2-year Locoregional Control Rate Research Articles

Phase I/II study of stereotactic body radiotherapy boost in patients with cervical cancer ineligible for intracavitary brachytherapy

PurposeStereotactic body radiotherapy (SBRT) boost is a promising treatment for cervical cancer patients who are ineligible for intracavitary brachytherapy (ICBT). The aim of this multicenter, single-arm, phase I/II study was to prospectively evaluate the efficacy and toxicity of SBRT boost.Materials and methodsICBT-ineligible patients with untreated cervical cancer were enrolled. Patients underwent whole-pelvic radiotherapy (45 Gy in 25 fractions) with SBRT boost to the primary lesion. In the phase I dose-escalation cohort (3 + 3 design), patients were treated with SBRT boost of 21 or 22.5 Gy in three fractions. Although dose-limiting toxicity was not confirmed, a dose of 21 Gy was selected for the phase II cohort because it was difficult to reproduce the pelvic organs position in two patients during the phase I trial. The primary endpoint was 2-year progression-free survival.ResultsTwenty-one patients (phase I, n = 3; phase II, n = 18) were enrolled between April 2016 and October 2020; 17 (81%) had clinical stage III–IV (with para-aortic lymph node metastases) disease. The median (range) follow-up was 40 (10–84) months. The initial response was complete response in 20 patients and partial response in one patient. The 2-year locoregional control, progression-free survival, and overall survival rates were 84%, 67%, and 81%, respectively. Grade ≥ 3 toxicity was confirmed in one patient each in the acute (diarrhea) and late (urinary tract obstruction) phases.ConclusionThese findings suggested that a SBRT boost is more effective than the conventional EBRT boost and can be an important treatment option for ICBT-ineligible patients with cervical cancer.Study registrationThis study was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN000036845).

Analyzing the impact of close margins and extra-resection margins on failure rates in postoperative oral cavity cancers.

Postoperative oral cancers with close margins belong to medium- to high-risk category for local failure. During re-surgery for close margins, there is sufficient doubt as to whether the re-excised tissue is from the same region as the close margin. Therefore, we planned a retrospective review of these cases of close margins that were re-excised with extra-resection margins (ERMs). Details of 2011 oral cavity patients resected at our hospital were retrieved. Cases with close margins were segregated and the status of ERMs was noted. The postoperative histopathological details, radiotherapy details, and failure patterns in all these cases were documented. The primary objective of the study was to assess the overall survival (OS) and disease-free survival (DFS) in cases with ERMs. The secondary objective was to assess the local and regional control rates and variation with the number and status of close and ERMs. OS, DFS, and local failure rates were defined from the date of registration. Statistical analysis was performed with the SPSS statistical software package. All survival analyses were performed using the Kaplan-Meier method. Log-rank test was used to test the statistical significance. A P-value of 0.05 was considered statistically significant. Sixty-four cases with a median age of 47 years (range: 29-76) were considered for the final analysis. The median follow-up was 40 months (range: 9.5-56.5). The 2-year OS and DFS rates were 91.5% and 88.5%, respectively. The crude local and regional failure rates were 10.9% and 3.1%, respectively. The 3-year locoregional control rate was 90.2%. The 2-year locoregional control rate for one close margin was significantly better as compared to more than one close margin (P = 0.049). No difference in survival and failure rates was found between the number of ERMs resected (one vs. two) and ≤ vs. > 3 mm close margin status. Two patients developed bone metastases. The survival rates and locoregional control rates did not differ much between the groups that had one or more ERMs. However, the locoregional control rates were better in cases with one close margin as compared to those with more than one close margin. A larger study with longer follow-up is needed to detect statistically significant differences in outcomes and identify the factors that portend poor prognosis in these cases with close margins and ERMs.

Outcomes among oropharyngeal and oral cavity cancer patients treated with postoperative volumetric modulated arctherapy.

Presently, there are few published reports on postoperative radiation therapy for oropharyngeal and oral cavity cancers treated with IMRT/VMAT technique. This study aimed to assess the oncological outcomes of this population treated with postoperative VMAT in our institution, with a focus on loco-regional patterns of failure. Between 2011 and 2019, 167 patients were included (40% of oropharyngeal cancers, and 60% of oral cavity cancers). The median age was 60 years. There was 64.2% of stage IV cancers. All patients had both T and N surgery. 34% had a R1 margin, 42% had perineural invasion. 72% had a positive neck dissection and 42% extranodal extension (ENE). All patients were treated with VMAT with simultaneous integrated boost with three dose levels: 66Gy in case of R1 margin and/or ENE, 59.4-60Gy on the tumor bed, and 54Gy on the prophylactic areas. Concomittant cisplatin was administrated concomitantly when feasible in case of R1 and/or ENE. The 1- and 2-year loco-regional control rates were 88.6% and 85.6% respectively. Higher tumor stage (T3/T4), the presence of PNI, and time from surgery >45 days were significant predictive factors of worse loco-regional control in multivariate analysis (p=0.02, p=0.04, and p=0.02). There were 17 local recurrences: 11 (64%) were considered as infield, 4 (24%) as marginal, and 2 (12%) as outfield. There were 9 regional recurrences only, 8 (89%) were considered as infield, and 1 (11%) as outfield. The 1- and 2-year disease-free survival (DFS) rates were 78.9% and 71.8% respectively. The 1- and 2-year overall survival (OS) rates were 88.6% and 80% respectively. Higher tumor stage (T3/T4) and the presence of ENE were the two prognostic factors significantly associated with worse DFS and OS in multivariate analysis. Our outcomes for postoperative VMAT for oral cavity and oropharyngeal cancers are encouraging, with high rates of loco-regional control. However, the management of ENE still seems challenging.

