Clinical effects of re-evaluating a lung SBRT failure mode and effects analysis in a radiotherapy department.

PURPOSE: The increasing complexity of radiation treatments can hinder its clinical success. This study aimed to better understand evolving risks by re-evaluating a Failure Mode and Effects Analysis (FMEA) in lung SBRT. METHODS: An experienced multidisciplinary team conducted an FMEA and made a reassessment 3 years later. A process map was developed with potential failure modes (FMs) identified. High-risk FMs and their possible causes and corrective actions were determined. The initial FMEA analysis was compared to gain a deeper perspective. RESULTS: We identified 232 FMs. The high-risk processes were plan approval, target contouring, and patient evaluation. The corrective measures were based on stricter standardization of plan approval, pre-planning peer review, and a supporting pretreatment checklist, which substantially reduced the risk priority number in the revised FMEA. In the FMEA reassessment, we observed that the increased complexity and number of patients receiving lung SBRT conditioned a more substantial presence of human factors and communication errors as causal conditions and a potential wrong dose as a final effect. CONCLUSIONS: Conducting a lung SBRT FMEA analysis has identified high-risk conditions that have been effectively mitigated in an FMEA reanalysis. Plan approval has shown to be a weak link in the process. The increasing complexity of treatments and patient numbers have shifted causal factors toward human failure and communication errors. The potential of a wrong dose as a final effect augments in this scenario. We propose that digital and artificial intelligence options are needed to mitigate potential errors in high-complexity and high-risk RT scenarios.

A multicentric randomized controlled phase III trial of adaptive and 18F-FDG-PET-guided dose-redistribution in locally advanced head and neck squamous cell carcinoma (ARTFORCE).

BACKGROUND AND PURPOSE: This multicenter randomized phase III trial evaluated whether locoregional control of patients with LAHNSCC could be improved by fluorodeoxyglucose-positron emission tomography (FDG-PET)-guided dose-escalation while minimizing the risk of increasing toxicity using a dose-redistribution and scheduled adaptation strategy. MATERIALS AND METHODS: Patients with T3-4-N0-3-M0 LAHNSCC were randomly assigned (1:1) to either receive a dose distribution ranging from 64-84 Gy/35 fractions with adaptation at the 10thfraction (rRT) or conventional 70 Gy/35 fractions (cRT). Both arms received concurrent three-cycle 100 mg/m2cisplatin. Primary endpoints were 2-year locoregional control (LRC) and toxicity. Primary analysis was based on the intention-to-treat principle. RESULTS: Due to slow accrual, the study was prematurely closed (at 84 %) after randomizing 221 eligible patients between 2012 and 2019 to receive rRT (N = 109) or cRT (N = 112). The 2-year LRC estimate difference of 81 % (95 %CI 74-89 %) vs. 74 % (66-83 %) in the rRT and cRT arm, respectively, was not found statistically significant (HR 0.75, 95 %CI 0.43-1.31,P=.31). Toxicity prevalence and incidence rates were similar between trial arms, with exception for a significant increased grade ≥ 3 pharyngolaryngeal stenoses incidence rate in the rRT arm (0 versus 4 %,P=.05). In post-hoc subgroup analyses, rRT improved LRC for patients with N0-1 disease (HR 0.21, 95 %CI 0.05-0.93) and oropharyngeal cancer (0.31, 0.10-0.95), regardless of HPV. CONCLUSION: Adaptive and dose redistributed radiotherapy enabled dose-escalation with similar toxicity rates compared to conventional radiotherapy. While FDG-PET-guided dose-escalation did overall not lead to significant tumor control or survival improvements, post-hoc results showed improved locoregional control for patients with N0-1 disease or oropharyngeal cancer treated with rRT.

Remodeling the tumor microenvironment to overcome treatment resistance in HPV-negative head and neck cancer.

