Nonmetastatic pancreatic cancer : Improved survival with chemoradiotherapy > 40 Gy after systemic treatment.

PURPOSE: The role of radiotherapy (RT) for nonmetastatic pancreatic cancer is still a matter of debate since randomized control trials have shown inconsistent results. The current retrospective single-institution study includes both resected and unresected patients with nonmetastasized pancreatic cancer. The aim is to analyze overall survival (OS) after irradiation combined with induction chemotherapy. PATIENTS AND METHODS: Of the 73 patients with nonmetastatic pancreatic cancer eligible for the present analysis, 42 (58%) patients had adjuvant chemoradiotherapy (CRT), while 31 (42%) received CRT as primary treatment. In all, 65 (89%) had chemotherapy at any time before, during, or after RT, and 39 (53%) received concomitant CRT. The median total dose was 50 Gy (range 12-77 Gy), while 61 (84%) patients received >40 Gy. RESULTS: With a median follow-up of 22 months (range 1.2-179.8 months), 14 (19%) are still alive and 59 (81%) of the patients have died, whereby 51 (70%) were cancer-related deaths. Median OS and the 2­year survival rate were 22.9 months (1.2-179.8 months) and 44%, respectively. In addition, 61 (84%) patients treated with >40 Gy had a survival advantage (median OS 23.7 vs. 17.3 months, p = 0.026), as had patients with 4 months minimum of systemic treatment (median OS 27.5 vs. 14.3 months, p = 0.0004). CONCLUSION: CRT with total doses >40 Gy after induction chemotherapy leads to improved OS in patients with nonmetastatic pancreatic cancer.

DART-bid for loco-regionally advanced NSCLC : Summary of acute and late toxicity with long-term follow-up; experiences with pulmonary dose constraints.

BACKGROUND: To report acute and late toxicity with long-term follow-up, and to describe our experiences with pulmonary dose constraints. METHODS: Between 2002 and 2009, 150 patients with 155 histologically/cytologically proven non-small cell lung cancer (NSCLC; tumor stages II, IIIA, IIIB in 6, 55 and 39%, respectively) received the following median doses: primary tumors 79.2 Gy (range 72.0-90.0 Gy), lymph node metastases 59.4 Gy (54.0-73.8 Gy), nodes electively 45 Gy; with fractional doses of 1.8 Gy twice daily (bid). In all, 86% of patients received 2 cycles of chemotherapy previously. RESULTS: Five treatment-related deaths occurred: pneumonitis, n = 1; progressive pulmonary fibrosis in patients with pre-existing pulmonary fibrosis, n = 2; haemorrhage, n = 2. In all, 8% of patients experienced grade 3 and 1.3% grade 4 pneumonitis; 11% showed late fibrotic alterations grade 2 in lung parenchyma. Clinically relevant acute esophagitis (grade 2 and 3) was seen in 33.3% of patients, 2 patients developed late esophageal stenosis (G3). Patients with upper lobe, middle lobe and central lower lobe tumours (n = 130) were treated with V20 (total lung) up to 50% and patients with peripheral lower lobe tumours (n = 14, basal lateral tumours excluded) up to 42%, without observing acute or late pulmonary toxicity >grade 3. Only patients with basal lateral lower lobe tumours (n = 5) experienced grade 4/5 pulmonary toxicity; V20 for this latter group ranged between 30 and 53%. The mean lung dose was below the QUANTEC recommendation of 20-23 Gy in all patients. The median follow-up time of all patients is 26.3 months (range 2.9-149.4) and of patients alive 80.2 months (range 63.9-149.4.). The median overall survival time of all patients is 26.3 months; the 2-, 5- and 8­year survival rates of 54, 21 and 15%, respectively. The local tumour control rate at 2 and 5 years is 70 and 64%, the regional control rate 90 and 88%, respectively. DISCUSSION AND CONCLUSION: Grade 4 or 5 toxicity occurred in 7/150 patients (4.7%), which can be partially avoided in the future (e.g. by excluding patients with pre-existing pulmonary fibrosis). Tolerance and oncologic outcome compare favourably to concomitant chemoradiation also in long-term follow-up.

Survival and local control rates of triple-negative breast cancer patients treated with boost-IOERT during breast-conserving surgery.

