Acute Side Effects of Proton Beam Therapy for Uveal Melanoma

E350

International Journal of Radiation Oncology  Biology  Physics

Materials/Methods: We reviewed the charts of all patients with cT1-2 squamous cell carcinoma of the oral tongue treated with primary surgery from 1990 e 2010 at a single institution. Tumor and margin characteristics were abstracted from the original surgical pathology analysis. Patients received adjuvant radiation for accepted indications. For those with a worrisome intra-operative margin, subsequent re-excisions of either the area of concern or the entire operative bed were interpreted as the true final margin; an initially positive margin on the primary tumor specimen was not interpreted as an indication for adjuvant therapy. Overall survival (OS), disease free survival (DFS) and local control (LRC) were calculated using the Kaplan Meier method. Predictors of LC, OS, and DFS were analyzed via univariate and multivariate analysis (MVA). Results: 223 patients met the inclusion criteria. Median age was 62 years; 23% proved to be stage III/IV on pathologic staging. Sixty-seven (30%) of patients were administered adjuvant radiation and 25 (11%) of patients received adjuvant chemoradiation. Patients treated with adjuvant radiation were more likely to have perineural invasion (P < 0.0001) and pathologic stage III-IV disease (P < 0.0001). The initial specimen margin was involved with carcinoma or severe dysplasia in 73 cases (33%). Of the patients whose initially involved margin was superseded, 48 (66%) did not receive adjuvant radiation. With a median follow-up of 4.8 years, the 5 yr actuarial LRC and DFS for patients treated with surgery alone and surgery plus adjuvant (chemo)radiation was 74% and 79% (P Z 0.62) and 66% and 67% (P Z 0.83). Patients with a positive margin on the initial specimen superseded by additional specimens had similar 5-year local control (86% v 84%, P Z 0.18) and DFS (63% v 68%, P Z 0.98) when compared to those with a clear margin on the initial specimen. On MVA, no factor evaluated (stage, perineural invasion, initial involved margin, adjuvant radiation, adjuvant chemoradiation, smoking pack years, or age at diagnosis) was associated with local recurrence. Conclusion: An initially positive margin that is rendered negative at the same surgical procedure does not increase the chance of local recurrence and should not be considered an independent indication for adjuvant radiation. Author Disclosure: I. Dhawan: None. T. Li: None. C. Fundakowski: None. M. Lango: None. J.A. Ridge: None. J. Liu: None. T.J. Galloway: None.

Treatment interruptions noted in 5 patients in control arm versus 7 in study arm due to more grade III /IV mucositis. Ryles tube feeding was required in 11 patients in control arm vs 6 in study arm. Grade I /II Neutropenia was common in control arm [44.83% vs 17.85%] Acute mucosal toxicity of grade III was higher in study arm [35.71% vs 20.69%]. Grade II skin reactions were predominant in study arm [64.29% vs 34.48%]. Grade II dysphagia reported higher in control arm [65.52% vs 53.57%] whereas grade III was more in study arm [35.72% vs 20.69%]. Grade III laryngeal edema was slightly higher in the study arm but was statistically insignificant. Grade II xerostomia was higher in study arm [17.86% vs 13.79%]. Predominant Late toxicities in control versus study arm - xerostomia grade I [51.85% vs 48.15%], fibrosis grade-I [37.03% vs 29.63%], trismus grade-II [11.11% vs 3.70%] and laryngeal edema grade-II [18.52% vs 22.22%] were observed. Complete response [CR] rate at primary site was higher at 1 month [67.85% vs 71.42%], 3 months [67.86% vs 75%] and at 6 months [66.67% vs 77.78%] in the study arm. CR rate at the nodal site was higher at 1 month [78.57% vs 67.82%], 3 months [82.14% vs 65.36%] and at 6 months [77.08% vs 62.96%] in the control arm. Better CR rates were seen with well and moderately differentiated SCC in the study arm. Conclusion: Accelerated chemo radiation therapy showed an optimum balance between improved tumor control and avoidance of excess late morbidity with manageable acute toxicities. Therefore in limited resource settings and high volume centers, modified fractionation schedules should constitute a new baseline for further exploration of radiation therapy in head and neck cancers. Author Disclosure: R. Das: RESIDENT IN TRAINING; AIIMS. D. Kumaran: RESIDENT IN TRAINING; AIIMS. N. Das: None. A. Gupta: None. A. Rai: None.