Despite intensive efforts and refined techniques, overall survival in HPV-negative head and neck cancer remains poor. Robust immune priming is required to elicit a strong and durable antitumor immune response in immunologically cold and excluded tumors like HPV-negative head and neck cancer. This review highlights how the tumor microenvironment could be affected by different immune and stromal cell types, weighs the need to integrate metabolic regulation of the tumor microenvironment into cancer treatment strategies and summarizes the emerging clinical applicability of personalized immunotherapeutic strategies in HPV-negative head and neck cancer.

Metastases-directed stereotactic body radiotherapy in combination with targeted therapy or immunotherapy: systematic review and consensus recommendations by the EORTC-ESTRO OligoCare consortium.

Stereotactic body radiotherapy (SBRT) for patients with metastatic cancer, especially when characterised by a low tumour burden (ie, oligometastatic disease), receiving targeted therapy or immunotherapy has become a frequently practised and guideline-supported treatment strategy. Despite the increasing use in routine clinical practice, there is little information on the safety of combining SBRT with modern targeted therapy or immunotherapy and a paucity of high-level evidence to guide clinical management. A systematic literature review was performed to identify the toxicity profiles of combined metastases-directed SBRT and targeted therapy or immunotherapy. These results served as the basis for an international Delphi consensus process among 28 interdisciplinary experts who are members of the European Society for Radiotherapy and Oncology (ESTRO) and European Organisation for Research and Treatment of Cancer (EORTC) OligoCare consortium. Consensus was sought about risk mitigation strategies of metastases-directed SBRT combined with targeted therapy or immunotherapy; a potential need for and length of interruption to targeted therapy or immunotherapy around SBRT delivery; and potential adaptations of radiation dose and fractionation. Results of this systematic review and consensus process compile the best available evidence for safe combination of metastases-directed SBRT and targeted therapy or immunotherapy for patients with metastatic or oligometastatic cancer and aim to guide today's clinical practice and the design of future clinical trials.

Nutritional status associates with immunotherapy clinical outcomes in recurrent or metastatic head and neck squamous cell carcinoma patients.

BACKGROUND: Beyond programmed death-ligand 1 (PD-L1) assessed by the combined positive score (CPS) and tumor mutational burden (TMB), no other biomarkers are approved for immunotherapy interventions. Here, we investigated whether additional clinical and pathological variables may impact on immunotherapy outcomes in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients. METHODS: R/M HNSCC patients treated with immunotherapy were reviewed. Analyzed variables at baseline included: clinicopathological, laboratory, and variables reflecting the host nutritional status such as the prognostic nutritional index (PNI) and albumin. The primary endpoint was progression free survival (PFS). The secondary endpoints were overall survival (OS) and objective response rate (ORR). Univariable and multivariable Cox models were fitted and random forest algorithm was used to estimate the importance of each prognostic variable. RESULTS: A total of 100 patients were treated with immunotherapy; 50% with single agent and 50% with experimental immunotherapy combinations. In the multivariable analysis, both ECOG performance status (HR: 1.73; 95%CI 1.07-2.82; p = 0.03) and PNI levels (10-point increments, HR: 0.66; 0.46-0.95; p = 0.03) were significantly associated with PFS. However, the derived neutrophil to lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) were not significantly associated with PFS (p-values > 0.15). In the OS analysis, albumin and PNI were the only statistically significant factors in the multivariable model (p < 0.001). CONCLUSIONS: In our cohort, PNI and ECOG performance status were most strongly associated with PFS in R/M HNSCC patients treated with immunotherapy. These results suggest that parameters informative of nutritional status should be considered before immunotherapy.

Transcriptomic and Proteomic Profiles for Elucidating Cisplatin Resistance in Head-and-Neck Squamous Cell Carcinoma.

