The use of interventional procedures for cancer pain. A brief review.

CONTEXT: Pain is a common experience in people living with cancer. Concerns around opioid prescribing have seen a move toward a multi-modality management approach, which includes interventional pain procedures. PURPOSE: In this paper we discuss the interventional pain procedures used to treat cancer pain at two major tertiary centers in Australia. METHODS AND RESULTS: This expert review provides practical insights on cancer pain management from healthcare providers in different specialties. These insights can be used to guide the management of a wide range of cancer pain types. CONCLUSIONS: Furthermore, this review identifies the need for a systematic and comprehensive approach to the management of cancer pain that is broader than that of a single specialty. With recent advances in pain management procedures, an interdisciplinary approach is essential in order to provide an up to date, patient tailored approach to pain management. This review will help inform the development of a cancer pain intervention registry.

Ghrelin Induces the Production of Hypothalamic NPY Through the AMPK-mTOR Pathway to Alleviate Cancer-induced Bone Pain.

BACKGROUND/AIM: Cancer-induced bone pain (CIBP) is one of the most common symptoms of bone metastasis of tumor cells. The hypothalamus may play a pivotal role in the regulation of CIBP. However, little is known about the exact mechanisms. MATERIALS AND METHODS: First, we established a CIBP model to explore the relationship among hypothalamic ghrelin, NPY and CIBP. Then, we exogenously administered NPY and NPY receptor antagonists to investigate whether hypothalamic NPY exerted an antinociceptive effect through binding to NPY receptors. Finally, we exogenously administered ghrelin to investigate whether ghrelin alleviated CIBP by inducing the production of hypothalamic NPY through the AMPK-mTOR pathway. Body weight, food intake and behavioral indicators of CIBP were measured every 3 days. Hypothalamic ghrelin, NPY and the AMPK-mTOR pathway were also measured. RESULTS: The expression of hypothalamic ghrelin and NPY was simultaneously decreased in cancer-bearing rats, which was accompanied by CIBP. Intracerebroventricular (i.c.v.) administration of NPY significantly alleviated CIBP in the short term. The antinociceptive effect of NPY was reversed with the i.c.v. administration of the Y1R and Y2R antagonists. The administration of ghrelin activated the AMPK-mTOR pathway and induced hypothalamic NPY production to alleviate CIBP. This effect of ghrelin on NPY and antinociception was reversed with the administration of a GHS-R1α antagonist. CONCLUSION: Ghrelin could induce the production of hypothalamic NPY through the AMPK-mTOR pathway to alleviate CIBP, which can provide a novel therapeutic mechanism for CIBP.

Microwave ablation combined with percutaneous vertebroplasty for treating painful non-small cell lung cancer with spinal metastases under real-time temperature monitoring.

PURPOSE: To retrospectively study the therapeutic effect and safety performance of the combination strategies of the computed tomography (CT)-guided microwave ablation (MWA) and percutaneous vertebroplasty (PVP) as a treatment for painful non-small cell lung cancer (NSCLC) with spinal metastases. MATERIALS AND METHODS: A retrospective review included 71 patients with 109 vertebral metastases who underwent microwave ablation combined with percutaneous vertebroplasty by the image-guided and real-time temperature monitoring. Treatment efficacy was determined by comparing visual analog scale (VAS) scores, daily morphine equivalent opioid consumption, and Oswestry Disability Index (ODI) scores before treatment and during the follow-up period. RESULTS: Technical success was achieved in all patients. The mean pre-procedure VAS score and morphine doses were 6.6 ± 1.8 (4-10) and 137.2 ± 38.7 (40-200) mg, respectively. The mean VAS scores and daily morphine doses at 24 h and 1, 4, 12, and 24 weeks postoperatively were 3.3 ± 1.9 and 73.5 ± 39.4 mg; 2.2 ± 1.5 and 40.2 ± 29.8 mg; 1.7 ± 1.2 and 31.3 ± 23.6 mg; 1.4 ± 1.1 and 27.3 ± 21.4 mg; and 1.3 ± 1.1 and 24.8 ± 21.0 mg, respectively (all P < 0.001). ODI scores significantly decreased (P < 0.05). Minor cement leakage occurred in 51 cases (46.8%), with one patient having a grade 3 neural injury. No local tumor progression was observed by follow-up imaging. CONCLUSIONS: MWA combined with PVP can significantly relieve pain and improve patients' quality of life, which implied this is an effective treatment option for painful NSCLC with spinal metastases. Additionally, its efficacy should be further verified through the mid- and long-term studies.

