CTNI-28. VOLUMETRIC AND DOSIMETRIC PATTERNS OF FAILURE ANALYSIS OF A PHASE II CLINICAL TRIAL OF 18F-DOPA-PET DIRECTED DOSE ESCALATED RADIOTHERAPY FOR GLIOBLASTOMA

While dose escalation of radiotherapy (DERT) has failed to improve overall survival (OS) or progression-free survival (PFS) for glioblastoma in previous studies, a recent phase II clinical trial utilizing 18F-DOPA-PET-directed DERT demonstrated improved PFS in MGMT-unmethylated patients and OS in MGMT-methylated patients compared to historical controls. This planned secondary analysis sought to determine 1) how 18F-DOPA-PET changes RT volumes beyond standard MRI-planning, 2) which patients benefit most and least from this protocol, 3) which are mostly likely to experience clinically significant radionecrosis after DERT, and 4) patterns of failure after DERT. For 69 evaluable patients, median MRI-defined, PET-defined, and combined low-dose gross tumor volumes (GTV51) were 54 cc (range 9-248), 23 cc (0.4-179), and 62 cc (10-260), respectively. Median MRI-defined, PET-defined, and combined high-dose GTVs (GTV76) were 32 cc (range 4-136), 6 cc (0.1-138), and 34 cc (4-162), respectively. 18F-DOPA-PET resulted in a median volumetric expansion of 13% (0-243%) and 5% (0-217%) from MRI-defined low-dose and high-dose GTV’s, respectively. Central failures ( >95% of recurrence tumor volume) occurred within the 76 Gy, 60 Gy, and 51 Gy isodose lines in 32 (46%), 60 (87%), and 64 (93%) patients, respectively. Recursive partitioning analysis stratified patients by OS and PFS. Patients with 18F-DOPA-PET-defined GTV76 > 7.8cc, MRI-defined GTV76 > 42.7cc, and MGMT promotor-unmethylated tumors had the shortest OS, while patients with smaller PET and MRI-defined tumors had the longest OS (median 10.4 vs. 64.6 months, p< 0.001). Similarly, PFS was worst in patients with 18F-DOPA-PET-defined GTV76 > 2.17 cc who had biopsy only (median PFS 3.2 months, p< 0.001). Patients with 18F-DOPA-PET-defined GTV51 > 50 cc had the highest risk of grade 3+ radionecrosis (p< 0.001). In conclusion, larger 18F-DOPA-PET and MRI-defined tumor volumes were associated with worse outcomes, and 18F-DOPA-PET-directed DERT appears to reduce risk of central recurrence in high-dose volumes.

Evaluation of Treatment Outcome and Acute Toxicity in Patients Undergoing Adjuvant Therapy in Ductal Carcinoma Pancreas: A Prospective Observational Study

Ductal adenocarcinoma of the pancreas is one of the commonly diagnosed cancers and is a leading cause of cancer mortality in the population. The prognosis of patients even after undergoing a complete resection is generally poor, with a median survival of 13–20 months and a 3-year survival of 30%. Therefore, adjuvant therapies including adjuvant chemoradiation and adjuvant chemotherapy are given in an effort to improve survival. In the authors’ centre, all patients undergoing resection are given adjuvant chemoradiation followed by adjuvant chemotherapy. This study was conducted to evaluate the acute toxicity and treatment outcome (patterns of failure, overall and disease-free survival) of patients undergoing adjuvant therapy in resected carcinoma pancreas. Adjuvant chemoradiation was well tolerated by most patients with resected carcinoma pancreas and all patients completed chemoradiation. Adjuvant chemotherapy was associated with high haematological toxicity, similar to previously published literature. However, treatment interruptions were higher and only 77% patients completed adjuvant chemotherapy. The adjuvant gemcitabine, given on Days 1, 8, and 15, for a 4-weekly schedule was poorly tolerated by the authors’ patient population and there were only fewer interruptions in patients who were switched to the 3-weekly schedule. Inclusion of a greater number of patients and longer follow-up of this study is required to clearly assess the patterns of failure and survival outcomes.

782 PATTERNS OF FAILURE AND ADEQUACY OF CLINICAL TARGET VOLUME (CTV) MARGINS IN PATIENTS TREATED WITH DEFINITIVE CHEMO-RADIATION IN ESOPHAGEAL CANCER

