Stereotactic Radiotherapy for Adrenal Metastases: A Multi-Institutional Review of Patient Characteristics and Outcomes - Turkish Society for Radiation Oncology SBRT Group Study (Trod SBRT 10-004).

INTRODUCTION: This study aimed to report the outcomes of stereotactic body radiotherapy (SBRT) for adrenal metastasis in a retrospective multi-institutional cohort. METHODS: The outcomes of 124 patients with 146 adrenal metastases who underwent SBRT within 11 years (2008-2019) were retrospectively evaluated. Survival outcomes were analyzed by the Kaplan-Meier method. Patient, tumor, and treatment characteristics and their effects on survival, local control (LC), and toxicity outcomes were analyzed by log-rank and multivariate Cox regression methods. RESULTS: The median age was 60 years. The most frequent primary tumor site was the lung, followed by the gastrointestinal system and breast. The adrenal gland was the only metastatic site in 49 (40%) patients. Median biologically effective dose (BED)10 was 61 Gy. The overall LC rate was 83%, and it was positively correlated with the BED10 and fraction dose. The 1- and 2-year local recurrence-free survival, overall survival (OS), and progression-free survival (PFS) rate was 79% and 69%, 83% and 60%, and 31% and 12%, respectively. OS significantly improved with non-lung cancer and <4-cm lesion and PFS with a fraction dose ≥8 Gy, BED10 >65 Gy, and an isolated adrenal metastasis. Fourteen patients reported an acute toxicity, and late toxicity was observed in 3 patients, including one grade 5. CONCLUSION: A satisfactory LC rate was achieved for adrenal metastasis via SBRT. A higher BED10 and fraction dose were positive prognostic factors for tumor control. However, the main problem is DM in these patients, and systemic treatment options are needed to be improved.

Upfront thoracic radiotherapy to primary lesion improves outcomes in patients with stage IV non-small cell lung cancer harboring EGFR mutations.

PURPOSE: The role of thoracic radiotherapy in the treatment of metastatic EGFR mutant non-small cell lung cancer (NSCLC) patients in literature data are insufficient.The purpose of this study was to examine the effectiveness of upfront thoracic radiotherapy in metastatic EGFR mutant NSCLC patients treated with chemotherapy or tyrosine kinase inhibitors (TKI). METHODS: This study was designed as a hospital-based retrospective observational case-series study. A total of 141 patients with metastatic EGFR mutant NSCLC who were followed in two different oncology centers in Turkey between 2014 and 2019 have been included into this study. RESULTS: The median patient age was 63 years (range 35-91). EGFR mutation results of exon 19 deletion, exon 21 mutation and exon 18 mutation were found in 82 (58.2%), 56 (39.7%) and 3 (2.1%) patients, respectively.The median follow-up time was 22 months and 94 (33.3%) patients died during follow-up. Median overall survival (OS) was 26 months and progression free survival (PFS) (for first line treatment) was 10 months for the whole cohort, respectively. Radiotherapy was given to the primary tumor site in 32 (22.6%) patients. Patients receiving radiotherapy to primary tumor site had better OS than those who had not (31 versus 23 months respectively, p=0.02). Survival advantage was also seen for patients group taking TKI at upfront setting (33 versus 23 months respectively, p=0.05). CONCLUSION: In this study, we have shown that upfront thoracic radiotherapy to primary lesion as combination with EGFR-TKI treatment may improve the outcome in advanced stage IV NSCLC patients harboring EGFR mutations.

Role of vaginal brachytherapy boost following adjuvant external beam radiotherapy in cervical cancer: Turkish Society for Radiation Oncology Gynecologic Group Study (TROD 04-002).

