Further Clarification of Pain Management Complexity in Radiotherapy: Insights from Modern Statistical Approaches.

BACKGROUND: The primary objective of this study was to assess the adequacy of analgesic care in radiotherapy (RT) patients, with a secondary objective to identify predictive variables associated with pain management adequacy using a modern statistical approach, integrating the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm and the Classification and Regression Tree (CART) analysis. METHODS: This observational, multicenter cohort study involved 1387 patients reporting pain or taking analgesic drugs from 13 RT departments in Italy. The Pain Management Index (PMI) served as the measure for pain control adequacy, with a PMI score < 0 indicating suboptimal management. Patient demographics, clinical status, and treatment-related factors were examined to discern the predictors of pain management adequacy. RESULTS: Among the analyzed cohort, 46.1% reported inadequately managed pain. Non-cancer pain origin, breast cancer diagnosis, higher ECOG Performance Status scores, younger patient age, early assessment phase, and curative treatment intent emerged as significant determinants of negative PMI from the LASSO analysis. Notably, pain management was observed to improve as RT progressed, with a greater discrepancy between cancer (33.2% with PMI < 0) and non-cancer pain (73.1% with PMI < 0). Breast cancer patients under 70 years of age with non-cancer pain had the highest rate of negative PMI at 86.5%, highlighting a potential deficiency in managing benign pain in younger patients. CONCLUSIONS: The study underscores the dynamic nature of pain management during RT, suggesting improvements over the treatment course yet revealing specific challenges in non-cancer pain management, particularly among younger breast cancer patients. The use of advanced statistical techniques for analysis stresses the importance of a multifaceted approach to pain management, one that incorporates both cancer and non-cancer pain considerations to ensure a holistic and improved quality of oncological care.

Adequacy of Pain Management in Patients Referred for Radiation Therapy: A Subanalysis of the Multicenter ARISE-1 Study.

BACKGROUND: Pain is a prevalent symptom among cancer patients, and its management is crucial for improving their quality of life. However, pain management in cancer patients referred to radiotherapy (RT) departments is often inadequate, and limited research has been conducted on this specific population. This study aimed to assess the adequacy and effectiveness of pain management when patients are referred for RT. Moreover, we explored potential predictors of adequate pain management. METHODS: This observational, prospective, multicenter cohort study included cancer patients aged 18 years or older who were referred to RT departments. A pain management assessment was conducted using the Pain Management Index (PMI), calculated by subtracting the pain score from the analgesic score (PMI < 0 indicated inadequate pain management). Univariate and multivariate analyses were performed to identify predictors of adequate pain management. RESULTS: A total of 1042 cancer outpatients were included in the study. The analysis revealed that 42.9% of patients with pain did not receive adequate pain management based on PMI values. Among patients with pain or taking analgesics and referred to palliative or curative RT, 72% and 75% had inadequate or ineffective analgesic therapy, respectively. The odds of receiving adequate pain management (PMI ≥ 0) were higher in patients undergoing palliative RT (OR 2.52; p < 0.001), with worse ECOG-PS scores of 2, 3 and 4 (OR 1.63, 2.23, 5.31, respectively; p: 0.017, 0.002, 0.009, respectively) compared to a score of 1 for those with cancer-related pain (OR 0.38; p < 0.001), and treated in northern Italy compared to central and southern of Italy (OR 0.25, 0.42, respectively; p < 0.001). CONCLUSIONS: In this study, a substantial proportion of cancer patients referred to RT departments did not receive adequate pain management. Educational and organizational strategies are necessary to address the inadequate pain management observed in this population. Moreover, increasing the attention paid to non-cancer pain and an earlier referral of patients for palliative RT in the course of the disease may improve pain response and treatment outcomes.

Adequacy of Pain Treatment in Radiotherapy Departments: Results of a Multicenter Study on 2104 Patients (Arise).

