Pancreas Cancer‐Associated Pain Management

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Introduction

Prevalence and Significance

Pancreas cancer may be the 11th most common cancer in the U.S., but it is the third leading cause of cancer death overall [1]. The most commonly presenting symptoms in patients with pancreas cancer are pain (abdominal or referred to the lower mid-back), jaundice, and weight loss [2]. Pain may occur secondary to obstruction of the duodenum and/or, more likely, secondary to perineural tumor invasion or nerve impingement [3, 4]. Symptom burden among patients with cancer can result in limitations in daily activities, poor functioning, disability, and overall impairment in quality of life (QOL) [5]. Proper management of symptoms, including pain, can greatly affect a patient’s ability to tolerate treatment protocols and improve his or her overall QOL.

The Pancreatic Cancer Action Network maintains a patient registry where patients are enrolled and voluntarily complete a health and symptoms survey. Preliminary analysis of survey respondents over a 2.5-year period (2016–2018) determined that 93% of the patients reported having pain related to the diagnosis of pancreas cancer and that 83% of those reported moderate to severe pain intensity levels [6]. This is similar to previously reported data indicating that pain is the third most common symptom after weight loss and jaundice [7]. About 90% of these patients reported discussing pain with their health care provider (HCP), and most then received recommendations or prescriptions to reduce pain intensity. Despite this, almost 50% of the respondents reported visits to the emergency room for symptoms related to pain, and 33% were hospitalized at least once for pain management.

Several recent reports have established that cancer-related pain affects patient survival in pancreatic and other cancers [811]. Poorly managed pain is associated with decreased caloric intake, poor sleep quality, and reduced or limited occupational and social activities. Inadequately treated pain can significantly affect a patient’s eligibility and tolerance for chemotherapy. Conversely, patients with less pain intensity and pain of shorter duration are reported to have a better QOL and longer survival [12, 13].

About 30% of the patients reported ongoing pain after initiation of tumor treatment or evidence of tumor reduction [14, 15]. So, despite response to chemotherapy, a sizeable percentage of patients will have ongoing abdominal pain. Here we review the pathophysiology and medical management of pain; possible local/focused therapies, such as radiation and nerve blocks; and selected complementary and alternative medicine therapies.

Pathophysiology

The pathophysiology of pain in pancreas cancer is complex and multifactorial. Accordingly, the management of pain in patients with pancreas cancer can be challenging and often requires a multifaceted approach. The two most common mechanisms leading to pain are pancreatic neuropathy and pancreatic duct obstruction.

Direct effects to nerves in pancreatic tissue can occur because of malignant cell infiltration and resulting inflammation. The phenomenon of perineural invasion, or malignant involvement of the protective sheath that surrounds bundles of axons, occurs in approximately 70% of pancreatic adenocarcinomas, reflecting the disease’s neurotropism [1618]. Malignant involvement of both intrapancreatic and extrapancreatic nerve plexuses, including the celiac plexus, is a common pathologic finding after surgical resection. Another pathologic hallmark of neuropathy is increased nerve density and nerve hypertrophy [19]. Several neurotransmitters, such as glutamate, substance P, nerve growth factor (NGF), and calcitonin gene–related peptide, along with inflammatory cells, have been implicated in the pathophysiology of pain in pancreas cancer [20]. In particular, macrophage infiltration into pancreatic tumors can increase secretion of NGF, leading to activation of pain sensation pathways [21]. Higher levels of NGF have been positively correlated with perineural invasion and pain intensity in pancreas cancer [22]. Afferent neurons respond to the release of neurotransmitters and carry these signals to their ultimate termination in the sensory cortex of the brain [16].

Pancreatic tumors frequently cause occlusion of the main pancreatic duct, which results in an increase in upstream intraductal and interstitial pressure [23]. Pancreatic tumor obstruction of the main pancreatic duct can cause pain via increased intraductal pressures and an ensuing pancreatic exocrine enzyme deficiency leading to malabsorption and postprandial pain [24, 25]. Pancreatic ductal stenting and subsequent lowered interstitial pressure have resulted in relief from obstructive pain in multiple studies [26, 27]. There is a paucity of data in pancreatic cancer, but studies of enzyme replacement treatment in pancreatic insufficiency and malabsorption from other conditions have demonstrated reduced abdominal pain [2830].

Finally, patients with pancreas cancer can also experience pain related to direct invasion of adjacent organs, distant metastases, and, less commonly, side effects of treatment including chemotherapy, radiation, or surgery. Treatment of these complications, although important, are out of scope for this review.

In summary, most pancreas cancer pain appears attributable to neuropathic mechanisms, although pancreatic insufficiency may play a role.

Systemic Therapy

Pain as a Clinical Trial Endpoint

Chemotherapy plays a crucial role in the management of pain and QOL metrics in patients with advanced pancreatic cancer. Historically, clinical trials with chemotherapy in pancreas cancer have included pain control and QOL as primary or secondary objectives. Burris et al. randomized 126 patients to single agent gemcitabine or fluorouracil (5-FU) [31]. The primary measure of efficacy in the trial was clinical benefit rate, defined as pain (analgesic consumption and pain intensity), Karnofsky performance status, and weight, with an improvement in one parameter without worsening in others. Patients in the gemcitabine arm experienced a significant improvement in alleviation of pain and disease-related symptoms (24% clinical benefit rate vs. 5% for 5-FU). The improvement in clinical benefit rate in addition to the improvement in survival resulted in the approval of gemcitabine for advanced pancreatic cancer. In the PRODIGE 4/ACCORD 11 trial, patients were randomized to mFOLFIRINOX (5-FU, oxaliplatin, irinotecan) or single agent gemcitabine [32]. The patients in both arms had QOL assessed using the European Organization for the Research and Treatment of Cancer QOL Questionnaire C30 (EORTC QLQ-C30) every 2 weeks. After 6 months of therapy, more than twice as many patients experienced a decrease in global health status in the gemcitabine arm compared with the FOLFIRINOX arm (p < .001). Patients treated with FOLFIRINOX had significantly increased time until definitive deterioration in their pain scores.

The benefit of chemotherapy in preserving QOL has also been demonstrated with second-line chemotherapy. In the NAPOLI-I trial, fluorouracil + leucovorin + nanoliposomal irinotecan demonstrated a survival benefit in patients pretreated with gemcitabine-based chemotherapy compared with 5-FU + leucovorin [33]. In an analysis of the study’s QOL data using the EORTC QLQ-C30, the addition of nanoliposomal irinotecan was associated with maintenance of most health-related QOL metrics, including pain [34].

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