Locoregional Tumor Control Research Articles

Interventional radiology procedures for metastatic spine tumors

ObjectiveInterventional radiology procedures can offer locoregional tumor control and palliative options for patients with metastatic disease to spine to relieve pain, to delay neurologic deficits, and to improve quality of life and daily function. FindingsMultiple thermal energies for percutaneous ablation of metastases to the spine exist and are chosen according to tumor characteristics, volume, and location. Vertebral augmentation is most often combined with ablation for structural stability. Intravascular embolization of metastases provides tumor palliative or presurgical devascularization. ConclusionAblation, vertebral augmentation, and intravascular embolization are efficacious minimally invasive options for the management of spinal tumors.

La radiothérapie des CBNPC de stade III : nouvelles techniques, nouvelles combinaisons

Defining the optimal treatment approach for patients with stage III non-small cell lung cancer, where the loco-regional disease extension renders a surgical approach obsolete, represents an important clinical challenge. In addition, many of these patients present with several comorbidities, compromising their tolerance to treatment. This article describes how innovative radiotherapy approaches try to enhance loco-regional tumour control as a first step towards improved survival, often by exploring novel avenues to dose-escalation, while at the same time focus on limiting early and long-term radiation-induced toxicity by applying the most advanced radiotherapy techniques. Moreover, the path towards new combinations with systemic agents, particularly immunotherapy building on the actual standard of combined chemo-radiotherapy with durvalumab in consolidation, is reported. This article wants to give a balanced view on the importance to investigate how we can obtain better local and metastatic disease control by intensifying our combined treatment strategies, while bearing in mind that many of our patients in daily clinical practice may not be able tolerate this. This urges us to also explore less disruptive treatment approaches for our more frail and aged patient population and define in a multidisciplinary manner the most optimal treatment strategy for each individual patient in our daily clinical practice.1877-1203/© 2024 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Magnetic Resonance Imaging–Guided Cryoablation of Prostate Cancer Lymph Node Metastasis

PurposeTo evaluate the safety and effectiveness of magnetic resonance (MR) imaging–guided cryoablation of prostate cancer metastatic lymph nodes (LNs). Materials and MethodsFifty-two patients with prostate cancer who underwent MR imaging–guided LN ablation from September 2013 to June 2022 were retrospectively reviewed. Of these, 6 patients were excluded because adequate ablation margins (3–5 mm) could not be achieved secondary to adjacent structures. The remaining 46 patients (mean age, 70 years [SD ± 7]) underwent 55 MR imaging–guided cryoablation procedures of metastatic LNs (25 in the pelvic sidewall, 20 within the pelvic region, and 10 in the abdomen) with procedural intent of complete ablation. Locoregional tumor control (ie, technical success in the target LN) was evaluated on initial follow-up positron emission tomography (PET) scans at a mean of 4 months (SD ± 2). Preablation and postablation prostate-specific antigen (PSA) levels were recorded. Imaging follow-up continued until a median of 27.5 months (range: 3–108 months). ResultsNinety-five percent (52/55) of treated LNs demonstrated no considerable activity on PET scans at initial follow-up at 4 months (SD ± 2). PSA decreased to an undetectable level of <0.1 ng/mL after cryoablation in 14 of 46 (30.4%) patients with corresponding lack of activity in 13 of 46 (28.2%) patients on continued PET imaging follow-up. Only 6 of 55 (10.9%) patients had transient adverse events, which all resolved with no long-term sequelae. ConclusionsMR imaging–guided percutaneous cryoablation of metastatic LNs is a safe and technically effective technique for treating metastatic prostate cancer in LNs.

Role of TORS as De-Escalation Strategy in HPV-Related Oropharyngeal Cancer, What We Need to Know.

Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) presents unique challenges and opportunities for treatment, particularly regarding de-escalation strategies to reduce treatment morbidity without compromising oncological outcomes. This paper examines the role of Transoral Robotic Surgery (TORS) as a de-escalation strategy in managing HPV-related OPSCC. We conducted a comprehensive literature review from January 2010 to June 2023, focusing on studies exploring TORS outcomes in patients with HPV-positive OPSCC. These findings highlight TORS's potential to reduce the need for adjuvant therapy, thereby minimizing treatment-related side effects while maintaining high rates of oncological control. TORS offers advantages such as precise tumor resection and the ability to obtain accurate pathological staging, which can guide the tailoring of adjuvant treatments. Some clinical trials provide evidence supporting the use of TORS in specific patient populations. The MC1273 trial demonstrated promising outcomes with lower doses of adjuvant radiotherapy (RT) following TORS, showing high locoregional tumor control rates and favorable survival outcomes with minimal side effects. ECOG 3311 evaluated upfront TORS followed by histopathologically directed adjuvant therapy, revealing good oncological and functional outcomes, particularly in intermediate-risk patients. The SIRS trial emphasized the benefits of upfront surgery with neck dissection followed by de-escalated RT in patients with favorable survival and excellent functional outcomes. At the same time, the PATHOS trial examined the impact of risk-adapted adjuvant treatment on functional outcomes and survival. The ongoing ADEPT trial investigates reduced-dose adjuvant RT, and the DART-HPV study aims to compare standard adjuvant chemoradiotherapy (CRT) with a reduced dose of adjuvant RT in HPV-positive OPSCC patients. These trials collectively underscore the potential of TORS in facilitating treatment de-escalation while maintaining favorable oncological and functional outcomes in selected patients with HPV-related OPSCC. The aim of this scoping review is to discuss the challenges of risk stratification, the importance of HPV status determination, and the implications of smoking on treatment outcomes. It also explores the evolving criteria for adjuvant therapy following TORS, focusing on reducing radiation dosage and volume without compromising treatment efficacy. In conclusion, TORS emerges as a viable upfront treatment option for carefully selected patients with HPV-positive OPSCC, offering a pathway toward treatment de-escalation. However, selecting the optimal candidate for TORS-based de-escalation strategies is crucial to fully leverage the benefits of treatment de-intensification.

37 Oral microbiome's impact on mucositis and locoregional tumor control in HNSCC patients undergoing radiotherapy

37 Oral microbiome's impact on mucositis and locoregional tumor control in HNSCC patients undergoing radiotherapy

Mathematical modeling of radiotherapy: impact of model selection on estimating minimum radiation dose for tumor control.

Radiation therapy (RT) is one of the most common anticancer therapies. Yet, current radiation oncology practice does not adapt RT dose for individual patients, despite wide interpatient variability in radiosensitivity and accompanying treatment response. We have previously shown that mechanistic mathematical modeling of tumor volume dynamics can simulate volumetric response to RT for individual patients and estimation personalized RT dose for optimal tumor volume reduction. However, understanding the implications of the choice of the underlying RT response model is critical when calculating personalized RT dose. In this study, we evaluate the mathematical implications and biological effects of 2 models of RT response on dose personalization: (1) cytotoxicity to cancer cells that lead to direct tumor volume reduction (DVR) and (2) radiation responses to the tumor microenvironment that lead to tumor carrying capacity reduction (CCR) and subsequent tumor shrinkage. Tumor growth was simulated as logistic growth with pre-treatment dynamics being described in the proliferation saturation index (PSI). The effect of RT was simulated according to each respective model for a standard schedule of fractionated RT with 2 Gy weekday fractions. Parameter sweeps were evaluated for the intrinsic tumor growth rate and the radiosensitivity parameter for both models to observe the qualitative impact of each model parameter. We then calculated the minimum RT dose required for locoregional tumor control (LRC) across all combinations of the full range of radiosensitvity and proliferation saturation values. Both models estimate that patients with higher radiosensitivity will require a lower RT dose to achieve LRC. However, the two models make opposite estimates on the impact of PSI on the minimum RT dose for LRC: the DVR model estimates that tumors with higher PSI values will require a higher RT dose to achieve LRC, while the CCR model estimates that higher PSI values will require a lower RT dose to achieve LRC. Ultimately, these results show the importance of understanding which model best describes tumor growth and treatment response in a particular setting, before using any such model to make estimates for personalized treatment recommendations.

Tumor Cell-Intrinsic PD-L1 Effects on Radiation-Induced Locoregional Antitumor Immunity