Electroacupuncture attenuates nociceptive behaviors in a mouse model of cancer pain.

Pain is a major symptom in cancer patients, and cancer-induced bone pain (CIBP) is the most common type of moderate and severe cancer-related pain. The current available analgesic treatments for CIBP have adverse effects as well as limited therapeutic effects. Acupuncture is proved effective in pain management as a safe alternative therapy. We evaluated the analgesic effect of acupuncture in treatment of cancer pain and try to explore the underlying analgesic mechanisms. Nude mice were inoculated with cancer cells into the left distal femur to establish cancer pain model. Electroacupuncture (EA) treatment was applied for the xenograft animals. Pain behaviors of mice were evaluated, followed by the detections of neuropeptide-related and inflammation-related indicators in peripheral and central levels. EA treatment alleviated cancer-induced pain behaviors covering mechanical allodynia, thermal hyperalgesia and spontaneous pain, and also down-regulated immunofluorescence expressions of neuropeptide CGRP and p75 in the skin of affected plantar area in xenograft mice, and inhibited expressions of overexpressed neuropeptide-related and inflammation-related protein in the lumbar spinal cord of xenograft mice. Overall, our findings suggest that EA treatment ameliorated cancer-induced pain behaviors in the mouse xenograft model of cancer pain, possibly through inhibiting the expressions of neuropeptide-related and inflammation-related protein in central level following tumor cell xenografts.

Randomized controlled trial of an app for cancer pain management.

PURPOSE: The primary objective of this investigation was to devise a mobile application for self-management of cancer-related discomfort, with the overarching goal of enhancing patients' overall well-being. Would the utilization of the self-management application result in an amelioration of life quality compared to conventional follow-up procedures? METHODS: Modules were meticulously devised with the collaborative expertise of oncology pain specialists employing the Delphi technique. Reliability of the consultation was assessed using Cronbach's α. After developing the app, a prospective randomized controlled study was conducted to evaluate the app's effect on participants' quality of life. The trial group used the app; the control group received a follow-up telephone consultation. Assessments of quality of life were conducted both at baseline and following a 4-week intervention period. RESULTS: After two rounds of Delphi expert consultation, the functional modules of Pain Guardian were determined to include five functional modules, including pain self-measurement (real-time dynamic recording of pain by patients), patient reminders (reminders of outbreaks of pain disposal, medication, and review), uploading of examination reports, online consultation, health education, and other functional modules. Cronbach's α was 0.81. Overall, 96 patients (including esophageal, gastric, colorectal, nasopharyngeal, pulmonary, pancreatic, breast, ovarian, uterine, bone, thoracic, bladder, cervical, soft tissue sarcoma, mediastinal, and lymphoma) with cancer pain were divided into the trial and control groups. There were no significant differences in basic information and quality of life at baseline between groups. After 4 weeks of intervention, quality of life was significantly higher in the trial group than in the control group. Patients' satisfaction with the app was high (93.7%). CONCLUSIONS: The primary obstacle encountered in the development of applications for managing cancer-related discomfort lies in the sensitive nature of the subject matter, potentially leading to patient apprehension regarding application usage for pain management. Consequently, meticulous attention to user preferences and anticipations is imperative, necessitating the creation of an application characterized by user-friendliness and medical efficacy. TRIAL REGISTRATION: Chinese Clinical Trials Registry ChiCTR1800016066; http://www.chictr.org.cn/showproj.aspx?proj=27153 . Date of Registration: 2018-05-09.

Netrin-1 Role in Nociceptive Neuron Sprouting through Activation of DCC Signaling in a Rat Model of Bone Cancer Pain.

