Introduction
Pancreatic cancer (PC) has become one of the top 10 leading causes of cancer death in China, according to the national cancer report released in 2022.[1] The global annual number of PC diagnosed patients has more than doubled in the last 2 decades, heavily adding its burden of disease.[2] However, only 15% to 20% diagnosed PC patients received surgical resection, about 40% PC patients were diagnosed with distant metastases, and the remaining 40% to 45% were diagnosed PC with locally advanced unresectable lesions. The prognosis associated with PC is extremely poor, with a median survival time of 9.8 months.[3] Even in patients who received surgical resection, a prolonged median survival time was 18.5 months with a median follow-up of 38.8 months.[4]
Pain could be the primary symptom during the early diagnosis of PC, and it could be the major problem during the late stage of PC that needs extremely multidisciplinary efforts. The prevalence of PC-related pain (PCRP) varies from 47% to 80% at diagnosis,[5,6] and increases to 90% for advanced cancer patients.[7] For patients with tumor at pancreatic body and tail, PCRP is the second commonest symptom (87%).[5] While for patients with tumor at pancreatic head, PCRP is the third commonest symptom after weight loss (92%) and jaundice (82%).[8] It is reported that the median survival time for patients with no pain, mild pain, and moderate-to-severe pain were 21.5, 15.0, and 10.0, months, respectively.[9] Pain plays significant role in the quality of life (QoL)[10] and the prognosis of PC as well.[11] Meanwhile, 60% PCRP patients remains undertreated, and most PCRP (89%) patients also combined with decreased general activity (74%), depressed mood state (74%), and worse sleep quality (67%). Thus, an effective, enough and multi-modal pain control strategy has become increasingly necessary, which is beneficial for PC patients’ QoL and survival expectancy.
Current management of PCRP is mainly empirical instead of mechanism-based since the mechanism of PCRP is not fully understood. In this review, we will summarize advances in the principal mechanism of PCRP, therapeutic effects of medication and (non-)invasive strategies.
Database search strategy
We conducted a literature search through PubMed and focused on the years 2015 to 2023. For mechanism of PCRP, keywords for searching include “perineural invasion,” “neural plasticity,” “chemotherapy-induced peripheral neuropathy.” For management of PCRP, various combinations of search terms were used, including pancrea*, pain, and management or therapy or treatment. Only English language and full-text articles were considered.
Mechanism of PCRP
The pathophysiology of PCRP is complex and multifactorial, of which pancreatic neuropathy is the most common mechanism. It is believed that the occurrence of pain is mainly related to the neurotropic nature of PC (see Fig. 1).
;)
Figure 1.:
Principal mechanism of PCRP. PCRP = pancreatic cancer-related pain.
Perineural invasion
PC has the malignant tendency to invade and damage surrounding sensory nerves, and perineural invasion (PNI) can be observed in 80% to 100% of PC.[12] PNI is also considered as a harbinger of poor prognosis for PC. It is recently believed that PNI not only brings injury to neurons, causes pain, but also precedes tumorigenesis of PC.[13] The neurotrophic nature of PC cell, anatomic proximity of PC and neural plexuses, and the reciprocal cell growth stimulation of PC cells and neurons have been speculated to be the explanation of the prevalence of PNI. Tumors located in the head of pancreas invade pancreaticus capitalis plexuses, and those located in the body and tail of pancreas prefer celiac plexuses,[14] and pain accordingly occurs more often in PC located in the body and tail of pancreas.
The molecular mechanism of PNI is complicated, mainly involves neurotrophins and their receptors (eg, nerve growth factor [NGF],[15] tyrosine receptor kinase-A [TrkA][16]), proteinases (metalloproteinases [MMP]),[17,18] cytokines (eg, transforming growth factor α [TGFα], epidermal growth factor [EGFR][19]), chemokines (eg, CX3CL1, CX3CR1[20]), and cell-surface markers (eg, MUC1, NCAM).[21] More details of effects of these factors were reported recently. HGF/c-Met pathway in pancreatic stellate cells (PSCs) facilitates and activates the mTOR/NGF axis to promote PNI.[22] Besides, hyperglycemia environment in PC elevates the expression of NGF by upregulating HIF-1α.[23] Paracrine NGF secreted by PC cells induces autophagy of Schwann cells in PNI which promotes reciprocal approaching of neuron axons and cancer cells.[24] MMPs were intermediates of NGF signal pathway,[18] L1 cell adhesion molecule (L1CAM),[25] stress-induced phosphoprotein 1 (STIP1),[26] and eEF1A2[27] to promote PNI.
PC caused PNI is often associated with the existence of pain, although the mechanism is still unclear. Increased NGF/TrkA expression levels in PC was found to be associated with more severe pain.[15] This was supported by restraint of Tanezumab (an NGF inhibitor), miR-21-5p (downstream of NGF) and TrkA blocking-up.[28] As PC cells thrive in the soft perineural space, both density of calcitonin gene-related peptide (CGRP) sensory fibers and of tyrosine hydroxylase (TH) sympathetic fibers in the pancreas were found to increase,[29] possibly in response to NGF signaling, therefore leading to hypersensitivity and gradual necrosis of nerve terminal endings and resulting in significant neurotrophic pain state.[30]
A recent research found that sonic hedgehog (sHH) signaling pathway could influence NGF signaling pathway, and increase the expression of substance P (SP) and CGRP in dorsal root ganglions in an NGF-dependent manner.[31] Specifically, sHH secreted from PC cells could activate the sHH signaling pathway in PSCs, and was followed by increased expression of NGF and brain-derived neurotrophic factor in PSCs and sensitization of pain ultimately.[32] Nonetheless, SP was demonstrated to promote PC metastasis and PNI,[33] indicating an even closer relationship among PC, PNI, and pain. SP was found to be expressed in neurites outgrowing from dorsal root ganglions as well as in PC cells, and activate cancer cell proliferation and invasion through its high affinity receptor NK-1R.[33] This finding provides us with a new insight into the reciprocal promotion and detrimental cycle between PNI, cancer metastasis, and pain.