Targeting PD-L1 is a beneficial strategy to reinvigorate antitumor immunity, however variable response and resistance are challenging and suggest the need for multimodality approaches. Tumor cell-intrinsic PD-L1 signals also regulate non-canonical pathogenic pathways that may impact treatment resistance. Ionizing radiation (IR) can induce antitumor immunity and has demonstrated therapeutic synergy with immunotherapy in some cases, however tumor-driven immunologic mechanisms affecting clinical outcomes remain incompletely understood. In this study, we investigated the impact of tumor cell-intrinsic PD-L1 signals on IR-induced locoregional immune response and tumor control. We used orthotopic B16-F10 melanoma (WT-B16) and 4T1 triple negative breast cancer (WT-4T1) murine tumor models, as well as PD-L1 disabled variants (KO) generated by CRISPR/Cas9, implanted bilaterally. IR (10 Gy) was targeted at one tumor alone to evaluate both direct and indirect IR effects based on tumor PD-L1 status. We evaluated response by tumor volume (TV) measurements, flow cytometry of tumor-infiltrating lymphocytes (TILs) and tumor draining lymph nodes (TDLNs) in both irradiated and unirradiated compartments, and granzyme B (GZB) PET imaging to assess functional in vivo changes. Chemokine-based multiplex assays were used to assess cell lines receiving IR (4Gy) and ex vivo tumor lysates and serum. IR-induced local tumor control was not significantly affected based on tumor PD-L1 status, however deactivation of tumor cell PD-L1 enhanced IR-induced regional tumor control. Unirradiated WT tumors in mice harboring irradiated KO but not irradiated WT tumors demonstrated a significant mean reduction in TV with instances of complete distant tumor regression. PET imaging demonstrated a nearly 2-fold higher concentration of GZB in KO versus WT tumors, in line with known locally immunosuppressive effects of tumor PD-L1. Remarkably, GZB levels were >1.5-fold higher in unirradiated WT tumors in mice harboring an irradiated KO versus WT tumor, which correlated with a 50% increase in PD-1+CD8+ T cells. Higher levels of CD62+CD44- naïve CD4+ (4-fold) and CD8+ (2-fold) memory T cells were seen in TDLNs of irradiated KO versus WT tumors. Cytokine levels positively correlated with immune recruitment and activation status, as CXCL10, CCL2 and CCL5 were significantly upregulated in PD-L1 KO versus WT tumors cells. Results from this study demonstrate cell-intrinsic PD-L1 inhibits IR-induced locoregional immune activation and frequency of regional tumor control, with clinical implications including therapeutic targeting of tumor cell-intrinsic PD-L1 signals to enhance IR-induced immunogenicity, utility of IR based on tumor PD-L1 status particularly in the metastatic setting, and immunotherapy combinations. Future studies investigating mechanisms of resistance to IR-induced immune activation to enhance responsiveness are warranted.

Molecular Classification Predicts Response to Radiotherapy in the Randomized PORTEC-1 and PORTEC-2 Trials for Early-Stage Endometrioid Endometrial Cancer.

The molecular classification of endometrial cancer (EC) has proven to have prognostic value and is predictive of response to adjuvant chemotherapy. Here, we investigate its predictive value for response to external beam radiotherapy (EBRT) and vaginal brachytherapy (VBT) in early-stage endometrioid EC (EEC). Data of the randomized PORTEC-1 trial (n = 714) comparing pelvic EBRT with no adjuvant therapy in early-stage intermediate-risk EC and the PORTEC-2 trial (n = 427) comparing VBT with EBRT in early-stage high-intermediate-risk EC were used. Locoregional (including vaginal and pelvic) recurrence-free survival was compared between treatment groups across the four molecular classes using Kaplan-Meier's methodology and log-rank tests. A total of 880 molecularly classified ECs, 484 from PORTEC-1 and 396 from PORTEC-2, were included. The majority were FIGO-2009 stage I EEC (97.2%). The median follow-up was 11.3 years. No locoregional recurrences were observed in EC with a pathogenic mutation of DNA polymerase-ε (POLEmut EC). In mismatch repair-deficient (MMRd) EC, locoregional recurrence-free survival was similar after EBRT (94.2%), VBT (94.2%), and no adjuvant therapy (90.3%; P = .74). In EC with a p53 abnormality (p53abn EC), EBRT (96.9%) had a substantial benefit over VBT (64.3%) and no adjuvant therapy (72.2%; P = .048). In EC with no specific molecular profile (NSMP EC), both EBRT (98.3%) and VBT (96.2%) yielded better locoregional control than no adjuvant therapy (87.7%; P < .0001). The molecular classification of EC predicts response to radiotherapy in stage I EEC and may guide adjuvant treatment decisions. Omitting radiotherapy seems to be safe in POLEmut EC. The benefit of radiotherapy seems to be limited in MMRd EC. EBRT yields a significantly better locoregional recurrence-free survival than VBT or no adjuvant therapy in p53abn EC. VBT is the treatment of choice for NSMP EC as it is as effective as EBRT and significantly better than no adjuvant therapy for locoregional tumor control.