Aim: The frequent inadequacy of pain management in cancer patients is well known. Moreover, the quality of analgesic treatment in patients treated with radiotherapy (RT) has only been rarely assessed. In order to study the latter topic, we conducted a multicenter, observational and prospective study based on the Pain Management Index (PMI) in RT Italian departments. Methods: We collected data on age, gender, tumor site and stage, performance status, treatment aim, and pain (type: CP­cancer pain, NCP­non-cancer pain, MP­mixed pain; intensity: NRS: Numeric Rating Scale). Furthermore, we analyzed the impact on PMI on these parameters, and we defined a pain score with values from 0 (NRS: 0, no pain) to 3 (NRS: 7−10: intense pain) and an analgesic score from 0 (pain medication not taken) to 3 (strong opioids). By subtracting the pain score from the analgesic score, we obtained the PMI value, considering cases with values < 0 as inadequate analgesic prescriptions. The Ethics Committees of the participating centers approved the study (ARISE-1 study). Results: Two thousand one hundred four non-selected outpatients with cancer and aged 18 years or older were enrolled in 13 RT departments. RT had curative and palliative intent in 62.4% and 37.6% patients, respectively. Tumor stage was non-metastatic in 57.3% and metastatic in 42.7% of subjects, respectively. Pain affected 1417 patients (CP: 49.5%, NCP: 32.0%; MP: 18.5%). PMI was < 0 in 45.0% of patients with pain. At multivariable analysis, inadequate pain management was significantly correlated with curative RT aim, ECOG performance status = 1 (versus both ECOG-PS3 and ECOG- PS4), breast cancer, non-cancer pain, and Central and South Italy RT Departments (versus Northern Italy).Conclusions: Pain management was less adequate in patients with more favorable clinical condition and stage. Educational and organizational strategies are needed in RT departments to reduce the non-negligible percentage of patients with inadequate analgesic therapy.

An Italian survey on "palliative intent" radiotherapy.

Background: The aim of this paper is to provide a comprehensive overview of the scenario on radiotherapy (RT) delivered with palliative intent in Italy. Materials and methods: A structured online questionnaire was submitted to Italian radiation oncologists in order to explore the clinical practice in different areas of palliation, namely: bone, lung, brain, liver, and emergencies suitable to RT. Results: 209 radiation oncologists took part in the study. Stereotactic body irradiation was found to be the preferred technique in lung and liver metastases, whereas 3D conformal RT was registered as the technique of choice for bone and brain metastases. The majority (98%) of participants stated to treat mainly radiotherapy emergencies with 3D conformal RT at doses ranging from 25 to 50 Gy. Re-irradiation is delivered by the majority of respondents, whereas post-treatment follow-up is done only by 51.4% of them. Conclusions: This nationwide study highlights some heterogeneity among Italian radiation oncologists regarding treatment and follow-up of metastatic cancer patients.

Intensity-modulated radiotherapy does not induce volumetric changes of the Bichat fat pad in nasopharyngeal cancer.

PURPOSE: To evaluate morphological and functional changes in the Bichat fat pad (BFP) after curative concurrent chemoradiotherapy in nasopharyngeal cancer (NPC) patients. METHODS: We retrospectively analyzed the volumetric, metabolic, and dosimetry parameters of BFPs in 7 NPC patients who underwent intensity-modulated radiotherapy (IMRT) between 2015 and 2020. Inclusion criteria were i) histologically confirmed diagnosis of NPC, ii) follow-up period of at least 12 months, iii) no history of previous irradiation or surgery in the maxillofacial area, and ìv) availability of pre- and posttreatment MRI and 18F­FDG PET-CT performed in our Institution. All patients had stage III-IVA disease (n = 7) and received platinum-based chemotherapy. Planned doses in 30 daily fractions/5 days per week were 66 Gy (2.2 Gy/die 5 days/week) to the gross tumor volume, 66 Gy (2.1-2.2 Gy/die 5 days/week) to the gross nodal volume, 60 Gy (2 Gy/die 5 days week) to clinical target volume (CTV)1, and 54 Gy (1.8 Gy/die 5 days/week) to CTV2. All patients completed the planned radiotherapy course in a median time of 42 days (range 42-43). Relationships between BFP volumes and the following DVH parameters were evaluated: mean dose, maximum dose (Dmax), and percentage of BFP volume receiving more than 5 to 65 Gy (V5 to V65). RESULTS: The pre-RT volumes of the left and right BFPs were 12.24 cc (range 6.51-20.01 cc) and 11.55 cc (range 5.78-17.53 cc), respectively. The mean volumes of left BFPPRE and BFPPOST were 12.24 cc (range 6.51-20.01cc) and 13.85 cc (range 7.54-20.21 cc), respectively, with no significant statistical differences (P > 0.05). No statistically significant correlations were found between dosimetry features and BFP volumetric changes (all P > 0.05). CONCLUSION: Our original results showed that chemoradiotherapy does not induce significant volumetric changes of the BFP. Further investigations are needed to evaluate the effects of higher radiation doses on BFP. This is the first real-world study on this issue.