A Phase II Study of Volume and Dose De-Intensification Following Transoral Robotic Surgery (TORS) and Neck Dissection for p16+ Oropharyngeal Squamous Cell Carcinoma

<h3>Purpose/Objective(s)</h3> Current efforts to de-intensify adjuvant therapy for patients with p16+ Oropharyngeal Squamous Cell Carcinoma (OPSCC) have focused on dose de-escalation (ECOG 3311) or volume reduction (AVOID trial). We conducted this prospective Phase II single institution study combining volume and dose de-intensification, in patients with pT0-T3 pN0-N2c p16+ OPSCC, with the goal of maintaining high rates of locoregional control (LRC) and reducing treatment-related toxicity. <h3>Materials/Methods</h3> Eligible patients had pT0-T3 N0-N2c p16+ OPSCC (per AJCC 7th Ed), s/p TORS and neck dissection, with < 5 positive lymph nodes, who met standard indications for adjuvant radiotherapy +/- chemotherapy. Adjuvant RT was delivered in 25 fractions over 5 weeks. The primary site was spared in patients with pT1-T2 tumors resected with negative margins and no LVI or PNI, as per the AVOID trial. If RT to the primary operative bed was indicated, patients received 50, 52.5, or 55 Gy for negative, close, or positive margins, respectively. The neck level(s) with confirmed pathologic disease received 50 Gy, and areas of minor or macroscopic ENE were boosted to 52.5 or 55 Gy, respectively. Other at-risk ipsilateral nodal regions received 45 Gy. The treated volume of the contralateral neck was reduced to mirror the pathologically involved nodal levels in the ipsilateral neck, and received 45 Gy. Concurrent chemotherapy was according to guidelines, but could be omitted in patients with ENE ≤ 1 mm. The trial was powered to demonstrate 2-year LRC rate > 90%. <h3>Results</h3> 118 patients were enrolled between October 2018 and July 2021. Patient characteristics are detailed in the Table. Median follow up is 23 months (range 6 - 40 months). One patient developed regional recurrence after developing distant metastases (DM). No other patients had locoregional failure (LRF), yielding an estimated 2-year LRC rate of 98.8% (95% CI, 92-99.8%). Eight patients (7%) developed DM, and one patient has died of metastatic disease. The TORS resection bed was spared in 55% of patients; due to proximity to level 2, the median dose to the operative bed in these cases was 32.5 Gy (range 16.5 – 46 Gy). Twenty patients had ENE > 1 mm (considered "high risk" per ECOG 3311) and none had LRF. At one-year post-RT, the median MDASI-HN "difficulty swallowing/chewing at its worst" score was 2 (IQR, 1-3), and "choking/coughing with swallowing at its worst" score was 1 (IQR, 0-3), on a scale from 0 (not present) to 10 (as bad as you can imagine). <h3>Conclusion</h3> The combination of adjuvant RT dose de-intensification over 5 weeks and volume reduction, with omission of the primary site in appropriate patients, and reducing the volume of the treated contralateral neck, appears safe. Additional follow up is warranted and ongoing.

Six-year follow-up from the weekly-three-weekly study comparing cisplatin once-a-week to once-every-three-weeks as concurrent chemoradiation for locally advanced head and neck squamous cell carcinoma.

6071 Background: In the weekly-3-weekly (W3W) study, cisplatin at 100 mg/m2 once-every-3-weeks led to superior locoregional control compared to cisplatin 30 mg/m2 once-a-week in combination with radical radiation for locally advanced head and neck squamous cell carcinoma (LAHNSCC). We report the updated analysis of the study. Methods: In this phase III open label non-inferiority study conducted between 2013 and 2017, 300 patients with LAHNSCC were randomly assigned to receive cisplatin 100 mg/m2 once-in-3-weeks or cisplatin 30 mg/m2 once-a-week, concurrently with radiation. The primary endpoint was locoregional control. Secondary outcomes included progression free survival (PFS), overall survival (OS), toxicity, and quality of life. Results: As of February 5, 2022 (median follow-up, 77.3 months), 132 patients (44%) have had an event for locoregional recurrence; 75 (50%) in the once-a-week cisplatin arm and 57 (38%) in the once-every-3-weeks cisplatin arm. The updated estimated cumulative 2-year locoregional control rates were 59.3% and 75.3% in the once-a-week and once-every-3-weeks cisplatin arms, respectively; absolute difference, 16% (95% CI, 7.19 to 24.81). The estimated 5-year locoregional control rates were 48.2% and 55.2% in the once-a-week and once-every-3-weeks cisplatin arms respectively; absolute difference, 7% (95% CI, -2.5 to 16.5). The median time to locoregional failure was 46.1 months (95% CI, 31.63 to 60.56) in the once-a-week cisplatin arm, and 57.9 months (95% CI, 47.1 to 68.6) in the once-every-3-weeks cisplatin arm; HR, 1.43 (95% CI, 1.01 to 2.02); P = 0.042. The estimated median PFS was 17.5 months (95% CI, 0 to 38.31) in the once-a-week cisplatin arm, versus 37.5 months (95% CI, 28.45 to 46.45) in the once-every-3-weeks cisplatin arm; HR, 1.13 (95% CI, 0.85 to 1.5); P = 0.41. Events for OS included 173 (57.7%) deaths; 109 (36.3%) patients are alive, and 18 (6%) are lost to follow-up. The 5-year OS in the once-a-week and once-every-3-weeks cisplatin arms were 43.1% and 48.6%, respectively. Estimated median OS was 38.5 months (95% CI, 16.3 to 60.7) in the once-a-week cisplatin arm, versus 57.3 months (95% CI, 38.6 to 75.9) in the once-every-3-weeks cisplatin arm; HR, 1.19 (95% CI, 0.89 to 1.6); P = 0.238. Details regarding chronic toxicities and second primaries will be presented. Conclusions: Long term follow-up confirms that cisplatin at 100 mg/m2 administered once-every-3-weeks concurrently with radical radiation for LAHNSCC leads to superior locoregional control and should remain the standard of care. The study was not powered to test for a difference in OS; OS was numerically higher in the once-every-3-weeks cisplatin arm, but the difference did not attain statistical significance. Clinical trial information: CTRI/2012/10/ 003062.