Dosimetric comparison of rectal carcinoma radiation therapy using three dimensional conformal radiation therapy and intensity modulated radiation therapy: an analytical observational study

Rectal cancer is the second most common cancer in large intestine. Recently, preoperative chemoradiotherapy has been generally used in the management of locally advanced rectal cancer on the basis of several benefits proven by clinical studies, in the aspect of better locoregional tumor control, reduced toxicity of normal organs, and an increased chance of preserving the anal sphincter, when compared with postoperative chemoradiotherapy. In this observational study, conducted between January 2017 and December 2021, pursuant to the recommendations of the radiation therapy oncology group (RTOG), all patients underwent CT simulation, a bladder protocol and target contouring. 10 patients were treated with intensity modulated radiotherapy (IMRT) and 10 with three-dimensional conformal radiation therapy (3DCRT). Planned target volume (PTV) coverage, homogeneity index (HI), conformity index (CI), and doses to organs at risk (OAR) were compared. Our findings showed that 3DCRT and IMRT have statistically significant differences in PTV coverage and dosages to OAR (p&lt;0.001), proving that IMRT achieves improved target dose coverage and superior normal tissue avoidance (bladder and intestine) compared to 3DCRT.

Surgical resection based on ontogenetic cancer field theory for cervical cancer: 10-year updated results of the MMR study.

5539 Background: Previously published findings from our center suggest that carcinoma of the cervix propagates within ontogenetic cancer fields, tissue compartments defined by staged morphogenesis. In the MMR study we aimed to determine whether surgical treatment that accounts for stage-associated, ontogenetic cancer fields and their associated lymphoid tissues results in locoregional tumor control without the need for adjuvant radiotherapy. Methods: The Leipzig School Mesometrial Resection Study (MMR study) is an ongoing, prospective, single-center, observational cohort study including patients with primary cervical cancer. All study participants undergo either total or extended mesometrial resection (TMMR or EMMR) and therapeutic lymph node dissection. Because this treatment strategy enables surgical removal of all locoregional at-risk tissues, no adjuvant radiotherapy is necessary, even in the presence of established risk factors. The trial is registered at the German Clinical Trials Register, number DRKS00015171. For this updated analysis, we identified patients in our institutional study database with primary cervical cancer staged IB1 – IIA2 according to the 2009 International Federation of Gynecology and Obstetrics staging system. Using the Kaplan-Meier estimator, we calculated recurrence free and overall survival. Results: Between October 16, 1999, and December 16, 2020, 420 patients were treated per protocol and followed up for a median of 136 months (IQR 77-190). The median age was 42 years (IQR 36-51). 329 patients (78.3%) had stage IB1, 58 (13.8%) stage IB2, 24 (5.7%) stage IIA1 and 9 (2.1%) stage IIA2 disease. Patients had either squamous cell (n = 297, 70.7%), adenocarcinoma (n = 104, 24.8%), adenosquamous (n = 18, 4.3%) or other (n = 1, 0.24%) histology. The nodal status was pN0 in 349 (83.1%) patients and pN1 in 71 (16.9%) of the cases. Clinically occult parametrial involvement was present in 47 (11.2%) patients. 10-year overall survival was 90.2% (95% confidence interval [CI] 87.1-93.4) and recurrence-free survival was 90.6% (95% CI 87.8-93.6). Stratified for lymph node status 10-year overall survival was 91.7% (95% confidence interval [CI] 88.5-95) for pN0 and 83.2% (95% confidence interval [CI] 74.6-92.9) for pN1. Recurrence-free survival was 93.8% (95% CI 91.2-96.5) for pN0 and 75.4% (95% CI 65.9-86.3) for pN1. Conclusions: Despite dispense of adjuvant radiotherapy, patients treated with total or extended mesometrial resection with therapeutic lymph node dissection have excellent survival outcomes. Additional multicenter studies are needed to further investigate and confirm our results. Clinical trial information: DRKS00015171 .

Pulmonary magnetic resonance-guided online adaptive radiotherapy of locally advanced non-small-cell lung cancer: the PUMA trial

BackgroundPatients with locally-advanced non-small-cell lung cancer (LA-NSCLC) are often ineligible for surgery, so that definitive chemoradiotherapy (CRT) represents the treatment of choice. Nevertheless, long-term tumor control is often not achieved. Intensification of radiotherapy (RT) to improve locoregional tumor control is limited by the detrimental effect of higher radiation exposure of thoracic organs-at-risk (OAR). This narrow therapeutic ratio may be expanded by exploiting the advantages of magnetic resonance (MR) linear accelerators, mainly the online adaptation of the treatment plan to the current anatomy based on daily acquired MR images. However, MR-guidance is both labor-intensive and increases treatment times, which raises the question of its clinical feasibility to treat LA-NSCLC. Therefore, the PUMA trial was designed as a prospective, multicenter phase I trial to demonstrate the clinical feasibility of MR-guided online adaptive RT in LA-NSCLC.MethodsThirty patients with LA-NSCLC in stage III A-C will be accrued at three German university hospitals to receive MR-guided online adaptive RT at two different MR-linac systems (MRIdian Linac®, View Ray Inc. and Elekta Unity®, Elekta AB) with concurrent chemotherapy. Conventionally fractioned RT with isotoxic dose escalation up to 70 Gy is applied. Online plan adaptation is performed once weekly or in case of major anatomical changes. Patients are followed-up by thoracic CT- and MR-imaging for 24 months after treatment. The primary endpoint is twofold: (1) successfully completed online adapted fractions, (2) on-table time. Main secondary endpoints include adaptation frequency, toxicity, local tumor control, progression-free and overall survival.DiscussionPUMA aims to demonstrate the clinical feasibility of MR-guided online adaptive RT of LA-NSCLC. If successful, PUMA will be followed by a clinical phase II trial that further investigates the clinical benefits of this approach. Moreover, PUMA is part of a large multidisciplinary project to develop MR-guidance techniques.Trial registrationClinicalTrials.gov: NCT05237453.

