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International Journal of Radiation Oncology biology physics www.redjournal.org Physics Contribution 4p Noncoplanar Stereotactic Body Radiation Therapy for Head-and-Neck Cancer: Potential to Improve Tumor Control and Late Toxicity Jean-Claude M. Rwigema, MD,* Dan Nguyen, BS,* Dwight E. Heron, MD,y Allen M. Chen, MD,* Percy Lee, MD,* Pin-Chieh Wang, PhD,* John A. Vargo, MD,y Daniel A. Low, PhD,* M. Saiful Huq, PhD,y Stephen Tenn, PhD,* Michael L. Steinberg, MD,* Patrick Kupelian, MD,* and Ke Sheng, PhD* *Department of Radiation Oncology, University of California Los Angeles, Los Angeles, California; and yDepartment of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania Received May 27, 2014, and in revised form Aug 27, 2014. Accepted for publication Sep 30, 2014. Summary Stereotactic body radiation therapy is increasingly used in head-and-neck cancer, mainly for recurrent previously irradiated head-andneck cancer. Recent data on reirradiation using SBRT suggest the potential to reduce severe late toxicity, while maintaining similar local control relative to conventionally fractionated radiation therapy. We tested 4p radiation therapy in recurrent, primary unresectable, and metastatic headand-neck cancer. Our results Purpose: To evaluate the potential benefit of 4p radiation therapy in recurrent, locally advanced, or metastatic head-and-neck cancer treated with stereotactic body radiation therapy (SBRT). Methods and Materials: Twenty-seven patients with 29 tumors who were treated using SBRT were included. In recurrent disease (nZ26), SBRT was delivered with a median 44 Gy (range, 35-44 Gy) in 5 fractions. Three patients with sinonasal mucosal melanoma, metastatic breast cancer, and primary undifferentiated carcinoma received 35 Gy, 22.5 Gy, and 40 Gy in 5 fractions, respectively. Novel 4p treatment plans were created for each patient to meet the objective that 95% of the planning target volume was covered by 100% of the prescription dose. Doses to organs at risk (OARs) and 50% dose spillage volumes were compared against the delivered clinical SBRT plans. Local control (LC), late toxicity, tumor control probability (TCP), and normal tissue complication probability were determined. Results: Using 4p plans, mean/maximum doses to all OARs were reduced by 22% to 89%/10% to 86%. With 4p plans, the 50% dose spillage volume was decreased by 33%. Planning target volume prescription dose escalation by 10 Gy and 20 Gy were achieved while keeping doses to OARs significantly improved or unchanged from clinical plans, except for the carotid artery maximum dose at 20-Gy escalation. At a Reprint requests to: Ke Sheng, PhD, Department of Radiation Oncology, 200 Medical Plaza, B265, University of California, Los Angeles, Los Angeles, CA 90095. Tel: (310) 853-1533; E-mail: ksheng@ mednet.ucla.edu Presented at the 56th Annual Meeting of the American Society for Radiation Oncology, September 14-17, 2014, San Francisco, CA. Int J Radiation Oncol Biol Phys, Vol. -, No. -, pp. 1e9, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.09.043 Conflict of interest: none. Supplementary material for this article can be found at www.redjournal.org. AcknowledgmentsdThe study was supported in part by Varian Medical Systems. The authors thank Karen Holeva for her support with data management. 