OBJECTIVE: There are a limited number of studies supporting vaginal brachytherapy boost to external beam radiotherapy in the adjuvant treatment of cervical cancer. The aim of this study was to assess the impact of the addition of vaginal brachytherapy boost to adjuvant external beam radiotherapy on oncological outcomes and toxicity in patients with cervical cancer. METHODS: Patients treated with post-operative external beam radiotherapy ± chemotherapy ± vaginal brachytherapy between January 2001 and January 2019 were retrospectively evaluated. The treatment outcomes and prognostic factors were analyzed in patients treated with external beam radiotherapy with or without vaginal brachytherapy. RESULTS: A total of 480 patients were included in the analysis. The median age was 51 years (range 42-60). At least two intermediate risk factors were observed in 51% of patients, while 49% had at least one high-risk factor. The patients in the external beam radiotherapy + vaginal brachytherapy group had worse prognostic factors than the external beam radiotherapy alone group. With a median follow-up time of 56 months (range 33-90), the 5-year overall survival rate was 82%. There was no difference in 5-year overall survival (87% vs 79%, p=0.11), recurrence-free survival (74% vs 71%, p=0.49), local recurrence-free survival (78% vs 76%, p=0.16), and distant metastasis-free survival (85% vs 76%, p=0.09) rates between treatment groups. There was no benefit of addition of vaginal brachytherapy to external beam radiotherapy in patients with positive surgical margins. In multivariate analysis, stage (overall survival and local recurrence-free survival), tumor histology (recurrence-free survival, local recurrence-free survival and distant metastasis-free survival), parametrial invasion (recurrence-free survival and distant metastasis-free survival), lymphovascular space invasion (recurrence-free survival), and lymph node metastasis (distant metastasis-free survival) were found as negative prognostic factors. CONCLUSION: Adding vaginal brachytherapy boost to external beam radiotherapy did not provide any benefit in local control or survival in patients with cervical cancer.

Multi-institutional validation of the ESMO-ESGO-ESTRO consensus conference risk grouping in Turkish endometrial cancer patients treated with comprehensive surgical staging.

In this study, 683 patients with endometrial cancer (EC) after comprehensive surgical staging were classified into four risk groups as low (LR), intermediate (IR), high-intermediate (HIR) and high-risk (HR), according to the recent consensus risk grouping. Patients with disease confined to the uterus, ≥50% myometrial invasion (MI) and/or grade 3 histology were treated with vaginal brachytherapy (VBT). Patients with stage II disease, positive/close surgical margins or extra-uterine extension were treated with external beam radiotherapy (EBRT)±VBT. The median follow-up was 56 months. The overall survival (OS) was significantly different between LR and HR groups, and there was a trend between LR and HIR groups. Relapse-free survival (RFS) was significantly different between LR and HIR, LR and HR and IR and HR groups. There was no significant difference in OS and RFS rates between the HIR and HR groups. In HR patients, the OS and RFS rates were significantly higher in stage IB - grade 3 and stage II compared to stage III and non-endometrioid histology without any difference between the two uterine-confined stages and between stage III and non-endometrioid histology. The current risk grouping does not clearly discriminate the HIR and IR groups. In patients with comprehensive surgical staging, a further risk grouping is needed to distinguish the real HR group.Impact statementWhat is already known on this subject? The standard treatment for endometrial cancer (EC) is surgery and adjuvant radiotherapy (RT) and/or chemotherapy is recommended according to risk factors. The recent European Society for Medical Oncology (ESMO), European Society of Gynaecological Oncology (ESGO) and European Society for Radiotherapy and Oncology (ESTRO) guideline have introduced a new risk group. However, the risk grouping is still quite heterogeneous.What do the results of this study add? This study demonstrated that the current risk grouping recommended by ESMO-ESGO-ESTRO does not clearly discriminate the intermediate risk (IR) and high-intermediate risk (HIR) groups.What are the implications of these findings for clinical practice and/or further research? Based on the results of this study, a new risk grouping can be made to discriminate HIR and IR groups clearly in patients with comprehensive surgical staging.

Stereotactic radiotherapy in patients with oligometastatic or oligoprogressive gynecological malignancies: a multi-institutional analysis.