Besides, neovascularization in PC is associated with the sensitization and activation of nociceptors through cross-talking between them. For example, artemin was found to promote neuron invasiveness of pancreatic adenocarcinoma, especially in vascular-rich areas, and increase the sensitivity and activation of neurons.[34,35] Hypertrophy and hyperplasia of stromal nerve fibers were observed in artemin-positive PC tumors, which was indicated by a nerve-specific phosphorylated protein GAP-43 abundant in destructed nerves.[34] The phenomenon that artemin induces migration and invasiveness of PC cells was further clarified by research on the mechanism of artemin-induced CXCR4 expression and activation. The study suggests that artemin mediates activation of NF-κB through activating Akt and ERK and lead to CXCR4 up-regulation and enhanced migration and invasion abilities of PC cells subsequently.[35]
Neural remodeling and plasticity
Increased neural density and hypertrophy were detected in PC patients, consistent with their abdominal pain and severity of pancreatic neuritis.[9] Neuroplastic changes mentioned above participated in all stages of PC, even before the appearance of cancer, and was associated with increased expression of nociceptive genes in sensory ganglia and pain-related behavioral changes.[36] Three kinds of neurons which were positive for CGRP, TH, and neurofilament protein 200, respectively, were detected with hypertrophy and increased density in PC KPPC (Kras G12D/+; Trp53 R172H/R172H; P48-Cre) mouse model and exhibited mechanical hypersensitivity.[37]
Several proteins participate in PC neural plasticity. Overexpressed IL-6-related stem cell promoting factor LIF by PC cells induces migration of Schwann cells and increases number of neurites, while inhibition of LIF reduces intratumoral nerve density[38] and could possibly control PCRP. Inhibition of CCL21 and CXCL10 secreted by sensory neurons upon PC cells activation could decrease the nociceptive hypersensitivity and nerve fiber hypertrophy, which further illustrates that the interaction between PC cells and neurons involves mediators generated by both cells, and that CXCL10/CXCR3 and CCL21/CCR7 signaling might become therapeutic targets for both halting the development of PC and cessation of PCRP.[39] Moreover, cancer-associated fibroblasts (CAFs) secreted SLIT2 also has the ability to increase nerve density through modulation of the N-cadherin/β-catenin pathway in Schwann cells.[40] These findings present a whole picture of the cross-talking among PC cells, sensory neurons, and CAFs in the context of neural remodeling.
The interaction of NGF and TRKA and/or p75NTR results in overexpression of transient receptor potential cation channel, subfamily V, member 1 (TRPV1),[41] an ion channel for Na+ and Ca2+, which releases CGRP and SP when activated by noxious stimuli, therefore generating pain signaling.[28,32] The inhibition of NGF not only mitigated pancreatic hyperalgesia and referred somatic pain but also resulted in a reduction in the current density and open probability of the TRPV1 channel.[41] TRPV1 is now included in “expanded cannabinoid system” as it responds to cannabinoids along with classical effector of cannabinoids, namely cannabinoid receptors 1 and 2, which are involved in nociceptive signals processing and inflammation controlling.[42] Recently, exploiting cannabinoids in PC treatment was considered as a promising strategy with triple advantage,[43] including encompassing both the repression of cancer progression, facilitation of gemcitabine by increasing the ROS-mediated growth inhibition and radiotherapy,[44] and the alleviation of pain burden associated with PC. But overall, the exploitation of cannabinoids is still poorly explored, of which the future is noncommittal and anticipated. Likewise, duloxetine (a serotonin-noradrenaline reuptake inhibitor) has antitumor effects while controlling pain in PC by enhancement of the noradrenergic pathway.[45] In contrast, mirogabalin (a selective voltage-gated calcium channel α2δ ligand) exhibits a positive effect on cancer-associated pain while concurrently promoting the proliferative potential of pancreatic ductal adenocarcinoma.[46]
In addition to hypersensitivity and hyperplasia of neurons, nociceptors alteration is also within the scope of neural plasticity. MiRNA was found to suppress key molecules especially nociceptive receptors related to chronic pain and was showed to participate in PCRP. Zhu et al found that in mouse model with PCRP, enhanced expression of miR-330 was induced in the spinal dorsal horn and was followed by decreased expression of GABABR2.[47] Attempt to alleviate PCRP through inhibiting miR-330 was successful, indicating that miR-330 was a potential target for resolving PCRP.[47]
Management of PCRP
Guidelines for pain management in PC all follow the principles of the “analgesic ladder” proposed by the WHO. Opioids are still the mainstay pharmacologic option, which should not be used alone, but as part of a multidisciplinary strategy including necessary adjuvant analgesics, intervention therapy, and psychological support. Anti-neuropathic medications, such as gabapentin, are often used, especially when PC often invades the abdominal plexus. In the advanced stage, more aggressive therapies are needed (see Table 1). It is important to note that patients themselves may reduce the dosage for fear of addiction, which actually is seldom a problem. Medical care should educate and guide patients and their family to follow the advice on time and dosage. Moreover, dynamic assessment of pain, with an emphasis on severity, quality, distress and functional consequences, is needed (see Fig. 2).
