Introduction
It is estimated that approximately 60% of patients with malignancies encounter chronic pain, with 56%–82% of cases reporting inadequate pain control. Colorectal cancer is the most common pelvic malignancy in both men and women. In 2018, over 1 million new cases were diagnosed in men and women. When separated out by gender-specific malignancies, ovarian cancer had the highest incidence with 21,750 new cases. Cervical cancer had the second highest incidence with about 13,800 new cases. In men, however, prostate cancer was the most common pelvic malignancy with 164,690 new cases in 2018. These malignancies along with many other causes of pelvic cancers can lead to malignant pelvic pain syndrome. With the progression of disease, malignant pelvic pain syndromes can be debilitating, limit functional status, and severely decrease quality of life. Chronic pain from increasing disease burden can present in multiple ways, including the mass effect from the primary tumor, invasion of nearby neurovascular structures, and metastatic disease to regional and distal sites. Furthermore, as improvements are made in diagnostic testing and treatments, there is a growing population of cancer survivors who face the unexpected burden of posttreatment chronic pain syndromes, such as radiation and chemotherapy-induced neuropathies. The World Health Organization (WHO) describes a cancer pain ladder aimed at guiding nonopioid and opioid pharmacological treatments in a stepwise fashion. When conservative therapy fails to provide adequate relief, interventional treatment options should be considered.
Etiology and Pathogenesis
Pelvic malignancies can induce pain from intestinal obstruction, compression of neurovascular structures, and tumor infiltration to nearby viscera. Extension to blood and lymphatic vessels leads to metastatic lesions, including involvement of the lungs, bone, and brain in patients with advanced-stage disease.
Female pelvic malignancies can involve the entire reproductive system including the vulva, vagina, uterus, fallopian tubes, and ovaries. These structures receive both sympathetic and parasympathetic innervation ( Table 4.1 ). The superior hypogastric plexus, which is located in the retroperitoneum and situated bilaterally along the anterior surface of the L5 vertebral body, is part of the pelvic autonomic nervous system and receives its innervation from the T10–L2 nerve roots. In women, the ovarian plexus branches from the superior hypogastric plexus and transmits nociceptive information from the uterus and cervix. The caudal ends of the sympathetic chains then converge to form the ganglion impar, which provides sympathetic innervation to pelvic viscera as well as carry both sympathetic and nociceptive fibers from the perineum, distal rectum, perianal region, and distal urethra. Parasympathetic innervation of the pelvis originates from the S2–S4 roots via the pelvic splanchnic nerves. In women, this supplies the vagina, cervix, and lower portion of the uterus. Somatic innervation, including afferent sensory fibers, also arises from S2–S4 to innervate the vagina, perineum, and vulva.
| Autonomic Innervation of the Pelvic Organs | |||
|---|---|---|---|
| Pelvic organ | Sympathetic innervation | Parasympathetic | Nerve plexus |
| Cervix | T10, T11, T12, L1 | S2, S3, S4 | Superior hypogastric plexus |
| Ovary | T10, T11, T12 | S2, S3, S4 | Superior and inferior hypogastric plexus |
| Uterus, fallopian tubes | T11, T12, L1 | S2, S3, S4 | Superior and inferior hypogastric plexus/Ovarian plexus |
| Testes | T10, T11, T12 | S2, S3, S4 | Renal/aortic plexus |
| Vas deferens, epididymis | T10, T11, T12, L1 | S2, S3, S4 | Renal/aortic plexus |
| Spermatic cord, tunica vaginalis | L1, L2 | S2, S3, S4 | Genitofemoral nerve |
| Prostate | L1, L2 | S2, S3, S4 | Superior and inferior hypogastric plexus |
| Bladder | T10, T11, T12, L1 | S2, S3, S4 | Superior and inferior hypogastric plexus |
| Rectum | T10, T11, T12, L1 | S2, S3, S4 | Inferior hypogastric plexus/ganglion impar |
Malignancies specific to men affect structures such as the prostate, scrotum, testes, vas deferens, spermatic cord, tunica vaginalis, and penis. The pelvic organs in men are also innervated by sympathetic and parasympathetic fibers. The renal plexus contains sympathetic fibers that innervate the testes, vas deferens, and epididymis. The superior hypogastric plexus contains nerves that supply the prostate and bladder. The inferior hypogastric plexus, which is located presacrally and on the lateral aspects of the rectum ventral to the S2–S4 vertebrae, supplies the rectum as well as the prostate and bladder. The spermatic cord and tunica vaginalis are innervated by the genital branch of the genitofemoral nerve (L1–L2).