To identify the novel genes involved in chemoresistance in head and neck squamous cell carcinoma (HNSCC), we explored the expression profiles of the following cisplatin (CDDP) resistant (R) versus parental (sensitive) cell lines by RNA-sequencing (RNA-seq): JHU029, HTB-43 and CCL-138. Using the parental condition as a control, 30 upregulated and 85 downregulated genes were identified for JHU029-R cells; 263 upregulated and 392 downregulated genes for HTB-43-R cells, and 154 upregulated and 68 downregulated genes for CCL-138-R cells. Moreover, we crossed-checked the RNA-seq results with the proteomic profiles of HTB-43-R (versus HTB-43) and CCL-138-R (versus CCL-138) cell lines. For the HTB-43-R cells, 21 upregulated and 72 downregulated targets overlapped between the proteomic and transcriptomic data; whereas in CCL-138-R cells, four upregulated and three downregulated targets matched. Following an extensive literature search, six genes from the RNA-seq (CLDN1, MAGEB2, CD24, CEACAM6, IL1B and ISG15) and six genes from the RNA-seq and proteomics crossover (AKR1C3, TNFAIP2, RAB7A, LGALS3BP, PSCA and SSRP1) were selected to be studied by qRT-PCR in 11 HNSCC patients: six resistant and five sensitive to conventional therapy. Interestingly, the high MAGEB2 expression was associated with resistant tumours and is revealed as a novel target to sensitise resistant cells to therapy in HNSCC patients.

Bariatric surgery improves metabolic and nonalcoholic fatty liver disease markers in metabolically healthy patients with morbid obesity at 5 years.

BACKGROUND: No studies have evaluated the effect of metabolic and bariatric surgery (MBS) on nonalcoholic fatty liver disease (NAFLD) and cardiometabolic markers in metabolically healthy patients with morbid obesity (MHMO) at midterm. OBJECTIVES: To assess the effect of MBS on NAFLD and cardiometabolic markers in MHMO patients and ascertain whether metabolically unhealthy patients with morbid obesity (MUMO) remain metabolically healthy at 5 years after MBS. SETTING: University hospital. METHODS: A total of 191 patients with a body mass index >40 kg/m2 and at least 5 years of follow-up were retrospectively analyzed. Lost to follow-up were 37.6% (151 of 401 patients). Patients were classified as MHMO if 1 or 0 of the cardiometabolic markers were present using the Wildman criteria. The degree of liver fibrosis was assessed using the NAFLD fibrosis score (NFS). RESULTS: Forty-one patients (21.5%) fulfilled the criteria for MHMO. They showed significant improvements in blood pressure (from 135.1 ± 22.1 and 84.2 ± 14.3 mm Hg to 117.7 ± 19.2 and 73.0 ± 10.9 mm Hg), plasma glucose (from 91.0 ± 5.6 mg/dL to 87.2 ± 5.2 mg/dL), homeostatic model assessment for insulin resistance (from 2.2 ± .9 to 1.0 ± .8), triglycerides (from 88.0 [range, 79.5-103.5] mg/dL to 61.0 [range, 2.0-76.5] mg/dL), alanine aminotransferase, gamma-glutamyl transpeptidase NFS (from -1.0 ± 1.0 to -1.9 ± 1.2), and high-density lipoprotein cholesterol (from 56.9 ± 10.5 mg/dL to 77.9 ± 17.4 mg/dL) at 5 years after surgery. A total of 108 MUMO patients (84.4%) who became metabolically healthy after 1 year stayed healthy at 5 years. CONCLUSIONS: MBS induced a midterm improvement in cardiometabolic and NAFLD markers in MHMO patients. Seventy-six percent of MUMO patients became metabolically healthy at 5 years after MBS.

Five microRNAs in Serum Are Able to Differentiate Breast Cancer Patients From Healthy Individuals.