AIM: The purpose of this work was to retrospectively evaluate survival and local control rates of triple-negative breast cancer subtypes classified as five marker negative (5NP) and core basal (CB), respectively, after breast-conserving surgery and intraoperative boost radiotherapy with electrons (IOERT) followed by whole breast irradiation. METHODS AND MATERIALS: A total of 71 patients with triple-negative breast cancer were enrolled, who were treated with lumpectomy, axillary lymph node dissection, and IOERT with 9.6 Gy (median Dmax) followed by normofractionated whole breast irradiation to median total doses of 54 Gy. Chemotherapy was applied in a neoadjuvant (12 %), adjuvant (75 %), or combinational setting (7 %). RESULTS: After a median follow-up of 97 months (range 4-170 months), 5 in-breast recurrences were detected (7.0 %). For all patients, 8-year actuarial rates for local control, metastases-free survival, disease-specific survival, and overall survival amounted to 89, 75, 80, and 69 %, respectively. All local recurrences occurred in grade 3 (G3) tumors irrespective of their specific immunohistochemical phenotype; thus, the local control rate for grades 1/2 (G1/2) was 100 % for both 5NP and CB, while for G3 it was 88 % for 5NP and 90 % for CB (p = 0.65 and 0.82, respectively, n.s.). For disease-specific survival, only the difference of the best-prognosis group 5-NP/G3 vs. the worst-prognosis cohort CB/G1/2 was statistically significant: 90 % vs. 54 % (p = 0.03). CONCLUSION: Boost-IOERT provides acceptable long-term in-breast control in triple negative breast cancer. The best subgroup in terms of disease-specific survival was represented by 5NP in combination with tumor grading G3.

miR-16-5p Is a Stably-Expressed Housekeeping MicroRNA in Breast Cancer Tissues from Primary Tumors and from Metastatic Sites.

For quantitative microRNA analyses in formalin-fixed paraffin-embedded (FFPE) tissue, expression levels have to be normalized to endogenous controls. To investigate the most stably-expressed microRNAs in breast cancer and its surrounding tissue, we used tumor samples from primary tumors and from metastatic sites. MiRNA profiling using TaqMan(®) Array Human MicroRNA Cards, enabling quantification of 754 unique human miRNAs, was performed in FFPE specimens from 58 patients with metastatic breast cancer. Forty-two (72%) samples were collected from primary tumors and 16 (28%) from metastases. In a cross-platform analysis of a validation cohort of 32 FFPE samples from patients with early breast cancer genome-wide microRNA expression analysis using SurePrintG3 miRNA (8 × 60 K)(®) microarrays from Agilent(®) was performed. Eleven microRNAs could be detected in all samples analyzed. Based on NormFinder and geNorm stability values and the high correlation (rho ≥ 0.8) with the median of all measured microRNAs, miR-16-5p, miR-29a-3p, miR-126-3p, and miR-222-3p are suitable single gene housekeeper candidates. In the cross-platform validation, 29 human microRNAs were strongly expressed (mean log2-intensity > 10) and 21 of these microRNAs including miR-16-5p and miR-29a-3p were also stably expressed (CV < 5%). Thus, miR-16-5p and miR-29a-3p are both strong housekeeper candidates. Their Normfinder stability values calculated across the primary tumor and metastases subgroup indicate that miR-29a-3p can be considered as the strongest housekeeper in a cohort with mainly samples from primary tumors, whereas miR-16-5p might perform better in a metastatic sample enriched cohort.

IOERT as anticipated tumor bed boost during breast-conserving surgery after neoadjuvant chemotherapy in locally advanced breast cancer--results of a case series after 5-year follow-up.

To evaluate retrospectively rates of local (LCR) and locoregional tumor control (LRCR) in patients with locally advanced breast cancer (LABC) who were treated with preoperative chemotherapy (primary systemic treatment, PST) followed by breast-conserving surgery (BCS) and either intraoperative radiotherapy with electrons (IOERT) preceding whole-breast irradiation (WBI) (Group 1) or with WBI followed by an external tumor bed boost (electrons or photons) instead of IOERT (Group 2). From 2002 to 2007, 83 patients with clinical Stage II or III breast cancer were enrolled in Group 1 and 26 in Group 2. All patients received PST followed by BCS and axillary lymph node dissection. IOERT boosts were applied by single doses of 9 Gy (90% reference isodose) versus external boosts of 12 Gy (median dose range, 6-16) in 2 Gy/fraction (ICRU). WBI in both groups was performed up to total doses of 51-57 Gy (1.7-1.8 Gy/fraction). The respective median follow-up times for Groups 1 and 2 amount 59 months (range, 3-115) and 67.5 months (range, 13-120). Corresponding 6-year rates for LCR, LRCR, metastasis-free survival, disease-specific survival and overall survival were 98.5, 97.2, 84.7, 89.2 and 86.4% for Group 1 and 88.1, 88.1, 74, 92 and 92% for Group 2, respectively, without any statistical significances. IOERT as boost modality during BCS in LABC after PST shows a trend to be superior in terms of LCR and LRCR in comparison with conventional boosts.