Table 1 - Indication of therapies for pancreatic cancer-related pain
| Therapy |
Indication |
Advantage |
Disadvantage |
| Analgesic ladder |
Usage for all stage |
Efficient pain relief; relatively easy to implement and popularize |
Addiction, resistance, and abuse of opioids; lead constipation, nausea, vomiting, and respiratory depression |
| Celiac plexus neurolysis |
Start from early stage, not for metastatic stage |
Effective for intractable pain; reduce the amount of opioids used |
Invasive procedure; relative few available doctors and hospitals performing this procedure; poor analgesic effect when tumor metastasis exists; transient orthostatic hypotension, diarrhea and back pain |
| Splanchnic nerve destruction |
For patients with unresectable pancreatic cancer |
Effective for intractable pain; long lasting pain relief |
Delayed deafferentation pain; accidental neurological damage |
| Radiation therapy |
For locally advanced pancreatic cancer, including older, frailer, or metastatic patients |
Reduce tumor volume |
Slow onset of action; radiation toxicity (inhibition of hematopoietic system, gastrointestinal reaction) |
| Chemotherapy |
For advanced pancreatic cancer |
Reduce tumor volume, local neural invasion and inflammation |
Short lasting of analgesia; may lead to chemotherapeutic pain |
| Intrathecal drug delivery |
For patients with high-dose opioid regimen, refractory or end-stage pain |
Effective for terminal or refractory pain; few drug-related side effects |
High cost; performed by pain specialists and few hospitals; main risks are bleeding and infection |
| Integrative therapy |
Usage for all stage, such as acupuncture and massage approaches |
Non-invasive; multiple methods; easily accepted for patients |
Insufficient theoretical basis |
| Anti-depression |
Usage for all stage, including drugs and psychotherapy |
Relieve the comorbidity of pain and depression; improve mood |
|
| Palliative care |
For advanced and terminal pancreatic cancer |
Improve QoL and outcome of medical services; make it easier for patients to accept reality |
|
| Dynamic pain assessment for all stages |
Figure 2.:
Flowchart of PCRP treatment. PCRP = pancreatic cancer-related pain.
Celiac plexus neurolysis
PCRP appears to originate primarily from the celiac plexus, whereas pain in the end stage of the disease may also involve other splanchnic and somatic nerves. Therefore, early celiac plexus neurolysis (CPN) after the onset of pain in PC may improve pain relief.[48,49] Regardless of the techniques used, CPN improves analgesia, decreases opioid consumption, and improves QoL.[50] The two most commonly practiced CPN routes are the posterior percutaneous CPN under CT or fluoroscopic guidance, and the endoscopic ultrasonography-guided CPN (EUS-CPN). There is evidence that percutaneous CPN relieves pain at 4 weeks, and significantly reduces opioid consumption at 4 and 8 weeks. The efficacy of EUS-CPN over conventional drug therapy in inducing analgesia has been reported.[51] Early application of EUS-CPN at diagnosis provides pain relief and lower morphine consumption. However, the trial excluded patients with metastatic disease, thus limiting the generalizability of the result. No large trials have compared percutaneous CPN and EUS-CPN. Prolongation of survival after performing CPN was reported in an early study,[52] but this was not reproduced in a later research,[53] and there is no robust evidence that CPN affects progression of PC.
Splanchnic nerve destruction
The greater splanchnic nerve, the lesser splanchnic nerve and the minimal splanchnic nerve contain pain afferent fibers that transmit the parenchymal organs such as liver, gallbladder, and pancreas. This is the theoretical basis of splanchnic nerve destruction (SND) in the treatment of related pain. For patients with advanced cancer who fail to obtain analgesia from conservative treatment, chemical damage can be used to permanently block the pancreatic pain nerve conduction pathway. The commonly used destructive chemical is anhydrous ethanol. Ethanol causes nerve injury by causing immediate precipitation of neurolipoproteins and mucin in the celiac plexus, resulting in demyelination of nerve fibers and subsequent axonal degeneration. When the axolemma is intact, the nerve can regenerate, allowing sensory recovery after 3 to 6 months, which explains the duration of pain relief by SND. The impact of SND on survival and QoL remains controversial. In a randomized trial, patients suffering moderate to severe pain received SND with either absolute alcohol (neurolysis) or normal saline (control). Pain relief with neurolysis was greater than control for the first 3 months, and opioid consumption with neurolysis was lower for the first 5 months. However, a significant reduction in survival was found in stage IV patients but not stage III patients in neurolysis. No differences in QoL were observed. It should be noted that this trial was not powered to assess survival as the primary end point, and patients included were palliative care patients who did not intend to receive any anticancer therapy, including chemotherapy, radiation, or targeted therapy.[52,54,55] In contrast, Lillemoe et al found that patients treated with neurolysis had longer survival than those with saline placebo.[52] Thus, SND appears to be an effective analgesic option for patients with unresectable PC. However, due to the spread and metastasis of the tumor, most of the advanced PC enwrapped the visceral and small nerves, so that the absolute alcohol could not fully contact the visceral and small nerves, leading the nerve not be completely damaged.
