Palliative radiotherapy indications during the COVID-19 pandemic and in future complex logistic settings: the NORMALITY model.

INTRODUCTION: The COVID-19 pandemic has challenged healthcare systems worldwide over the last few months, and it continues to do so. Although some restrictions are being removed, it is not certain when the pandemic is going to be definitively over. Pandemics can be seen as a highly complex logistic scenario. From this perspective, some of the indications provided for palliative radiotherapy (PRT) during the COVID-19 pandemic could be maintained in the future in settings that limit the possibility of patients achieving symptom relief by radiotherapy. This paper has two aims: (1) to provide a summary of the indications for PRT during the COVID-19 pandemic; since some indications can differ slightly, and to avoid any possible contradictions, an expert panel composed of the Italian Association of Radiotherapy and Clinical Oncology (AIRO) and the Palliative Care and Supportive Therapies Working Group (AIRO-palliative) voted by consensus on the summary; (2) to introduce a clinical care model for PRT [endorsed by AIRO and by a spontaneous Italian collaborative network for PRT named "La Rete del Sollievo" ("The Net of Relief")]. The proposed model, denoted "No cOmpRoMise on quality of life by pALliative radiotherapy" (NORMALITY), is based on an AIRO-palliative consensus-based list of clinical indications for PRT and on practical suggestions regarding the management of patients potentially suitable for PRT but dealing with highly complex logistics scenarios (similar to the ongoing logistics limits due to COVID-19). MATERIAL AND METHODS: First, a summary of the available literature guidelines for PRT published during the COVID-19 pandemic was prepared. A systematic literature search based on the PRISMA approach was performed to retrieve the available literature reporting guideline indications fully or partially focused on PRT. Tables reporting each addressed clinical presentation and respective literature indications were prepared and distributed into two main groups: palliative emergencies and palliative non-emergencies. These summaries were voted in by consensus by selected members of the AIRO and AIRO-palliative panels. Second, based on the summary for palliative indications during the COVID-19 pandemic, a clinical care model to facilitate recruitment and delivery of PRT to patients in complex logistic scenarios was proposed. The summary tables were critically integrated and shuffled according to clinical presentations and then voted on in a second consensus round. Along with the adapted guideline indications, some methods of performing the first triage of patients and facilitating a teleconsultation preliminary to the first in-person visit were developed. RESULTS: After the revision of 161 documents, 13 papers were selected for analysis. From the papers, 19 clinical presentation items were collected; in total, 61 question items were extracted and voted on (i.e., for each presentation, more than one indication was provided from the literature). Two tables summarizing the PRT indications during the COVID-19 pandemic available from the literature (PRT COVID-19 summary tables) were developed: palliative emergencies and palliative non-emergencies. The consensus of the vote by the AIRO panel for the PRT COVID-19 summary was reached. The PRT COVID-19 summary tables for palliative emergencies and palliative non-emergencies were adapted for clinical presentations possibly associated with patients in complex clinical scenarios other than the COVID-19 pandemic. The two new indication tables (i.e., "Normality model of PRT indications") for both palliative emergencies and palliative non-emergencies were voted on in a second consensus round. The consensus rate was reached and strong. Written forms facilitating two levels of teleconsultation (triage and remote visits) were also developed, both in English and in Italian, to evaluate the patients for possible indications for PRT before scheduling clinical visits. CONCLUSION: We provide a comprehensive summary of the literature guideline indications for PRT during COVID-19 pandemic. We also propose a clinical care model including clinical indications and written forms facilitating two levels of teleconsultation (triage and remote visits) to evaluate the patients for indications of PRT before scheduling clinical visits. The normality model could facilitate the provision of PRT to patients in future complex logistic scenarios.

Prognostic Score in Radiotherapy Practice for Palliative Treatments (PROPHET) Study for Bone Metastases: An Investigation Into the Clinical Effect on Treatment Prescription.