2 International Journal of Radiation Oncology Biology Physics Rwigema et al. show improved organ sparing and the potential to safely enhance tumor control with dose escalation. median follow-up of 10 months (range, 1-41 months), crude LC was 52%. The 2-year LC of 39.2% approximated the predicted mean TCP of 42.2%, which increased to 45.9% with 4p plans. For 10-Gy and 20-Gy dose escalation, 4p plans increased TCP from 80.1% and 88.1% to 85.5% and 91.4%, respectively. The 7.4% rate of grade 3 late toxicity was comparable to the predicted 5.6% mean normal tissue complication probability for OARs, which was significantly reduced by 4p planning at the prescribed and escalated doses. Conclusions: 4p plans may allow dose escalation with significant and consistent improvements in critical organ sparing, tumor control, and coverage. Ó 2014 Elsevier Inc. Introduction Despite improvements in the multimodality treatment of primary head-and-neck cancer, local recurrence after primary treatment remains significant and accounts for more than 50% of disease-related mortality (1). Stereotactic body radiation therapy (SBRT) has emerged as a salvage treatment strategy with many clinical applications in patients with head-and-neck cancer. In particular, for those with unresectable recurrent previously irradiated head-and-neck cancer, a number of studies, including a single-institution phase 1 and multi-institution phase 2 trials, have demonstrated the feasibility of SBRT, with efficacy similar to that of intensity modulated radiation therapy (IMRT) and 3-dimensional conformal radiation therapy (2-6). Others have investigated the use of SBRT in the primary setting of locally advanced unresectable primary or metastatic headand-neck cancers, or to overcome radioresistance among other cancers (7-9). The rates of severe late toxicities pose a major concern when contemplating head-and-neck cancer reirradiation, mainly owing to the poor tolerance of critical structures surrounding the previously irradiated treatment target. Current SBRT data, although not randomized, suggest the possibility of reducing severe late complications when compared with conventionally fractionated radiation therapy, owing to the highly precise delivery of radiation dose to the target volume with minimal dose to surrounding organsat-risk (OARs) (10). The most common SBRT regimen, consisting of 5 fractions delivered on alternating days (QOD), has been shown to be generally safer than treatment delivered on consecutive days (QD). Specifically, the rates of grade 3 late toxicities with QOD seem to be on average 10% (4, 5, 7) and seem to increase to approximately 20% with QD (11, 12). Studies have also evaluated radiosensitization with concurrent cetuximab, image guidance, optimal treatment target definition, and treatment duration, as well as quality of life after SBRT, to further demonstrate the feasibility and improved outcomes of SBRT (3, 13-17). Although the improved local tumor control and treatment safety of SBRT seem promising, the limited 2-year local control (LC) rates of 30 to 52% (4-7) and the potential for severe toxicities with SBRT make SBRT a challenging salvage option for patients who cannot afford a second local failure coupled with added toxicity. Therefore, in the present study, we sought to investigate whether 4p planning could improve the dosimetry and quality of SBRT plans delivered using a variety of standard techniques, to determine whether the risk of severe late complications can be further reduced without causing a decline in LC. The 4p system has already been shown to potentially provide improved dose conformality, reduced dose spillage to normal OARs, and lower integral dose when compared with volumetric modulated arc therapy (VMAT) in SBRT for central lung tumors, liver tumors, and prostate cancer (18-20). For central lung tumors, dose escalation was also safely achieved (19). In this work we tested whether dose escalation was feasible in previously irradiated or advanced head-and-neck cancer. Methods and Materials Twenty-seven patients (median age 66 [range, 42-87] years; 14 