INTRODUCTION: Data supporting stereotactic body radiotherapy for oligometastatic patients are increasing; however, the outcomes for gynecological cancer patients have yet to be fully explored. Our aim is to analyze the clinical outcomes of stereotactic body radiotherapy in the treatment of patients with recurrent or oligometastatic ovarian cancer or cervical cancer. METHODS: The clinical data of 29 patients (35 lesions) with oligometastatic cervical cancer (21 patients, 72%) and ovarian carcinoma (8 patients, 28%) who were treated with stereotactic body radiotherapy for metastatic sites were retrospectively evaluated. All patients had <5 metastases at diagnosis or during progression, and were treated with stereotactic body radiotherapy for oligometastatic disease. Patients with ≥5 metastases or with brain metastases and those who underwent re-irradiation for primary site were excluded. Age, progression time, mean biologically effective dose, and treatment response were compared for overall survival and progression-free survival. RESULTS: A total of 29 patients were included in the study. De novo oligometastatic disease was observed in 7 patients (24%), and 22 patients (76%) had oligoprogression. The median follow-up was 15.3 months (range 1.9-95.2). The 1 and 2 year overall survival rates were 85% and 62%, respectively, and the 1 and 2 year progression-free survival rates were 27% and 18%, respectively. The 1 and 2 year local control rates for all patients were 84% and 84%, respectively. All disease progressions were observed at a median time of 7.7 months (range 1.0-16.0) after the completion of stereotactic body radiotherapy. Patients with a complete response after stereotactic body radiotherapy for oligometastasis had a significantly higher 2 year overall survival and progression-free survival compared with their counterparts. In multivariate analysis, early progression (≤12 months) and complete response after stereotactic body radiotherapy for oligometastasis were the significant prognostic factors for improved overall survival. However, no significant factor was found for progression-free survival in the multivariable analysis. No patients experienced grade 3 or higher acute or late toxicities. CONCLUSIONS: Patients with early detection of oligometastasis (≤12 months) and with complete response observed at the stereotactic body radiotherapy site had a better survival compared with their counterparts. Stereotactic body radiotherapy at the oligometastatic site resulted in excellent local control rates with minimal toxicity, and can potentially contribute to long-term survival.

Is there any benefit of paraaortic field irradiation in pelvic lymph node positive endometrial cancer patients? A propensity match analysis.

We evaluated the survival outcomes and recurrence patterns of endometrial cancer (EC) patients with pelvic lymph node metastases who received postoperative radiotherapy (RT) to the pelvis (P-RT) or to the pelvis plus paraaortic lymph nodes (PA-RT) with or without systemic chemotherapy (ChT). The data from 167 patients with stage IIIC1 EC treated with postoperative RT or RT and ChT were collected retrospectively. Those patients with pelvic lymph node metastases were treated with either P-RT (106 patients, 63%) or PA-RT (61 patients, 37%). The median follow-up time for the entire cohort was 49 (range = 5-199) months. The patients receiving adjuvant ChT and RT had significantly higher 5-year OS rates (77% vs. 33%, p < .001) and 5-year PFS rates (71% vs. 30%, p < .001) when compared to those receiving adjuvant RT alone. The patients receiving P-RT and ChT had significantly higher 5-year OS rates and 5-year PFS rates when compared to those treated with adjuvant PA-RT in the entire cohort and matched cohort. Adjuvant ChT together with RT is the strongest predictor of the OS and PFS. Prophylactic PA-RT is unnecessary, even if ChT is used together with P-RT in EC patients with pelvic lymph node metastasis.Impact statementWhat is already known on this subject? Local and distant recurrence risks are relatively higher in patients with stage IIIC disease, postoperative adjuvant treatment is required to reduce the recurrence risk. Adjuvant RT is a common approach for patients with locally advanced EC. Optimal target volume for RT in patients with stage IIIC EC remains controversial. We demonstrated that extended field RT is unnecessary, even if ChT is used together with pelvic RT in stage IIIC EC patients.What do the results of this study add? We demonstrated that adjuvant ChT together with RT is the strongest predictor of the OS and PFS for EC patients with pelvic lymph node metastases. Extended field RT is unnecessary, even if ChT is used together with pelvic RT in EC patients with pelvic lymph node metastases.What are the implications of these findings for clinical practice and/or further research? Although adjuvant treatment modalities are associated with improvements in survival, distant metastasis still remains the most common site of recurrence in advanced EC patients. Thus, further research is warranted to identify improved combined modality strategies to optimise the outcomes for EC patients with pelvic lymph node metastasis.