A Dosimetric Analysis of Locoregional Failure Using Deformable Image Registration in Hypopharyngeal Cancer After Sequential-Boost Intensity-Modulated Radiotherapy

<h3>Purpose/Objective(s)</h3> Sequential boost (SQB) is an IMRT approach that is considered comparable to simultaneous-integrated boost. Dosimetric analysis in SQB using two planning CTs requires advanced dose-accumulation techniques, such as a deformable image registration (DIR) workflow. The purpose of this study was to assess patterns of failure and identify dosimetric features for hypopharyngeal cancer patients treated with SQB-IMRT. <h3>Materials/Methods</h3> Between 2013 and 2019, 102 hypopharyngeal cancer patients were treated with definitive SQB-IMRT. In short, both the PTV-high risk, including the primary tumor and metastatic lymph nodes, and the PTV-low risk, including elective nodal regions, received 46 Gy at 2 Gy/fraction using the first planning CT. The PTV-high risk sequentially received an additional 24 Gy using a second planning CT. The doses for the first and second plans were accumulated and registered onto the second planning CT using the DIR workflow. All locoregional recurrences were contoured on the follow-up CT and registered with the second planning CT. Recurrences were classified as in-field (more than 95% of the recurrence volume (Vrec) received 95% of the prescribed dose), marginal (20-95%), or out-of-field (less than 20%). The toxicity was also evaluated using CTCAE ver4.0. <h3>Results</h3> The median age was 66 years. Stage I, II, III and IV diseases were diagnosed in 3, 23, 20 and 56 patients, respectively. Eighty-three patients (81%) received concurrent chemoradiotherapy, and 19 patients (19%) received radiation therapy alone. The median total dose was 70 Gy. The median follow-up period was 22 months for all patients and 24 months for survivors. The 2-year overall survival rate and locoregional control rate were 79% and 57%, respectively. Thirty-four (33%) locoregional recurrences were observed. All locoregional failures were defined as in-field, and there was no marginal or out-of-field recurrence. The median mean dose and of the Vrec were 72.5 Gy (range, 71.6-74.1). In the patients who experienced locoregional failure, the median mean dose to the elective nodal region was assessed to be 60.1 (range, 55.4-68.4) Gy, and no recurrence occurred in the area. Late toxicities 6 months after RT were evaluated in 34 patients, and 24%, 3%, 25% and 2% of the patients experienced grade 2 and 3 dysphagia, grade 2 dry mouth and G2 dysgeusia, respectively. There were no grade 4/5 late toxicities. <h3>Conclusion</h3> In the detailed dosimetric analysis using DIR, all locoregional relapses after SQB-IMRT were in-field recurrences in the high-dose region. There was no recurrence in the prophylactic dose area, in which the accumulated dose reached as high as 60 Gy. More aggressive treatment for gross tumors and lower prophylactic doses may contribute to improved treatment outcomes and reduced side effects.

Development of a Hypoxia-Immune Prognostic Classifier for Head-and-Neck Cancer Patients Undergoing Radiotherapy ― Results From a Prospective Imaging Trial

Tumor-infiltrating lymphocytes (TILs) correlate with an improved outcome of head-and-neck squamous cell cancer (HNSCC) patients undergoing radiotherapy and are influenced by the tumor microenvironment and tumor-associated hypoxia. The present analysis is based on a prospective imaging trial and analyzes the value of TILs and tumor-associated hypoxia to stratify HNSCC patients according to their response to radiotherapy.A total of 49 patients with locoregionally advanced HNSCCs were prospectively enrolled in this trial and underwent longitudinal hypoxia PET imaging using fluoro-18 misonidazole ([18F]FMISO) in weeks 0, 2 and 5 during chemoradiation. Tumor hypoxia was assumed for a tumor-to-background SUV (contralateral sternocleidomastoid muscle) exceeding 1.4, and an early hypoxia response was defined as a decrease in the normalized maximum intratumoral SUV (FMISO-SUVindex) between weeks 0 and 2. Pre-treatment tumor biopsies were analyzed for TILs and the hypoxia tissue marker carbonic anhydrase IX (CAIX). Trial patients were stratified into 4 subgroups based on their TIL numbers (> 100 vs. < 100 TILs/HPF) and expression of CAIX (above vs. below median H-score), and locoregional control (LRC) and progression-free survival (PFS) rates for all subgroups were assessed using Cox and subsequent concordance analyses (Harrell's C).High TIL levels correlated with improved LRC (HR = 0.279, P = 0.011) and PFS (HR = 0.276, P = 0.006). Similarly, a decrease in the FMISO-SUVindex within the first 2 weeks of treatment corresponded with better LRC (HR = 0.321, P = 0.015) and PFS (HR = 0.402, P = 0.043). Harrell's C was 0.68, when TILs and early hypoxia PET response were combined. The hypoxia PET-based hypoxia-immune classifier separated 3 distinct prognostic patient subgroups, a favorable (TILhigh/ early PET response), and intermediate (TILhigh/no early PET response or TILlow/early PET response) and a poor (TILlow/no early PET response) prognostic group with 2-year LRC of 71%, 33% and 0%, respectively. Low pre-treatment tissue levels of CAIX were also prognostic for improved LRC (HR = 0.352, P = 0.050) but not PFS (HR = 0,468, P = 0,087). Harrell's C was 0.66 for CAIX and TILs separately and 0.71 for the combination. The immunohistochemistry-based immune-hypoxia classifier similarly stratified between a favorable (CAIXlow/TILhigh), an intermediate (CAIXlow/TILlow or CAIXhigh/TILhigh) and a poor (CAIXhigh/TILlow) subgroup with 2-year LRC rates of 73%, 62% and 11%, respectively.We developed a hypoxia PET-based hypoxia-immune classifier that was able to separate HNSCC patients into 3 distinct prognostic subgroups based on their tumor biology. These subgroups could also be stratified in a clinically feasible, immunohistochemistry-based classifier with comparable model accuracy. Therefore, this hypoxia-immune classifier could help to stratify prognoses of HNSCC patients undergoing radiotherapy pending validation in an external cohort.