Neoadjuvant chemotherapy for locally advanced head and neck squamous cell carcinoma - Is it still relevant? A practice pattern survey among oncologists of India.

Concurrent chemotherapy is the recommended treatment for locally advanced head and neck (H&N) squamous cell carcinoma, and neoadjuvant chemotherapy (NACT) is debated with a few special indications. NACT for advanced head and neck cancer has been studied in clinical trials for more than 2 decades without clear demonstration of the benefit for loco regional tumor control or overall patient survival. Its benefit remains controversial in the absence of clear evidence to define its role. However, there is widespread use of NACT among oncologists. We conducted an online survey to find out the frequency, pattern, prevalence, and aims for use of NACT in locally advanced head and neck cancers among radiation, medical, and surgical oncologists. Oncologists across India who expressed interest to participate in our survey were asked to complete a short online questionnaire designed to identify the current practice pattern of NACT in head and neck cancer. A mobile app-based questionnaire was sent to 200 oncologists across the country to assess the pattern of NACT use and to solicit their most frequent therapy approach for patients with locoregionally advanced head and neck cancer. One hundred and fifty (150) oncologists completed and returned the survey (75%), and 130 were finalized (94 radiation oncologists, 19 medical oncologists, and 17 surgical oncologists). The single most common treatment approach reported for patients with locoregionally advanced H&N cancer was that of sequential chemoradiation (61%), specifically NACT with the TPF regimen (78.5%), followed by radiation therapy. The primary objectives cited by respondents for the use of NACT included the desire to buy time for definitive treatment (20%) and to achieve R0 resection (19.2%). Use of NACT in most patients was more preferred by medical oncologists (21.1%) and radiation oncologists (19.1%) than surgical oncologists (11.8%). Thus, there is not much difference in perception in practice of NACT in radiation, medical, and surgical oncologists. A minimum of two cycles of NACT was preferred by more than half of the doctors (55.4%) with 59.6% radiation oncologists using it before further assessment. Although level I evidence for inferior outcomes with NACT as compared to concurrent chemoradiation therapy is there, the use of NACT is quite common among various oncologists in the country because of reasons such as buying time for definitive treatment, achieving R0 resection, better outcome and survival, partial response, better tolerability, better distant control, LN size regression, down-staging of primary tumor, selection of chemosensitive patients, reducing the volume of the radiation field, and better tolerability of subsequent Chemoradiation (CTRT) intensity of subsequent chemoradiation therapy.

Adjuvant Therapy for Elderly Breast Cancer Patients after Breast-Conserving Surgery: Outcomes in Real World Practice.

We aimed to evaluate the standard of care of adjuvant radiotherapy (RT) after breast-conserving surgery (BCS) in elderly female patients (≥65 years) treated outside of clinical trials and to identify potential factors related to the omission of RT and the interaction with endocrine therapy (ET). All women treated with BCS at two major breast centers between 1998 and 2014 were evaluated. Data were provided by the Tumor Registry Munich. Survival analyses were conducted using the Kaplan-Meier method. Prognostic factors were identified using multivariate Cox regression analysis. The median follow-up was 88.4 months. Adjuvant RT was performed in 82% (2599/3171) of patients. Irradiated patients were younger (70.9 vs. 76.5 years, p < 0.001) and were more likely to receive additional chemotherapy (p < 0.001) and ET (p = 0.014). Non-irradiated patients more often had non-invasive DCIS tumors (pTis: 20.3% vs. 6.8%, p < 0.001) and did not undergo axillary surgery (no axillary surgery: 50.5% vs. 9.5%, p < 0.001). Adjuvant RT was associated with improved locoregional tumor control after BCS in invasive tumors (10-year local recurrence-free survival (LRFS): 94.0% vs. 75.1%, p < 0.001, 10-year lymph node recurrence-free survival (LNRFS): 98.1% vs. 93.1%, p < 0.001). Multivariate analysis confirmed significant benefits for local control with postoperative RT. Furthermore, RT led to increased locoregional control even in patients who received ET (10-year LRFS 94.8% with ET + RT vs. 78.1% with ET alone, p < 0.001 and 10-year LNRFS: 98.2% vs. 95.0%, p = 0.003). Similarly, RT alone had significantly better locoregional control rates compared to ET alone (10-year LRFS 92.6% with RT alone vs. 78.1% with ET alone, p < 0.001 and 10-year LNRFS: 98.0% vs. 95.0%, p = 0.014). The present work confirms the efficacy of postoperative RT for breast carcinoma in elderly patients (≥65 years) treated in a modern clinical setting outside of clinical trials, even in patients who receive ET.