DART-bid: dose-differentiated accelerated radiation therapy, 1.8 Gy twice daily: high local control in early stage (I/II) non-small-cell lung cancer.

BACKGROUND: While surgery is considered standard of care for early stage (I/II), non-small-cell lung cancer (NSCLC), radiotherapy is a widely accepted alternative for medically unfit patients or those who refuse surgery. International guidelines recommend several treatment options, comprising stereotactic body radiation therapy (SBRT) for small tumors, conventional radiotherapy ≥ 60 Gy for larger sized especially centrally located lesions or continuous hyperfractionated accelerated RT (CHART). This study presents clinical outcome and toxicity for patients treated with a dose-differentiated accelerated schedule using 1.8 Gy bid (DART-bid). PATIENTS AND METHODS: Between April 2002 and December 2010, 54 patients (median age 71 years, median Karnofsky performance score 70%) were treated for early stage NSCLC. Total doses were applied according to tumor diameter: 73.8 Gy for < 2.5 cm, 79.2 Gy for 2.5-4.5 cm, 84.6 Gy for 4.5-6 cm, 90 Gy for > 6 cm. RESULTS: The median follow-up was 28.5 months (range 2-108 months); actuarial local control (LC) at 2 and 3 years was 88%, while regional control was 100%. There were 10 patients (19%) who died of the tumor, and 18 patients (33%) died due to cardiovascular or pulmonary causes. A total of 11 patients (20%) died intercurrently without evidence of progression or treatment-related toxicity at the last follow-up, while 15 patients (28%) are alive. Acute esophagitis ≤ grade 2 occurred in 7 cases, 2 patients developed grade 2 chronic pulmonary fibrosis. CONCLUSION: DART-bid yields high LC without significant toxicity. For centrally located and/or large (> 5 cm) early stage tumors, where SBRT is not feasible, this method might serve as radiotherapeutic alternative to present treatment recommendations, with the need of confirmation in larger cohorts.

Hypofractionated stereotactic radiotherapy of acoustic neuroma: volume changes and hearing results after 89-month median follow-up.

PURPOSE: The goal of this work was to evaluate toxicity and local control following hypofractionated stereotactic radiation treatment with special focus on changes in tumor volume and hearing capacity. PATIENTS AND METHODS: In all, 29 patients with unilateral acoustic neuroma were treated between 2001 and 2007 within a prospective radiation protocol (7 × 4 Gy ICRU dose). Median tumor volume was 0.9 ml. Follow-up started at 6 months and was repeated annually with MRI volumetry and audiometry. Hearing preservation was defined as preservation of Class A/B hearing according to the guidelines of the American Academy of Otolaryngology (1995). RESULTS: No patient had any intervention after a median imaging follow-up of 89.5 months, one patient showed radiological progression. Transient increase of tumor volume developed in 17/29 patients, whereas 22/29 patients (75.9%) presented with a volume reduction at last follow-up. A total of 21 patients were eligible for hearing evaluation. Mean pure tone average (PTA) deteriorated from 39.3 to 65.9 dB and mean speech discrimination score (SDS) dropped from 74.3 to 38.1%. The 5-year actuarial Class A/B hearing preservation rate was 50.0 ± 14.4%. CONCLUSION: Radiation increases only minimally, if at all, the hearing deterioration which emerges by observation alone. Presbyacusis is not responsible for this deterioration. Transient tumor enlargement is common. Today radiation of small- and medium-sized acoustic neuroma can be performed with different highly conformal techniques as fractionated treatment or single low-dose radiosurgery with equal results regarding tumor control, hearing preservation, and side effects. Hypofractionation is more comfortable for the patient than conventional regimens and represents a serious alternative to frameless radiosurgery.

Durvalumab impacts progression-free survival while high-dose radiation >66 Gy improves local control without excess toxicity in unresectable NSCLC stage III: Real-world data from the Austrian radio-oncological lung cancer study association registry (ALLSTAR).