Purpose: Bone metastases frequently occur during malignant disease. Palliative radiation therapy (PRT) is a crucial part of palliative care because it can relieve pain and improve patients' quality of life. Often, a clinician's survival estimation is too optimistic. Prognostic scores (PSs) can help clinicians tailor PRT indications to avoid over- or undertreatment. Although the PS is supposed to aid radiation oncologists (ROs) in palliative-care scenarios, it is unclear what type of support, and to what extent, could impact daily clinical practice. Methods and Materials: A national-based investigation of the prescriptive decisions on simulated clinical cases was performed in Italy. Nine clinical cases from real-world clinical practice were selected for this study. Each case description contained complete information regarding the parameters defining the prognosis class according to the PS (in particular, the Mizumoto Prognostic Score, a validated PS available in literature and already applied in some clinical trials). Each case description contained complete information regarding the parameters defining the prognosis class according to the PS. ROs were interviewed through questionnaires, each comprising the same 3 questions per clinical case, asking (1) the prescription after detailing the clinical case features but not the PS prognostic class definition; (2) whether the RO wanted to change the prescription once the PS prognostic class definition was revealed; and (3) in case of a change of the prescription, a new prescriptive option. Three RO categories were defined: dedicated to PRT (RO-d), nondedicated to PRT (RO-nd), and resident in training (IT). Interviewed ROs were distributed among different regions of the country. Results: Conversion rates, agreements, and prescription trends were investigated. The PS determined a statistically significant 11.12% of prescription conversion among ROs. The conversion was higher for the residents and significantly higher for worse prognostic scenario subgroups, respectively. The PS improved prescriptive agreement among ROs (particularly for worse-prognostic-scenario subgroups). Moreover, PS significantly increased standard prescriptive approaches (particularly for worse-clinical-case presentations). Conclusions: To the best of our knowledge, the PROPHET study is the first to directly evaluate the potential clinical consequences of the regular application of any PS. According to the Prophet study, a prognostic score should be integrated into the clinical practice of palliative radiation therapy for bone metastasis and training programs in radiation oncology.

Systemic effect of radiotherapy before or after nivolumab in lung cancer: an observational, retrospective, multicenter study.

BACKGROUND: The combination of radiotherapy (RT) and programmed death 1 inhibitors seems to increase antitumor immune responses. OBJECTIVE: To assess the outcome and the role of the best combination sequence, i.e. immunotherapy given before, during, and/or after RT, in patients with non-small cell lung cancer (NSCLC). METHODS: We conducted an observational, retrospective analysis of 95 consecutive patients with advanced NSCLC who received any radiotherapy treatment and nivolumab, as clinically indicated. Median overall survival (OS) and the 95% confidence interval (CI) were estimated with the Kaplan-Meier method. Cox model was used to obtain hazard ratio (HR) and associated 95% CI with statistical inference by log-rank statistic. RESULTS: Median OS was 11.9 months (95% CI, 6.6-17.2). Patients who received radiotherapy during an immune checkpoint inhibitor treatment started more than 60 days before showed a better outcome than patients who started immunotherapy over 60 days after RT ending (HR, 2.90 [1.37-6.12], p = 0.005; median OS, 22.4 months vs 8.6 months, p = 0.005). Median progression-free survival was 6.3 months (95% CI, 4.6-8.0). CONCLUSIONS: This study shows that combining irradiation with nivolumab for the treatment of advanced NSCLC leads to improved OS. The optimal time window for the combination of RT and immunotherapy seems to play a critical role for therapeutic antitumor response derived by abscopal effect.

Resilience in Radiotherapy Services During the COVID-19 Emergency: Collaboration Between the Regional Radiation Oncology Departments of Lazio, Abruzzo and Molise.

AIM: Radiation therapy is a cornerstone of oncological treatment and oncological patients show greater risk of developing complications related to COVID-19 infection. Stringent social restrictions have ensured a significant reduction in the spread of the virus, but also gave rise to a number of critical issues for radiation oncology wards. For this reason, the Directors of the Radiation Oncology Departments (RODs) of Lazio, Abruzzo and Molise regions shared their experience and ideas in order to create a common document that may assist in facing the negative impacts of the pandemic on radiation oncology wards and patients. PATIENTS AND METHODS: The study was conducted according to the Estimate-Talk-Estimate method. Five issues were proposed and rated. Among approved issues, statements were proposed anonymously, then harmonized and finally voted on according to a Likert scale from 1 to 9. Those for which an agreement of 7-9 was observed were finally approved. RESULTS: The document was developed with 42 statements dealing about safety measures for patients and staff, organization of clinical and work activities, usage of Information Technology systems for meetings/smart working. An agreement was recorded for 34 statements. CONCLUSION: This document sets out some recommendations for RODs and can provide valuable management information for Oncological Radiotherapy wards.

