other options must be explored. Chemotherapy may provide meaningful palliation, but few patients achieve durable control even with multiagent regimens. Although reirradiation has been advocated as a possible modality for salvaging patients with recurrent disease confined to the head and neck, it has been discouraged because of concerns over normal tissue complications, including soft-tissue necrosis, fibrosis, transverse myelopathy/myelitis, and radionecrosis of the mandible and cartilage of the head and neck. The introduction of highly conformal techniques such as three-dimensional conformal radiotherapy (3D-CRT) and IMRT has renewed interest in aggressive reirradiation programs. The primary tenets of these programs have been to limit the size of the radiation field, reduce the re-treatment doses, and adopt altered fractionation schemes to minimize toxicity. It is now generally accepted that cytotoxic doses in excess of 60 Gy are necessary to optimize salvage

Fig. 2. Progression-free and overall survival. (A) Kaplan-Meier curve depicts progression-free survival for 23 patients completing stereotactic body radiotherapy with known disease status. The dashed lines represent the 95% confidence intervals. (B) Kaplan-Meier curve depicts overall survival for 25 patients completing stereotactic body radiotherapy. The dashed lines represent 95% confidence intervals. Tick marks represent censoring times/events.

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Fig. 3. Representative stereotactic body radiotherapy plan for case shown in Fig. 1. Note sharp dose gradient between gross tumor volume (GTV) and spinal cord.

probability in patients with recurrent SCCHN (12). Reirradiation alone has been shown to result in up to 50% local control, although significant debilitating risks including fatal toxicity have been reported (26). Approaches that combine therapeutic modalities, such as reirradiation and concomitant chemotherapy, have shown a better chance for long-term cure, with median survival rates of 15–35% for 2 years, although at the expense of increased toxicities and a significant risk for toxic death (5–10%) (3, 13, 27, 28). More recently, approaches using 3D-CRT and IMRT with or without hyperfractionation have been reported (29–31). Response rates have been reported as high as 60–70% but were associated with significant Grade 3 and 4 toxicities ranging from 10% to 40%. However, in many patients, the close proximity of recurrent disease to critical structures, such as the mandible, spinal cord, and parotid glands, has often made reirradiation virtually impossible, particularly if the tissue tolerance has already been exceeded and the time to recurrence interval is short, usually <6 months (11, 32, 33). When compared with 3D-CRT, IMRT has been shown to produce improved local control rates. There is clearly room for additional dose escalation or tumor sensitization to further improve the local control rates. Our unpublished data with the concurrent use of cetuximab with SBRT suggests a 28% improvement in the risk of local disease progression when compared with SBRT alone. Furthermore, in the absence of prospective or retrospective data comparing salvage reirradiation using IMRT with or without image guidance vs. SBRT, there is only speculation regarding comparability of

outcomes. This clinical trial is the first attempt to establish benchmark data to allow future comparisons of these salvage modalities. In the present study, we found that in the short term SBRT was feasible and safe. The dose-escalation schema outlined in Table 2 was followed without a DLT. The overall response rate in this group of heavily pretreated patients was 28% (CR + PR). No Grade 3 or 4 toxicities were noted among our patients. Toxicity of reirradiation has been associated with volume of normal tissue irradiated, dose per fraction, and interval since the last course of treatment (34, 35). The lack of toxicity in our trial was likely related to the highly conformal treatments plans. The results of the Phase I clinical trial confirm our previous experience treating patients with recurrent SCCHN with SBRT (20) without compromise of target coverage. Although overall quality of life declined marginally in those patients who completed the quality-of-life survey, this finding may simply reflect short follow-up and the nature of their advanced disease and its progression. Similar findings in patients with advanced, recurrent HNSCC have been reported (36, 37). Positron emission tomography–computed tomography has been shown to be potentially more sensitive and specific than CT alone in the assessment of response in head-and-neck cancer patients treated with radiotherapy (38–40). In patients previously treated, metabolic response may precede anatomic response seen on CT. Furthermore, reliance on single-dimensional measurement in RECIST, rather than

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a volumetric approach, clearly has limitations in measuring response in previously treated patients, in whom scar tissue may obscure response evaluation. Our data show good agreement between PET and CT for the assessment of CR and PD. However, 7 of 12 cases of SD by CT scan showed marked partial metabolic response on PET. Additionally, 2 cases of PR by CT scan that initially showed an increase in FDG uptake were ultimately were confirmed as PD on subsequent follow-up. These data suggest that FDG-PET is a more sensitive surrogate early biomarker of beneficial response to treatment than CT imaging alone. Although a standard method to measure metabolic change in the assessment of therapeutic response remains to be established, the additional information provided by PET might provide more reliable indicators of treatment response (41).

CONCLUSIONS The present study represents the first prospective, Phase I clinical trial of SBRT reirradiation in head-and-neck cancer. Prior studies were retrospective or combined patients with different cancers (20, 42, 43). We did not reach an MTD, and we did not appreciate late toxicities in our patients; however, we had a relatively short follow-up period. Stereotactic body radiotherapy seems to be feasible, well-tolerated, and a potential alternative to surgery or external beam radiation. Stereotactic body radiotherapy may be a more convenient and effective form of reirradiation given the relatively short time required for delivery of the scheduled treatment fractions. On the basis of the results of this trial, we have initiated a Phase II clinical trial incorporating concurrent cetuximab with SBRT.

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