Primary and adjuvant intensity-modulated radiotherapy in oropharyngeal carcinoma patients from a single institution.

To retrospectively access outcome, adverse events and prognostic factors in oropharyngeal carcinoma (OPC) patients treated with intensity-modulated radiotherapy (IMRT). Ninety-eight OPC patients were treated between 2000 and 2015. Thirty-three patients received definitive and 65 adjuvant radiotherapy. Seventy-one percent had simultaneous chemotherapy. Patients were systematically followed up (mean 114 months, range 19-197 months). Statistical analysis used Kaplan-Meier method, Cox regression analysis, and log-rank test. Adverse events were classified according to common toxicity criteria version (CTCAE) 4.03. The 1-, 5-, and 10-year overall survival rates in the adjuvant vs. definitive cohort were 90.8% vs. 66.7%, 67.4% vs. 33.1%, and 57.7% vs. 16.5%. Survival in the adjuvant cohort was significantly longer than in the definitive cohort (P < 0.00005). Patients <65 years had a significantly longer survival than older patients. Locoregional tumor control rates after 1-, 5-, and 10 years in the adjuvant vs. definitive cohort were 90.2% vs. 66.7%, 82.2% vs 45.4%, and 72.1% vs. 30.3%. Locoregional tumor control in the adjuvant cohort was significantly longer than in the definite cohort (P < 0.005). Distant metastases were diagnosed in 20.4% of all patients. Most patients had mild CTCAE grade 1 and 2 adverse events and mild late adverse events including xerostomia, dysphagia, and lymphedema. Intensity-modulated radiotherapy for OPC is an important part of the treatment algorithm alone and in particular after surgery while the additional benefits of chemotherapy might be age dependent. Despite advanced tumor stages, nearly half of our patients were alive in the long term. The majority of patients had relatively mild chronic adverse events.

Early-Stage Primary Lung Neuroendocrine Tumors Treated With Stereotactic Body Radiation Therapy: A Multi-Institution Experience

Current guidelines recommend surgery as standard of care for primary lung neuroendocrine tumor (LNET). Given that LNET is a rare clinical entity, there is a lack of literature regarding treatment of LNET with stereotactic body radiation therapy (SBRT). We hypothesized that SBRT could lead to effective locoregional tumor control and long-term outcomes. We retrospectively reviewed 48 tumors in 46 patients from 11 institutions with a histologically confirmed diagnosis of LNET, treated with primary radiation therapy. Data were collected for patients treated nonoperatively with primary radiation therapy between 2006 and 2020. Patient records were reviewed for lesion characteristics and clinical risk factors. Kaplan-Meier analysis, log-rank tests, and Cox multivariate models were used to compare outcomes. Median age at treatment was 71 years and mean tumor size was 2 cm. Thirty-two lesions were typical carcinoid histology, 7 were atypical, and 9 were indeterminate. The most common SBRT fractionation schedule was 50 to 60 Gy in 5 daily fractions. Overall survival at 3, 6, and 9 years was 64%, 43%, and 26%, respectively. Progression-free survival at 3, 6, and 9 years was 88%, 78%, and 78%, respectively. Local control at 3, 6, and 9 years was 97%, 91%, and 91%, respectively. There was 1 regional recurrence in a paraesophageal lymph node. No grade 3 or higher toxicity was identified. This is the largest series evaluating outcomes in patients with LNET treated with SBRT. This treatment is well tolerated, provides excellent locoregional control, and should be offered as an alternative to surgical resection for patients with early-stage LNET, particularly those who may not be ideal surgical candidates.

Fat Grafts Show Higher Hypoxia, Angiogenesis, Adipocyte Proliferation, and Macrophage Infiltration than Flaps in a Pilot Mouse Study.