Pain REduction with bone metastases STereotactic radiotherapy (PREST): A phase III randomized multicentric trial.

BACKGROUND: Palliative antalgic treatments represent an issue for clinical management and a challenge for scientific research. Radiotherapy (RT) plays a central role. Techniques such as stereotactic body radiotherapy (SBRT) were largely investigated in several phase 2 studies with good symptom response, becoming widely adopted. However, evidence from randomized, direct comparison of RT and SBRT is still lacking. METHODS/DESIGN: The PREST trial was designed as an interventional study without medicinal treatment. It is a phase 3, open-label, multicentric trial randomized 1:1. Inclusion criteria include painful spinal bone metastases presenting with a pain level > 4 (or > 1 if being treated with an analgesic) on the Numeric Rating Scale (NRS); expected intermediate/high prognosis (greater than 6 months) according to the Mizumoto prognostic score; low spine instability neoplastic score (SINS) sores (< 7); magnetic resonance imaging (MRI) assessment of the bulky lesion. Patients will be assigned to either standard conventional radiotherapy involving 4 Gy × 5 fractions (fx) to the whole involved vertebra or SBRT by intensity modulated radiotherapy with simultaneous integrated boost (IMRT-SIB) involving 7 Gy × 3 fx to the whole involved vertebra + 10 Gy × 3 fx on the macroscopic lesion (gross tumor volume (GTV)). In the experimental arm, the GTV will be contoured by registration with baseline MRI. DISCUSSION: The primary endpoint is overall pain reduction, defined in terms of variation between baseline and 3-month evaluation; pain will be measured using the NRS. Secondary endpoints include pain control duration; retreatment rates (after a minimum interval of 1 month); local control assessed with RECIST criteria; symptom progression free survival; progression-free survival; overall survival; and quality of life (at 0, 30, and 90 days). Accrual of 330 lesions is planned. The experimental arm is expected to have an improvement in overall pain response rates of 15% with respect to the standard arm (60% according to Chow et al. (Int J Radiat Oncol Biol Phys. 82(5):1730-7, 2012)). TRIAL REGISTRATION: ClinicalTrials.gov, NCT03597984 . Registered on July 2018.

Carcinoma of the vulva: clinical results of exclusive and adjuvant radiotherapy.

BACKGROUND: The aim of this study was to evaluate the historical cohort of 61 patients with carcinoma of the vulva, treated with radiation therapy from 1986 to 1997. PATIENTS AND METHODS: Twenty-seven patients were submitted to radiation therapy alone and 34 received radiotherapy post limited surgery in early stages and post radical vulvectomy in advanced stages. The dose range varied from 59 to 63 Gy in post-operative patients and 65 Gy to 71 Gy in curative patients. RESULTS: Five-year Overall Survival (OS) and Disease-Free Survival (DFS) for patients treated with irradiation alone and for those treated with post-operative radiotherapy were 50.8% and 69.7%, respectively, without significant statistical difference. For OS multivariate analysis showed statistical difference for stage and age variables, and for stage variable in the case of DFS. CONCLUSION: In early stage vulvar cancer patients OS and DFS are good, with high control rate and low incidence of adverse effect. In loco-regionally-advanced patients, especially in those with stage IV or with > 2 positive lymph nodes, the outcomes are poor.

Radiotherapy in the treatment of stage III-IV hypopharyngeal carcinoma.

BACKGROUND: The aim of this study was to evaluate the role of radiation therapy alone, employing standard fractionation, in stage III-IV hypopharyngeal carcinoma. MATERIALS AND METHODS: Fourteen (38.9%) stage III and 22 (61.1%) stage IV patients with hypopharyngeal carcinoma were submitted, with curative intent, to exclusive radiotherapy to the primary tumor and regional draining lymph nodes, level II, III, IV, V and VI. Total dose ranged from 68 to 72 Gy. RESULTS: The 5-year overall survival (OS) and disease-specific survival (DSS) rates were 15.6% and 28.1%, respectively. Five-year OS in stage III and IV patients was, respectively, 33% and 5% (p=0.028) and DSS was, respectively, 50% and 16% (p=0.029). Five-year OS and DSS rate in N0 versus N+ patients were respectively 37.5% and 75% versus 8.3% and 12.5% (p=0.07 and p=0.05). CONCLUSION: Overall survival at 5 years for III-IV hypopharyngeal tumor treated with radiotherapy alone is poor. It is possible that the addition of the best radiation fractionation to the best concurrent chemotherapy may improve the results, with acceptable toxicity.

