Cancer Pain

ImportanceConventional external beam radiotherapy (cEBRT) and stereotactic body radiotherapy (SBRT) are commonly used treatment options for relieving metastatic bone pain. The effectiveness of SBRT compared with cEBRT in pain relief has been a subject of debate, and conflicting results have been reported.ObjectiveTo compare the effectiveness associated with SBRT vs cEBRT for relieving metastatic bone pain.Data sourcesA structured search was performed in the PubMed, Embase, and Cochrane databases on June 5, 2023. Additionally, results were added from a new randomized clinical trial (RCT) and additional unpublished data from an already published RCT.Study selectionComparative studies reporting pain response after SBRT vs cEBRT in patients with painful bone metastases.Data extraction and synthesisTwo independent reviewers extracted data from eligible studies. Data were extracted for the intention-to-treat (ITT) and per-protocol (PP) populations. The study is reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.Main outcomes and measuresOverall and complete pain response at 1, 3, and 6 months after radiotherapy, according to the study's definition. Relative risk ratios (RRs) with 95% CIs were calculated for each study. A random-effects model using a restricted maximum likelihood estimator was applied for meta-analysis.ResultsThere were 18 studies with 1685 patients included in the systematic review and 8 RCTs with 1090 patients were included in the meta-analysis. In 7 RCTs, overall pain response was defined according to the International Consensus on Palliative Radiotherapy Endpoints in clinical trials (ICPRE). The complete pain response was reported in 6 RCTs, all defined according to the ICPRE. The ITT meta-analyses showed that the overall pain response rates did not differ between cEBRT and SBRT at 1 (RR, 1.14; 95% CI, 0.99-1.30), 3 (RR, 1.19; 95% CI, 0.96-1.47), or 6 (RR, 1.22; 95% CI, 0.96-1.54) months. However, SBRT was associated with a higher complete pain response at 1 (RR, 1.43; 95% CI, 1.02-2.01), 3 (RR, 1.80; 95% CI, 1.16-2.78), and 6 (RR, 2.47; 95% CI, 1.24-4.91) months after radiotherapy. The PP meta-analyses showed comparable results.Conclusions and relevanceIn this systematic review and meta-analysis, patients with painful bone metastases experienced similar overall pain response after SBRT compared with cEBRT. More patients had complete pain alleviation after SBRT, suggesting that selected subgroups will benefit from SBRT.

Cancer pain, a highly prevalent and distressing symptom among cancer patients, has a seriously harmful effect on their life and presents a complex challenge in clinical management. Despite extensive research efforts and the existence of clinical guidelines, significant controversies persist regarding the molecular mechanisms underpinning cancer pain as well as the most effective management strategies. This review systematically delves into the neurobiological underpinnings of cancer pain, centering on the interplay of peripheral and central sensitization, cellular stress and dysfunction, as well as the crucial roles of various signaling pathways and epigenetic regulation in its pathogenesis. In terms of treatment, the fundamental strategy involves a comprehensive initial assessment of cancer pain, followed by targeted interventions based on the assessment findings. It advocates for a multimodal approach that integrates pharmacological with non-pharmacological therapies. However, ongoing debates surround issues related to opioid rotation protocols and the long-term safety of opioid use. Furthermore, it underscores the underexplored potential of personalized therapies targeting molecular pathways and the need for standardized, interdisciplinary pain assessment tools. By bridging mechanistic research and clinical practice, this work potentially provides a framework for refining guideline implementation, advancing targeted therapies, and improving patient-centered care, thereby contributing to the evolution of precision oncology and holistic pain management paradigms.

Bone cancer pain (BCP) affects ~70% of patients in advanced stages, primarily due to bone metastasis, presenting a substantial therapeutic challenge. Here, we profile orphan G protein-coupled receptors in the dorsal root ganglia (DRG) following tumor infiltration, and observe a notable increase in GPR160 expression. Elevated Gpr160 mRNA and protein levels persist from postoperative day 6 for over 18 days in the affected DRG, predominantly in small-diameter C-fiber type neurons specific to the tibia. Targeted interventions, including DRG microinjection of siRNA or AAV delivery, mitigate mechanical allodynia, cold, and heat hyperalgesia induced by the tumor. Tumor infiltration increases DRG neuron excitability in wild-type mice, but not in Gpr160 gene knockout mice. Tumor infiltration results in reduced H3K27me3 and increased H3K27ac modifications, enhanced binding of the transcription activator Sp1 to the Gpr160 gene promoter region, and induction of GPR160 expression. Modulating histone-modifying enzymes effectively alleviated pain behavior. Our study delineates a novel mechanism wherein elevated Sp1 levels facilitate Gpr160 gene transcription in nociceptive DRG neurons during BCP in rodents.

Bone cancer pain occurs in up to 70% of patients with skeletal metastases and is accompanied by depression, severely diminishing quality of life. Current pharmacological strategies provide only partial relief, and the neurobiological mechanisms linking nociceptive and affective processing remain poorly defined. Herein, in a mouse model of Lewis lung carcinoma, we identify a previously uncharacterized astrocyte-neuron signaling axis in the posterior piriform cortex that underlies bone cancer pain with comorbid depression. Through metabolomic, proteomic, and fiber photometry approaches, we show that astrocytic phenotypic transition from the neuroprotective A2 to the neurotoxic A1 state triggers metabolic reprogramming, downregulates ATP/adenosine/adenosine A2A receptor signaling, and upregulates the norepinephrine transporter, impairing noradrenergic transmission. Interventions targeting astrocyte phenotypes, including minocycline and Lcn2 knockdown, normalized the posterior piriform cortex neurochemistry and alleviated both nociceptive and affective symptoms. These findings define a mechanistic framework in which astrocytic dysfunction orchestrates pain and depression, and highlight astrocyte-directed strategies for treating cancer pain-depression comorbidity.