Abstract
Dear Editor:
Pancreatic cancer continues to be a challenging disease for a multitude of reasons. Unfortunately, this devastating disease is usually diagnosed when patients become symptomatic. Consequently, it is diagnosed in a late state with patients often suffering from pain. Although the incidence of pancreatic cancer is significantly less than many other cancers, ∼8/100,000 globally, it is the fourth most common cause of death from cancer. 1 Our understanding of pancreatic cancer has evolved drastically over the past 20 years. It has now been linked to genetic inherited mutations. Among these mutations are KRAS2, p16/CDKN2A, TP53, and SMAD4/DPC4. 2
Like all pain associated with cancer, pancreatic cancer pain can be divided into multiple categories, which include, but is not limited to, nociceptive and neuropathic pain. Despite heavy doses of opioids and adjuvant medications to help with pancreatic cancer pain, it is estimated that 14% of patients still suffer from refractory visceral and somatic pain. 3 Given that the presenting symptom in 30–60% of pancreatic cancer patients is pain, it becomes of paramount importance to manage these patients' pain early on in the diagnosis. 4 Furthermore, pancreatic cancer can undergo perineural invasion, which can generate substantial pain. In fact, now it is thought that the level of perineural invasion correlates with overall prognosis. 5
To better comprehend the pain associated with pancreatic cancer, it is important to understand the ways in which it manifests. Nociceptive pain is better defined as pain that is from an identifiable source or lesion. Nociceptive pain is mediated by nociceptors, which are modulated by electrical stimulation in the form of mechanical changes and tissue inflammatory markers. This type of pain is transferred to the central nervous system through A-delta and C fibers, which have their cell bodies located in the dorsal root ganglia.
Nociceptive pain can be further subdivided into somatic and visceral components. Somatic pain is localizable pain that results from direct activation of nerve fibers from a source lesion. Alternatively, visceral pain is poorly localized pain arising from internal organs. The less localized pain stems from the lower density of nociceptors on the viscera. The nerve fibers that modulate visceral pain travel with autonomic fibers, which explains why this kind of pain can be related to autonomic disturbances such as nausea. Furthermore, visceral pain pathways also travel with somatic pathways; therefore, visceral pain can be referred pain in concordance with particular somatic tissue. Neuropathic pain, on the other hand, originates from a lesion that is associated with the nervous system, versus the periphery in nociceptive pain. This type of pain is best described as abnormal triggering of pain sensation unrelated to, or out of proportion to, a given stimulus. 6
Pancreatic cancer pain is thought to be in part mediated by the celiac plexus. The celiac plexus is the largest of the three main sympathetic plexuses. 7 One of the original ways to treat pancreatic cancer pain involved a celiac plexus block, and this was first described by Kappis in the early part of the 20th century. 8 Since its original inception, the method and techniques of performing the block have evolved into what is performed today. Multiple prospective trials were instituted in the 1990s in an attempt to compare pain control with traditional analgesics and celiac plexus block. Polati et al. performed a randomized double-blind clinical trial of neurolytic celiac plexus block in patients with pancreatic cancer and observed a significant pain relief with lower use of pharmacologic therapy in the treatment group. 9 Anatomically, the celiac plexus originates in the retroperitoneum of the abdomen, anterolateral to the aorta, at approximately the level of the first lumbar vertebral body, celiac trunk, and superior mesenteric artery with the renal arteries lying just inferior to the plexus. 10 It is made up of preganglionic sympathetic efferent nerve fibers, which are composed of the greater, lesser, and least splanchnic nerves. These splanchnic nerves originate from the thoracic sympathetic chain at T5-T10, T10-T11, and T12, respectively. 11 The celiac plexus receives feedback from the distal stomach, pancreas, gallbladder, duodenum, small intestine, and large intestine, thus a successful block will lead to profound diarrhea. Neurologic compromise is a potential adverse side effect of celiac plexus neurolysis. The mechanism for this outcome is poorly understood, but it is postulated that it may be due to vascular vasospasm of feeding arteries to the spinal cord. As a result, case reports have illustrated incidences of lower extremity weakness, and or permanent paralysis. 12
Beyond celiac plexus block and neurolysis, intrathecal drug delivery is another modality for pain control. Intrathecal administration of medication is a longstanding practice for purposes of anesthesia. It dates back to the late 19th century when August Bier injected cocaine intrathecally for procedures involving the lower extremities. 13 This novel technique of direct administration of medication into the intrathecal space has since evolved considerably with new mixtures and classes of medications being injected. Given the successful use of intrathecal medications, it was logical to consider long-term implantable devices to provide pain relief. In 1981, the first documented implantable intrathecal delivery device was used in chronic pain that was associated with malignancy. 14 Intrathecal administration continues to play an important role in modulating pancreatic cancer pain particularly in those that are on high-dose opioid regimen who have failed celiac plexus block.