BACKGROUND: Chemo-radioimmunotherapy with total radiation doses of 60-66 Gy in 2 Gy fractions is the standard of care for non-small cell lung cancer (NSCLC) UICC stage III. The Austrian radio-oncological lung cancer study association registry (ALLSTAR) is a prospective multicentre registry intended to document clinical practice at the beginning of the Durvalumab era. PATIENTS AND METHODS: Patients were eligible if they had pathologically verified unresectable NSCLC stage III with a curative treatment option. Chemo-radiation combined with immunotherapy was performed according to local treatment practices. The endpoints were local control (LC), progression-free survival (PFS) and toxicity. RESULTS: Between 2020/03 and 2023/04, 12/14 (86 %) Austrian radiation-oncology centres recruited 188 patients (median 17, range: 1-89). PD-L1 testing was performed in 173/188 (93 %) patients. The median interval between the end of chemoradiotherapy and start of Durvalumab was 14 days (range: 1-65). About 40 % (75/188) of the patients received a total radiation dose of > 66 Gy (range: 67.1-100), which improved 2-year LC (86 % versus 60 %, HR = 0.41; 95 %-CI: 0.17-0.98; log-rank p-value < 0.05). Median PFS for patients with Durvalumab was 25.8 months (95 %-CI: 21.9-not reached) compared to 15.7 months (95 %-CI: 13.2-27.8) for those without (HR = 1.88; 95 %-CI: 1.16-3.05; log-rank p-value < 0.01). The rates of esophageal and pulmonary toxicities were 34.6 % and 23.9 %, respectively, including one case of grade 4 pneumonitis. In the subcohort of 75 patients who received > 66 Gy, 19 (25 %) cases of pulmonary toxicity grades 1-3 were observed. CONCLUSION: While Durvalumab impacts PFS, LC can be improved by total radiation doses > 66 Gy without excess toxicity.

Pretreatment 18-FDG-PET/CT parameters can serve as prognostic imaging biomarkers in recurrent NSCLC patients treated with reirradiation-chemoimmunotherapy.

BACKGROUND AND PURPOSE: Our study aimed to assess whether quantitative pretreatment 18F-FDG-PET/CT parameters could predict prognostic clinical outcome of recurrent NSCLC patients who may benefit from ablative reirradiation. MATERIALS AND METHODS: Forty-eight patients with recurrent NSCLC of all UICC stages who underwent ablative thoracic reirradiation were analyzed. Twenty-nine (60%) patients received immunotherapy with or without chemotherapy in addition to reirradiation. Twelve patients (25%) received reirradiation only and seven (15%) received chemotherapy and reirradiation. Pretreatment 18-FDG-PET/CT was mandatory in initial diagnosis and recurrence, based on which volumetric and intensity quantitative parameters were measured before reirradiation and their impact on overall survival, progression-free survival, and locoregional control was assessed. RESULTS: With a median follow-up time of 16.7 months, the median OS was 21.8 months (95%-CI: 16.2-27.3). On multivariate analysis, OS and PFS were significantly influenced by MTV (p < 0.001 for OS; p = 0.006 for PFS), TLG (p < 0.001 for OS; p = 0.001 for PFS) and SUL peak (p = 0.0024 for OS; p = 0.02 for PFS) of the tumor and MTV (p = 0.004 for OS; p < 0.001 for PFS) as well as TLG (p = 0.007 for OS; p = 0.015 for PFS) of the metastatic lymph nodes. SUL peak of the tumor (p = 0.05) and the MTV of the lymph nodes (p = 0.003) were only PET quantitative parameters that significantly impacted LRC. CONCLUSION: Pretreatment tumor and metastastic lymph node MTV, TLG and tumor SUL peak significantly correlated with clinical outcome in recurrent NSCLC patients treated with reirradiation-chemoimmunotherapy.

Chemo-Radio-Immunotherapy for NSCLC III: ESR/ATS Thresholds for DLCO Correlate with Radiation Dosimetry and Pneumonitis Rate.

INTRODUCTION: Durvalumab following chemoradiotherapy (CRT) for non-small cell lung cancer stage III has become the standard of care (SoC) in the past few years. With this regimen, 5-year overall survival (OS) has risen to 43%. Therefore, adequate pulmonary function (PF) after treatment is paramount in long-term survivors. In this respect, carbon monoxide diffusing capacity (DLCO), which represents the alveolar compartment, seems to be a suitable measure for residual lung capacity. The aim of the current analysis was to correlate DLCO with pneumonitis and radiation dose. PATIENTS AND METHODS: One hundred and twelve patients with histologically confirmed NSCLC III treated between 2015/10 and 2022/03 were eligible for this study. Patients received two cycles of platinum-based induction chemotherapy followed by high-dose radiotherapy (RT). As of 2017/09, durvalumab maintenance therapy was administered for one year. The clinical endpoints were based on the thresholds jointly published by the European Respiratory Society (ERS) and the American Thoracic Society (ATS). Pre-treatment DLCO of 60% was correlated to the incidence of pneumonitis, whereas the post-treatment DLCO decline of 10% was related to radiation dose. RESULTS: Patients with a pre-treatment DLCO < 60% had a higher probability of pneumonitis (n = 98; r = 0.175; p-value 0.042), which could be reproduced in the subgroup of patients who did not receive durvalumab (n = 40; r = 0.288; p-value 0.036). In these individuals, the decline in DLCO ≥ 10% depended significantly on the size of the lung volume receiving between 45% and 65% (V65-45%) of the total radiation dose (r = 0.354; p-value = 0.020) and V20 Total Lung (r = 0.466; corrected p-value = 0.042). CONCLUSIONS: The current analysis revealed that DLCO is a predictor for clinically relevant pneumonitis and a monitoring tool for post-treatment lung function as it correlates with radiation dose. This underlines the importance of peri-treatment lung function testing.