Overall, there is evidence showing the efficiency of CPN and SND for PCRP, and it is generally agreed that CPN and SND are best reserved for patients with advanced PC, but both techniques are seldom performed in PC patients possibly because the expertise is not widely available. According to a nationwide survey in Japan, 47.5% to 79.8% pain specialists had not performed interventional procedures including CPN in the past 3 years, only 18.1% interventional radiology specialists indicated that they conducted CPN by themselves.[56] Several barriers existed for the implementation of the therapies. Studies showed that usually only pain specialists and interventional radiology physicians are able to provide CPN and SND, but a lack of time and training of experts are barriers to the implementation. Promoting opportunities for physicians intending for further specialization of the treatment of PCRP can increase the popularization of interventional procedures.
Radiation therapy
Pain relief resulted from radiation therapy is relatively satisfying,[57,58] although it takes several weeks to witness effect. For pain due to tumor related ductal obstruction or PNI, radiation therapy can help by decreasing the overall amount of tumor, thus lessening the ductal obstruction, and decreasing PNI by reducing the release of inflammatory mediators.[9,59] Both conventional and more technologically advanced radiation therapy are reported to be effective in addressing pain associated with locally advanced PC.[58,60] About half of PC patients can achieve complete pain relief.[57,60,61] Additionally, older, frailer adults, and patients with metastatic tumor also benefited.[57] More technologically advanced radiation therapy approaches, such as stereotactic body radiation therapy (SBRT), have been introduced to deliver higher doses of radiation in a more conformal manner. A systematic review of SBRT for PCRP revealed that 54% of patients achieved complete pain relief.[62] Furthermore, when combined with plexus block, radiation therapy can further prolong pain medication-free survival, demonstrating that radiation therapy can be used alone or combined with other modalities.[61]
Chemotherapy
Chemotherapy plays a crucial role in the management of PCRP by reducing tumor amount, local neural invasion, and inflammation, while slowing progression of cancer and elevating patients’ QoL simultaneously. Pain control was routinely set as an important outcome when evaluating the effect of specific chemotherapy regimen. A systematic review reported chemotherapy brought improved survival without compromising health-related QoL or pain control.[63] However, the relationship between PCRP and chemotherapy should not be interpreted from a unidirectional perspective. Controlling pain benefits tolerance of chemotherapy of patients as they are in better physical and mental state with less pain.
But chemotherapy can bring additional pain to PC patients; this kind of pain should not be neglected and is in need of distinction from pain caused by PC itself. The mechanism of chemotherapy caused pain is under research, and chemotherapy-induced peripheral neuropathy (CIPN) is believed to be the predominant contributor. Chemotherapy induces inflammation, oxidative stress, and alterations in neuronal signaling pathways that lead to dysfunction of nerve. For paclitaxel, a transient elevation in the systemic levels of interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-10 (IL-10) was detected in patients undergoing treatment with paclitaxel.[64] In mice, the development of mechanical hypersensitivity induced by paclitaxel was mitigated through intrathecal administration of phenyl N-butylnitrone, a scavenger of reactive oxygen species (ROS).[65] Besides, superoxide anion production, lipid peroxidation, protein (carbonylated proteins), and DNA oxidation were induced by oxaliplatin in the mouse model.[66] Oxidative stress was further stated by the protective effect on astrocytes of corresponding antioxidants.[66] Additionally, oxaliplatin could trigger prolonged depolarization, which can initiate the reversal mode of the Na+/Ca2+ exchanger 2, leading to the pathological buildup of calcium ions and subsequent axonal damage,[67] therefore generating pain. Aside from the direct impact on neurites, oxaliplatin promotes the secretion of some inflammatory mediates like IL-6 and TNF-α from satellite glial cells, which sensitize sensory neurons.[68] Nevertheless, mechanism of CIPN of a specific chemotherapy drug is complex and in need of deeper exploration from molecular to cellular and neural circuit layers.
Intrathecal drug delivery
Intrathecal administration of analgesics plays an important role in treating PCRP particularly in those with high-dose opioid regimen who have failed CPN, refractory pain, or end-stage pain. With precise dosage of analgesics injected to spinal dorsal horn, it allows treatment of pain with fewer side effects. Injectable drugs included morphine, fentanyl, local anesthetics, baclofen, and/or clonidine. Combination strategies using an opioid, a local anesthetic, and an N-type voltage-gated calcium channel blocker have been shown to be stable and successful. An observational study evaluating intrathecal drug delivery for refractory PCRP[69,70] demonstrated 50% to 75% relief in mean pain levels.
Integrative therapy
Given the poor prognosis and great emotional stress of PC, patients often seek integrative therapies to help manage the disease. Established guidelines for PC emphasize the importance of supportive care to maintain QoL, addressing nutritional requirements, psychosocial needs, pain relief, and integrative modalities, such as acupuncture and massage, in all stages of the disease.[71,72] Multiple studies have showed that massage therapy is efficient in reduction of pain, anxiety, and depression in cancer patients, including those with PC.[73] Acupuncture, which has been widely used for cancer pain in China, appears to be moderately effective in selected patients.[74,75] With a sterile needle applied by micropunctate insertions along specific meridian points, acupuncture takes effect by affecting the differential release of neurotransmitters.[76,77] An analgesic effect was found in PC patients using electroacupuncture. Patients were treated on Jiaji points T8-T12 bilaterally for 30 minutes once a day for 3 days, and decreased pain level maintained for 2 days after cessation of treatment.[78] However, acupuncture is operator dependent and with short-lasting effect, it can be a supplementary treatment to other therapies.