BACKGROUND: Bone cancer pain (BCP) is a common primary or metastatic bone cancer complication. Netrin-1 plays an essential role in neurite elongation and pain sensitization. This study aimed to determine the role of netrin-1 from the metastatic bone microenvironment in BCP development and identify the associated signaling pathway for the strategy of BCP management. METHODS: The rat BCP model was established by intratibial implantation of Walker 256 cells. Von Frey filaments measured the mechanical pain threshold. Movement-induced pain was assessed using limb use scores. Expressions of associated molecules in the affected tibias or dorsal root ganglia (DRG) were measured by immunofluorescence, immunohistochemistry, real-time quantitative polymerase chain reaction, or western blotting. Transduction of deleted in colorectal cancer (DCC) signaling was inhibited by intrathecal injection of DCC-siRNA. RESULTS: In BCP rats, the presence of calcitonin gene-related peptide (CGRP)-positive nerve fibers increased in the metastatic bone lesions. The metastatic site showed enrichment of well-differentiated osteoclasts and expressions of netrin-1 and its attractive receptor DCC. Upregulation of DCC and increased phosphorylation levels of focal adhesion kinase (FAK) and Rac family small GTPase 1/Cell division cycle 42 (Rac1/Cdc42) were found in the DRG. Intrathecal administration of DCC-siRNA led to a significant reduction in FAK and Rac1/Cdc42 phosphorylation levels in the DRG, decreased nociceptive nerve innervation, and improved pain behaviors. CONCLUSIONS: Netrin-1 may contribute to the activation of the BCP by inducing nociceptive nerve innervation and improving pain behaviors.

Everything old is new again. revisiting hypophysectomy for the treatment of refractory cancer-related pain: a systematic review.

Cancer-related pain is a common and debilitating condition that can significantly affect the quality of life of patients. Opioids, NSAIDs, and antidepressants are among the first-line therapies, but their efficacy is limited or their use can be restricted due to serious side effects. Neuromodulation and lesioning techniques have also proven to be a valuable instrument for managing refractory pain. For patients who have exhausted all standard treatment options, hypophysectomy may be an effective alternative treatment. We conducted a comprehensive systematic review of the available literature on PubMed and Scielo databases on using hypophysectomy to treat refractory cancer-related pain. Data extraction from included studies included study design, treatment model, number of treated patients, sex, age, Karnofsky Performance Status (KPS) score, primary cancer site, lead time from diagnosis to treatment, alcohol injection volume, treatment data, and clinical outcomes. Statistical analysis was reported using counts (N, %) and means (range). The study included data from 735 patients from 24 papers treated with hypophysectomy for refractory cancer-related pain. 329 cancer-related pain patients were treated with NALP, 216 with TSS, 66 with RF, 55 with Y90 brachytherapy, 51 with Gamma Knife radiosurgery (GK), and 18 with cryoablation. The median age was 58.5 years. The average follow-up time was 8.97 months. Good pain relief was observed in 557 out of 735 patients, with complete pain relief in 108 out of 268 patients. Pain improvement onset was observed 24 h after TSS, a few days after NALP or cryoablation, and a few days to 4 weeks after GK. Complications varied among treatment modalities, with diabetes insipidus (DI) being the most common complication. Although mostly forgotten in modern neurosurgical practice, hypophysectomy is an attractive option for treating refractory cancer-related pain after failure of traditional therapies. Radiosurgery is a promising treatment modality due to its high success rate and reduced risk of complications.

[The Fusion of Cancer Treatment and Cancer Pain Management].