Prospective evaluation of quality of life effects in patients undergoing palliative radiotherapy for brain metastases.

BACKGROUND: Recently published results of quality of life (QoL) studies indicated different outcomes of palliative radiotherapy for brain metastases. This prospective multi-center QoL study of patients with brain metastases was designed to investigate which QoL domains improve or worsen after palliative radiotherapy and which might provide prognostic information. METHODS: From 01/2007-01/2009, n=151 patients with previously untreated brain metastases were recruited at 14 centers in Germany and Austria. Most patients (82 %) received whole-brain radiotherapy. QoL was measured with the EORTC-QLQ-C15-PAL and brain module BN20 before the start of radiotherapy and after 3 months. RESULTS: At 3 months, 88/142 (62 %) survived. Nine patients were not able to be followed up. 62 patients (70.5 % of 3-month survivors) completed the second set of questionnaires. Three months after the start of radiotherapy QoL deteriorated significantly in the areas of global QoL, physical function, fatigue, nausea, pain, appetite loss, hair loss, drowsiness, motor dysfunction, communication deficit and weakness of legs. Although the use of corticosteroid at 3 months could be reduced compared to pre-treatment (63 % vs. 37 %), the score for headaches remained stable. Initial QoL at the start of treatment was better in those alive than in those deceased at 3 months, significantly for physical function, motor dysfunction and the symptom scales fatigue, pain, appetite loss and weakness of legs. In a multivariate model, lower Karnofsky performance score, higher age and higher pain ratings before radiotherapy were prognostic of 3-month survival. CONCLUSIONS: Moderate deterioration in several QoL domains was predominantly observed three months after start of palliative radiotherapy for brain metastases. Future studies will need to address the individual subjective benefit or burden from such treatment. Baseline QoL scores before palliative radiotherapy for brain metastases may contain prognostic information.

Durvalumab after Sequential High Dose Chemoradiotherapy versus Standard of Care (SoC) for Stage III NSCLC: A Bi-Centric Trospective Comparison Focusing on Pulmonary Toxicity.

Introduction: The standard of care (SoC) for unresectable stage III non-small-cell lung cancer (NSCLC) is durvalumab maintenance therapy after concurrent chemoradiation in patients with PD-L1 > 1%. However, the concurrent approach is only amenable for about one-third of patients due to co-morbidities. Although sequential regimens are usually not regarded as curative, these schedules applied in a dose-escalated manner may be similarly radical as SoC. As combining high-dose radiation and durvalumab remains a question of debate this retrospective bi-center study aims to evaluate pulmonary toxicity after high-dose chemoradiotherapy beyond 70 Gy compared to SoC. Patients and Methods: Patients with NSCLC stage III received durvalumab after either sequential high-dose chemoradiation or concomitant SoC. Chemotherapy consisted of platinum combined with either pemetrexed, taxotere, vinorelbine, or gemcitabine. The primary endpoint was short-term pulmonary toxicity occurring within six months after the end of radiotherapy (RT). Results: A total of 78 patients were eligible for this analysis. 18F-FDG-PET-CT, cranial MRT, and histological/cytological verification were mandatory in the diagnostic work-up. The high-dose and SoC group included 42/78 (53.8%) and 36/78 (46.2%) patients, respectively, which were matched according to baseline clinical variables. While the interval between the end of RT and the start of durvalumab was equal in both groups (p = 0.841), more courses were administered in the high-dose cohort (p = 0.031). Pulmonary toxicity was similar in both groups (p = 0.599), whereas intrathoracic disease control was better in the high-dose group (local control p = 0.081, regional control p = 0.184). Conclusion: The data of this hypothesis-generating study suggest that sequential high-dose chemoradiation followed by durvalumab might be similar to SoC in terms of pulmonary toxicity and potentially more effective with respect to intra-thoracic disease control. Larger trials with a prospective design are warranted to validate these results.

Carbon Monoxide Diffusing Capacity (DLCO) Correlates with CT Morphology after Chemo-Radio-Immunotherapy for Non-Small Cell Lung Cancer Stage III.