Clinical Outcomes of Pencil Beam Scanning Proton Therapy in Locally Advanced Non-Small Cell Lung Cancer: Propensity Score Analysis.

Simple SummaryWe analyzed the oncologic outcomes and toxicities after intensity-modulated radiation therapy (IMRT) or pencil beam scanning proton therapy (PBSPT) in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiation therapy. Due to an imbalance in baseline characteristics between IMRT and PBSPT, we used propensity score-based statistical analysis. Regarding radiation therapy planning, PBSPT exhibited superior sparing of the lung, heart, and spinal cord compared to intensity-modulated (photon) radiotherapy in patients with advanced NSCLC. However, PBSPT resulted in higher incidence of grade 3 or more dermatitis and esophagitis compared to IMRT. Despite declined baseline lung function, PBSPT demonstrated a comparable rate of symptomatic radiation pneumonitis compared to IMRT. PBSPT could be an effective and safe treatment technique with comparable locoregional control.This study compared the efficacy and safety of pencil beam scanning proton therapy (PBSPT) versus intensity-modulated (photon) radiotherapy (IMRT) in patients with stage III non-small cell lung cancer (NSCLC). We retrospectively reviewed 219 patients with stage III NSCLC who received definitive concurrent chemoradiotherapy between November 2016 and December 2018. Twenty-five patients (11.4%) underwent PBSPT (23 with single-field optimization) and 194 patients (88.6%) underwent IMRT. Rates of locoregional control (LRC), overall survival, and acute/late toxicities were compared between the groups using propensity score-adjusted analyses. Patients treated with PBSPT were older (median: 67 vs. 62 years) and had worse pulmonary function at baseline (both FEV1 and DLCO) compared to those treated with IMRT. With comparable target coverage, PBSPT exhibited superior sparing of the lung, heart, and spinal cord to radiation exposure compared to IMRT. At a median follow-up of 21.7 (interquartile range: 16.8–26.8) months, the 2-year LRC rates were 72.1% and 84.1% in the IMRT and PBSPT groups, respectively (p = 0.287). The rates of grade ≥ 3 esophagitis were 8.2% and 20.0% after IMRT and PBSPT (p = 0.073), respectively, while corresponding rates of grade ≥ 2 radiation pneumonitis were 28.9% and 16.0%, respectively (p = 0.263). PBSPT appears to be an effective and safe treatment technique even for patients with poor lung function, and it does not jeopardize LRC.

Locoregional control using highly conformal flank target volumes and volumetric-modulated arc therapy in pediatric renal tumors: Results from the Dutch national cohort

Background and purposeIn pediatric renal tumors, conventional two opposing photon beams have been used to cover the postoperative flank target volume for decades. This single center study describes the locoregional outcome using highly conformal flank target volumes adjusted for postoperative changes and intra-fraction motion combined with Volumetric-Modulated Arc Therapy (VMAT). Materials and methodsBetween 01-2015 and 12-2019, 36/161 newly diagnosed patients with renal tumors underwent flank only irradiation (n = 30) or flank + whole lung irradiation (n = 6) using highly conformal target volumes in line with the SIOP-RTSG consensus statement. VMAT consisted of full-arc 10MV photon beams optimized for constraints of the organs at risk. In case of locoregional relapses, image co-registration and dose reconstruction was performed. Each relapse was classified as either ‘infield’ (V95%relapse: ≥99.0%), ‘marginal’ (V95%relapse: 20.0–98.9%) or ‘outfield’ (V95%relapse: 0–19.9%). ResultsAt a median follow-up from diagnosis of 3.1 years (range:0.4–5.7), the estimated 2-year Locoregional Control Rate, Disease-Free Interval and Overall Survival were 94%, 91% and 94%, respectively. Locoregional relapse was observed in two patients. One patient had a combined tumor bed and regional recurrence, classified as infield (V95%relapse: 100%) and outfield (V95%relapse: 1.2%). The second patient had a regional relapse in the inferior vena cava classified as marginal recurrence (V95%relapse: 93%). Relapses would not have been adequately covered by conventional beams. ConclusionsThis single center analysis provides encouraging evidence that excellent locoregional control can be obtained by using highly conformal flank target volumes with VMAT in pediatric renal tumors. The safety of this approach will be validated in a prospective multicenter study.