Over 137,000 breast reconstructions are performed annually by American Society of Plastic Surgeons (ASPS) members. Vascularized flaps and avascular lipofilling each account for over 33,000 autologous reconstructions. Although clinical and experimental observations suggest biologic differences with diverging effects on locoregional tumor control, comparative animal models are lacking. The authors standardized existing techniques in immunocompetent mice, laying the foundation for in vivo models of autologous breast reconstruction combinable with orthotopic tumor implantations. Twenty-five groin flaps and 39 fat grafts were transferred in female BALB/c-mice. Adipocytes were tracked via Hoechst-Calcein-DiI staining ( n = 2 per group), and postoperative volume retentions were compared via magnetic resonance imaging ( n = 3 per group) on days 1, 11, 21, and 31. Proliferation indices, microvessel densities, tissue hypoxia, and macrophage infiltrates were compared via Ki67, CD31, pimonidazole, and hematoxylin-eosin staining on days 5, 10, 15, 20, and 30 ( n = 4 per group). Viable adipocytes were present in both groups. Graft volumes plateaued at 42.7 ± 1.2% versus 81.8 ± 4.0% of flaps ( P < 0.001). Initially, grafts contained more hypoxic cells (day 5: 15.192 ± 1.249 versus 1.157 ± 192; P < 0.001), followed by higher proliferation (day 15: 25.2 ± 1.0% versus 0.0 ± 0.0%; P < 0.001), higher microvessel numbers (day 30: 307.0 ± 13.2 versus 178.0 ± 10.6; P < 0.001), and more pronounced macrophage infiltrates (graded 3 versus 2; P < 0.01). This comparative murine pilot study of vascularized flaps versus avascular lipofilling suggests differences in volume retention, proliferation, angiogenesis, hypoxia, and inflammation. The biological differences of fat grafting versus flap transfer are not fully understood because no single comparative experimental model has been established to date. The authors present the first comparative small animal model of both techniques, which will allow the gaining of deeper insights into their biological effects.

Photodynamic therapy in glioblastoma: Detection of intraoperative inadvertent 5-ALA mediated photodynamic therapeutical effect after gross total resection.

Glioblastoma (GBM) remains the most frequent and lethal primary brain tumor in adults, despite advancements in surgical resection techniques and adjuvant chemo- and radiotherapy. The most frequent recurrence pattern (75-90%) occurs in the form of continuous growth from the border of the surgical cavity, thus emphasizing the need for locoregional tumor control. Fluorescence-guided surgical resection using 5-ALA has been widely implemented in surgical protocols for such tumors. Recent literature also highlights the applicability of 5-ALA-mediated photodynamic therapy to obtain locoregional tumor control further. This study aims to identify if 5-ALA mediated photodynamic therapeutic effect after gross total glioblastoma resection has inadvertently occurred due to the exposition of protoporphyrin IX charged peripheral tumoral cells to operative room light sources. Of 146 patients who were intervened from glioblastoma between 2015 and 2020, 33 were included in the present study. Strict gross total resection (without supralocal resection) had been accomplished, and adjuvant chemoradiotherapy protocol was administered. Two comparison groups were created regarding the location of the recurrence (group A: up to 1 centimeter from the surgical cavity, and group B: beyond 1 centimeter from the surgical cavity). The cutoff point was determined to be 1 centimeter because of the visible light penetrance to the normal brain tissue. In univariate analysis, both groups only differed regarding 5-ALA administration, which was significantly related to a minor relative risk of presenting the recurrence within the first centimeter from the surgical cavity (Relative Risk = 0,655 (95% CI 0,442-0,970), p-value=0,046). Results obtained in univariate analysis were corroborated posteriorly in multivariate analysis (RR=0,730 (95% CI 0,340-0,980), p=0,017). In the present study, a probable inadvertent 5-ALA photodynamic therapeutical effect has been detected in vivo. This finding widely opens the door for further research on this promising theragnostic tool.