Breast cancer is the cancer with the most incidence and mortality in women. microRNAs are emerging as novel prognosis/diagnostic tools. Our aim was to identify a serum microRNA signature useful to predict cancer development. We focused on studying the expression levels of 30 microRNAs in the serum of 96 breast cancer patients vs. 92 control individuals. Bioinformatic studies provide a microRNA signature, designated as a predictor, based on the expression levels of five microRNAs. Then, we tested the predictor in a group of 60 randomly chosen women. Lastly, a proteomic study unveiled the overexpression and downregulation of proteins differently expressed in the serum of breast cancer patients vs. that of control individuals. Twenty-six microRNAs differentiate cancer tissue from healthy tissue, and 16 microRNAs differentiate the serum of cancer patients from that of the control group. The tissue expression of miR-99a, miR-497, miR-362, and miR-1274, and the serum levels of miR-141 correlated with patient survival. Moreover, the predictor consisting of miR-125b, miR-29c, miR-16, miR-1260, and miR-451 was able to differentiate breast cancer patients from controls. The predictor was validated in 20 new cases of breast cancer patients and tested in 60 volunteer women, assigning 11 out of 60 women to the cancer group. An association of low levels of miR-16 with a high content of CD44 protein in serum was found. Circulating microRNAs in serum can represent biomarkers for cancer prediction. Their clinical relevance and the potential use of the predictor here described are discussed.

Therapy-Induced Modulation of the Tumor Microenvironment: New Opportunities for Cancer Therapies.

Advances in immunotherapy have achieved remarkable clinical outcomes in tumors with low curability, but their effects are limited, and increasing evidence has implicated tumoral and non-tumoral components of the tumor microenvironment as critical mediators of cancer progression. At the same time, the clinical successes achieved with minimally invasive and optically-guided surgery and image-guided and ablative radiation strategies have been successfully implemented in clinical care. More effective, localized and safer treatments have fueled strong research interest in radioimmunotherapy, which has shown the potential immunomodulatory effects of ionizing radiation. However, increasingly more observations suggest that immunosuppressive changes, metabolic remodeling, and angiogenic responses in the local tumor microenvironment play a central role in tumor recurrence. In this review, we address challenges to identify responders vs. non-responders to the immune checkpoint blockade, discuss recent developments in combinations of immunotherapy and radiotherapy for clinical evaluation, and consider the clinical impact of immunosuppressive changes in the tumor microenvironment in the context of surgery and radiation. Since the therapy-induced modulation of the tumor microenvironment presents a multiplicity of forms, we propose that overcoming microenvironment related resistance can become clinically relevant and represents a novel strategy to optimize treatment immunogenicity and improve patient outcome.

TSPAN1: A Novel Protein Involved in Head and Neck Squamous Cell Carcinoma Chemoresistance.

Sensitization of resistant cells and cancer stem cells (CSCs) represents a major challenge in cancer therapy. A proteomic study revealed tetraspanin-1 (TSPAN1) as a protein involved in acquisition of cisplatin (CDDP) resistance (Data are available via ProteomeXchange with identifier PXD020159). TSPAN1 was found to increase in CDDP-resistant cells, CSCs and biopsies from head and neck squamous cell carcinoma (HNSCC) patients. TSPAN1 depletion in parental and CDDP-resistant HNSCC cells reduced cell proliferation, induced apoptosis, decreased autophagy, sensitized to chemotherapeutic agents and inhibited several signaling cascades, with phospho-SRC inhibition being a major common target. Moreover, TSPAN1 depletion in vivo decreased the size and proliferation of parental and CDDP-resistant tumors and reduced metastatic spreading. Notably, CDDP-resistant tumors showed epithelial-mesenchymal transition (EMT) features that disappeared upon TSPAN1 inhibition, suggesting a link of TSPAN1 with EMT and metastasis. Immunohistochemical analysis of HNSCC specimens further revealed that TSPAN1 expression was correlated with phospho-SRC (pSRC), and inversely with E-cadherin, thus reinforcing TSPAN1 association with EMT. Overall, TSPAN1 emerges as a novel oncogenic protein and a promising target for HNSCC therapy.

Autophagy inhibition as a promising therapeutic target for laryngeal cancer.