Consolidation cetuximab after concurrent triplet radiochemotherapy+cetuximab in patients with advanced head and neck cancer: A randomized phase II study

Background and purposePreclinical data suggest that cetuximab should be continued after end of concurrent radiotherapy+cetuximab due to its efficacy against residual tumor cells in the irradiated tumor bed. Based on this concept the phase II add-on cetuximab (AOC) study was designed. Materials and methodsAltogether 63 patients with advanced head and neck cancer were treated with radiochemotherapy (70 Gy, cisplatin 40 mg/m2 weekly) in combination with concurrent cetuximab (loading dose 400 mg/m2, then 250 mg/m2 weekly). Thereafter patients were randomized to cetuximab consolidation (500 mg/m2 biweekly × 6) or no further treatment. The primary endpoint was the 2-year locoregional control (LRC) rate. As translational research endpoints serum markers were analyzed before and during treatment and CT-based quantitative image analysis (radiomics) was performed. ResultsMedian follow-up was 24 months. The 2-year LRC rates were 67.9% and 67.7% in the treatment arms with and without consolidation cetuximab, respectively. Higher than median levels of three serum markers were negatively associated with the 2-year LRC rate in the overall patient cohort: Osteopontin, IL8 and FasL2 (p ≤ 0.05). A radiomics model consisting of two radiomics features could be built showing that higher entropy and higher complexity of tumor Hounsfield unit distribution indicates worse LRC (concordance index 0.66). No correlation was found between biological and imaging markers. ConclusionsThere was no evidence that consolidation cetuximab would improve the 2-year LRC rate. Prognostic biological and imaging markers could be identified for the overall patient cohort. Studies with larger patient numbers are needed to correlate biological and imaging markers.

A Randomized Phase II Translational Research Study in Patients with Advanced Head and Neck Cancer to Investigate the Effects of Standard Chemoradiation and Add-on Concurrent Epidermal Growth Factor Receptor (EGFR) Inhibitor ± Consolidation EGFR Inhibitor

Preclinical data suggest that cetuximab should be continued after end of concurrent RT/cetuximab due to its efficacy against residual tumor cells and angiogenesis in the irradiated tumor niche. Based on this concept the phase II add-on cetuximab (AOC) study was designed. Altogether 59 patients with advanced head and neck cancer, stages T3-4 Nx or Tx N2b-c, were treated with radiochemotherapy (70 Gy, cisplatin 40mg/m2 weekly) in combination with concurrent cetuximab (loading dose 400mg/m2, then 250mg/m2 weekly). Thereafter patients were randomized to cetuximab consolidation (500 mg/m2 biweekly x 6) or no further treatment. The primary endpoint was the 2-year locoregional control (LRC) rate. As translational research endpoints serum markers were analyzed before and during treatment and CT-based quantitative image analysis (radiomics) of the 3D primary tumor volume was performed. The 2-year LRC rates were 67.9% and 67.7% in the treatment arms with and without consolidation cetuximab. Higher than median levels prior to treatment of three serum markers were negatively associated with the 2-year LRC rate in the overall patient cohort: Osteopontin, IL8 and FasL2 (p<0.05). A radiomics model consisting of 2 radiomic features could be built showing that higher entropy and higher complexity of tumor Hounsfield unit distribution indicates worse LRC (CI 0.66). No correlation was found between biological and imaging markers. Consolidation cetuximab does not improve LRC when continued after end of RCT/cetuximab. Independent prognostic biological and imaging markers could be identified for the overall patient cohort. Studies with larger patient numbers are needed to identify the biological basis of imaging features.

Cervical Cancer Outcomes in Elderly Women Treated with EBRT and Brachytherapy +/- Concurrent Chemotherapy

Cervical cancer is commonly viewed as a cancer affecting middle-aged women. However, more than 15% of cervical cancer cases occur in women over age 65. It is uncertain whether literature from trials, in which older women are a minority of the study population, appropriately guides their treatment and describes their natural history. The goal of this study was to evaluate cervical cancer treatment patterns and outcomes in older women in order to better counsel patients and optimize management. We performed a retrospective institutional analysis on women 69 and above with primary cervical cancer treated from 1999 - 2018. Included patients were treated with definitive, curative intent radiotherapy. We excluded patients with distant metastases, those treated palliatively, and those receiving surgery as primary treatment. We evaluated overall patient survival, use of chemotherapy, and recurrence patterns. This study was IRB approved. 65 eligible patients were included. Median age was 77 years (range 69-88), ranging in stage from IB1 to IIIB (IB1: 15 pts; IB2: 6 pts; IIA (NOS): 6 pts; IIA1: 3 pts; IIA2: 3 pts, IIB: 17 pts; IIIA: 2 pts, IIIB: 13 pts). Most were squamous cell carcinoma (83.1%), followed by adenocarcinoma (13.9%) and other (3%). Median external beam radiation (EBRT) dose was 45 Gy and median brachytherapy (BT) dose was 27.5 Gy. BT varied by era, but the majority were treated with HDR BT, with 53/65 (81.5%) HDR, 10/65 (15.4%) LDR, and 2/65 (3.1%) discontinuing treatment prior to brachytherapy. 86.2% received intracavitary BT and 10.8% received combined intracavitary/interstitial BT. Median total duration of therapy (EBRT + BT) was 50 days. The vast majority of women completed their intended course of radiation therapy, with a completion rate of 90.8%. 37 pts (56.9%) received concurrent chemotherapy, most commonly weekly cisplatin. Of those women, 5 (13.5%) discontinued chemotherapy due to adverse effects. With a median follow up of 24 months, 15 pts (24.6%) developed a recurrence, with 3 relapsing locally, 1 relapsing regionally, 9 relapsing with distant metastases only, and 2 relapsing both distantly and regionally. The 2-year local control rate was 91.4% and the loco-regional control rate was 82.9%. The 2-year overall survival was 75.1%. The 2-year disease-free survival was 61.4%. Due to small patient numbers and imbalance in stage between those receiving/not receiving concurrent chemotherapy, no conclusions can be made about the impact of chemotherapy on disease outcomes. The outcomes of elderly patients treated with definitive radiotherapy for cervical cancer are comparable to those of younger women, with the vast majority of patients able to complete therapy, resulting in 2-year loco-regional control rates over 80%. In conclusion, definitive radiation therapy, including brachytherapy, should be encouraged for older women presenting with cervical cancer.