Non-stereotactic radiotherapy in older cancer patients.

Old or very old oncological patients represent a heterogeneous and frail population due to concomitant comorbidities. Whether radiotherapy alone or in combination with novel cancer drugs may provide a clear benefit in this setting of patients is still a matter of debate. The aim of our review is to analyze the evaluation process and the different therapeutic possibilities in older cancer patients, focusing on the different and most disparate applications of radiotherapy. We reviewed the most recent literature on radiotherapy in older patients providing clinical evidence of treatment related toxicity, tolerance and outcomes using standard fractionated and/or hypofractionated irradiation alone or in combination with chemotherapy, targeted and immunotherapy. In older cancer patients unfit for systemic therapy or surgery, radiotherapy represents a valid therapeutic approach, both with curative and palliative intents, ensuring excellent patient compliance in terms of local toxicity and adherence to therapy.

A non-surgical COMBO-therapy approach for locally advanced unresectable pancreatic adenocarcinoma: preliminary results of a prospective study.

In this short report we present a series of thirteen patients with locally advanced, unresectable, pancreatic cancer treated with a COMBO-Therapy consisting of: STEP-1: induction chemotherapy; STEP-2: concomitant chemoradiotherapy; STEP-3: stereotactic body radiotherapy boost. After four weeks from the end of each step all patients had a re-staging and a surgical re-evaluation. All patients completed STEP-1 and STEP-2. STEP-3 has been successfully delivered to 8/13 patients with a median dose of 12 Gy (range 10-21 Gy) in 1-3 fractions. The median LC was 20 months (range 10-32) with a 2-year LC of 72.9%, and none of the patients developed G3 acute or late toxicities. The median OS was 21.5 months (range 12-34), and the 2-year OS was 53.9%; the median PFS was 17.5 months (range 10-27). Our non-surgical COMBO-Therapy has demonstrated a feasible profile with good tolerance. Further prospective protocols are needed to confirm our preliminary results.

Spine eburnation in a metastatic lung cancer patient treated with immunotherapy and radiotherapy. The first case report of bystander effect on bone.

INTRODUCTION: Metastatic non-small cell lung cancer (NSCLC) is nowadays treated with a multimodal therapeutic approach including immunotherapy, targeted therapy and radiotherapy. Radiation therapy, in addition to immune checkpoint inhibitors, gives rise to a particular radiobiological effect known as "bystander effect" consisting of the radiation-induced damage in nearby unirradiated cells. CASE REPORT: We report a case of a 79-year-old female patient with stage IV NSCLC treated with concomitant immuno-radiotherapy who showed a bystander effect on bone.Management and outcome: Primary tumour biopsy revealed an adenocarcinoma with a PDL1 expression >50%, while staging exams showed a right pulmonary lesion with a partial involvement of the contiguous rib and a single brain metastasis. The patient refused chemotherapy, so that Pembrolizumab 2 mg/Kg was administered every 3 weeks. After two administrations, the single brain metastasis was treated using stereotactic radiosurgery while the site of primitive lung cancer received an 8 Gy-single fraction 3 D-conformal radiotherapy. Three months after irradiation a chest CT showed a radiological remission of about 10% of the GTV and a partial eburnation of the vertebra located nearby the target volume. The CT images of a PET/CT at six months showed a complete vertebral eburnation. At the last follow-up, the patient was free of disease (brain MRI, spinal MRI and PET/CT). DISCUSSION: The present case alerts for unusual side effects provoked by bystander phenomenon in patients treated with a combination of immunotherapy and irradiation. Immune activation exacerbates the bystander effect causing normal tissues toxicities beyond what immunotherapies are causing by themselves.