Esophageal cancer is a locally aggressive malignancy with dismal overall survival (OS) rates. Approximately 50–60% of patients fail loco-regionally after definitive chemoradiation (CTRT). There is a lack of consensus regarding clinical target volume (CTV) margins. Improved diagnostic investigations and patterns of failure (POF) data, suggested scope of reduced CTV margins. In this retrospective study, we evaluated the POF (defined as first site of failure) and the adequacy of CTV margins. Methods All patients treated with CTRT between Jan 2013 to Dec 2017 were included. CTV margin was given as 3–5 cm cranio-caudal and 1–1.5 cm radial from gross tumor volume (GTV). Patients were treated either with combined technique (anterior–posterior followed by conformal) or with volumetric arc radiotherapy to a dose of 60-63Gy in 30–35 fractions. PET-CT/CT thorax and upper GI-endoscopy were performed at regular intervals. Loco-regional failure (LRF) was defined as recurrence at local site or regional nodes respectively and classified as infield, marginal and out-field. CT was co-registered with planning CT to document these failures. Results 158 patients were eligible. Twenty-one patients were excluded as they either progressed or did not attend the first follow-up. Median age was 57 years, >90% had squamous histology, and most common subsite was upper third. Median follow-up was 45.8 months, 53 patients (41.7%) had progression. Local recurrence (LR) was seen in 37 (69.8%), followed by regional in 25 (47.1%) and distant in 21 patients (39.6%). All LR were within the GTV. Of regional failures, 50% were within GTV and 50% were outside the radiotherapy portals. This suggest that 3 cm cranio-caudal CTV margin was adequate. Conclusion Our study demonstrated that loco-regional recurrence was the most common pattern of failure after definitive CTRT. As majority of loco-regional failures were within the GTV, hence, 3 cm cranio-caudal CTV margins appear to be adequate enough for control of microscopic disease. Further prospective studies are needed to validate the use of 3 cm CTV margins in definitive CTRT for esophageal cancer.

Salvage surgery for patients with residual/persistent diseases after improper or insufficient treatment of oral squamous cell carcinoma: can we rectify these mistakes?

Background Patterns of failure after treatment of oral and squamous cell carcinomas (OSCC) are diversified, with recurrences being one of the common causes. A special group of patients are sometimes encountered in the outpatient clinic for improper or insufficient initial treatment with reports of positive margins, implying residual/persistent diseases. The question of whether these patients can be surgically salvaged remain unanswered. Methods A retrospective study was performed between January 2013 and December 2017 for patients with residual or rapid recurrent (within 3 months) OSCCs, who received salvage surgeries in our institution. The patients with residual/persistent OSCCs were those with microscopic or macroscopic positive surgical margins, while those with rapid recurrent OSCCs were those with close or negative margins, but unabated painful symptoms right after treatment. Both clinicopathological and prognostic variables were analyzed. The focus was also directed towards lessons for possible initial mistakes, resulting in these residual/persistent diseases. Results Of 103 patients, 68 (66%) were men, with mean age of 56.3 years. The overall survival reached 60.2%. Regarding the primary OSCC status, most of our patients (n = 75, 72.8%) were diagnosed with ycT2–3 stages. Besides, most patients were found with macroscopic residual diseases (52.4%) before our salvage surgery. The sizes of the residual/persistent OSCCs were generally under 4 cm (87.3%) with minimally residual in 21 (20.4%). Among all the variables, primary T stage (p = 0.003), and residual lesion size (p < 0.001) were significantly associated with the prognosis in multivariate analysis. Though the causes for the initial surgical failure were multifactorial, most were stemmed from poor planning and unstandardized execution. Conclusions Cases with residual/persistent OSCCs were mostly due to mistakes which could have been avoided under well-round treatment plans and careful surgical practice. Salvage surgery for cases with smaller residual/persistent OSCCs is still feasible with acceptable outcomes.

TERT Promoter Mutations Are Enriched in Oral Cavity Cancers and Associated With Locoregional Recurrence

PURPOSE Telomerase reverse transcriptase ( TERT) promoter mutations are prognostic in many cancers and have been observed in human papillomavirus (HPV)–negative head and neck squamous cell carcinomas (HNSCCs). However, the role of TERT promoter mutations in HPV-negative HNSCCs remains poorly understood in these cancers, which have increased risk for locoregional failure (LRF). PATIENTS AND METHODS We retrospectively identified patients who were diagnosed with HNSCC between July 1, 2004, and October 12, 2017, at Memorial Sloan Kettering Cancer Center and whose tumors underwent next-generation sequencing using the MSK-IMPACT panel. Patients with HPV-positive oropharyngeal squamous cell carcinoma (SCC) were excluded. Cumulative incidence of LRF, patterns of failure, and overall survival were measured. RESULTS We identified 117 patients with SCC of the oral cavity (OSCC), larynx, hypopharynx, or HPV-negative oropharynx whose tumors underwent next-generation sequencing. Sequencing was performed on 95 tumors that were obtained after recurrence and 22 that were obtained before recurrence. TERT promoter mutations were enriched in OSCC compared with laryngopharyngeal cancers (81.1% v 7.0%; P < .001), which was the largest genetic difference between these anatomic disease subsites. TERT promoter mutations were associated with LRF in OSCCs (Gray's test, P < .001) and in the overall cohort (Gray's test, P < .001). On multivariate analysis, TERT promoter mutations were associated with an increased risk for LRF (subdistribution hazard ratio, 2.82; 95% CI, 1.47 to 5.42; P = .0019), independent of oral cavity primary site and TP53 mutation status. CONCLUSION TERT promoter status is associated with the cumulative incidence of LRF and patterns of failure. TERT promoter mutations may define a subset of OSCCs with unique pathogenesis that is associated with an increased risk of LRF. Validation in prospective cohorts is warranted.