Clinical results of carbon-ion radiotherapy with separation surgery for primary spine/paraspinal sarcomas

To evaluate the clinical outcome of combination of carbon-ion radiotherapy with separation surgery (CIRT-SS) in patients with primary spinal/paraspinal sarcoma (PSPS) and epidural spinal cord compression (ESCC). CIRT-SS was performed in 11 consecutive patients. Patients treated in the primary and salvage settings were categorized into Group A (n = 8) and Group B (n = 3), respectively. Clinical results and imaging findings were collected, with a particular focus on ESCC grade, treatment-associated adverse events (AEs), and the locoregional control (LRC) rate and overall survival (OS). The median follow-up period from the start of CIRT-SS was 25months (7-57months). ESCC was improved by SS in all cases. No patients exhibited radiation-induced myelopathy (RIM), but three developed Grade 3 vertebral compression fracture (VCF) during follow-up. Locoregional recurrences were observed in four patients [Group A: 1 (12.5%), Group B: 3 (100%)]. Over the entire follow-up period, three patients developed distant metastases and two patients died. The 2-year LRC rate and OS were 70% and 80%, respectively. CIRT-SS in the primary setting achieved acceptable LRC and OS without RIM in patients with PSPS and with ESCC. VCF was the most frequent AE associated with CIRT-SS.

Feasibility of Re-irradiation using carbon ions for recurrent head and neck malignancies after carbon-ion radiotherapy

Background and purposeLocoregional recurrence after carbon-ion radiotherapy (CIRT) for primary head and neck malignancies, such as malignant mucosal melanoma, adenoid cystic carcinoma, and sarcoma, occurs occasionally. However, the treatment options are limited. We report on the toxicity and efficacy of re-irradiation using carbon ions for recurrent head and neck malignancies after CIRT. Materials and methodsData of 48 patients with recurrent head and neck malignancies treated with re-irradiation with CIRT at our institution (2007–2016) were retrospectively analyzed. Twenty-one patients (43.8%) had malignant mucosal melanoma, 17 (35.4%) had adenoid cystic carcinoma, six (12.5%) had bone and soft tissue sarcomas, and four patients (8.3%) had other disease types. Tumor recurrences at re-irradiation were located in the paranasal cavity (n = 18, 37.5%), nasal cavity (n = 9, 18.8%), nasopharynx (n = 4, 8.3%), orbit (n = 3, 6.3%), cavernous sinus (n = 3, 6.3%), and at other sites (n = 11, 22.9%). The median dose of initial CIRT and that at re-irradiation were 57.6 Gy and 54.0 Gy (relative biological effectiveness [RBE]), respectively. None of the patients received concurrent chemotherapy. ResultsThe median follow-up period after re-irradiation was 27.1 months. Five patients (10.4%) developed Grade 3 acute toxicities and 18 (37.5%) developed Grade ≥3 late toxicities, including Grade 5 central nervous system necrosis in one patient. The 2-year local control, locoregional control, progression-free survival, and overall survival rates were 40.5, 33.5%, 29.4%, and 59.6%, respectively. ConclusionRe-irradiation using carbon ions may be a reasonable treatment option with tolerable toxicity for patients with recurrent head and neck malignancies after CIRT.

Outcomes of radiotherapy in advanced external auditory canal cancer.

External auditory canal cancer (EACC) is a rare malignant tumor. In the present study, we retrospectively evaluated the treatment results in patients with advanced EACC who were treated using external-beam radiotherapy (EBRT) combined with chemotherapy or radical surgery. Overall, 21 patients with Stage III (n = 8) or Stage IV (n = 13) EACC who underwent initial treatment at our hospital between 2003 and 2016 were enrolled in this study. The 2-year overall survival (OS) and locoregional control (LRC) rates of all patients were 62% and 71%, respectively. The 2-year OS and LRC rates in patients who had received EBRT and concurrent chemotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF, n = 6) were 100%. These results were higher than the 2-year OS and LRC rates of 62% and 69%, respectively, in patients who had received radical surgery and EBRT (n = 13). The rates were 0% in those who had neither received TPF nor undergone surgery in addition to EBRT (n = 2). Grade 3 bone or soft tissue necrosis was observed in 2 patients who had undergone surgery and postoperative EBRT. Our data suggest that the combination therapy of EBRT and surgery and/or chemotherapy may be the most effective treatment options for advanced EACC, and EBRT with concurrent chemotherapy with TPF is potentially the most acceptable.