Curative Radiotherapy in Elderly Patients With Muscle Invasive Bladder Cancer: The Prognostic Role of Sarcopenia.

BACKGROUND/AIM: To evaluate the impact of sarcopenia in muscle invasive bladder cancer (MIBC) elderly patients submitted to curative radiotherapy. PATIENTS AND METHODS: Patients received radiotherapy between 2013 and 2018, and the skeletal muscle index was calculated to classify them as sarcopenic or non-sarcopenic. Primary endpoints were overall survival (OS), cancer specific survival (CSS), 90-day mortality and toxicity. RESULTS: A total of 28 patients with a median age of 85 years met our inclusion criteria and 8 of them were sarcopenic. With a median prescribed dose of 61 Gy and a median follow-up of 24.5 months, OS rates in the sarcopenic and non-sarcopenic groups were 100% and 84.4% at 3 months, 57.1% and 56.6% at 12 months, 38.1% and 50.3% at 24 months and 38.1% and 33.5% at 48 months, respectively; the CSS rates were 100% and 94.1% at 3 months and 68.6% and 88.2% at 12, 24 and 48 months, respectively. The actuarial 90-day mortality rate was 17.9% for the whole cohort, and 20% and 12.5% for the non-sarcopenic and sarcopenic groups, respectively. The radio-induced toxicity was similar in both groups. CONCLUSION: Sarcopenia cannot be considered a negative prognostic factor for MIBC elderly patients treated with external beam radiotherapy. Irradiation is therefore a feasible and effective choice for these patients, especially if unfit for surgery.

Vaginal Mucosal Melanoma: a Complete Remission after Immunotherapy and '0-7-21' Radiotherapy Regimen (24 Gy/3 fractions/21 days).

We present the case of a patient with vaginal mucosal melanoma who underwent complete remission after immunotherapy and '0-7-21' radiotherapy regimen (24 Gy/3 fractions/21 days). An 80-year-old woman had a biopsy of a voluminous vaginal lesion and received a histological diagnosis of melanoma with angiomatoid aspects. The patient underwent immunotherapy with pembrolizumab 2 mg/kg every 3 weeks and was sent to our attention for planning radiotherapy as the extent of the lesion did not make it susceptible to surgery.Considering the concomitant administration of pembrolizumab, we chose to treat this patient with a modulated intensity radiation therapy technique delivering a hypofractionated dose of 24 Gy in 3 fractions delivered on days 0, 7, and 21. We observed a complete clinical remission of the melanoma 12 months after radiotherapy and she has been alive for 18 months with no clinical signs of local recurrence.

Simultaneous Integrated Boost Radiotherapy in Unresectable Stage IV (M0) Head and Neck Squamous Cell Cancer Patients: Daily Clinical Practice.

AIM: To evaluate clinical outcome in locally-advanced stage IV (M0) head and neck cancer patients treated using intensity-modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) in daily clinical practice. BACKGROUND: Despite SIB-IMRT has been reported as a feasible and effective advanced head and neck cancer treatment, there are few data about its concurrent use with systemic therapies. MATERIAL AND METHODS: We reviewed 41 staged IV (M0) head and neck cancer patients treated in two radiotherapy units in the city of Messina (Italy) during the last six years, using intensity modulated techniques-SIB. 22/41 patients had concomitant chemotherapy or cetuximab. Acute and late toxicities, objective response (OR) rate, local control (LC) and overall survival (OS) have been evaluated. RESULTS: 37/41 patients received the planned doses of radiotherapy, 2 patients died during the therapy. The major acute regional toxicities were skin reaction and mucositis. A case of mandibular osteoradionecrosis was recorded. At completion of treatment, OR was evaluated in 38 patients: 32/38 patients (84.2%) had complete (55.3%) and partial (28.9%) response. The 1- and 5-year LC rates were 73.4% and 69.73%, respectively. The 1-, 3-, and 5-year OS rates were 85.93%, 51.49% and 44.14%, respectively. No statistically significant differences in outcomes have been observed in patients treated with radiotherapy alone vs. irradiation concomitant to chemo/biotherapy. The median OS was 45 months. CONCLUSION: SIB-IMRT is safeand can be used with concomitant chemotherapy/biotherapy in real-life daily clinical practice. SIB-IMRT alone is a valid alternative in patients unfit for systemic therapies.