Radiotherapy After Skin-Sparing Mastectomy and Implant-Based Breast Reconstruction.

INTRODUCTION: We evaluated the cosmetic results of radiotherapy (RT) after implant-based reconstruction (IBR). PATIENTS AND METHODS: We retrospectively evaluated 170 patients with 171 breast cancers treated between December 2004 and January 2016 in 2 university hospitals. RT fields were reconstructed breast (RB) only in 24 (14%), and RB and regional lymphatics in 147 (86%) breasts, respectively. All but 1 patient received a total 50 Gy with conventional fractionation. All patients received systemic chemotherapy. One hundred thirty-eight (81%) patients received hormonal therapy; 118 tamoxifen and 20 aromatase inhibitor. RESULTS: Median follow-up time was 46.8 months (range, 1-163 months). The 5-year disease-free and overall survival rate was 83% and 93%, respectively. Cosmetic results were considered excellent in 111 (65%), fair in 46 (27%), and bad in 14 (8%) RB by patients. Thirty-four (20%) RB had restorative surgery; because of surgeons' preference because of implant natural life time span in 5, and contracture, fibrosis, deformation, or dislocation of the implant, or cellulitis in the remaining. Statistically significant adverse factors in univariate analysis for impaired cosmetic outcome were bolus use on the RB, lymphatic irradiation, and volume that received at least 110% of the prescribed dose being > 1%. The use of bolus material was the only prognostic factor for deterioration of the cosmetic result in multivariate analysis. CONCLUSION: RT after IBR yields acceptable cosmetic results. Although only 111 (65%) of RBs were considered to have excellent cosmetic results, only a small percentage of patients needed reoperation because of bad cosmetic outcome.

The hematologic parameters in metastatic castration-resistant prostate cancer patients treated with abiraterone acetate.

Currently, there are no predictive markers of response to abiraterone. We calculated neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) at baseline and at 4 and 12 weeks after initiation of abiraterone, and we evaluated prostate-specific antigen (PSA) response every 4 weeks in 102 metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone either pre- or postchemotherapy. With a median follow-up was 24.0 months (range: 0.3-54.9), median overall survival (OS) was 20.8 months. High-NLR patients who remained high or who returned to low NLR after 4 and 12 weeks showed significantly worse OS than patients with low baseline NLR. NLR and prostate-specific antigen response to abiraterone was a significant predictor of OS and progression-free survival (PFS) in metastatic castration-resistant prostate cancer patients treated with abiraterone delivered either pre- or postchemotherapy.

Prognostic values of ADCmean and SUVmax of the primary tumour in cervical cancer patients treated with definitive chemoradiotherapy.