Radiotherapy alone and chemoirradiation in recurrent squamous cell carcinoma of the vulva.

AIM: To evaluate the role of radiotherapy alone or combined with chemotherapy in the treatment of recurrent vulvar cancer, emphasising the prognostic factors and outcomes. MATERIALS AND METHODS: Twenty women with loco-regional recurrence of vulvar carcinoma were retrospectively reviewed. Eleven patients were managed with a combination of chemotherapy and radiotherapy, seven out of these with concomitant radio-chemotherapy and four with neo-adjuvant chemotherapy. Nine patients were submitted to radiotherapy alone. The total dose of radiation therapy ranged from 30 Gy to 70 Gy. RESULTS: The median follow-up was 6 months (range 2-70 months). The 5-year overall and disease-free survival for the entire cohort was 20%. The outcomes included 6 complete response (CR), 10 partial response (PR) and 4 no change (NC). Patients with one site of recurrence and size of lesion < or = 3 cm were long survivors and disease-free at 5 years; all these women received a total dose of radiation therapy > or = 6480 cGy. CONCLUSION: We emphasize the importance of the number, site and diameter of recurrences as prognostic indicators; the outcomes of these patients were also affected by the total dose of radiation therapy.

Transrectal ultrasound color Doppler in the evaluation of recurrence of anal canal cancer.

OBJECTIVE: aim was to obtain elements for a differential diagnosis between post-radiation fibrosis and residual tumor or local relapse in anal canal cancer through detection of presence/absence of intralesional blood flow. Transrectal ultrasound and color Doppler were compared. METHODS: 43 patients underwent transrectal ultrasound sonography and color Doppler before and after therapy to assess intralesional blood flow and flow pattern (spotty and linear signals). All diagnostic imaging results were compared to histological analysis. Specificity was submitted to statistical analysis using McNemar test. RESULTS: before therapy 34 lesions (79%) showed color signal; no signal in 9 (21%), which were excluded from our analysis. Eighteen of the 34 patients considered, presented complete response to therapy, 14 partial response and two no response. After therapy, signal disappeared in 17 patients (94%); one false-positive (6%) presented spotty signals; 16 of 34 patients presented changed color signal. Color Doppler showed higher specificity than grey scale transrectal ultrasound in the differentiation of fibrosis from tumor. Response was confirmed by histological examination, considered gold standard. McNemar test demonstrated the significance of color Doppler (P < 0.0001). CONCLUSION: color Doppler considerably increases transrectal ultrasound specificity in differentiating tumor relapse from fibrosis in anal canal cancer.

TRUS staging and follow-up in patients with anal canal cancer.

PURPOSE: The aim of our study was to define the role of grey-scale transrectal ultrasound in the evaluation, staging and follow-up of patients with histologically diagnosed anal canal cancer. MATERIALS AND METHODS: Seventy-six patients underwent digital rectal examination, anoscopy, abdomino-pelvic CT, inguinal and transrectal ultrasound; Fifty-five received combined chemoradiotherapy, whereas 21 received only radiotherapy due to clinical contraindications to chemotherapy. Before and after treatment TNM and UT staging were compared. After treatment we evaluated the sensitivity of transrectal ultrasound in the differentiation of post-radiation fibrosis from residual tumor/local relapse (gold standard: histological analysis). Ultrasound examination was carried out to assess inguinal and perirectal lymph node involvement, and Computed Tomography to detect abdominal lymph nodes. RESULTS: In all stages, except stage 4, there were differences between TNM and UT staging, as TNM is often understaged. After treatment ultrasound showed a sensitivity of 71 percent in the differentiation of fibrosis from residual tumor (the results were confirmed by histopathologic analysis), of 93 percent in the identification of perirectal lymph nodes and of 95 percent in the identification of inguinal lymph nodes. CONCLUSIONS: Transrectal ultrasound is very useful in the staging and follow-up of anal canal carcinoma, in the evaluation of initial tumor volume and reduction after therapy. Ultrasound is useful in the distinction of fibrosis from residual tumor after therapy and as biopsy guidance.