2862 Comparison of Accelerated Versus Conventional Fractionated Chemoradiation Therapy in Locally Advanced Head and Neck Squamous Cell Carcinoma R. Das,1,2 D. Kumaran,2 N. Das,1 A. Gupta,1 and A.K. Rai1; 1VMMC and Safdarjung Hospital, New Delhi, India, 2All India Institute of Medical Sciences, New Delhi, India Purpose/Objective(s): To evaluate a) The efficacy of accelerated versus conventional fractionated radiation therapy with 3 weekly concomitant cisplatin in locally advanced squamous cell carcinoma [SCC] of head and neck patients excluding nasopharynx and maxillary sinus b) To determine and compare acute and late toxicities. Materials/Methods: A randomized study comparing: Arm A [control arm] - 5 fractions of radiation per week of 2Gy/day in telecobalt with compensators to a dose of 66Gy/33# over 61/2 weeks with concurrent cisplatin 100mg/m2 3 weekly on day 1, 22 and 43. ARM B [study arm]6 fractions of radiation per week of 2Gy/day in telecobalt with compensators to a dose of 66Gy/33# over 51/2 weeks with concurrent cisplatin 100mg/m2 3 weekly on day 1 and day 22. Toxicities were weekly assessed. Subsequently followed up with clinical examination monthly till 6 months & CT /MRI was done at first month and 6 month post treatment. Results: Standard statistical and Fischer’s test were applied. 60 patients were recruited in this study. In Control arm, 29 patients completed treatment versus 28 in study arm. Clinico-pathologic characteristics were comparable in both arms. Most patients were of oropharynx [17vs19]. Majority were T3 stage [44.82%vs50%] and N1 [55.17% vs 35.72%]

2863 Acute Side Effects of Proton Beam Therapy for Uveal Melanoma D.M. Trifiletti,1 R. Dagan,1 J. Bolling,2 R. Slopsema,1 M. MamaluiHunter,1 D. Yeung,1 K. Helow,1 and M.S. Rutenberg1; 1University of Florida Health Proton Therapy Institute, Jacksonville, FL, 2Mayo Clinic, Jacksonville, FL Purpose/Objective(s): There are limited data available describing the acute side effects associated with proton beam therapy (PBT) for the definitive management of patients with uveal melanoma. We report our initial experience with acute toxicities related to PBT for uveal melanoma. Materials/Methods: From 2012 to 2016, 55 patients were treated definitively for uveal melanoma with hypofractionated PBT. Tantalum fiducials were sutured onto the sclera prior to treatment planning for daily alignment. Treatment consisted of 60 CGE delivered in 15 CGE/fx on consecutive days using passive scattering PBT on a fixed beam eyeline. Prospectively recorded acute treatment related side effects within 180 days of treatment were analyzed. Results: Median follow-up was 1.1 years (range: 0.1- 3.0 years). The median age at treatment was 60 years old (range: 26 - 94). Twenty-nine right eyes and 26 left eyes were treated; T1 Z 9, T2 Z 17, T3 Z 17, and T4 Z 12. All patients but one (iris melanoma) had disease involving the posterior uveal structures. The median tumor size was 14.5 mm (range: 5.2 - 21.0) in maximum diameter and 6.0 mm (range: 1.2 - 13.0) in thickness. The median interval between tantalum clip placement and PBT was 13 days (range: 4 - 28). 82% had conjunctivitis and 9% had eyelid dysfunction following tantalum clip placement prior to PBT. At 6 weeks post-PBT conjunctivitis and radiation dermatitis were the most common toxicities, occurring in 49%, and 42% of patients, respectively. At 3 months, conjunctivitis, dermatitis, and epiphora occurred in 38%, 25% and 36% of patients, respectively. At 6 months, these side effects decreased in frequency (20%, 18% and 29%, respectively). There were 6 events of grade 3 toxicity consisting of eye pain (1), cataract (1), complete retinal detachment requiring surgery (1), and epiphora (3). There was one grade 4 toxicity (retinopathy) that occurred at 6 months postPBT. One patient was enucleated 3 months post-PBT due to tumor