male) with 29 malignant tumors previously treated using SBRT at the University of California Los Angeles (nZ8) and at the University of Pittsburgh Cancer Institute (nZ19) from February 2007 to October 2013 were included in the study. Details of patient and previous treatment characteristics are shown in Table 1. For recurrent previously irradiated tumors (nZ26), SBRT was delivered with a median 44 Gy (range, 35-44 Gy) in 5 fractions QOD at a median interval of 20 months from the initial radiation therapy course of a median 70 Gy (range, 45-131.2 Gy) for primary disease. Four patients had previously received multiple courses of radiation therapy with cumulative doses >110 Gy and required SBRT for focal recurrences in the neck (nZ3) and maxillary sinus (nZ1) (Table 1). Seven patients (25.9%) had concurrent cetuximab with SBRT reirradiation at 400 mg/m2 on day 7 then 250 mg/m2 on day 0 and þ8. Three patients with sinonasal mucosal melanoma, metastatic breast cancer, and unresectable primary undifferentiated carcinoma had received 35 Gy, 22.5 Gy, and 40 Gy in 5 fractions QOD, respectively. Different radiosurgery systems were utilized to deliver SBRT, including CyberKnife (nZ6) (Accuray, Sunnyvale CA), Novalis Tx (nZ9) (Varian Medical Systems, Palo Alto, CA; and BrainLAB, Feldkirchen, Germany), Trilogy (nZ8), and TrueBeam STx (nZ6) (Varian Medical Systems). The clinical plans used static IMRT (nZ24), noncoplanar VMAT (nZ1), and coplanar VMAT 4p SBRT for head-and-neck cancer Volume - Number - 2014 Table 1 Patient and treatment characteristics Patient Age Prior RT no. (y) Gender Histology dose (Gy)* 1 2 3 4 5 6 7a 7b 8 9 10 11 12 13 14 15 16 17a 17b 18 19 20 21 22 23 24 25 26 27 3 59 77 86 71 67 71 78 78 83 75 62 54 80 61 85 72 50 61 61 42 54 75 79 70 65 46 60 70 70 M F M M M M M M F M M M F F F M M F F F M F M F F M M F F SCC SCC UC SCC SCC SCC AC SCC SNMM SCC SCC UC PCT SCC AC SCC SCC UC UC SCC AC SCC SCC MC MC ACC SCC SCC SCC 131 45 NA 45 Unknown 86.4 NA 129 NA 66.6 71.3 70 70.2 70 68.4 63 70 112 112 70 64 70 68.8 61.2 Unknown 66 70 70 64 Primary site SBRT dose (Gy)y Oropharynx Oral tongue Pterygoid Base of tongue Larynx Tongue Breast Oropharynx Nasal cavity Parotid Larynx Nasopharynx Thyroid Nasopharynx Parotid Larynx Base of tongue Sinonasal Sinonasal Nasopharynx Oropharynx Base of tongue Larynx Palate Parotid Parotid BOT/FOM Oropharynx Oral cavity 40 40 40 40 40 35 22.5 40 35 44 35 44 44 44 44 44 40 44 44 44 44 40 44 44 44 44 44 40 44 SBRT site TV (cm3) Machine Neck 18.9 Novalis-Tx Base of tongue 83.4 Novalis-Tx Pterygoid 32.3 Novalis-Tx Base of tongue 209.4 Novalis-Tx Larynx 5.9 Novalis-Tx Neck 202.8 Novalis-Tx Neck 41.6 Novalis-Tx Neck 6.2 Novalis-Tx Nasal cavity 78.5 Novalis-Tx Cervical spine 41.9 Cyberknife Neck 15.7 Cyberknife Base of skull 83.9 Cyberknife Retrostyloid 75 Cyberknife Base of skull 38 Cyberknife Parotid 22.4 Cyberknife Hypopharynx 50.6 TrilogyTM Oropharynx 12.7 TrilogyTM Maxillary sinus 2.8 TrilogyTM Neck 3.7 TrilogyTM Nasopharynx 89 TrilogyTM Oropharynx 25.8 TrilogyTM Base of tongue 13.6 TrilogyTM Larynx 63.3 TrilogyTM Maxillary sinus 9.7 TrueBeam-STX Parotid 74.4 TrueBeam-STX Submandibular 63.3 TrueBeam-STX Base of tongue 195 TrueBeam-STX Oropharynx 16.5 TrueBeam-STX Palate 40.5 TrueBeam-STX Technique C-VMAT S-IMRT S-IMRT C-VMAT S-IMRT S-IMRT C-VMAT C-VMAT NC-VMAT S-IMRT S-IMRT S-IMRT S-IMRT S-IMRT S-IMRT S-IMRT S-IMRT S-IMRT S-IMRT S-IMRT S-IMRT S-IMRT S-IMRT S-IMRT S-IMRT S-IMRT S-IMRT S-IMRT S-IMRT Abbreviations: AC Z adenocarcinoma; ACC Z acinic cell carcinoma; BOT/FOM Z base of tongue/floor of mouth; MC Z myeloepithelial carcinoma; C-VMAT Z coplanar volumetricemodulated arc therapy; NC-VMAT Z noncoplanar volumetricemodulated arc therapy; PCT Z papillary carcinoma