As pain management has evolved, new methods have developed for controlling pain associated with pancreatic cancer. Spinal cord stimulation (SCS) has been a strategy for pain control since the 1960s. The concept focused on the Gate Control Theory of Pain (GCT), established by Melzack and Wall. 15 The GCT establishes that peripheral stimuli can open or close the gate to the central nervous system to allow perception of pain. The premise of SCS is to modulate this gateway, thereby modulating the perception of pain.
The procedure involves directly placing electrode leads over the dorsal surface of the epidural space. Similar to the placement of a traditional epidural, a loss of resistance technique is employed through a paramedian interlaminar approach. A caveat for SCS lead placement versus epidural catheter placement is that typically the target epidural entry site is multiple vertebral spaces above the needle entry site. 16 Caution must be made to maintain the leads dorsally, since ventral transposition of the leads can lead to unwanted motor activation with stimulation. Typically leads are placed a few millimeters on either side of the midline depending on symptomatology (Fig. 1).
Case reports illustrate that SCS can provide significant pain improvement in pancreatitis and pancreatic cancer. In a case report of five patients with severe abdominal pain due to nonalcoholic chronic pancreatitis by Khan et al., greater than 50% pain relief after SCS trial was noted in all five patients. 17 Furthermore, they also all had a decrease in analgesic use and improvement in quality of life. In their procedure, they accessed the epidural space in the lower thoracic spine (T9-T10) and the leads were then advanced to the midthoracic level (T5-T6). These patients then went on to permanent implantation of SCS.
One of the pitfalls of SCS, until recently, was the lack of MRI compatibility. Oncologic patients, particularly pancreatic cancer patients, are very likely to need multiple imaging modalities, including MRI, to assess their cancer. An MRI scan can lead to overheating of the lead, lead damage, thermal injury, device damage, as well as dislodgment of lead location. Companies now have integrated MRI compatibility in their SCS devices. The technology focuses on distribution of the MRI energy over the entirety of the lead, thereby reducing focused heating and energy dispersion. The device also has less ferromagnetic material, thereby reducing the risk of movement of the lead.
SCS delivery has also evolved along with its MRI compatibility. Traditional delivery of SCS provided low-frequency, ∼50 Hz, stimulation. This resulted in a paresthesia-like phenomenon, which would be sensed by the patient. However, now with higher frequencies possible, 1–10,000 Hz, better overall results have been appreciated in patients with pain. Not only have the uncomfortable paresthesias been removed due to higher frequency stimulation, but overall pain relief has also been shown to be improved. Furthermore, the placement of the leads themselves is easier since paresthesias no longer have to be elicited to identify correct lead positioning. Kapural et al. illustrated in a RCT that when compared with conventional low-frequency stimulation, those who received high-frequency stimulation at 10,000 Hz had better overall pain control. 18
However, the most surprising element of SCS in patients with pancreatic cancer is the potential for therapeutic modulation. Certain cancers are known to be hypoxic and ischemic in nature. As a result, delivery of chemotherapy to these tissues is altered and less responsive. It is postulated that by modulating blood flow, therapy delivery can be improved, and can thereby change disease course. Clavo et al. studied blood flow in patients with head and neck cancer and implanted cervical SCS. 19 When studied, they found that SCS allowed for increased oxygen delivery to the tumor area.
SCS overall has shown great effectiveness in combating chronic abdominal pain associated with pancreatic cancer. With the continued evolution of the understanding of neuromodulation and the advancement of the technology, the implementation of SCS in pancreatic cancer-related abdominal pain is an alternative option to traditional neurolysis, intrathecal medication delivery, and pharmacologic pain management.