Stereotactic Body Radiation Therapy With Simultaneous Integrated Boost in Patients With Spinal Metastases.

Stereotactic body radiation therapy in patients with spine metastases maximizes local tumor control and preserves neurologic function. A novel approach could be the use of stereotactic body radiation therapy with simultaneous integrated boost delivering modality. The aim of the present study is to report our experience in the treatment of spine metastases using a frameless radiosurgery system delivering stereotactic body radiation therapy-simultaneous integrated boost technique. The primary endpoints were the pain control and the time to local progression; the secondary ones were the overall survival and toxicity. A total of 20 patients with spine metastases and 22 metastatic sites were treated in our center with stereotactic body radiation therapy-simultaneous integrated boost between December 2007 and July 2018. Stereotactic body radiation therapy-simultaneous integrated boost treatments were delivered doses of 8 to 10 Gy in 1 fraction to isodose line of 50%. The median follow-up was 35 months (range: 12-110). The median time to local progression for all patients was not reached and the actuarial 1-, 2-, and 3-years local free progression rate was 86.36%. In 17 of 20 patients, a complete pain remission was observed and 3 of 20 patients had a partial pain remission (complete pain remission + partial pain remission: 100%). The median overall survival was 38 months (range 12-83). None of the patients experienced neither radiation adverse events (grade 1-4) nor reported pain flair reaction. None of the patients included in our series experienced vertebral compression fracture. Spine radiosurgery with stereotactic body radiation therapy-simultaneous integrated boost is safe. The use of this modality in spine metastases patients provides an excellent local control.

Stereotactic body radiation therapy and radiofrequency ablation for the treatment of liver metastases: How and when?

Limited liver metastases represent a clinical challenge. Surgical approach is the most frequently reported treatment option, however, some patients are not eligible for surgical interventions. Relatively recent technologic advances have permitted the safe use of ablative techniques employed in the cure of hepatic metastases. Among these, radiofrequency ablation (RFA) and stereotactic body radiotherapy (SBRT) have emerged as valid treatments in a significant proportion of patients with intrahepatic oligometastatic disease. This review offers an up-to-date of current available literature on this issue focusing on the use and outcomes of RFA and SBRT, according to the PICO (Population, Intervention, Comparison and Outcomes) criteria.

Aminaphtone therapy in patients with type 1 diabetes and albuminuria: a case report.

INTRODUCTION: Microalbuminuria in type 1 diabetes is the earliest manifestation of diabetic microangiopathy (nephropathy). To date, the pharmacological approach to microangiopathy has not been shown to be useful. By using aminaphtone to control nephrologic complications of insulin-dependent diabetes mellitus we first obtained a significant improvement in microalbuminuria confirming this new pharmacological approach for insulin-dependent diabetes mellitus organospecific complications control. CASE PRESENTATION: After being treated with standard therapy for insulin-dependent diabetes mellitus (insulin) for more than 20 years, a 49-year-old white man affected by insulin-dependent diabetes mellitus adopted the standard therapy aminaphtone for a period of 2 months.This therapy allowed a significant reduction of proteinuria from baseline evaluation that immediately increased after he stopped aminaphtone therapy. CONCLUSIONS: Aminaphtone therapy, used globally in the treatment and prevention of endothelial dysfunctions, could be an interesting option for patients with insulin-dependent diabetes mellitus with the express purpose of preventing diabetic nephropathy.