RTID-04. GLIOTARGET: A DANISH NATIONWIDE PHASE I/II PLATFORM TRIAL FOCUSING ON INDIVIDUALIZED TARGETED TREATMENT FOR NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS BASED ON GENOMIC PROFILING

INTRODUCTION The survival in glioblastoma has been unchanged since 2005. The introduction of targeted treatments, which have improved survival in several cancers has yet to influence the treatment of glioblastoma. In Gliotarget, we will individualize the targeted treatment, and give it in the primary setting alongside standard therapy with the intention to improve the likelihood of effect. METHODS Gliotarget is a biomarker enriched phase I/II platform trial with initially 4 predefined biomarker selected arms, one miscellaneous biomarker arm and one control arm. All patients receive standard therapy with concomitant radiochemotherapy and adjuvant Temozolomide. The experimental treatment is given alongside the adjuvant Temozolomide. Molecular analysis, including Whole Genome Sequencing, is performed on all patients, to identify actionable biomarkers. The miscellaneous arm gathers patients with not previously defined biomarkers upon which the weekly molecular tumor board decides to treat. Gliotarget includes newly diagnosed IDH-wt glioblastoma patients. In addition, to exclude the patients where the inherent poor prognosis might conceal the drug efficacy, the patients must have a 50% probability of being alive 12 months after initial surgery, according to a prognostic model developed in our institution. The sample size is calculated with Simon’s two-stage design using treatment effect at 9-months progression free survival (PFS9). We anticipate 9 patients for stage one and 24 in total, for each arm. Treatment effect is defined as 65% of the patients in an experimental arm reaching PFS9. For the survival analysis, supplementing the control arm data with leveraged external controls taken from our prospectively registered database will decrease the probability of false positive results. CONCLUSION Gliotarget complements the field of ongoing platform trials with its distinctive trial design. The chosen biomarkers and treatments will be presented at the annual meeting. Enrollment is set to open in Q4 2021.

Feasibility of Stereotactic Body Radiation Therapy on Unresectable Stage III NSCLC with Peripheral Primary Tumor: A Prospective Study (GFPC 01-14)

Concomitant radiochemotherapy (RTCT) is the standard treatment for unresectable stage III non-small cell lung cancer (NSCLC). However, in patients with a peripheral primary tumor, the irradiated volume may include a large portion of normal lung and RT-CT is not possible. This multicenter phase II trial in unresectable stage III NSCLC with peripheral primary tumor evaluated the feasibility of stereotactic body radiation therapy (SBRT) in peripheral tumor after concomitant radio-chemotherapy (RT-CT). Nineteen patients were included and analyzed (median age, 60.9 years; male, 78%; adenocarcinoma, 74%; median size of peripheral primary tumor, 19 mm). At 6 months, the disease control rate was 79% (15/19). SBRT toxicity was generally mild with one (5%) patient having grade 3 lung toxicity. Recruitment for this study was stopped prior to completion, firstly due to the approval of adjuvant durvalumab after RT-CT, which was not anticipated in the design, and secondly due to the small number of stage III NSCLC patients with a peripheral tumor that was accessible to SBRT. Nevertheless, the combination of RT-CT and SBRT appeared to be feasible and safe.

Duration of acute esophageal toxicity in concomitant radio-chemotherapy for non-small cell lung cancer with different fractionation schedules

Objectives: In our previous prospective trial on accelerated hypofractionated concomitant radiochemotherapy (AHRT-CHT) for non-small-cell lung cancer (NSCLC) the incidence of grade ≥3 acute esophageal toxicity (AET) was similar to that reported for conventionally fractionated concomitant radiochemotherapy (CFRT-CHT), but its duration was prolonged. Thus, we aimed to compare the duration of grade ≥3 AET between AHRT-CHT and CFRT-CHT. Methods: Clinical data of 76 NSCLC patients treated with CFRT-CHT (60–66 Gy/2 Gy) during 2015–2020 were retrospectively compared with the data of 92 patients treated with AHRT-CHT (58.8 Gy/2.8 Gy) in the prospective trial. The maximum grade of AET, incidence, and duration of grade ≥3 AET were the endpoints. Univariate and multivariate analyses were applied to correlate clinical and treatment variables with these endpoints. Results: Neither the maximum grade of AET (p = 0.71), nor the incidence of grade ≥3 AET (p = 0.87) differed between the two groups. The number of CHT cycles delivered (2 vs 1, p = 0.005) and higher esophagus mean BED (p = 0.009) were significant predictors for a higher maximum grade of AET; older age was a significant predictor for higher incidence of grade ≥3 AET (p = 0.03). The median duration of grade≥3 AET in AHRT-CHT and CFRT-CHT group was 30 days (range 5-150) vs 7 days (range 3-20), respectively, p = 0.0005. In multivariate analysis, only the AHRT-CHT schedule (p=0.003) was a significant predictor for a longer duration of grade≥3 AET. Conclusions Despite similar incidence of grade≥3 AET, its duration is significantly prolonged in NSCLC patients treated with AHRT-CHT compared to CFRT-CHT. Advances in knowledge Reporting only the rate of grade≥3 AET in clinical trials may underestimate the real extent of the esophageal toxicity; its duration should also be routinely reported.