We analysed the correlation of 18F-fluorodeoxyglucose uptake into primary tumours using the maximum standardised uptake value (SUVmax) and the mean apparent diffusion coefficient (ADCmean) values in magnetic resonance imaging (MRI) with the clinical and pathological factors in patients with cervical cancer who were treated with concurrent chemoradiotherapy. The patients were stratified according to the primary tumour pre-treatment ADCmean and SUVmax cut-off values. There were significant correlations between the SUVmax of the primary tumour and tumour size, and the treatment response. The correlation between the ADCmean and FIGO stage, tumour size, and the lymph node metastasis was significant. The SUVmax was significantly and inversely correlated with the ADCmean for cervical cancer (r = -0.44, p <.001). In the multivariate analysis, the primary tumour ADCmean, treatment response and the lymph node metastasis emerged as significant independent predictors of both OS and DFS, and of the primary tumour SUVmax for DFS. Tumour size has a borderline significance for OS. High SUVmax and low ADCmean of the primary tumour are important predictive factors for identifying high-risk patients with cervical cancer who are treated with definitive chemoradiotherapy. These results point to a future role for the diffusion-weighted MRI and for 18F-fluorodeoxyglucose positron emission tomography, not only in the staging of cervical cancer but as an aid in the selection of an adjuvant treatment regimen after chemoradiotherapy for individual patients. Impact statement What is already known on this subject? A negative correlation between primary tumour SUVmax derived from positron emission tomography (PET/CT) and ADCmin derived from diffusion weighted magnetic resonance imaging (DW-MRI) in various cancer types and cervical cancer has been demonstrated. However, the prognostic value of primary tumour SUVmax and ADCmean in cervical cancer patients treated with definitive chemoradiotherapy is not well studied yet. What the results of this study add? The patients with high-risk features (larger tumours, extensive stage, lymph node metastasis) had higher primary tumour SUVmax and lower ADCmean values. Primary tumour ADCmean and lymph node metastasis emerged as significant independent predictors of both overall and disease-free survival. This study demonstrated that the functional biomarkers delivered from PET-CT and DW-MRI are important in predicting the treatment outcomes in the squamous cell carcinoma of cervix treated with definitive chemoradiotherapy, where clinical and radiological findings are very important, since these patients are not staged surgically. What are the implications of these findings for clinical practice and/or further research? Based on these findings, there may be a future role of DW-MRI and FDG/PET-CT not only in the staging of cervical cancer but as an aid in the selection of an adjuvant treatment regimen after chemoradiotherapy (ChRT) for individual patients.

Local recurrence outcomes after breast conserving surgery and adjuvant radiotherapy in ductal carcinoma in situ of the breast and a comparison with ECOG E5194 study.

PURPOSE: Turkish Radiation Oncology Study Group investigated local recurrence rates and prognostic factors in patients with ductal carcinoma in situ (DCIS) of the breast treated with breast conservative surgery (BCS) followed by radiotherapy (RT) and Eastern Cooperative Oncology Group (ECOG) Study E5194 were compared with the original study. PATIENTS AND METHODS: Totally 252 patients were evaluated retrospectively. Prognostic factors that might influence local control (age, nuclear grade, comedo necrosis, surgical margins, tumor size, hormone receptor status) were compared. The eligibility criteria of ECOG 5194 were stratified into two groups as in the original study and were compared for local control. RESULTS: The median follow-up time was 59 (21-220) months. Local recurrence was observed in 9 patients (3.6%) who had invasive carcinoma (3 patients) and DCIS (6 patients). Ten years local control rates was 91.8% respectively. We found that the risk of ipsilateral breast recurrence was significantly higher in women younger than 50 years old (p = 0.016). In addition, a statistically significant trend was found in patients with tumor larger than 1 cm and HER2 positive tumors (p = 0.051, p = 0.068 respectively). When 12-year results were compared with the ECOG 5194, adjuvant RT produced an absolute difference of 11% in low-intermediate and 20% in high grade in local control. CONCLUSION: In our study, the 10-year local control rate was 92% and younger than 50 years old was the most important unfavorable prognostic factor for local recurrence. There was provided 20% absolute local control with adjuvant radiotherapy which eligibility criteria of ECOG 5194 high grade group.

Dosimetric comparison of 3-dimensional conformal radiotherapy, volumetric modulated arc therapy, and helical tomotherapy for postoperative gastric cancer patients.