Cancer treatment and cancer pain management constitute a dual approach aimed at improving the quality of life for patients. Their relationship must be complementary. Advances in cancer treatment have been remarkable, leading to increased survival rates in most types of cancer. However, there is a concern about the growing number of patients living with pain. Compared to the advancements in cancer treatment, progress in cancer pain management has been slow. As a basis for this observation, the available opioid analgesics and adjuvant pain-relieving medications have not increased significantly when compared to several years ago, and breakthrough treatments have yet to emerge. Even upon surveying guidelines both domestically and internationally, recommendations for cancer pain treatment are notably ambiguous. In recent years, however, opioid analgesics have proven to be a"double-edged sword". While they play a central role in cancer pain management, they also have cellular effects on tumor proliferation or suppression. This effect varies depending on the type of cancer, and it may be influenced differently by the content of cancer treatment, such as cytotoxic anticancer drugs, molecular targeted drugs, immune checkpoint inhibitors, and more. It may be time to recognize that cancer pain management has an impact on cancer treatment itself. Therefore, a crucial attitude is needed for closer collaboration between experts in cancer treatment and cancer pain management, fostering a co-creative approach in clinical and research settings. Professions such as pharmacists and nurses are essential for bridging this gap. To achieve the fusion beyond the integration of cancer treatment and cancer pain management, a transdisciplinary team, surpassing the boundaries of an interdisciplinary team, is necessary.

Classical cannabinoid receptors as target in cancer-induced bone pain: a systematic review, meta-analysis and bioinformatics validation.

To test the hypothesis that genetic and pharmacological modulation of the classical cannabinoid type 1 (CB1) and 2 (CB2) receptors attenuate cancer-induced bone pain, we searched Medline, Web of Science and Scopus for relevant skeletal and non-skeletal cancer studies from inception to July 28, 2022. We identified 29 animal and 35 human studies. In mice, a meta-analysis of pooled studies showed that treatment of osteolysis-bearing males with the endocannabinoids AEA and 2-AG (mean difference [MD] - 24.83, 95% confidence interval [95%CI] - 34.89, - 14.76, p < 0.00001) or the synthetic cannabinoid (CB) agonists ACPA, WIN55,212-2, CP55,940 (CB1/2-non-selective) and AM1241 (CB2-selective) (MD - 28.73, 95%CI - 45.43, - 12.02, p = 0.0008) are associated with significant reduction in paw withdrawal frequency. Consistently, the synthetic agonists AM1241 and JWH015 (CB2-selective) increased paw withdrawal threshold (MD 0.89, 95%CI 0.79, 0.99, p < 0.00001), and ACEA (CB1-selective), AM1241 and JWH015 (CB2-selective) reduced spontaneous flinches (MD - 4.85, 95%CI - 6.74, - 2.96, p < 0. 00001) in osteolysis-bearing male mice. In rats, significant increase in paw withdrawal threshold is associated with the administration of ACEA and WIN55,212-2 (CB1/2-non-selective), JWH015 and AM1241 (CB2-selective) in osteolysis-bearing females (MD 8.18, 95%CI 6.14, 10.21, p < 0.00001), and treatment with AM1241 (CB2-selective) increased paw withdrawal thermal latency in males (mean difference [MD]: 3.94, 95%CI 2.13, 5.75, p < 0.0001), confirming the analgesic capabilities of CB1/2 ligands in rodents. In human, treatment of cancer patients with medical cannabis (standardized MD - 0.19, 95%CI - 0.35, - 0.02, p = 0.03) and the plant-derived delta-9-THC (20 mg) (MD 3.29, CI 2.24, 4.33, p < 0.00001) or its synthetic derivative NIB (4 mg) (MD 2.55, 95%CI 1.58, 3.51, p < 0.00001) are associated with reduction in pain intensity. Bioinformatics validation of KEGG, GO and MPO pathway, function and process enrichment analysis of mouse, rat and human data revealed that CB1 and CB2 receptors are enriched in a cocktail of nociceptive and sensory perception, inflammatory, immune-modulatory, and cancer pathways. Thus, we cautiously conclude that pharmacological modulators of CB1/2 receptors show promise in the treatment of cancer-induced bone pain, however further assessment of their effects on bone pain in genetically engineered animal models and cancer patients is warranted.

Cannabinoids for Cancer-related Pain Management: An Update on Therapeutic Applications and Future Perspectives.