P14.11 Severe treatment-induced myelosuppression is more frequent in female malignant glioma patients and associated with reduced overall survival

BACKGROUND An association of treatment-related myelotoxicity with female gender has been previously suggested. However, a systematic analysis of the prognostic relevance of radiochemotherapy-related cytopenia involving the different blood cell lineages is lacking. MATERIAL AND METHODS We retrospectively analyzed cytopenia during temozolomide-based concomitant radiochemotherapy (RCT) in 493 glioma patients. Histological grading, molecular pathology, surgical procedures and median overall survival (OS) were recorded. The extent of cytopenia was correlated with gender and outcome. RESULTS Treatment-induced severe cytopenia (leuko-, lympho-, neutro- and thrombocytopenia) occurred much more often in female than in male glioma patients (40.8 vs. 13.9%, p-value <0.0001). In female patients with IDH-wildtype high-grade astrocytomas there was a negative correlation of severe leuko-, lympho- and thrombocytopenia during temozolomide RCT with OS (36 vs. 54, 37 vs. 54 and 36 vs. 57 weeks, respectively; all p-values <0.05). In male patients there was also a trend for this unfavorable effect. Additionally, severe cytopenia correlated with reduced temozolomide dose exposure during RCT (all p-values <0.05 in total cohort) and reduced dose exposure was independently associated with worse OS (p-values <0.05 in the total and female cohort). CONCLUSION Our data confirm that women are at higher risk for treatment-induced cytopenia during RCT which is associated with a significant decrease in OS. From our data, it appears plausible that reduced temozolomide dose exposure during RCT is at least in part responsible for this finding. Immunosuppression of patients with severe cytopenia may be an independent contributor to adverse outcome.

Prevention and management of acute esophageal toxicity during concomitant chemoradiotherapy for locally advanced lung cancer

Background: Standard treatment for locally advanced non-small cell lung cancer (LA-NSCLC) is concomitant chemoradiotherapy. The survival benefit of combined treatment is partially counterbalanced by an increased rate of acute esophageal toxicity. Several pharmaceutical products are available for prevention and management of esophagitis, including Faringel Plus. Aim: To assess the incidence and the grade, identify the correlations with clinical, dosimetric, and therapeutic variables, and analyse the role of Faringel Plus as a pharmaceutical preventive measure against acute esophageal toxicity. Methods: Patients with LA-NSCLC treated with concomitant radiochemotherapy were retrospectively reviewed. Acute esophagitis and dysphagia were graded according to Common Terminology Criteria for Adverse Events version 5.0. Clinical, dosimetric, and therapeutic correlations were investigated using χ2 test. Results: Among the 23 analysed patients, 18 (78.3%) and 1 (4.3%) developed G2 and G3 esophagitis, respectively; G1–2 dysphagia were reported in 11 cases (47.8%). No statistically significant correlation between the variables considered and acute esophageal toxicity was identified. In the group of patients who received Faringel Plus as preventive treatment (10 subjects, 43.5%), dysphagia presentation time was significantly longer ( p = 0.038); esophagitis onset time was longer and symptoms duration was shorter. Faringel Plus allowed a reduction in the use of analgesic drugs. Conclusions: Acute mild esophageal toxicity was confirmed to be a common side effect in this setting. No clinical-dosimetric parameter has been demonstrated to be effective in predicting acute esophageal toxicity. The use of Faringel Plus appears effective as a therapeutic and prophylactic tool to manage acute esophageal toxicity.