PURPOSE: To compare dosimetric data for the planning target volume (PTV) and organs at risk (OARs) between 3-dimensional conformal radiotherapy (3DCRT), volumetric modulated arc therapy (VMAT), and helical tomotherapy [1]. MATERIALS AND METHODS: The dosimetric data for 15 gastric cancer patients treated with 3DCRT, VMAT, or HT techniques were used. Cumulative dosimetric parameters, homogeneity index (HI), and conformal index (CI) were compared for the PTV and OARs. RESULTS: The average maximum doses of PTV were significantly higher in VMAT plans than in 3DCRT (p = 0.04) and HT (p = 0.02) plans, whereas minimum dose values were significantly lower in 3DCRT plans compared with VMAT (p < 0.001) and HT (p = 0.02) plans. Liver mean dose (D mean) and D mean values for both kidneys were significantly lower in HT plans than in 3DCRT and VMAT plans. The doses in high dose regions (V30-V45) using 3DCRT plans were significantly higher compared to both VMAT and HT plans. The bowel V5-V30 and V45 was significantly less in HT plans compared to VMAT plans. There were no significant differences in dose sparing of the spinal cord. CONCLUSIONS: The HT plans reduced the maximum dose applied to the target and improved the conformality and homogeneity of radiation, while providing sufficient PTV coverage.

Outcomes of aggressive treatment in esophageal cancer patients with synchronous solitary brain metastasis.

The aim of the present study was to investigate the outcomes of esophageal cancer (EC) patients with isolated synchronous brain oligometastasis (oligo-BM) treated with chemoradiotherapy (CRT) of the primary site and localized treatment of the BM with surgery, radiotherapy (RT) or radiosurgery. Of 125 EC patients investigated, seven patients (6%) had solitary BM. Six patients were diagnosed prior to, and one patient was diagnosed during, treatment. All patients were treated with neoadjuvant chemotherapy and whole-brain RT (WBRT) for BM. All but one patient received definitive CRT with a median RT dose of 50.4 Gy using conventional fractionation RT. The median age at diagnosis was 59 years (range, 48-77 years). Six patients succumbed to mortality, and one continued to receive systemic chemotherapy at the last visit. The median survival time of the patients was 18.9 months (range, 10.0-27.2 months). Median time to progression after completion of the treatments was 8 months (range, 3-9 months). Two patients had progression of the primary tumor, and one patient had progression of the BM. The neurological status of three patients with BM who were identified during the staging work-up did not deteriorate as a consequence of WBRT. In conclusion, the present study has demonstrated that aggressive treatment of the primary tumor and oligo-BM in patients with EC may prolong the survival time.

PREVENTION OF RADIATION-INDUCED RETINOPATHY WITH AMIFOSTINE IN WISTAR ALBINO RATS.

PURPOSE: To evaluate the radioprotective efficacy of amifostine on irradiated mature rat retina. METHODS: A total of 108 Wistar albino rats were categorized into 3 groups, namely, apoptosis (n = 48), acute effects (n = 40), and late changes in retinal cell layers (n = 20). Each group was further subcategorized into 4 arms: control, amifostine (A), radiotherapy + placebo (RT), and RT + A arms, respectively. Intraperitoneal amifostine (260 mg/kg) was administrated to A and RT + A arms 30 minutes before irradiation. Control and A groups were sham-irradiated, whereas a single dose of 20 Gy whole-cranium irradiation was delivered to RT and RT + A arms. Apoptosis was assessed in 8, 12, and 18 hours after irradiation. Electron microscope was used 2 weeks after irradiation for evaluation and scoring of early morphologic changes in retina. Late effects were assessed and scored accordingly by using both the electron and the light microscope on Week 10. RESULTS: At acute phase, although no notable change was seen in 8 hours, significant increase in apoptosis was detected in 12 hours in RT arm (P = 0.029). Comparative analyses between the groups in 3 different time points displayed a higher apoptotic rate in RT group than the RT + A group (P = 0.008). Similarly, comparisons between groups for late effects on the basis of electron microscopic findings revealed lower scores in the RT + A than the RT arm (P < 0.001). CONCLUSION: This study suggested a potential radioprotective role for amifostine on mature rat retina by reducing radiation-induced apoptosis in retinal cells. These results form a basis for such preclinical investigations and call for future clinical studies.