Pain is a debilitating phenomenon that dramatically impairs the quality of life of patients. Many chronic conditions, including cancer, are associated with chronic pain. Despite pharmacological efforts that have been conducted, many patients suffering from cancer pain remain without treatment. To date, opioids are considered the preferred therapeutic choice for cancer-related pain management. Unfortunately, opioid treatment causes side effects and inefficiently relieves patients from pain, therefore alternative therapies have been considered, including Cannabis Sativa and cannabinoids. Accumulating evidence has highlighted that an increasing number of patients are choosing to use cannabis and cannabinoids for the management of their soothing and non-palliative cancer pain and other cancer-related symptoms. However, their clinical application must be supported by convincing and reproducible clinical trials. In this review, we provide an update on cannabinoid use for cancer pain management. Moreover, we tried to turn a light on the potential use of cannabis as a possible therapeutic option for cancer-related pain relief.

Cancer Pain Management with Traditional Chinese Medicine: Current Status and Future Perspectives.

Cancer pain, especially the moderate-to-severe pain experienced by patients with advanced cancer, is still one of the most challenging clinical problems. The current mainstream pharmacological treatment for cancer pain involves applying opioid medications and other pain-killing drugs. However, analgesic drugs have many adverse effects such as addiction, tolerance, and other formidable clinical and social issues. Thus, finding a new therapeutic approach to treat cancer pain is essential. Traditional Chinese medicine (TCM) has been increasingly applied in clinical practice because of its good efficacy and few side effects. However, its mechanisms of action in treating pain are still under investigation. The most important mechanism of cancer pain is that a large amount of pain-causing substances are secreted from cancer cells and promote their growth and invasion. The physical and chemical stimulations of these substances exist along with the cancer growth, leading to constantly increased pain sensation. Whether cancer pain can be alleviated by inhibiting cancer cells from releasing the substances and changing the microenvironment around the cancer mass, or even by eliminating pain-causing substances, is largely unknown. Based on TCM theory, this study reported that the aforementioned approach could effectively manage different cancer pains by tonifying qi, clearing and activating channels and meridians, and strengthening body resistance. The TCM therapies activate blood circulation, remove blood stasis, and nourish the heart. Commonly used Chinese herbal drugs include Corydalis yanhusuo, Angelica dahurica, and Ligusticum chuanxiong. Instead of using conventional analgesics to reduce pain, we should focus on using TCM modalities to alleviate cancer pain and increase the quality of life in patients suffering from cancer pain. TCM should provide us with a new strategy for managing cancer pain.

Current cannabis use and pain management among US cancer patients.

BACKGROUND: National studies reporting the prevalence of cannabis use have focused on individuals with a history of cancer without distinction by their treatment status, which can impact symptom burden. While pain is a primary motivation to use cannabis in cancer, the magnitude of its association with cannabis use remains understudied. METHODS: We examined cannabis use and pain management among 5523 respondents of the Behavioral Risk Factor Surveillance System with a cancer history. Survey-weighted prevalence proportions of respondents' cannabis use are reported, stratified on cancer treatment status. Regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) of cancer-related pain and cannabis use. RESULTS: Cannabis use was slightly more prevalent in those undergoing active treatment relative to those who were not undergoing active treatment (9.3% vs. 6.2%; P=0.05). Those under active treatment were more likely to use cannabis medicinally (71.6% vs. 50.0%; P=0.03). Relative to those without cancer-related pain, persons with pain under medical control (OR 2.1, 95% CI, 1.4-3.2) or uncontrolled pain were twice as likely to use cannabis (OR 2.0, 95% CI, 1.1-3.5). CONCLUSIONS: Use of cannabis among cancer patients may be related to their treatment and is positively associated with cancer-related pain. Future research should investigate the associations of cannabis use, symptom burden, and treatment regimens across the treatment spectrum to facilitate interventions.

Effectiveness of CT-guided percutaneous cordotomy in intractable cancer pain: Experience in 14 patients.

BACKGROUND: Severe and treatment-resistant pain is a major issue for patients with cancer. Cordotomy is an effective approach for addressing severe cancer-related pain. It is based on blocking the transmission of pain by damaging the lateral spinothalamic tract. METHODS: Computed tomography guided cordotomy was performed on 14 patients who did not respond to medical and interventional pain management methods. RESULTS: Fourteen patients with cancer pain underwent CT-guided percutaneous cordotomy. Pain relief was reported in 86% of the patients. The visual analog scale values before and after cordotomy were compared and a significant difference was found (p = 0.0001). The improvement in the Karnofsky Performance Scale score of the patients was found to be statistically significant (p = 0.0001). CONCLUSION: We believe that CT-guided cordotomy, performed by experienced hands in a team of experienced individuals and applied to the right patients, is an effective treatment. However, it is crucial to exercise extreme caution regarding potential side effects and serious complications during the cordotomy procedure.