of thyroid; SNMM Z sinonasal mucosal melanoma; SCC Z squamous cell carcinoma; S-IMRT Z static intensity modulated radiation therapy; TV Z tumor volume; UC Z undifferentiated carcinoma. a, b denote patients with 2 lesions. * Total prior prescription dose. y SBRT dose in 5 fractions. (nZ4). Figure 1a shows typical beam orientation patterns of 4p planning compared with static IMRT, coplanar VMAT, and noncoplanar VMAT. All clinical plans were initially generated and optimized using treatment planning systems corresponding to the different techniques used clinically. All clinical and 4p plans were then imported into CERR (Computational Environment for Radiotherapy Research, Washington University, St. Louis, MO) and dose distributions evaluated using identical settings. The novel 4p treatment planning process has been previously described (17-19). Briefly, the 4p method is a highly noncoplanar and nonisocentric planning system developed on C-arm gantry linear accelerators. For each patient a candidate pool was created consisting of 1162 beams evenly distributed throughout the 4p solid sphere angle space, with approximately 6 of separation between adjacent beams. A beam geometry solution space was initially created using the 3-dimensional surface images of a human subject and the treatment machine to determine the minimal distances between the x-ray source and the tumor for each beam angle. A collision buffer of 4 cm was added to the distances. If the resultant distance was >100 cm, extended source-to-tumor distances were used. Beams that still resulted in collision of the gantry and couch or patient due to reaching the couch movement limits were excluded. Of the remaining candidate beams, 30 intensity modulated beams were automatically selected to meet the objective of 95% of the planning target volume (PTV) covered by 100% of the prescription dose. The candidate beams were segmented into 5 5-mm2 beamlets. This was followed by the calculation of 2.5 2.5 2.5-mm3 resolution dose matrices using an inhouse convolution/superposition code with 6-MV polyenergetic kernels. A column generation algorithm (21) was used to iteratively select and optimize the beams until the desired number of 30 beams was reached. In addition to the plans adhering to their original prescription doses, dose escalation plans of 10 Gy and 20 Gy 4 Rwigema et al. International Journal of Radiation Oncology Biology Physics maintain a consistent correlation between R50 and normal tissue toxicity, V50 was defined according to the original prescription dose in the dose-escalated plans. Planning target volume coverage was determined and compared with the clinical plans by evaluating the dose that covered 95%, 98%, and 99% of the PTV, as well as the PTV minimum and maximum doses (ie lowest and highest point doses in the PTV corresponding to the volume of 1 voxel). Crude and actuarial LC and late toxicity rates, as well as tumor control probability (TCP) and normal tissue complication probability (NTCP) were determined. Local control was defined as any reduction in tumor volume and/or metabolic activity as assessed with follow-up positron emission tomography/CT and/or MRI as well as clinical examination. Kaplan-Meier analysis was used to determine actuarial LC rates. Toxicity was graded according to the Common Terminology Criteria for Adverse Events, version 3 (22). TCP was calculated as: TCPZexpð Dc V expðaBEDÞÞ ð2Þ where Dc is the clonogens density Z 107/cm3, V is the tumor GTV volume, and BED is the biological equivalent dose calculated assuming a/b Z 10 Gy for the tumor (22). The TCP was determined at tumor radiosensitivities (a) of 0.15/Gy, 0.25/Gy, and 0.35/Gy (23, 24). NTCP was calculated according to the Lyman model (23), defined as: 2 Zt 1 x NTCPZpffiffiffiffiffiffi exp dx ð3Þ 2 2p N where ½D TD50 ðvÞ ð4Þ ½m TD50 ðvÞ V vZ ð5Þ Vref TD v ZTD 1 )vn ð6Þ and TD50 is the dose that led to a 50% complication rate, n is the volume dependence parameter, m is the slope of the complication probability dose curve, Vref is the reference volume, V is the actual volume irradiated, and v is the fractional volume irradiated (25). Statistical comparisons for between groups were performed with a paired t test for data with a normal distribution, otherwise a nonparametric Wilcoxon rank test was used to compare means all with a statistical significance of PZ.05 (2-tailed). tZ Fig. 1. (a) Typical entrance patterns of 4p beams versus volumetric modulated arc therapy (VMAT) (coplanar and noncoplanar) beams and static intensity modulated radiation therapy (IMRT) beams. (b) Axial, coronal, and sagittal CT views with dose wash of the clinical case and the 4p plans at prescription and escalated planning target volume doses for a single patient. The color bar was adjusted to be uniform between all cases. All 4p plans spare the carotid artery (axial view) compared with the clinical plan. A color version of this figure is available at www.redjournal.org. additional dose to the PTV were also created on the clinical and 4p planning systems and evaluated using CERR. Doses to OARs and 50% dose spillage volume index (R50) were compared against the delivered clinical SBRT plans. R50 was used as a measure of the high dose gradient outside the PTV. R50 was defined as: V50 ð1Þ R50 Z VPTV where V50 is the total volume receiving 50% or more of the prescription dose, and VPTV is the volume of the PTV. To Results At the same prescription dose (4pPD), the mean and maximum (Dmax) doses to OARs were reduced with 4p plans compared with clinical plans. Significant reductions (P<.05) were observed for the spinal cord, the brainstem, pharyngeal constrictor muscles, parotid glands, the larynx, the mandible, the cochlea, and the optic apparatus (ie chiasm, eye, lens, and optic nerves), whereas statistically nonsignificant (P>.05) reductions were obtained for the 4p SBRT for head-and-neck cancer Volume - Number - 2014 brachial plexus, the carotid artery, and the cervical esophagus (Table 2). Dose spillage outside the PTV, as measured by R50, was reduced by 33% (P<.001) (Table 3). Coverage of the PTV was improved according to respective increases in PTV maximum and mean doses, D95, D98, and D99 by 4.4%, 5.5%, 2.4%, 4.7%, and 6.5%, respectively (P<.01). The 1.7% increase in PTV minimum dose was not statistically significant (PZ.69). Planning target volume prescription dose escalations by 10 Gy (4pPD þ 10 Gy) in 5 fractions were achieved with a simultaneous reduction in R50 by 5.7% (PZ.07, Table 3), and doses to OARs significantly improved or were unchanged from clinical plans (Table 2). For 20-Gy escalation (4pPD þ 20 Gy) in 5 fractions, R50 was increased by 24.2% (PZ.001, Table 3); however, doses to OARs were still significantly improved or unchanged from clinical plans, except for a significant increase in Dmax for the carotid artery (Table 2). When patients with tumors partially or completely wrapping the carotid artery were excluded (nZ9), the reductions in carotid artery mean dose and Dmax were maintained with dose escalation at both levels (Table 2). Figure 1b shows a planning CT with a dose color wash for a typical 4p case in axial, coronal, and sagittal projections. The dose spillage reduction with 4p plans, as demonstrated with improved R50, was consistent with the observed steep dose fall-off outside the PTV that resulted in reduced volume receiving 50% of the original prescription Table 2 5 dose even in the 10-Gy dose-escalated plan. Figure 