Introduction: Curatively intended chemo-radio-immunotherapy for non-small cell lung cancer (NSCLC) stage III may lead to post-therapeutic pulmonary function (PF) impairment. We hypothesized that the decrease in global PF corresponds to the increase in tissue density in follow-up CTs. Hence, the study aim was to correlate the dynamics in radiographic alterations to carbon monoxide diffusing capacity (DLCO) and FEV1, which may contribute to a better understanding of radiation-induced lung disease. Methods: Eighty-five patients with NSCLC III were included. All of them received two cycles of platinum-based induction chemotherapy followed by high dose radiation. Thereafter, durvalumab was administered for one year in 63/85 patients (74%). Pulmonary function tests (PFTs) were performed three months and six months after completion of radiotherapy (RT) and compared to baseline. At the same time points, patients underwent diagnostic CT (dCT). These dCTs were matched to the planning CT (pCT) using RayStation® Model Based Segmentation and deformable image registration. Differential volumes defined by specific isodoses were generated to correlate them with the PFTs. Results: In general, significant correlations between PFTs and differential volumes were found in the mid-dose range, especially for the volume of the lungs receiving between 65% and 45% of the dose prescribed (V65−45%) and DLCO (p<0.01). This volume range predicted DLCO after RT (p-value 0.03) as well. In multivariate analysis, DLCO (p-value 0.040) and FEV1 (p-value 0.014) predicted pneumonitis. Conclusions: The current analysis revealed a strong relation between the dynamics of DLCO and CT morphology changes in the mid-dose range, which convincingly indicates the importance of routinely used PFTs in the context of a curative treatment approach.

High Dose Thoracic Re-Irradiation and Chemo-Immunotherapy for Centrally Recurrent NSCLC.

INTRODUCTION: Thoracic re-irradiation for recurrent lung cancer dates back four decades, when the first small series on 29 patients receiving palliative doses was published. With 5-year overall survival rates of 57% in PDL-1 positive patients after primary chemo-radio-immunotherapy, the number of patients who experience loco-regional relapse will increase in the near future. In this context, centrally recurring lung tumors pose a major treatment challenge. Hence, the aim of the current review is to compile the available evidence on curatively intended thoracic re-irradiation for this special clinical situation. METHODS: A systematic literature search according to the PRISMA guidelines was performed. A study was included when the following criteria were met: (1) 66% of the patients had NSCLC, (2) a total dose of 50 Gy in the second course and/or a biologically effective dose of at least 100 Gy in both treatment courses was administered, (3) re-irradiation was administered with modern radiation techniques, (4) 50% or more of the patients had a centrally located relapse, (5) the minimum cohort size was 30 patients. RESULTS: Of the initial 227 studies, 11 were analyzed, 1 of which was prospective. Median overall survival (OS) was 18.1 months (range 9.3-25.1), median progression free survival (PFS) was nine months (range 4.5-16), and median loco-regional control (LRC) was 12.1 months (range 6.5-20). Treatment-related mortality rates ranged from 2% to 14%. The total dose at re-irradiation correlated with both LRC (p-value = 0.012) and OS (p-value = 0.007) with a close relation between these two clinical endpoints (p-value = 0.006). The occurrence of acute toxicity grade 1 to 4 depended on the PTV size at re-irradiation (p-value = 0.033). CONCLUSION: The evidence regarding curative re-irradiation for centrally recurrent NSCLC is primarily based on scarce retrospective data, which are characterized by a high degree of heterogeneity. The OS in this clinically challenging situation is expected to be around 1.5 years after re-treatment. Patients with a good performance score, younger age, small tumors, and a longer interval to recurrence potentially benefit most from re-irradiation. In this context, prospective trials are warranted to achieve substantial advances in the field.

Hsa-miR-3651 could serve as a novel predictor for in-breast recurrence via FRMD3.

BACKGROUND: MicroRNAs are small non-coding RNAs with pivotal regulatory functions in multiple cellular processes. Their significance as molecular predictors for breast cancer was demonstrated in the past 15 years. The aim of this study was to elucidate the role of hsa-miR-3651 for predicting of local control (LC) in early breast cancer. RESULTS: By means of high-throughput technology, hsa-miR-3651 was found to be differentially expressed between patients who experienced local relapse compared to those without (N = 23; p = 0.0035). This result could be validated in an independent cohort of 87 patients using RT-qPCR (p < 0.0005). In a second analysis step with a chip-based microarray containing 70,523 probes of potential target molecules, FERM domain protein 3 (FRMD3) was found to be the most down-regulated protein (N = 21; p = 0.0016). Computational analysis employing different prediction algorithms revealed FRMD3 as a likely downstream target of hsa-miR-3651 with an 8mer binding site between the two molecules. This could be validated in an independent patient set (N = 20, p = 0.134). CONCLUSION: The current study revealed that hsa-miR-3651 is a predictor of LC in early breast cancer via its putative target protein FRMD3. Since microRNAs interfere in multiple pathways, the results of this hypothesis generating study may contribute to the development of tailored therapies for breast cancer in the future.