Cost-effectiveness analysis of epidural morphine/ropivacaine treatment in patients with cancer pain.

BACKGROUND: Cancer pain is one of the main causes of human suffering, which can generate disabilities and compromise quality of life, giving rise to several psychosocial and economic consequences. AIMS: This quantitative study sought to perform a cost-effectiveness pharmacoeconomic analysis to assess the impact of implanting epidural morphine associated with ropivacaine treatment in gastrointestinal cancer patients with pain that is difficult clinical control, compared with conventional oral treatment. MATERIALS AND METHODS: The study population consisted of 24 patients with gastrointestinal neoplasia who underwent treatment for cancer pain that was difficult to clinically control. 12 patients each were recruited into the control and intervention groups, respectively. While patients in the control group were administered drug treatment orally, patients in the intervention group underwent a surgical procedure for subcutaneous implantation of a catheter that allowed epidural administration of morphine and ropivacaine. For pain assessment, the Visual Analogue Scale was applied. Data analysis had a descriptive character of costs, taking into account the costs for the year 2021. The study perspective was the Brazilian public healthcare provider, referred to as the Unified Health System (Sistema Único de-SUS in Portuguese). Costs were computed over the time horizon corresponding to the duration of treatment, from the first medical consultation (when the treatment was defined) to the end (end of treatment, disease progression, or death). Treatment duration was divided into three phases (first 60 days, support with palliative care, and end-of-life care). To assess the robustness of the economic analysis, sensitivity analyses were performed, considering the effectiveness of pain reduction on the Visual Analogue Scale, and a comparison of results using the median prices of pharmaceutical components used in the study. RESULTS: The mean age of patients was 59.3 years. The results from the cost-effectiveness analysis showed the epidural morphine/ropivacaine treatment to be more effective with regard to pain reduction on the pain scale, particularly for end-of-life care, when compared to the conventional oral treatment, however, at a significantly higher cost. DISCUSSION: From the accomplishment of this research, it was observed that the application of the pain assessment scale is a way to better interpret and understand the patient's pain, facilitating care planning and decision-making by health professionals, as well as monitoring the effectiveness of the proposed new treatment. CONCLUSION: To present a better cost-effectiveness ratio, a reduction in the cost of the new epidural technology or an increase in the value of the existing oral intervention would be required. However, the latter is not feasible and unlikely to occur. A value judgement to decide whether the incremental benefit associated with the use of the new intervention is worth the extra cost will have to be made by the healthcare provider. Interventions that can relieve cancer pain symptoms should be investigated continuously, in search of evidence to support clinical practice and promote better quality of life for patients.

Differences in efficacy and safety between intrathecal infusion devices in cancer pain.

BACKGROUND: Intrathecal infusion therapy is widely accepted for cancer pain patients when conventional analgesic treatments are not sufficient. There are different types of devices for carrying out this therapy: partially externalized devices (PED), used when life expectancy is under 3 months, and totally implanted devices (TID), when it is larger. Our objective is to compare the efficacy, functionality, and complication rate in both types. METHODS: We included 132 patients with mild-severe cancer pain, treated with intrathecal infusion therapy by fixed flow devices, PED, or TID, during the study time. Demographic, physical oncologic, and pain control data of the patients were recorded prior to starting therapy and at months 1, 3, and 6. Functionality status and complications were also collected from the patient's medical records and clinical files. RESULTS: Pain control improved after starting therapy, with an overall reduction of 4.75 points in VAS score at 1 month in the both groups, without significant differences between them, keeping it at 3 months and 6. 33.3% of the patients developed complications and were more frequent in the PED group, being catheter dislocation the most common. Patients with TID required more often hospital admission to solve the complication. CONCLUSIONS: Intrathecal infusion therapy has been shown to be a very effective and safe therapy for the treatment of moderate to severe oncologic pain. There are no significant differences between PED and TID in terms of degree of pain control, therapeutic success, efficacy on episodic or nocturnal pain, or the presence of serious complications.