2a and b show example doseevolume histograms, which demonstrate the improved dosimetry with 4p plans compared with clinical plans. At escalated doses, doseevolume histograms still indicated OAR doses lower with 4p plans than was observed in nonescalated clinical plans (Fig. 2b). At a median follow-up of 10 months (range, 141 months), the crude LC of our cohort was 52%. The median overall survival (OS) was 12 months with a corresponding 2-year LC of 39.2% (actuarial data not shown). The calculated individual patient TCP for clinical plans and 4p plans is shown in Table E1 (available online at www.redjournal.com). Figure 3 shows the mean TCP curves for both clinical and 4p plans at a of 0.35. The clinical TCP of 42.2% at initial prescription dose approximated the patient cohort’s LC at 39.2%, suggesting that the radiosensitivity of tumors in the study cohort is closer to 0.35. Predicted TCP results using a of 0.25 and 0.15 were <10%, significantly different from the clinical observation, thus not shown here. Using 4p planning, clinical TCP increased to 45.9% (PZ.02). The slight increase was due to reduced cold spots by 4p as seen in Figure 2a. At 10-Gy and 20-Gy escalation, the clinical TCP was respectively increased from 80.5% and 88.1% to 85.5% (PZ.24) and 91.4% (PZ.32) with 4p plans. There were 3 late toxicities (11.1%), consisting of grade 2 dysphagia, grade 3 dysphagia, and grade 3 Reductions in mean and maximum doses to organs at risk from clinical plans in comparison with 4p planning 4pPD 4pPD þ 10 Gy 4pPD þ 20 Gy Organ at risk Mean (%) P* Dmax (%) P* Mean (%) P* Dmax (%) P* Spinal cord Brainstem Mandible Ipsilateral parotid Contralateral parotid Pharyngeal constrictor muscles Larynx Cervical esophagus Ipsilateral carotid Ipsilateral carotidz Contralateral carotid Brachial plexus Ipsilateral cochlea Contralateral cochlea Ipsilateral lens Contralateral lens Ipsilateral eye Contralateral eye Ipsilateral optic nerve Contralateral optic nerve Chiasm 60 53 45 66 66 55 <.001 .017 <.001 .002 .004 <.001 53 46 22 60 60 40 <.001 .006 .001 <.001 <.001 <.001 50 40 33 54 57 40 <.001 .066 .001 .007 .009 <.001 40 34 4 48 48 24 <.001 .022 .714 .001 .001 .010 57 74 22 58 55 48 82 86 82 89 72 70 68 77 81 .004 .067 .014 .080 .003 .203 .002 .004 .090 .126 .041 .023 .006 .015 .010 35 49 10 41 57 32 65 77 74 86 43 41 28 56 67 .038 .336 .096 .121 .001 .383 .004 .005 .064 .106 .051 .028 .220 .014 .017 47 66 2 49 41 33 78 82 76 78 56 60 54 70 74 .006 .110 .845 .163 .008 .401 .003 .004 .081 .117 .025 .016 .007 .015 .013 Abbreviation: PD Z prescription dose. * Paired t test P values. y Negative values reflect increased doses to organs at risk. z With patients with tumors partially or completely wrapping the carotid excluded. 18 31 11y 26 33 13 56 72 70 71 38 24 9 48 59 .404 .570 .230 .431 .006 .877 .011 .005 .060 .106 .048 .268 .748 .027 .034 Mean (%) P* Dmax (%) P* 40 30 26 42 45 33 .001 .164 .016 .030 .025 .001 30 5 9y 36 38 14 .008 .827 .289 .014 .014 .187 43 61 19y 41 28 19 65 59 53 67 33 50 39 67 67 .042 .141 .086 .272 .020 .619 .004 .008 .030 .228 .061 .033 .009 .014 .023 7 26 26y 14 18 6y 39 52 48 64 23 15 2 41 57 .953 .684 .041 .786 .040 .772 .041 .009 .061 .113 .373 .442 .954 .068 .055 6 International Journal of Radiation Oncology Biology Physics Rwigema et al. Table 3 Planning target volume (PTV) statistics for clinical planning as compared with 4p planning at different dose levels 4pPD Parameter PTV mean dose (Gy) PTV max dose (Gy) PTV min dose (Gy) D95 (Gy) D98 (Gy) D99 (Gy) R50 Clinical, mean SD 41.5 45.8 29.7 40.3 38.8 37.2 5.3 5.3 6.6 10.3 5.0 5.3 6.2 2.1 4pPD þ 10 Gy Mean SD P* .005 .003 .69 <.001 .001 .006 <.001 43.9 47.9 30.2 41.3 40.7 39.8 3.5 5.4 6.6 10.1 5.1 5.1 5.4 1.6 Mean SD P* <.001 <.001 <.001 <.001 <.001 <.001 .07 54.6 59.1 42.1 51.4 50.5 49.2 5.0 5.5 6.7 14.7 5.2 5.3 5.9 1.9 4pPD þ 20 Gy Mean SD P* <.001 <.001 <.001 <.001 <.001 <.001 .001 63.4 68.0 40.6 60.1 58.9 57.1 6.6 4.4 5.5 15 3.9 4.2 5.7 2.9 Abbreviation as in Table 2. * Paired t test P values. osteoradionecrosis. Individual OAR NTCP data are shown in Table E2 (available online at www.redjournal.com). The NTCP for structures corresponding to observed late toxicities, namely pharyngeal constrictor muscles, cervical esophagus, and larynx and the mandible, were respectively reduced by 14.6%, 3.8%, 4.9%, and 17.6% from clinical plans to 4p plans at the original prescription dose (Table E2). Overall, 4p planning reduced the mean NTCP at the all dose levels by approximately a factor of 3 at all dose levels (P<.0001) (Fig. 3b, Table E2). Fig. 2. Doseevolume histogram with fractional volume plotted against dose, with a clinical plan compared with (a) 4pPD plan, and (b) 4pPD þ 10 Gy plan and 4pPD þ 20 Gy plan. PCM Z pharyngeal constrictor muscles; PD Z prescription dose; PTV Z planning target volume. Discussion The prognosis of recurrent head-and-neck cancer after salvage reirradiation is poor, and management of these patients remains challenging. The Radiation Therapy Oncology Group (RTOG) 96-10 and RTOG 99-11 prospective trials and others reported 2-year LC of 11%-37% and median OS at 8.2-12.5 months (26-32) in patients reirradiated using 3-dimensional techniques with concurrent chemotherapy. Grade 3 late toxicities ranged from 8% to 33% (26-32). With the advent of IMRT, reirradiation with chemotherapy saw further improvements in LC, with 2-year rates of 19%-67%, which translated into a median OS benefit of 1527.6 months (33-35). Yet the observed severe late complications rate of 12%-32% remained largely unchanged (33-35), and notably treatment-related deaths occurred in approximately 10% of patients with either IMRT or 3-dimensional conformal radiation therapy (26, 35). Emerging SBRT data suggested an opportunity to preserve LC gains registered with IMRT, while potentially reducing severe late toxicities (36). The 2-year LC of 39.2%, a median OS of 12 months, and a 7.4% rate of grade 3 late complications were consistent with results from other SBRT series (4-7, 10-12). Whereas a randomized, phase 3 trial is ultimately warranted to compare results of SBRT and conventionally fractionated radiation therapy, efforts are clearly needed to carefully augment LC in the salvage of recurrent head-andneck cancer to improve patient survival. Herein, we purposed to ameliorate SBRT outcomes with 4p planning, with the goal to reduce late toxicities while attempting to improve local tumor control. We demonstrated that better dosimetry is achievable with reduction in doses to OARs obtained (Fig. 2, Table 2) and dose spillage outside the PTV, while improving PTV coverage (Fig. 1b, Table 3). Improvements were observed in all previously treated patients regardless of planning technique and treatment machine selection. We also found that even with a 10-Gy total PTV dose escalation, the reduction in dose spillage was maintained with a corresponding reduction in OAR doses. Although dose spillage was increased for 4pPD þ 20 Gy, doses to OARs were still reduced or unchanged, except for the carotid artery when patients with tumors wrapping the carotid artery were included. Volume - Number - 2014 4p SBRT for head-and-neck cancer 7 Fig. 3. (a) Mean tumor control probability (TCP) and (b) mean normal tissue control probability (NTCP) for the entire patient cohort for both clinical (dashed) and 4p plans; (c) 4p planning may enhance the therapeutic index by increasing the separation between TCP and NTCP curves. PD Z prescription dose. Carotid