Radiation therapy for the treatment of macroscopic canine anal gland tumors - a retrospective study

Canine anal gland tumors are locally invasive and early metastasize to the loco-regional pelvic lymph nodes. Radiation therapy is a good method for loco-regional tumor control, especially in inoperable tumors. Since the organs in the pelvic area are sensitive to both acute and late radiation damage (chronic diarrhea, bleeding, strictures or intestinal perforations) and such damage mainly depends on the fraction size, we examined the radiation protocol used in this study with a reduced number of fractions (hypofractionated) regarding effectiveness and side effects. This retrospective study describes 13 dogs with macroscopic anal gland carcinoma that were irradiated with imaging-guided, intensity-modulated radiation therapy with a hypofractionated curative protocol of 12 × 3,8 Gy. Gross pathology was either in the region of the anal gland and/or in the sublumbar lymph nodes. Ten of the 13 dogs had advanced tumor diseases (stage 3a or 3b). The acute radiation reactions were mild to moderate and had been reported for some of the dogs in a previous study. The mean study time was 572 days (range 105-1292 days). Disease progression was observed or suspected in 7/13 dogs during the study period: local or loco-regional progression occurred in 3 dogs (23 %) and distant metastases in 4 dogs (31 %). Median progression-free survival was 480 days (95 %CI, 223-908), median survival was 597 days (95 %CI, 401-908). One year after treatment, 76,9 % (95 %CI, 53,5-100) of the dogs were still alive. The likelihood of tumor progression was lower with increasing age, otherwise none of the examined tumor or patient factors showed a prognostic influence on progression or survival time. No clinically relevant late side effects were observed apart from slight alopecia, pigmentation changes or dry, scaly skin, Medium to long-term tumor control can be expected in dogs with macroscopic anal gland tumors treated with a moderately hypofractionated radiation therapy protocol (12 × 3,8 Gy). During long-term monitoring no serious side effects or side effects requiring treatment were observed.

A rare late leptomeningal carcinomatosis from a local advanced squamous cell laryngeal carcinoma after a long-time locoregional tumor control: case report and literature review

Brain metastases in squamous cell carcinomas of the head and neck are extremely rare. More rarely late leptomenengeal metastases (LMMs) manifested after 10 years of laryngeal carcinoma complex treatment are diagnosed. We present a patient with a local advanced well-differentiated laryngeal carcinoma (LC) without metastases in the cervical lymph nodes/pT4 N0 M0 (G1), which was treated in 2011 by total laryngectomy and intensity modulated radiotherapy (IMRT). After 10 years, against the background of the laryngeal tumor control, two brain metastases (BMs) occur, followed by leptomeningeal carcinomatosis (LMC). Against the background of this rare clinical case and literary review, we focus on the necessary radiotherapy in late BMs, followed by leptomengial carcinomatosis. The prognosis for such distant brain incidents is extremely unfavorable. In a small number of late BMs near the ventricles, the prevention of LMC requires a whole brain radiotherapy (WBRT), followed by overdose by IMRT or radiosurgery (RS). Due to the rare cases of late cerebral and leptomenengeal metastases in head and neck squamous cell carcinomas (HNSCC), there are still no prospective studies to determine optimal complex treatment.

VoiceS: voice quality after transoral CO2 laser surgery versus single vocal cord irradiation for unilateral stage 0 and I glottic larynx cancer—a randomized phase III trial

BackgroundSurgery and radiotherapy are well-established standards of care for unilateral stage 0 and I early-stage glottic cancer (ESGC). Based on comparative studies and meta-analyses, functional and oncological outcomes after both treatment modalities are similar. Historically, radiotherapy (RT) has been performed by irradiation of the whole larynx. However, only the involved vocal cord is being treated with recently introduced hypofractionated concepts that result in 8 to 10-fold smaller target volumes. Retrospective data argues for an improvement in voice quality with non-inferior local control. Based on these findings, single vocal cord irradiation (SVCI) has been implemented as a routine approach in some institutions for ESGC in recent years. However, prospective data directly comparing SVCI with surgery is lacking. The aim of VoiceS is to fill this gap.MethodsIn this prospective randomized multi-center open-label phase III study with a superiority design, 34 patients with histopathologically confirmed, untreated, unilateral stage 0-I ESGC (unilateral cTis or cT1a) will be randomized to SVCI or transoral CO2-laser microsurgical cordectomy (TLM). Average difference in voice quality, measured by using the voice handicap index (VHI) will be modeled over four time points (6, 12, 18, and 24 months). Primary endpoint of this study will be the patient-reported subjective voice quality between 6 to 24 months after randomization. Secondary endpoints will include perceptual impression of the voice via roughness – breathiness – hoarseness (RBH) assessment at the above-mentioned time points. Additionally, quantitative characteristics of voice, loco-regional tumor control at 2 and 5 years, and treatment toxicity at 2 and 5 years based on CTCAE v.5.0 will be reported.DiscussionTo our knowledge, VoiceS is the first randomized phase III trial comparing SVCI with TLM. Results of this study may lead to improved decision-making in the treatment of ESGC.Trial registrationClinicalTrials.gov NCT04057209. Registered on 15 August 2019. Cantonal Ethics Committee KEK-BE 2019-01506