To identify the putative relevance of autophagy in laryngeal cancer, we performed an immunohistochemistry study to analyze the expression of the proteins involved in this process, namely, LC3, ATG5 and p62/SQSTM1. Additionally, Prostate tumor-overexpressed gene 1 protein (PTOV1) was included due to its potential relevance in laryngeal cancer. Moreover, as cancer resistance might involve autophagy in some circumstances, we studied the intrinsic drug resistance capacity of primary tumor cultures derived from 13 laryngeal cancer biopsies and their expression levels of LC3, ATG5, p62 and PTOV1. Overall, our results suggest that (i) cytoplasmic p62 and PTOV1 can be considered prognostic markers in laryngeal cancer, (ii) the acquisition of resistance seems to be related to PTOV1 and autophagy-related protein overexpression, (iii) by increasing autophagy, PTOV1 might contribute to resistance in this model and (iv) the expression of autophagy-related proteins could classify a subgroup of laryngeal cancer patients who will benefit from a therapy based upon autophagy inhibition. Our study suggests that autophagy inhibition with hydroxychloroquine could be a promising strategy for laryngeal cancer patients, particularly those patients with high resistance to the CDDP treatment that in addition have autophagy upregulation.

Effectiveness of radiotherapy for metastatic spinal cord compression in patients with short life expectancy.

AIM: To analyze the effect of radiotherapy (RT) in patients with metastatic spinal cord compression (MSCC) and poor prognosis in our center. BACKGROUND: RT is an effective treatment for MSCC. MATERIALS AND METHODS: Prospective evaluation on patients with MSCC and limited survival (according to Rades' scale), and treated with single-dose 8 Gy RT (February 2013-August 2014). Pain, ambulatory status and sphincter control were recorded. Pain relief was evaluated following the International Bone Metastases Consensus Working Party Guidelines. Ambulatory status was evaluated with Frankel's scale. Spinal fracture and instability were recorded. Health aspects were evaluated via a short survey and measuring the time spent on RT. RESULTS: 35 patients were included. 51% had unfavorable histologies; 60% bone fracture and 17% spinal instability. Median Karnofsky score was 60; 100% were on high doses of opioids. Median survival was 1.5 months. 49% had a partial pain response at 2 weeks post-radiation, and 47% at one month. Significant reductions in pain intensity were present at 2 weeks (Visual analog scale, VAS score, from 8 ± 1.5 to 5 ± 1.9). Negligible effects were observed on motor and bladder function, along with side effects. KPS score was maintained during follow-up. 80% of patients spent ≤5% of their remaining lifetime on RT. A survey comparison between clinical judgment and the results according to treatment decision consider that these patients merit treatment evaluation. CONCLUSIONS: A moderate pain response tailored to life expectancy can be obtained in patients treated with radiation. 8-Gy single-dose is an option for patients with limited survival.

Dose variations in tumor volumes and organs at risk during IMRT for head-and-neck cancer.

Many head-and-neck cancer (HNC) patients treated with radiotherapy suffer significant anatomical changes due to tumor shrinkage or weight loss. The purpose of this study was to assess dose changes over target volumes and organs at risk during intensity-modulated radiotherapy for HNC patients. Sixteen HNC IMRT patients, all requiring bilateral neck irradiation, were enrolled in the study. A CTplan was performed and the initial dose distribution was calculated. During the treatment, two subsequent CTs at the 15th (CT15) and 25th (CT25) fractions were acquired. The initial plan was calculated on the CT15 and CT25, and dose-volume differences related to the CTplan were assessed. For target volumes, mean values of near-maximun absorbed dose (D2%) increased at the 25th fraction, and doses covering 95% and 98% of volume decreased significantly at the 15th fraction. Contralateral and ipsilateral parotid gland mean doses increased by 6.1% (range: -5.4, 23.5%) and 4.7% (range: -9.1, 22.3%), respectively, at CT25. The D2% in the spinal cord increased by 1.8 Gy at CT15. Mean absorbed dose increases at CT15 and CT25 were observed in: the lips, 3.8% and 5.3%; the oral cavity, 3.5% and 2.5%; and lower middle neck structure, 1.9% and 1.6%. Anatomical changes during treatment of HNC patients affect dose distribution and induce a loss of dose coverage to target volumes and an overdosage to critical structures. Appropriate organs at risk have to be contoured and monitored in order to know if the initial plan remains suitable during the course of the treatment. Reported dosimetric data can help to identify patients who could benefit from adaptive radiotherapy.