Volume 96  Number 2S  Supplement 2016 progression, but without treatment related toxicity. There were no grade 5 toxicities. Median visual acuity for early stage tumors (T1/T2) remained stable from pre-treatment baseline to 6 months post-PBT. Median visual acuity in locally advanced tumors (T3/4) remained stable from baseline to 3 months post-treatment, however, declined at 6 months postPBT (p Z 0.035). Conclusion: Hypofractionated proton beam therapy is generally well tolerated, though, 13% of patients experienced  grade 3 acute side effects. Author Disclosure: D.M. Trifiletti: None. R. Dagan: None. J. Bolling: None. R. Slopsema: None. M. Mamalui-Hunter: None. D. Yeung: None. K. Helow: None. M.S. Rutenberg: None.

2864 A Risk Prediction Model for Head and Neck (HN) Radiation Toxicities: Dosimetric Insights Associated With the Risk of Clinical Aspiration S.P. Robertson,1 X. Hui,2 Z. Cheng,3 C. Gui,4 M.R. Bowers,4 J. Moore,3 J. Maclean,5 J. O’Hare,5 P. Graham,5 P. Wu,5 T. Omari,6 M. Szczesniak,5 C.G. Gourin,3 I.J. Cook,5 T.R. McNutt,1 and H. Quon2; 1Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 2Johns Hopkins University, Department of Radiation Oncology and Molecular Radiation Sciences, Baltimore, MD, 3Johns Hopkins University School of Medicine, Baltimore, MD, 4Johns Hopkins University, Baltimore, MD, 5University of New South Wales, St. George Hospital, Sydney, Australia, 6Flinders University, Adelaide, Australia Purpose/Objective(s): Increasing clinical evidence suggests that aspiration from HN (chemo) radiation therapy can lead to increased patient mortality that manifests over years of follow-up care. This has contributed to limited insights into potential risk factors. Recently our group has begun to identify potential risk factors related to the risk of aspiration including laryngeal irradiation and dosimetry to the cricopharyngeal (CP) muscle. The aim of this study was to investigate the dosimetric risk factors for any clinical aspiration grading (NCI-CTCAE) to ultimately minimize the risk of developing grade 5 toxicity. Materials/Methods: Prospectively collected data was queried from the local Oncospace learning health system. This includes CTCAE aspiration as the primary endpoint, as well as FOIS diet level, penetration-aspiration scale (PAS) and the Sydney Swallow Questionnaire (SSQ). Dose-volume histogram (DVH) points were also extracted at 5% volume increments (21 points per OAR) for the larynx, CP muscle, and the superior (SPC), middle (MPC), and inferior (IPC) pharyngeal constrictor muscles. A backward elimination stepwise regression was applied to examine critical DVH points for the occurrence of aspiration. Subsequently, univariate analyses were performed to quantify the association between the indicted DVH points and risk of aspiration. Finally, we conducted stratification analysis by different age groups based on patients above or below the mean age to further refine the associations. Results: From a total of 987 patients in the Oncospace database, 748 were queried having aspiration scores in follow-up. Of those, dose data was available for the larynx (N Z 176), CP muscle (N Z 166), and pharyngeal constrictors (N Z 218). Stepwise regression revealed the importance of the larynx dose to 50% volume (D50; odds ratio [OR]: 1.05; P Z 0.002), CP muscle D20 (OR: 1.04; P Z 0.024), and ICP D30 (OR: 1.05; P Z 0.001). After stratifying by mean age (58.8  11.8), larynx D50 (OR: 1.06; P Z 0.008) and ICP D30 (OR: 1.07; P Z 0.003) were only significant for the older subgroup. The related clinical outcomes of FOIS, PAS, and SSQ were all significantly related to aspiration (P  0.001). Conclusion: Preliminary analysis confirms that dose to the larynx, cricopharyngeus, and inferior pharyngeal constrictor may all be important for grade  2 aspiration. Increased attention to these structures may help to further validate these relationships and yield important insights to reduce the risk of clinical aspiration. Author Disclosure: S.P. Robertson: None. X. Hui: Research Grant; Philips Radiation Oncology Systems, Elekta. Z. Cheng: Research Grant; Toshiba

Poster Viewing E351 Medical Research. C. Gui: None. M.R. Bowers: Research Grant; Elekta. J. Moore: None. J. Maclean: None. J. O’Hare: None. P. Graham: None. P. Wu: None. T. Omari: None. M. Szczesniak: None. C.G. Gourin: None. I.J. Cook: None. T.R. McNutt: Research Grant; Philips Radiation Oncology Systems, Elekta, Toshiba Medical Research. H. Quon: None.