HGG-40. EXCEPTIONAL SYNCHRONOUS OCCURENCE OF A BRAF V600E MUTANT GLIOBLASTOMA AND A H3.3K27M MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA: A CASE REPORT

We report herein the case of a 17-year-old female who presented with intracranial hypertension and diplopia. Magnetic resonance imaging showed a large left cystic and solid temporoparietal lesion, associated with an infiltrating lesion of the brainstem, hypointense in T1 and hyperintense in FLAIR sequences, without enhancement after injection of gadolinium. Complete resection of the parietal mass and biopsy of the brainstem lesion were performed. Histopathological analysis of the parietal mass showed glioblastoma (WHO grade IV) with no IDH1/2 or H3.3/H3.1 gene mutation detected by Sanger sequencing. Immunohistochemistry found the expression of the proteins of mismatch repair system. Whole exome and RNA sequencing identified a BRAF-V600E mutation. The brainstem lesion was a diffuse midline glioma, H3K27M-mutant (grade IV) according to the 2016 WHO classification. Pan-genomic SNP arrays of the 2 tumors showed distinct genetic alterations. The parietal glioblastoma displayed complex genomic alterations whereas the brainstem glioma harbored chromosome 7q gain, chromosome 9p and 10 losses, and RB, TP53 and CDKN2A homozygous deletions. The patient was treated by concomitant radiochemotherapy (according to Stupp protocol). After 12 cycles of temozolomide, there was complete remission persistant in the parietal lobe. The brainstem tumor was stable but progressed after 3 months of temozolomide discontinuation. Treatment with mTOR inhibitors was initiated. At 21-month follow-up, the patient remains with few symptoms. No predisposition syndrome was identified in the patient or her family. Concurrent glioblastomas with distinct driver gene mutations are exceptional.

Management of the Uncommon Bladder Cancers: A Single-Center Experience over 10 Years

Background. Under the name of uncommon bladder cancers are gathered rare histological entities which represent less than 5% of bladder tumors. There is not a clear and consensual therapeutic management for these entities. Purpose. To review a single-institution 10-year experience with rare form of bladder cancers detailing the diagnosis, treatment, and patient outcome. Materials and Methods. We performed a retrospective review of 27 medical records of rare bladder cancer form treated at our center between February 2006 and February 2015. The clinicopathologic features are reported with emphasis on treatment and survival. Results. Mean patient age was 65.5 ± 20 yr and 70% of patients were males. Smoking background was found in 16 cases, chronic bladder irritation factors were found in 12 cases, and past urinary tract infection was found in 11 cases. The main symptom was total hematuria (93%) causing an anemia in 16 cases. The two mean histological forms were epidermoid carcinoma (37%) and adenocarcinoma (22%). 26% of patients were found to have extended invasive tumors (T4) at diagnosis. Metastatic disease was confirmed in 8 cases. Our patients were managed by a wide range of therapeutic modalities as total cystectomy with bilateral lymph node dissection (63%), palliative chemotherapy (30%), or concomitant radiochemotherapy (7%). 55.6% of patients were alive one year after diagnosis. Epidermoid carcinoma has the best prognosis followed by leiomyosarcoma and sarcomatoid carcinoma. Neuroendocrine carcinoma has the worst outcome. The overall 5-year survival rate is 33.3%. Conclusion. The rarity and small size of these tumors justify the absence of clear and consensual therapeutic management. No role of total cystectomy concerning the conclusions could be drawn but elements suggest this may be the treatment of choice. The highly aggressive nature of those lesions justifies an aggressive and fast therapy when feasible which gives the best outcomes.

Patient satisfaction in Ambulatory Radiochemotherapy: a study based on the Out-Patsat35 questionnaire

Objective: The aim of our study is to define the main factors contributing to the satisfaction of patients undergoing radiochemotherapy in outpatient setting. Materials and Methods: 100 Patients undergoing ambulatory concomitant radiochemotherapy in National Institute of Oncology at Rabat in Morocco were invited to complete the OUT-PATSAT35 questionnaire, evaluating perception of doctors, nurses and aspects of care organization, translated on Arabic language. The data were collected from different patients, over a period of three months. Statistical analysis was performed to determine which parameters had the greatest influence on overall satisfaction. Results: Overall satisfaction with the provided care was high with a mean satisfaction score of 3.19. Significant correlations were found between overall satisfaction and each of the following survey items: professional skills provided by doctors, behavior of doctors towards patients (patients support), behaviors of nurses towards patients, human qualities of nurses (politeness, respect, kindness and patience), care information provided by nurses, waiting time to get a medical consultation appointment, speed of execution of radiological examination and treatment and service organization. Linear regression analysis demonstrated that service organization, behavior of doctors and nurses towards patients, and care information provided by nurses were the strongest predictors for overall satisfaction, followed by waiting time to get a medical consultation appointment, speed of execution of radiological examination and treatment. Conclusion: Our study shows that the majority of our patients are satisfied with the level of our service, but the waiting time to get a medical consultation appointment, and speed of execution of radiological examination and treatment needs to be developed.