Patterns of Failure and Clinical Outcomes of Post-operative Buccal Mucosa Cancers Treated with Ipsilateral Radiation Therapy

Loco-regional failure in carcinoma buccal mucosa (BM) after radical resection and adjuvant radiotherapy (RT) generally entails a bad prognosis. Usually, adjuvant RT (if indicated), is delivered to tumor bed and bilateral neck nodes. However, selected patients could be treated with ipsilateral RT to tumor bed and neck nodes (IL-RT). Literature on patterns of failure in this group of patients is sparse. We aimed to analyse the failure patterns and survival outcome in these cohort of patients treated at our institute. Eighty patients of post-operative BM cancers treated with IL-RT from June 2013 to May 2017 were included in this retrospective analysis. RT dose was 60-66 Gray in 30-33 fractions over 6-6.5 weeks delivered by linear accelerator using 3-dimensional conformal radiotherapy techniques. All outcomes were evaluated from the time of registration. Local, regional and loco-regional control was defined as time from registration to failure in tumor bed, regional nodes or both, respectively. Disease free survival (DFS) and overall survival (OS) were defined as time from registration to failure at any site (local, regional or distant) and death from any cause, respectively. Kaplan Meier method was used for all outcome analysis. The median age was 45.5 years (range 30-80). Patient characteristics are described in table 1. Median RT completion time and the overall treatment time were 6.2 weeks (range 5.9-7.1) and 11.6 weeks (range 8.5-19), respectively. 62 patients received 60 Gy, one patient 64 Gy and the rest received 66 Gy. The median follow-up time was 24.4 months (range 5-54.2).The 2-year local, regional and loco-regional control rates were 91.9%, 87.6% and 80.5%, respectively. The 2-year DFS and 2-year OS rates were 76.4% and 82.8%, respectively. The crude rates of failures at primary site, ipsilateral and contralateral neck were 12.5%, 12.5% and 3.7%, respectively. All patients with contralateral neck recurrence had N2 disease. Five patients (6.25%) had distant failures. Sixteen patients (20%) died of cancer and 2 patients died of non-malignant causes. The incidence of contralateral recurrence in BM cancer patients treated with primary surgery and adjuvant IL-RT is low. BM cancer with 1-3 risk factors may be treated with IL-RT, except, patients with N2 nodal status, who are at higher risk of contralateral regional recurrence.Abstract MO_23_2678; Table 1Patient CharacteristicsDistributionGender (Male: Female)75: 5T stage (T1: T2: T3: T4)10%: 43%: 26%: 21%N stage (N0: N1: N2)63%: 19%: 18%Overall TNM stage (I: II: III: IV) (As per AJCC 7th edition)5%: 30%: 23%: 42%Risk factors for post-operative RT (>pT3: pN+: PNI: LVI: Close margins: Tumor thickness)*52: 40: 18: 24: 13: 55Number of risk factors for post-op RT (1: 2: 3: >4)10%: 60%: 17.5%: 12.5%Grade (1: 2: 3)42: 34: 4*The total may not add up to 100% because of presence of multiple factors. Abbreviations: RT=Radiotherapy; PNI=Peri-neural invasion; LVI=Lympho-vascular invasion Open table in a new tab

Rapid In-Field Failures Following Adjuvant Radiation for Buccal Squamous Cell Carcinoma

Squamous cell carcinoma originating in the buccal mucosa and retromolar trigone (RMT) have historically poor outcomes. Difficulties in discriminating tumor origin often result in these subsites being combined in surgical and pathological reports. We aimed to determine if making this anatomical distinction has implications for treatment design and clinical outcomes. Following institutional review board approval, we reviewed all of our oral cavity cases from the last 10 years and identified 27 tumors from either the buccal mucosa or RMT which underwent surgery with reconstruction followed by radiation therapy. We reviewed all pre-operative imaging and examination reports to accurately determine the site of origin. For patients who developed a local failure, we fused the pre-treatment imaging, simulation CT, and follow up imaging to determine the location of failures relative to the radiation field. All recurrences were biopsy proven. We used the Kaplan-meier method to calculate 2-year locoregional control and 2-year disease free survival. Patient characteristics can be found in table 1. The median prescribed radiation dose was 60 Gy and the median time from surgery to radiation was 50 (32-133) days. The 2-year locoregional control rates for buccal mucosa versus RMT respectively were 32.7% versus 68.4%. The 2-year disease free survival rates were 35.9% versus 68.4%. The median times to failure were 12.00 (4.9-115.0) months versus 18.5 (4.5-61.0) months. All buccal mucosa failures occurred within the high dose PTV with a median dose of 60 Gy within the failure region. Following locoregional failure 10 of the 12 patients have died, with a median time from local failure to death of 109 (4-529) days. Squamous cell carcinomas of the buccal mucosa have a dismal prognosis characterized by rapid in field failure. By contrast, RMT cancers may have more favorable outcomes. Therefore, differentiating tumor origin is important for prognostication and treatment. For buccal cancers, interval diagnostic imaging before radiation and treatment intensification should be explored.Abstract MO_6_2507; Table 1Patient CharacteristicsCharacteristicBuccal n=13 (%)RMT n=14 (%)Median Age (y)5857Male10 (77)12 (86)Female3 (23)2 (14)T stageT13 (23)2 (14)T24 (31)2 (14)T301 (7)T4a6 (46)8 (57)T4b01 (7)N stageN09 (69)5 (36)N12 (15)2 (14)N2a00N2b2 (15)7 (50)Overall StageI2 (15)0II4 (31)1 (7)III02 (14)IVA7 (54)10 (71)IVB01 (7)Positive Margin4 (31)8 (57)PNI4 (31)6 (43)LVSI1 (8)6 (43)ECE1 (8)5 (36)Chemo6 (46)7 (50)RT Dose (Median)6066 Open table in a new tab

Treatment outcomes of unknown primary squamous cell carcinoma of the head and neck.