Re-Irradiation for Locally Recurrent Lung Cancer: A Single Center Retrospective Analysis.

The treatment of locally recurrent lung cancer is a major challenge for radiation-oncologists, especially with data on high-dose reirradiation being limited to small retrospective studies. The aim of the present study is to assess overall survival (OS) for patients with locally recurrent lung cancer after high-dose thoracic reirradiation. Thirty-nine patients who were re-irradiated for lung cancer relapse between October 2013 and February 2019 were eligible for the current retrospective analysis. All patients were re-irradiated with curative intent for in-field tumor recurrence. The diagnostic work-up included a mandatory 18F-FDG-PET-CT scan and-if possible-histological verification. The ECOG was ≤2, and the interval between initial and second radiation was at least nine months. Thirty patients (77%) had non-small cell lung cancer (NSCLC), eight (20%) had small cell lung cancer (SCLC), and in one patient (3%) histological confirmation could not be obtained. More than half of the patients (20/39, 51%) received re-treatment with dose differentiated accelerated re-irradiation (DART) at a median interval of 20.5 months (range: 6-145.3 months) after the initial radiation course. A cumulative EQD2 of 131 Gy (range: 77-211 Gy) in a median PTV of 46 mL (range: 4-541 mL) was delivered. Patients with SCLC had a 3 mL larger median re-irradiation volume (48 mL, range: 9-541) compared to NSCLC patients (45 mL, range: 4-239). The median cumulative EQD2 delivered in SCLC patients was 84 Gy (range: 77-193 Gy), while NSCLC patients received a median cumulative EQD2 of 135 Gy (range: 98-211 Gy). The median OS was 18.4 months (range: 0.6-64 months), with tumor volume being the only predictor (p < 0.000; HR 1.007; 95%-CI: 1.003-1.012). In terms of toxicity, 17.9% acute and 2.6% late side effects were observed, with a toxicity grade >3 occurring in only one patient. Thoracic high dose reirradiation plays a significant role in prolonging survival, especially in patients with small tumor volume at recurrence.

Impact of reirradiation, chemotherapy, and immunotherapy on survival of patients with recurrent lung cancer: A single-center retrospective analysis.

BACKGROUND: Given the limited curative treatment options for recurrent lung cancer patients, the aim of our retrospective study was to investigate whether these patients would benefit in terms of overall survival (OS) by adding immunotherapy to high-dose reirradiation. MATERIALS AND METHODS: Between 2013 and 2019, 47 consecutive patients with in-field tumor recurrence underwent high-dose thoracic reirradiation at our institute. Twenty patients (43%) received high-dose reirradiation only, while 27/47 (57%) additionally had systemic therapy (immunotherapy and/or chemotherapy). With the exception of one patent, the interval between first and second radiation was at least 9 months. All patients had an Eastern cooperative oncology group ≤2. The diagnostic work-up included a mandatory fluorodeoxyglucose-positron emission tomography-computed tomography scan and histological verification. The primary endpoint was OS after completion of the second course of irradiation. RESULTS: In the whole cohort of 47 patients, the median overall survival (mOS) after reirradiation was 18.9 months (95% confidence interval [CI] 16.5-21.3 months), while in the subgroup of 27 patients who received additional systemic treatment after reirradiation, mOS amounted to 21.8 months (95% CI 17.8-25.8 months). Within this group the comparison between reirradiation combined with either immunotherapy (n = 21) or chemotherapy (n = 6) revealed a difference in OS, which was in favor of the first (log-rank p value = 0.063). Three patients (11%) experienced acute side effects and one (4%) showed a late hemorrhage grade 3. CONCLUSION: Patients who received immunotherapy and reirradiation lived longer than those who did not receive immunotherapy.

In-field stereotactic body radiotherapy (SBRT) reirradiation for pulmonary malignancies as a multicentre analysis of the German Society of Radiation Oncology (DEGRO).