Temozolomide radiochemotherapy for high-grade glioma patients with hemodialysis: a case series of 7 patients

Background The pharmacokinetics of temozolomide (TMZ) in patients with severe renal impairments (creatinine clearance, <36 mL/min/m2) or in hemodialysis (HD) patients has not been investigated. TMZ and its metabolic products are mainly excreted in urine, as retention of these in the body may result in increased adverse events in HD patients. Methods Seven HD patients with high-grade gliomas from 6 institutions were included in the study. Patient characteristics, treatment schedule, clinical course, pathological/molecular findings, and adverse events were evaluated. Results The histopathological diagnoses were isocitrate dehydrogenase (IDH) wild-type glioblastoma in 4 cases, not other specified (NOS) glioblastoma in 2 cases, and IDH-mutant anaplastic astrocytoma in 1 case. Five of the 7 patients completed radiotherapy (48-60 Gy) with concomitant TMZ (75 mg/m2) followed by adjuvant 5-day TMZ (150 mg/m2) every 28 days. During the entire course of treatment with TMZ, severe (Common Terminology Criteria for Adverse Events [CTCAE] ≥ Grade 3) lymphocytopenia occurred in 57%, neutropenia in 0%, and thrombocytopenia in 14% of the patients. Generally, the frequency and degree of myelosuppression do not increase in HD patients with high-grade gliomas. Two of the 7 (28.5%) patients died of infectious disease despite having no direct correlation to myelosuppression; that is similar to the death rate of 21.9% resulting from infection in HD patients in Japan. Conclusions Decreasing the dose of TMZ might not be required in HD patients with high-grade gliomas during concomitant radiochemotherapy and maintenance therapy. However, careful clinical and hematological observation is required to avoid critical hematotoxicity and infection.

ACT-18 SHOULD THE DOSE OF TEMOZOLOMIDE BE DECREASED FOR PATIENTS WITH HIGH-GRADE GLIOMAS WHO ARE ON HEMODIALYSIS?

BACKGROUND The pharmacokinetics of temozolomide in patients with severe renal impairments (creatinine clearance less than 36 mL/min/m2) or in hemodialysis patients has not been investigated. Temozolomide and its metabolic products are mainly excreted in urine, as retention of these in the body may result in increased adverse events in hemodialysis patients harboring a high-grade glioma. METHODS Eight hemodialysis patients with high-grade gliomas from seven institutions were included in the study. Patient characteristics, treatment schedule, clinical course, pathological/molecular findings, and adverse events were evaluated. RESULTS The histopathological diagnoses were Isocitrate dehydrogenase (IDH) wild-type glioblastoma in four cases, Not other specified (NOS) glioblastoma in two cases and IDH-mutant anaplastic astrocytoma in one case. Five of the seven patients completed radiotherapy (48–60 Gy) with concomitant temozolomide (75 mg/m2) followed by adjuvant 5-day temozolomide (150 mg/m2) every 28 days. During the entire course of treatment with temozolomide, severe (Common Terminology Criteria for Adverse Events (CTCAE) more than grade 3) lymphocytopenia occurred in 57%(41.7–61%: non hemodialysis patients data, the same as below), neutropenia in 0%(1–15.4%) and thrombocytopenia in 14%(0–16.7%) of the patients. Generally, the frequency and degree of myelosuppression do not increase in hemodialysis patients with high-grade gliomas. Two of the seven (28.5%) patients died of infectious disease despite having no direct correlation to myelosuppression that is similar rate of 21.9% of the death results from infection in hemodialysis patients in Japan. CONCLUSIONS The high-grade glioma patients under study on hemodialysis did not require decreasing doses of Temozolomide during concomitant radiochemotherapy and maintenance therapy. However, careful clinical and hematological observation is required to avoid critical hematotoxicity and infection.