Management of PCRP-related depression
Patients with PC have a high prevalence of depression. A meta-analysis including 457 PC patients estimates that 43% of patients experience depression after diagnosis.[79] Current evidences suggest that pain and depression are often co-existed and highly intertwined, which may co-exacerbate physical and psychological symptoms. It is usually necessary to combine antidepressant, anxiolytic and anticonvulsant drugs to enhance the analgesic effect. Psychotherapy should also be considered. Patients with pain and depression experience reduced physical, mental, and social function, as opposed to patients with only pain or only depression. A cohort study included 23,745 patients with adenocarcinoma of the pancreas, concluded that patients without depression had a median survival of 3.1 months, while 2.1 months for patients with depression.[80] Another prospective cohort study including 108 PC patients suggested early psychiatric intervention may maintain health related QoL.[81] The mechanism of comorbidity of pain and depression is still not clear, possible through the neuroendocrine and immune systems, mainly the involvement of the hypothalamic-pituitary-adrenal axis. Several molecular mechanisms have been associated with PC related depression, such as high cytokine levels, in particular IL-6, and overexpression of indoleamine 2,3-dioxygenase, with subsequent disturbances in tryptophan and serotonin metabolism.[79,81,82]
End of life palliative care
Near the end of life, pain management for advanced and terminal PC can become very challenging, and an interdisciplinary approach including palliative care specialist, is needed. An important goal of palliative care in taking a holistic approach to care and treatment, is to improve the QoL of patients with advanced cancer by alleviating symptoms and problems caused by illness and its treatment.[83] A retrospective study showed that patients with advanced PC benefited from a palliative care program by requiring less chemotherapy and less admission to intensive care and hospital.[84] Even for patients with newly diagnosed incurable cancer (including PC), early provision of palliative care can improve QoL, reduce depression, and enhance the ability to cope with poor diagnosis and prognosis.[85,86] Although evidence for the efficacy of early palliative care interventions is still sparse, it is generally accepted that this should be recommended for all patients with advanced PC.
Conclusion
PCRP is a complex and multifactorial pain state that consists of multiple neuropathological changes. Accordingly, the management of PCRP needs a comprehensive and multifaceted strategy targeting clinical manifestation and underlying mechanism. Current management of PCRP is rather etiology based on the mechanism of PCRP, including PNI, neural remodeling, inflammation and relative cytokines, more standardized multimodal analgesia regimen based on available evidence could be proposed increasingly. It is worth noting that, for some seemingly well-known and even simple treating methods, their standardized implementation is still lacking and with low penetration rate. Therefore, training specialized physicians who can carry out cancer pain management including interventional therapy makes sense. In conclusion, while seeking for a breakthrough in the mechanism of PCRP, the current optimal care should be based on the local medical situation (including physician, technique, medical insurance, etc), and a multidisciplinary team including pain specialists, interventional radiologist, gastrointestinal surgeon, palliative medicine physician, and psychologist should be collaborated to formulate a pain therapy covering the survival time of patients with PCRP.
Limitations of the article
The mechanism of PCRP in this review only discusses the principal mechanism of PCRP solely caused by cancer, and pain generated from treatment of PC is not fully discussed except for the classical chemotherapy-induced pain. Besides, unlike meta-analyses, evaluation of literature about management of PCRP are relatively rough, partial, and does not include data integration. It is better to summarize the mechanism, and discuss or predict future directions for management corresponding to the mechanism.
Acknowledgments
None.
Author contributions
AZ and LS designed the project. MW and AZ collected the data and wrote the manuscript. MW and AZ designed the illustration. LS critically revised the manuscript and illustration. All authors approved the final version of the manuscript.
Financial support
This work was supported by the National High Level Hospital Clinical Research Funding (2022-PUMCH-B-007 and 2022-PUMCH-A-147).
Conflicts of interest
The authors declare no conflicts of interest.
Declaration of participant consent
This is a literature review article so there is no participant consent to provide as no data or figures are derived from participants.
Ethics approval
Not applicable.
References
[1]. Zheng R, Zhang S, Zeng H, et al. Cancer incidence and mortality in china, 2016. J Nat Cancer Cent. 2022;2:1–9.
[2]. Zhou M, Wang H, Zeng X, et al. Mortality, morbidity, and risk factors in china and its provinces, 1990-2017: a systematic analysis for the global burden of disease study 2017. Lancet. 2019;394:1145–1158.
[3]. Park B, Seo J, Han J, et al. Trends in treatment patterns and survival outcomes in pancreatic cancer: a nationwide population-based study in Korea. Eur J Cancer. 2023;189:112932.
[4]. Augustinus S, Schafrat PJM, Janssen BV, et al. Nationwide impact of centralization, neoadjuvant therapy, minimally invasive surgery, and standardized pathology reporting on r0 resection and overall survival in pancreatoduodenectomy for pancreatic cancer. Ann Surg Oncol. 2023;30:5051–5060.
[5]. Grahm AL, Andrén-Sandberg A. Prospective evaluation of pain in exocrine pancreatic cancer. Digestion. 1997;58:542–549.
[6]. Lakatos G, Balázs A, Kui B, et al. Pancreatic cancer: multicenter prospective data collection and analysis by the Hungarian pancreatic study group. J Gastrointestin Liver Dis. 2016;25:219–225.
[7]. Mercadante S, Adile C, Giarratano A, et al. Breakthrough pain in patients with abdominal cancer pain. Clin J Pain. 2014;30:510–514.
[8]. Hendifar AE, Petzel MQB, Zimmers TA, et al. Pancreas cancer-associated weight loss. Oncologist. 2019;24:691–701.