HPV+ head and neck cancer-derived small extracellular vesicles communicate with TRPV1+ neurons to mediate cancer pain.

ABSTRACT: Severe pain is often experienced by patients with head and neck cancer and is associated with a poor prognosis. Despite its frequency and severity, current treatments fail to adequately control cancer-associated pain because of our lack of mechanistic understanding. Although recent works have shed some light of the biology underlying pain in HPV-negative oral cancers, the mechanisms mediating pain in HPV+ cancers remain unknown. Cancer-derived small extracellular vesicles (cancer-sEVs) are well positioned to function as mediators of communication between cancer cells and neurons. Inhibition of cancer-sEV release attenuated pain in tumor-bearing mice. Injection of purified cancer-sEVs is sufficient to induce pain hypersensitivity in naive mice that is prevented by QX-314 treatment and in Trpv1-/- mice. Cancer-sEVs triggered calcium influx in nociceptors, and inhibition or ablation of nociceptors protects against cancer pain. Interrogation of published sequencing data of human sensory neurons exposed to human cancer-sEVs suggested a stimulation of protein translation in neurons. Induction of translation by cancer-sEVs was validated in our mouse model, and its inhibition alleviated cancer pain in mice. In summary, our work reveals that HPV+ head and neck squamous cell carcinoma-derived sEVs alter TRPV1+ neurons by promoting nascent translation to mediate cancer pain and identified several promising therapeutic targets to interfere with this pathway.

Impact of Short-Course Palliative Radiation Therapy on Pancreatic Cancer-Related Pain: Prospective Phase 2 Nonrandomized PAINPANC Trial.

PURPOSE: Clinical evidence is limited regarding palliative radiation therapy for relieving pancreatic cancer-related pain. We prospectively investigated pain response after short-course palliative radiation therapy in patients with moderate-to-severe pancreatic cancer-related pain. METHODS AND MATERIALS: In this prospective phase 2 single center nonrandomized trial, 30 patients with moderate-to-severe pain (5-10, on a 0-10 scale) of pancreatic cancer refractory to pain medication, were treated with a short-course palliative radiation therapy; 24 Gy in 3 weekly fractions (2015-2018). Primary endpoint was defined as a clinically relevant average decrease of ≥2 points in pain severity, compared with baseline, within 7 weeks after the start of treatment. Secondary endpoint was global quality of life (QoL), with a clinically relevant increase of 5 to 10 points (0-100 scale). Pain severity reduction and QoL were assessed 9 times using the Brief Pain Inventory and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C15-PAL, respectively. Both outcomes were analyzed using joint modeling. In addition, acute toxicity based on clinician reporting and overall survival (OS) were assessed. RESULTS: Overall, 29 of 30 patients (96.7%) received palliative radiation therapy. At baseline, the median oral morphine equivalent daily dose was 129.5 mg (range, 20.0-540.0 mg), which decreased to 75.0 mg (range, 15.0-360.0 mg) after radiation (P = .021). Pain decreased on average 3.15 points from baseline to 7 weeks (one-sided P = .045). Patients reported a clinically relevant mean pain severity reduction from 5.9 to 3.8 points (P = .011) during the first 3 weeks, which further decreased to 3.2 until week 11, ending at 3.4 (P = .006) in week 21 after the first radiation therapy fraction. Global QoL significantly improved from 50.5 to 60.8 during the follow-up period (P = .001). Grade 3 acute toxicity occurred in 3 patients and no grade 4 to 5 toxicity was observed. Median OS was 11.8 weeks, with a 13.3% 1-year actuarial OS rate. CONCLUSIONS: Short-course palliative radiation therapy for pancreatic cancer-related pain was associated with rapid, clinically relevant reduction in pain severity, and clinically relevant improvement in global QoL, with mostly mild toxicity.