2865 Pooled Analysis of Late Toxicity From 2 Randomized Phase 2 Trials of Induction Chemotherapy (IC) and Chemoradiation Therapy (CRT) for Locally Advanced Head and Neck Squamous Cell Cancer (LA-HNSCC) J.M. Melotek,1 V.M. Villaflor,1 T.Y. Seiwert,1 M. Kocherginsky,1 T.G. Karrison,1 R.J. Brisson,1 E.A. Blair,1 K.M. Stenson,2 M. Lingen,1 E. Cohen,3 E.E. Vokes,1 and D.J. Haraf1; 1University of Chicago, Chicago, IL, 2Rush University, Chicago, IL, 3University of California San Diego, La Jolla, CA Purpose/Objective(s): It is unknown how late toxicity varies between hyperfractionated and accelerated CRT platforms for LA-HNSCC. Additionally, it is unclear to what extent recent efforts utilizing response-adapted volume de-escalation (RAVD) have reduced late toxicity compared to treatment with conventional radiation therapy (RT) volumes. Materials/Methods: In Trial 1, pts with LA-HNSCC were randomized to 2 cycles of induction chemotherapy (IC; cetuximab, paclitaxel, carboplatin) and either Cetux-FHX (cetuximab, 5-FU, hydroxyurea, and 1.5 Gy twicedaily RT every other week to 75 Gy) or Cetux-PX (cetuximab, cisplatin, and accelerated RT with delayed concomitant boost to 72 Gy in 42 fractions). Conventional RT volumes were used. In Trial 2, pts with LAHNSCC received 2 cycles of IC (cisplatin, paclitaxel, cetuximab  everolimus) followed by RAVD. Good responders (GR) with 50% reduction in the sum of gross tumor diameters received radical volume de-escalation with TFHX (paclitaxel, 5-FU, hydroxyurea, and 1.5 Gy twice-daily RT every other week to 75 Gy) encompassing exclusively gross disease. Pts with <50% response (NR) received limited volume de-escalation treating only the first echelon of uninvolved nodes to 45 Gy, followed by a sequential boost to gross disease to 75 Gy. Intensity-modulated RT was used in both trials. Results: Pooled baseline characteristics for N Z 57 on Cetux-FHX, N Z 53 on Cetux-PX, N Z 37 GR, and N Z 52 NR include: median age 57; 84.4% male; 67.8% oropharynx; 52.3% HPV-positive; 55.8% T3; 92.5% N2; 31.7% 10 pack-year history; 42.7% underwent post-CRT neck dissection. G-tube rates during CRT and post-CRT are shown in the Table. There was no significant difference in G-tube rates within Trial 1 for Cetux-FHX vs Cetux-PX during CRT (P Z 0.84) or at 6 mos (P Z 1.00), 12 mos (P Z 0.76), and 24 mos (P Z 0.68) post-CRT. G-tube rates were significantly less within Trial 2 for GR vs NR during CRT (P Z 0.02) and at 6 mos (P < 0.01) and 12 mos (P Z 0.03) post-CRT. The rates of G-tube dependency for NR and Trial 1 pts were similar on treatment (P Z 0.28) and at 6 mos (P Z 1.00), 12 mos (P Z 0.78), and 24 mos (P Z 0.65) post-CRT. Regression analysis revealed only T-stage as a significant predictor of G-tube dependency during CRT (OR 1.94 for T3, P Z 0.03), while treatment arm (OR 0.15 for GR, P Z 0.03) and tumor site (OR 1.99 for larynx/hypopharynx, P Z 0.04) were significant predictors at 6 mos post-CRT. Only tumor site remained significant at 12 and 24 mos post-CRT.

Abstract 2865; Table 1. G-tube Dependent (%) Trial 1 1 2 2

Arm Cetux-FHX Cetux-PX GR NR

During Treatment 66.1 64.2 51.4 75.0

6 Mos Post- 12 Mos Post- 24 Mos PostCRT CRT CRT 34.0 35.4 5.7 35.4

10.6 13.0 0.0 14.6

8.9 4.8 0.0 6.5