[9]. Ceyhan GO, Bergmann F, Kadihasanoglu M, et al. Pancreatic neuropathy and neuropathic pain—a comprehensive pathomorphological study of 546 cases. Gastroenterology. 2009;136:177–186.e1.
[10]. Damm M, Weniger M, Kölsch A-K, et al. The quality of pain management in pancreatic cancer: a prospective multi-center study. Pancreatology. 2020;20:1511–1518.
[11]. Dell’Aquila E, Fulgenzi C, Minelli A, et al. Prognostic and predictive factors in pancreatic cancer. Oncotarget. 2020;11:924–941.
[12]. Silverman DA, Martinez VK, Dougherty PM, et al. Cancer-associated neurogenesis and nerve-cancer cross-talk. Cancer Res. 2021;81:1431–1440.
[13]. Saloman JL, Albers KM, Li D, et al. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer. Proc Natl Acad Sci U S A. 2016;113:3078–3083.
[14]. Pour PM, Bell RH, Batra SK. Neural invasion in the staging of pancreatic cancer. Pancreas. 2003;26:322–325.
[15]. Zhu Z, Friess H, diMola FF, et al. Nerve growth factor expression correlates with perineural invasion and pain in human pancreatic cancer. J Clin Oncol. 1999;17:2419–2428.
[16]. Ma J, Jiang Y, Jiang Y, et al. Expression of nerve growth factor and tyrosine kinase receptor a and correlation with perineural invasion in pancreatic cancer. J Gastroenterol Hepatol. 2008;23:1852–1859.
[17]. Xu X, Lu X, Chen L, et al. Downregulation of mmp1 functions in preventing perineural invasion of pancreatic cancer through blocking the nt-3/trkc signaling pathway. J Clin Lab Anal. 2022;36:e24719.
[18]. Okada Y, Eibl G, Guha S, et al. Nerve growth factor stimulates mmp-2 expression and activity and increases invasion by human pancreatic cancer cells. Clin Exp Metastasis. 2004;21:285–292.
[19]. Xiao Z, Xu H, Strosberg JR, et al. Egfr is a potential therapeutic target for highly glycosylated and aggressive pancreatic neuroendocrine neoplasms. Int J Cancer. 2023;153:164–172.
[20]. Korbecki J, Simińska D, Kojder K, et al. Fractalkine/cx3cl1 in neoplastic processes. Inte J Mol Sci. 2020;21:3723.
[21]. Bapat AA, Hostetter G, Von Hoff DD, et al. Perineural invasion and associated pain in pancreatic cancer. Nat Rev Cancer. 2011;11:695–707.
[22]. Qin T, Xiao Y, Qian W, et al. Hgf/c-met pathway facilitates the perineural invasion of pancreatic cancer by activating the mtor/ngf axis. Cell Death Dis. 2022;13:387.
[23]. Zhang L, Zhang W, Zhang X, et al. High-glucose microenvironment promotes perineural invasion of pancreatic cancer via activation of hypoxia inducible factor 1α. Oncol Rep. 2022;47:64.
[24]. Zhang W, He R, Yang W, et al. Autophagic Schwann cells promote perineural invasion mediated by the ngf/atg7 paracrine pathway in pancreatic cancer. J Exp Clin Cancer Res. 2022;41:48.
[25]. Na’ara S, Amit M, Gil Z. L1cam induces perineural invasion of pancreas cancer cells by upregulation of metalloproteinase expression. Oncogene. 2019;38:596–608.
[26]. Jing Y, Liang W, Liu J, et al. Stress-induced phosphoprotein 1 promotes pancreatic cancer progression through activation of the FAK/AKT/MMP signaling axis. Pathol Res Pract. 2019;215:152564.
[27]. Xu C, Hu D-m, Zhu Q. Eef1a2 promotes cell migration, invasion and metastasis in pancreatic cancer by upregulating mmp-9 expression through Akt activation. Clin Exp Metastasis. 2013;30:933–944.
[28]. Peng T, Guo Y, Gan Z, et al. Nerve growth factor (ngf) encourages the neuroinvasive potential of pancreatic cancer cells by activating the Warburg effect and promoting tumor derived exosomal miRNA-21 expression. Oxid Med Cell Longev. 2022;2022:8445093.
[29]. Lindsay TH, Jonas BM, Sevcik MA, et al. Pancreatic cancer pain and its correlation with changes in tumor vasculature, macrophage infiltration, neuronal innervation, body weight and disease progression. Pain. 2005;119:233–246.
[30]. di Mola FF, di Sebastiano P. Pain and pain generation in pancreatic cancer. Langenbecks Arch Surg. 2008;393:919–922.
[31]. Han L, Jiang J, Xue M, et al. Sonic hedgehog signaling pathway promotes pancreatic cancer pain via nerve growth factor. Reg Anesth Pain Med. 2020;45:137–144.
[32]. Han L, Ma J, Duan W, et al. Pancreatic stellate cells contribute pancreatic cancer pain via activation of sHH signaling pathway. Oncotarget. 2016;7:18146–18158.
[33]. Li X, Ma G, Ma Q, et al. Neurotransmitter substance p mediates pancreatic cancer perineural invasion via NK-1R in cancer cells. Mol Cancer Res. 2013;11:294–302.
[34]. Gao L, Bo H, Wang Y, et al. Neurotrophic factor artemin promotes invasiveness and neurotrophic function of pancreatic adenocarcinoma in vivo and in vitro. Pancreas. 2015;44:134–143.