Data of thoracic in-field reirradiation with two courses of stereotactic body radiotherapy (SBRT) is scarce. Aim of this study is to investigate feasibility and safety of this approach. Patients with a second course of thoracic SBRT and planning target volume (PTV) overlap were analyzed in this retrospective, multicenter study. All plans and clinical data were centrally collected. 27 patients from 8 centers have been amenable for evaluation: 12 with non-small-cell lung cancer, 16 with metastases, treated from 2009 (oldest first course) to 2020 (latest second course). A median dose of 38.5 Gy to the 65%-isodose over a median of 5 fractions was prescribed in the first course and 40 Gy in 5 fractions for the second SBRT-course. Median PTV of the second SBRT was 29.5 cm3, median PTV overlap 22 cm3. With a median interval of 20.2 months between the two SBRT-courses, 1-year OS, and -LCR were 78.3% and 70.3% respectively. 3 patients developed grade 1 and one grade 2 pneumonitis. No grade > 2 toxicity was observed. Peripheral location and dose were the only factors correlating with tumor control. A second SBRT-course with PTV overlap appears safe and achieves reasonable local control.

Long-term outcome of mitomycin C- and 5-FU-based primary radiochemotherapy for esophageal cancer.

BACKGROUND AND PURPOSE: For definitive radiochemotherapy, 5-fluorouracil/cisplatin protocols have been considered the standard of care for esophageal carcinoma over the last 2 decades. By contrast, most patients treated at the University Hospital, LMU Munich, Germany, received 5-fluorouracil/mitomycin C. The objective of this retrospective analysis was to determine the value of 5-fluorouracil/mitomycin-C-based therapy. PATIENTS AND METHODS: Tumor stage, treatment received, and outcome data of patients treated for esophageal cancer between 1982 and 2007 were collected; endpoint of the analysis was overall survival. RESULTS: 298 patients with inoperable cancer of the esophagus were identified (16.8% adenocarcinoma, 77.5% squamous cell carcinoma). At diagnosis, 61.7% (184/298) had UICC stage III-IV, 54.4% (162/298) positive lymph nodes, and 26.5% (79/298) metastatic disease. 74.5% of all patients (222/298) received radiation doses between 55 and 65 Gy, 65.8% (196/298) were subjected to concomitant chemotherapy. The median follow-up period (patients alive) was 4.1 years. A significant increase of overall survival (p < 0.0001) in the radiochemotherapy versus the radiotherapy-alone group was observed. 52% (102/196) in the 5-fluorouracil/ mitomycin C group had tumor stages comparable to the RTOG 85-01 study cohort (T1-3 N0-1 M0). The median survival in this subgroup was 18.2 months, 3- and 5-year survival rates were 22.7% (21/102) and 15.0% (13/102), respectively. CONCLUSION: Despite being nominally inferior to platinum-based radiochemotherapy, the overall survival rates are in a similar range. Thus, the mitomycin-C-based radiochemotherapy approach may considered to be as effective as the standard therapy. However, there is no randomized trial available in order to prove the equality.

Radiation dose escalation with modified fractionation schedules for locally advanced NSCLC: A systematic review.

Concomitant chemo-radiotherapy (cCRT) with 60 Gy in 30 fractions is the standard of care for stage 111 non-small cell lung cancer (NSCLC). With a median overall survival of 28.7 months at best and maximum locoregional control rates of 70% at two years, the prognosis for these patients is still dismal. This systematic review summarizes data on dose escalation by alternative fractionation, which has been explored as a primary strategy to improve both local control and overall survival over the past three decades. A Pubmed literature search was performed according to the PRISMA guidelines. Because of the large variety of radiation regimens total doses were converted to EQD2,T . Only studies using an EQD2,T of at least 49.5 Gy, which corresponds to the conventional 60 Gy in six weeks, were included. In a total of 3256 patients, the median OS was 17 months (range 7.4-30 months). While OS was better for patients treated after the year 2000 (P = 0.003) or with a mandatory 18 F-FDG-PET-CT in the diagnostic work-up (P = 0.001), treatment sequence did not make a difference (P = 0.106). The most commonly reported toxicity was acute esophagitis (AE) with a median rate of 24% (range 0%-84%). AE increased at a rate of 0.5% per Gy increment in EQD2,T (P = 0.016). Dose escalation above the conventional 60 Gy using modified radiation fractionation schedules and shortened OTT yield similar mOS and LRC regardless of treatment sequence with a significant EQD2,T dependent increase in AE. KEY POINTS: Significant findings Modified radiation dose escalation sequentially combined with chemotherapy yields similar outcome as concomitant treatment. OS is better with the mandatory inclusion of FDG-PET-CT in the diagnostic work-up. The risk of acute esophagitis increases with higher EQD2,T . What this study adds Chemo-radiotherapy (CRT) with modified dose escalation regimens yields OS and LC rates in the range of standard therapy regardless of treatment sequence. This broadens the database of curative options in patients who are not eligible concomitant CRT.