artery blowout syndrome (CBS) is a serious and often fatal complication in reirradiation. Published data reveal that CBS rates can be high in reirradiation with SBRT, especially in patients with tumors wrapping the carotid artery, nearby skin involvement, or necrosis at time of recurrence (37, 38). Cengiz et al (12) reported a 17.8% rate CBS in patients with tumors wrapping around the carotid artery among 46 patients reirradiated with CyberKnife. They found that CBS occurred when the tumor encompassed 180 of the carotid artery while receiving 100% of the prescription dose under a QD regimen, but when they adopted QOD, CBS rates were significantly reduced (12, 39). Our results suggest that 4p SBRT can add to the benefit of a QOD regimen and render patients who were otherwise relatively contraindicated suitable for reirradiation with SBRT. The optimized noncoplanar SBRT (4p) allowed for improvement in TCP at all dose levels, while simultaneously keeping NTCP lower when compared with clinical plans. Thus, our results suggest that 4p may enhance the therapeutic ratio, because TCP and NTCP curves are separated further relative to clinical planning (Fig. 3c). Patients with radioresistant, previously irradiated tumors or primary radioresistant tumors, such as sinonasal mucosal melanoma (8) as in this study, might benefit from the higher prescription dose. Conversely, 2 patients had a decrement in TCP when the dose was further increased from 10 Gy to 20 Gy with 4p planning (Table E1). This finding may be explained by the fact that during 4p optimization, PTV coverage may be compromised to preserve high-priority OAR constraints. Thus, dose escalation should be considered within the context of an individual patient’s anatomic and clinical factors. To implement 4p delivery in the clinic using C-arm linear accelerators, practical considerations such as avoidance of couch and gantry collision, as well as achieving optimal treatment delivery time, must be evaluated. We created a beam geometry solution space based on the computer-aided design (CAD) model of the machine and patients. Collisions were predicted and prevented using this model. To eliminate the risk of collision and maintain targeting accuracy, the patients would need to be well immobilized. Increasing the collision buffer might further improve the safety, but it would lead to an increased number of beams using extended source-to-tumor distances, slightly degrading the multileaf collimator resolution and dosimetry. Positioning the couch and gantry manually for such a large number of noncoplanar, nonisocentric beams would be impractical and likely unsafe. However, this task would be feasible with robotized couch and gantry maneuvering. According to our measurement of a delivered 4p plan, the total time used for couch and gantry traversing through 30 static beams would be <200 seconds. As with all studies involving TCP and NTCP modeling, there can be significant uncertainties stemming from inaccuracies in estimated radiobiological parameter values. The 8 Rwigema et al. LC rate predicted by the TCP model is close to the observation (42.2% vs 39.2%), indicating that the estimated tumor radiobiological parameters are reasonable. Similarly, the predicted mean NTCP rate of 5.6% approximated the actual 7.4% rate of severe (grade 3) late toxicities. The validity of linear quadratic cell survival in the SBRT dose range has also been questioned, particularly for fractional dose over 10 Gy, which would be the upper limit of the dose escalated plans. Nevertheless, this uncertainty is unlikely to influence the significant changes in TCP and NTCP observed in this study and overall conclusions. 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