[35]. Wang J, Wang H, Cai J, et al. Artemin regulates cxcr4 expression to induce migration and invasion in pancreatic cancer cells through activation of NF-κB signaling. Exp Cell Res. 2018;365:12–23.
[36]. Stopczynski RE, Normolle DP, Hartman DJ, et al. Neuroplastic changes occur early in the development of pancreatic ductal adenocarcinoma. Cancer Res. 2014;74:1718–1727.
[37]. Hirth M, Xie Y, Höper C, et al. Genetic mouse models to study pancreatic cancer-induced pain and reduction in well-being. Cells. 2022;11:2634.
[38]. Bressy C, Lac S, Nigri J, et al. Lif drives neural remodeling in pancreatic cancer and offers a new candidate biomarker. Cancer Res. 2018;78:909–921.
[39]. Hirth M, Gandla J, Höper C, et al. Cxcl10 and ccl21 promote migration of pancreatic cancer cells toward sensory neurons and neural remodeling in tumors in mice, associated with pain in patients. Gastroenterology. 2020;159:665–681.e13.
[40]. Secq V, Leca J, Bressy C, et al. Stromal slit2 impacts on pancreatic cancer-associated neural remodeling. Cell Death Dis. 2015;6:e1592.
[41]. Zhu Y, Colak T, Shenoy M, et al. Nerve growth factor modulates trpv1 expression and function and mediates pain in chronic pancreatitis. Gastroenterology. 2011;141:370–377.
[42]. Michalski CW, Oti FE, Erkan M, et al. Cannabinoids in pancreatic cancer: Correlation with survival and pain. Int J Cancer. 2008;122:742–750.
[43]. Selvaggi F, Melchiorre E, Casari I, et al. Perineural invasion in pancreatic ductal adenocarcinoma: from molecules towards drugs of clinical relevance. Cancers. 2022;14:5793.
[44]. Luongo M, Marinelli O, Zeppa L, et al. Cannabidiol and oxygen-ozone combination induce cytotoxicity in human pancreatic ductal adenocarcinoma cell lines. Cancers. 2020;12:2774.
[45]. Kajiwara I, Sano M, Ichimaru Y, et al. Duloxetine improves cancer-associated pain in a mouse model of pancreatic cancer through stimulation of noradrenaline pathway and its antitumor effects. Pain. 2020;161:2909–2919.
[46]. Itaya T, Sano M, Kajiwara I, et al. Mirogabalin improves cancer-associated pain but increases the risk of malignancy in mice with pancreatic cancer. Pain. 2023;164:1545–1554.
[47]. Zhu M, Wang L, Zhu J, et al. Microrna-330 directs downregulation of the gaba(b)r2 in the pathogenesis of pancreatic cancer pain. J Mol Neurosci. 2020;70:1541–1551.
[48]. Lou S. Endoscopic ultrasound-guided celiac plexus neurolysis to alleviate intractable pain caused by advanced pancreatic cancer. Surg Laparosc Endosc Percutan Tech. 2019;29:472–475.
[49]. Puli SR, Reddy JB, Bechtold ML, et al. Eus-guided celiac plexus neurolysis for pain due to chronic pancreatitis or pancreatic cancer pain: a meta-analysis and systematic review. Dig Dis Sci. 2009;54:2330–2337.
[50]. Mercadante S, Klepstad P, Kurita GP, et al. Sympathetic blocks for visceral cancer pain management: a systematic review and EAPC recommendations. Crit Rev Oncol Hematol. 2015;96:577–583.
[51]. Wyse JM, Carone M, Paquin SC, et al. Randomized, double-blind, controlled trial of early endoscopic ultrasound-guided celiac plexus neurolysis to prevent pain progression in patients with newly diagnosed, painful, inoperable pancreatic cancer. J Clin Oncol. 2011;29:3541–3546.
[52]. Lillemoe KD, Cameron JL, Kaufman HS, et al. Chemical splanchnicectomy in patients with unresectable pancreatic cancer. A prospective randomized trial. Ann Surg. 1993;217:447–455; discussion 456.
[53]. Oh TK, Lee WJ, Woo SM, et al. Impact of celiac plexus neurolysis on survival in patients with unresectable pancreatic cancer: a retrospective, propensity score matching analysis. Pain Physician. 2017;20:E357–E365.
[54]. Süleyman Ozyalçin N, Talu GK, Camlica H, et al. Efficacy of coeliac plexus and splanchnic nerve blockades in body and tail located pancreatic cancer pain. Eur J Pain. 2004;8:539–545.
[55]. Arcidiacono PG, Calori G, Carrara S, et al. Celiac plexus block for pancreatic cancer pain in adults. Cochrane Database Syst Rev. 2011;2011:CD007519.
[56]. Uehara Y, Matsumoto Y, Kosugi T, et al. Availability of and factors related to interventional procedures for refractory pain in patients with cancer: a nationwide survey. BMC Palliat Care. 2022;21:166.
[57]. Ebrahimi G, Rasch CRN, van Tienhoven G. Pain relief after a short course of palliative radiotherapy in pancreatic cancer, the academic medical center (amc) experience. Acta Oncol. 2018;57:697–700.
[58]. Wolny-Rokicka E, Sutkowski K, Grządziel A, et al. Tolerance and efficacy of palliative radiotherapy for advanced pancreatic cancer: a retrospective analysis of single-institutional experiences. Mol Clin Oncol. 2016;4:1088–1092.
[59]. Koulouris AI, Banim P, Hart AR. Pain in patients with pancreatic cancer: prevalence, mechanisms, management and future developments. Dig Dis Sci. 2017;62:861–870.