Management of squamous cell carcinoma of the head and neck: updated European treatment recommendations.

Squamous cell carcinoma of the head and neck requires a multidisciplinary management. Risk factors for adjuvant radiotherapy are stage III-IV, perineural involvement or vascular tumor embolism. If there are positive margins or extracapsular extension chemoradiotherapy is needed. For patients with nonresectable disease we recommend treatment with concomitant chemoradiation, although this has important acute and late toxicity. Concomitant EGF receptor inhibitors and taxane-based induction chemotherapy are new strategies under study that have demonstrated some benefits but are not yet the standard treatment. Intensity-modulated radiotherapy allows one to decrease radiation dose to organs. Preclinical work in signaling pathways and other oncogenic factors (e.g., human papillomavirus infection) will be the key to improving outcomes of head and neck cancer patients in the future.

Prognostic significance of vascular endothelial growth factor and cyclooxygenase-2 in patients with rectal cancer treated with preoperative radiotherapy.

PURPOSE: To analyze the prognostic value of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in patients with locally advanced rectal cancer treated with preoperative radiotherapy. METHODS: Eighty-one patients with locally advanced rectal cancer were studied. All patients received preoperative pelvic radiotherapy. Forty-seven patients received concomitant chemotherapy. Surgical resection was performed 4-8 weeks later in all patients. Immunohistochemical examination of COX-2 and VEGF was performed on the preirradiation diagnostic biopsies. An immunohistochemical score established from the extension and intensity of the markers was used for analysis. The log-rank test and proportional hazards regression analysis were used to calculate the probability that the biomarkers were associated with patient outcome. RESULTS: COX-2 expression was positive in 38 tumors (51%) while VEGF expression was positive in 43 (57%). The only clinicopathological parameter significantly associated with COX-2 or VEGF expression was performance status. None of the 2 markers were found to predict treatment response. There was no statistically significant correlation between COX-2 and VEGF. Univariate analysis identified pathological stage (pT, pN) as prognostic for disease-free survival. When VEGF expression was analyzed, disease-free survival was reduced among patients with VEGF-positive tumors (p = 0.047). This was specifically related to metastases-free survival (p = 0.016). These results were not observed for COX-2. After multivariate analysis, the pT and pN stage remained as independent prognostic factors. CONCLUSIONS: VEGF-positive expression is an indicator of poor disease-free survival, specifically linked to distant metastasis. More aggressive treatment strategies are warranted in pT3-4 and pN1-2 rectal cancer patients.

The expression of epidermal growth factor receptor results in a worse prognosis for patients with rectal cancer treated with preoperative radiotherapy: a multicenter, retrospective analysis.

BACKGROUND AND PURPOSE: Expression of epidermal growth factor receptor (EGFR) is observed in 50-70% of colorectal carcinoma and is associated with poor prognosis. The aim of this study was to determine the prognostic value of EGFR status before radiotherapy in a group of patients with locally advanced rectal cancer treated with preoperative radiotherapy. PATIENTS AND METHODS: Eighty-seven patients were studied retrospectively. Treatment consisted of pelvic radiotherapy, in 50 patients with concomitant chemotherapy and surgical resection. Immunohistochemistry for EGFR was determined at the preradiation biopsy and in the resected specimens. Immunohistochemical analysis for EGFR expression was evaluated according to extension and staining intensity. We defined positive staining (EGFR positive), when extension was 5% or more. RESULTS: A total of 52 of 87 tumors showed EGFR positive status at biopsy (60%) and EGFR expression was associated neither with clinical tumor stage nor with clinical nodal stage. EGFR positive expression was linked to a lack of pathologic complete response to preoperative radiotherapy (P=0.006). Disease-free survival was lower among patients with EGFR positive status before radiotherapy (P=0.003). In a multivariate analysis EGFR expression at biopsy was a statistically significant predictor of disease-free survival, RR=2.88(1.1-7.8), P=0.036. CONCLUSIONS: EGFR is expressed in a significant number of rectal tumors. EGFR-positive expression before radiotherapy is an indicator for poor response and low disease-free survival.