BackgroundTreatment modality of unknown primary squamous cell carcinoma of the head and neck (SCCHN) remains controversial.ObjectivesTo evaluate the treatment outcomes and prognostic factors of unknown primary SCCHN.Materials and methodsPatients with unknown primary SCCHN from April 1995 to March 2013 were recruited retrospectively.ResultsSixty-nine patients were enrolled. The median time of follow-up was 55.5 months. The 2-year loco-regional control rate of all the patients was 60.4%. Multivariate Cox regression analysis revealed that N3 stage, extracapsular spread, distant metastasis, and treatment modality were significantly associated with neck recurrence. The actuarial 5-year disease-specific survival rates of neck dissection, neck dissection plus adjuvant therapy, radiotherapy alone, and combined therapy were 80.0%, 61.7%, 33.3%, and 68.8%, respectively (p = 0.046). The 5-year disease-specific survival rates of N1/N2a, N2b/N2c, and N3 stage were 83.9%, 64.3%, and 36.7%, respectively (p = 0.013). Univariate regression analysis revealed that neck recurrence, supraclavicular node involvement, distant metastasis, N3 stage, and unhealthy lifestyle habits were correlated with disease-specific mortality, especially the first three parameters. Patient’s occupation and comorbidity were not significantly correlated with survival.ConclusionsComposite therapy is mandatory for advanced unknown primary SCCHN. Supraclavicular node involvement and unhealthy lifestyle habits, such as betel nut chewing, indicate a poor prognosis.

The impact of margin reduction on outcome and toxicity in head and neck cancer patients treated with image-guided volumetric modulated arc therapy (VMAT)

Background and purposeIn recent decades, outcomes of patients with head and neck cancer (HNC) have improved as a result of implementing several strategies, such as chemoradiation. However, these improvements were achieved at the cost of increased toxicity. One way to reduce radiation-related toxicity is by reducing the margins. Materials and methodsBetween 2013 and 2016, 206 consecutive patients were treated with CTV-PTV margin of 5 mm and subsequently 208 patients with 3 mm margin. This study evaluates the impact of reducing clinical target volume (CTV) to planning target volume (PTV) margin on outcome and toxicity. ResultsAll patients were treated with volumetric modulated arc therapy (VMAT) with daily-image guidance using cone-beam CT (CBCT). Overall acute grade 3 toxicity was significantly lower in 3 mm-group, compared to 5 mm-group (53.8% vs. 65%, respectively, p = 0.032). The same was true for acute grade 3 mucositis (30.8% vs. 42.2%, p = 0.008) and for acute grade 3 dysphagia (feeding tube-dependence) (22.1% vs. 33.5%, p = 0.026). The incidence of ongoing feeding tube-dependence after 3 months of radiotherapy was 11.1% and 20.4%, respectively (p = 0.012). The 2-year incidence of late grade ≥2 xerostomia was 15.8% and 19.4% (p = 0.8). The 2-year loco-regional control rates of patients treated in 3 mm and 5 mm-groups were 79.9% and 79.2% (p = 1.0). The figures for disease-free survival were 71.5% and 72.7 (p = 0.6) and for overall survival were 75.2% and 75.1% (p = 0.9). ConclusionReducing the CTV-PTV margin from 5 to 3 mm combined with daily CBCT-guided VMAT reduced the severity, frequency, and duration of radiation-related toxicity without jeopardizing outcome.

A prospective study on neoadjuvant chemoradiotherapy plus anti-EGFR monoclonal antibody followed by surgery for locally advanced cervical cancer.

BackgroundTo investigate the efficacy and safety of neoadjuvant chemoradiotherapy plus anti-epidermal growth factor receptor monoclonal antibody followed by surgery for locally advanced cervical cancer (LACC).Patients and methodsPatients with histologically proven LACC were enrolled into this prospective study. All patients received intensity-modulated radiation therapy with conventional fractionation. Weekly cisplatin or nedaplatin was administered concurrently with intensity-modulated radiation therapy. Nimotuzumab, a humanized anti-epidermal growth factor receptor monoclonal antibody, was given at a dose of 200 mg per week for 6 cycles. Approximately 1 month after the completion of neoadjuvant treatment, the patients were assessed for clinical tumor response and operability based on MRI and gynecological examination. For those who were considered to be candidates for surgery, radical hysterectomy, and pelvic lymph node dissection were performed 5–6 weeks after the completion of neoadjuvant therapy.ResultsTwenty-eight patients were enrolled. Clinical complete response and partial response were found in 8 (28.5%) and 20 (71.5%) patients, respectively. Four patients were not eligible for surgery and 2 patients refused surgery although they were assessed as surgical candidates. They were not included in this analysis. Radical hysterectomy and pelvic lymph node dissection were performed for the remaining 22 patients. Among them, 8 (36.4%) had complete pathology response, 9 (40.9%) presented with persistent atypical cells or cervical intraepithelial neoplasia, and 5 (22.7%) presented with macroscopic and/or microscopic residual disease, according to the pathological evaluation. Median follow-up time was 22 months (range, 5–39 months). The 2-year locoregional control rate, progression-free survival rate, distant metastasis-free survival rate, and overall survival rate were 95.0%, 85.2%, 84.0%, and 90.0%, respectively. Acute toxicities were mild in general and easily manageable. Chronic toxicities were mainly limited to grade 1. No severe late toxicities were observed.ConclusionConcurrent chemoradiotherapy plus nimotuzumab followed by surgery is highly effective and safe in LACC. Further studies are warranted to confirm the findings.