[60]. Morganti AG, Trodella L, Valentini V, et al. Pain relief with short-term irradiation in locally advanced carcinoma of the pancreas. J Palliat Care. 2003;19:258–262.
[61]. van Geenen RC, Keyzer-Dekker CM, van Tienhoven G, et al. Pain management of patients with unresectable peripancreatic carcinoma. World J Surg. 2002;26:715–720.
[62]. Buwenge M, Macchia G, Arcelli A, et al. Stereotactic radiotherapy of pancreatic cancer: a systematic review on pain relief. J Pain Res. 2018;11:2169–2178.
[63]. Kristensen A, Vagnildhaug OM, Grønberg BH, et al. Does chemotherapy improve health-related quality of life in advanced pancreatic cancer? A systematic review. Crit Rev Oncol Hematol. 2016;99:286–298.
[64]. Pusztai L, Mendoza TR, Reuben JM, et al. Changes in plasma levels of inflammatory cytokines in response to paclitaxel chemotherapy. Cytokine. 2004;25:94–102.
[65]. Shim HS, Bae C, Wang J, et al. Peripheral and central oxidative stress in chemotherapy-induced neuropathic pain. Mol Pain. 2019;15:1744806919840098.
[66]. Di Cesare Mannelli L, Zanardelli M, Failli P, et al. Oxaliplatin-induced oxidative stress in nervous system-derived cellular models: could it correlate with in vivo neuropathy? Free Radic Bio Med. 2013;61:143–150.
[67]. Ballarini E, Malacrida A, Rodriguez-Menendez V, et al. Sodium-calcium exchanger 2: a pivotal role in oxaliplatin induced peripheral neurotoxicity and axonal damage? Int J Mol Sci. 2022;23:10063.
[68]. Schmitt L-I, Leo M, Kutritz A, et al. Activation and functional modulation of satellite glial cells by oxaliplatin lead to hyperexcitability of sensory neurons in vitro. Mol Cell Neurosci. 2020;105:103499.
[69]. Carvajal G, Dupoiron D, Seegers V, et al. Intrathecal drug delivery systems for refractory pancreatic cancer pain: observational follow-up study over an 11-year period in a comprehensive cancer center. Anesth Analg. 2018;126:2038–2046.
[70]. Dupoiron D, Leblanc D, Demelliez-Merceron S, et al. Optimizing initial intrathecal drug ratio for refractory cancer-related pain for early pain relief. A retrospective monocentric study. Pain Med. 2019;20:2033–2042.
[71]. Tempero MA, Malafa MP, Al-Hawary M, et al. Pancreatic adenocarcinoma, version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021;19:439–457.
[72]. Ducreux M, Cuhna AS, Caramella C, et al. Cancer of the pancreas: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(Suppl 5):vv56–vv68.
[73]. Moffat GT, Epstein AS, O’Reilly EM. Pancreatic cancer-a disease in need: optimizing and integrating supportive care. Cancer. 2019;125:3927–3935.
[74]. Amr YM, Makharita MY. Comparative study between 2 protocols for management of severe pain in patients with unresectable pancreatic cancer: one-year follow-up. Clin J Pain. 2013;29:807–813.
[75]. Wu X, Chung VC, Hui EP, et al. Effectiveness of acupuncture and related therapies for palliative care of cancer: overview of systematic reviews. Sci Rep. 2015;5:16776.
[76]. Zhang R, Lao L, Ren K, et al. Mechanisms of acupuncture-electroacupuncture on persistent pain. Anesthesiology. 2014;120:482–503.
[77]. Han JS. Acupuncture: neuropeptide release produced by electrical stimulation of different frequencies. Trends Neurosci. 2003;26:17–22.
[78]. Chen H, Liu TY, Kuai L, et al. Electroacupuncture treatment for pancreatic cancer pain: a randomized controlled trial. Pancreatology. 2013;13:594–597.
[79]. Barnes AF, Yeo TP, Leiby B, et al. Pancreatic cancer-associated depression: a case report and review of the literature. Pancreas. 2018;47:1065–1077.
[80]. Boyd CA, Benarroch-Gampel J, Sheffield KM, et al. The effect of depression on stage at diagnosis, treatment, and survival in pancreatic adenocarcinoma. Surgery. 2012;152:403–413.
[81]. Sugimoto H, Kawashima H, Ohno E, et al. The prognostic factors and trajectory of HRQOL in patients with pancreatic cancer who received psychiatric intervention. J Gastroenterol Hepatol. 2016;31:685–690.
[82]. Pop VV, Seicean A, Lupan I, et al. Il-6 roles—molecular pathway and clinical implication in pancreatic cancer—a systemic review. Immunol Lett. 2017;181:45–50.
[83]. Anon. Policies and managerial guidelines for national cancer control programs. Rev Panam Salud Publica. 2002;12:366–370.
[84]. Jang RW, Krzyzanowska MK, Zimmermann C, et al. Palliative care and the aggressiveness of end-of-life care in patients with advanced pancreatic cancer. J Natl Cancer Inst. 2015;107:dju424.
[85]. Temel JS, Greer JA, El-Jawahri A, et al. Effects of early integrated palliative care in patients with lung and GI cancer: a randomized clinical trial. J Clin Oncol. 2017;35:834–841.
[86]. Ferrell BR, Temel JS, Temin S, et al. Integration of palliative care into standard oncology care: American Society of Clinical Oncology Clinical Practice guideline update. J Clin Oncol. 2017;35:96–112.