Depression and pain are also highly related and overlapping in their symptoms and pathophysiology. For instance, depression has been linked to higher levels of stress hormones and cytokines, which in turn increases inflammation and pain. Chronic pain also causes changes in areas of the brain involved with mood regulation, such as the anterior cingulate cortex and prefrontal cortex, and can also worsen symptoms of depression, especially when it interferes with functional status, sleep, and sexual function. Both pain and mood utilize serotonin, norepinephrine, and epinephrine, so treatments targeting these neurotransmitters have the potential to treat both.
Clinical Features
As previously discussed, pelvic malignancies can cause somatic, visceral, and neuropathic pain and present with a wide range of symptomatology. Therefore, a comprehensive history, including a detailed pain diary, is essential. Visceral pain tends to be diffused and poorly localized, while neuropathic pain may present with features of burning, numbness, allodynia, and hyperalgesia.
The location of the pain varies from patient to patient and can include the low back, abdomen, pelvis, and lower extremities. Groin and penile pain can be referred from the kidneys, ureters, or testicles, as these are innervated by the T10–L1 nerve roots. Scrotal pain in men can be referred from the prostate, urethra, bladder, or seminal vesicle due to S2–S4 innervation. In women, uterine involvement often causes midline lower abdominal pain, while cervical involvement can cause lower back pain. Ovarian pain is less predictable and typically occurs late in the clinical course.
In addition, being diagnosed with a malignancy and having to cope with chronic pain often cause mood disorders such as depression and anxiety. In a study of Veterans Affairs patients, symptoms of depression were found in approximately 25% of cancer patients. This commonly manifests as lack of energy and difficulty sleeping. Depressive symptoms are more common in cancer patients ranging from 41 to 88 years old. Lack of emotional support defined as having someone to talk to was also linked to depressive symptoms. Patients who report that pain interferes with their daily life are also more likely to have depression, emphasizing the importance of early pain management. This is particularly important for patients who suffer chronic pelvic pain, given the impact that their pain syndrome may have on their sexual health and sexual identity.
Diagnosis
Pelvic pain can be caused by a variety of cancer and disease processes. The diagnostic process starts with a comprehensive history and physical exam. A thorough pain evaluation is critical. A detailed pain description should include the onset of pain, location, quality, intensity, duration, temporal characteristics, alleviating, and aggravating factors. A pain diary can assist with patient recall and recognizing pain patterns. Self-reported pain assessment tools are utilized on the initial encounter and reassessed on subsequent visits. The three most commonly used measures include numerical rating scale, visual analog scale, and adjective rating scale. It is also important to be aware that patients can have discrepancies in their behavior compared to the self-reported pain score due to coping mechanisms. There are active and passive coping mechanisms. Active coping mechanisms include problem solving, collecting information and refocusing on the problem, and regulation of emotion. Passive coping mechanisms are avoidance and escape. Active coping has been shown to decrease the intensity of pain and overall improve the quality of life while passive coping can increase the perception of pain and decrease the quality of life. Any psychological factors should be considered in an assessment when obtaining a self-reported pain score.
Laboratory tests and diagnostic imaging are also typically obtained. Common laboratory tests include complete blood count, comprehensive metabolic panel, coagulopathy panel, magnesium, and phosphate. Ultrasound is often used as the initial imaging modality to identify gynecologic malignancies such as ovarian, uterine, and vaginal cancer. Computed tomography (CT) and magnetic resonance imaging (MRI) are commonly ordered to confirm the diagnosis and further assess location, mass characteristics, and stage. Other studies may be utilized to further assess for metastatic disease, including positron emission tomography scan and endoscopic procedures such as esophagogastroduodenoscopy, colonoscopy, and cystoscopy. Tumor markers assist with diagnosis and surveillance including prostate-specific antigen, cancer antigen 125 (CA-125), calcitonin, alpha fetoprotein, human chorionic gonadotropin, and carcinoembryonic antigen. A definitive diagnosis can be made with fine needle biopsy, core needle biopsy, excisional or incisional biopsy, and endoscopic biopsy.
Physical Exam Findings
Physical exam findings are often limited, and the patient’s history and symptoms should guide the exam. A general exam provides useful information about a patient’s level of distress, mood, nutritional status, and the ability to ambulate. An abdominal exam may be significant for localized or diffuse tenderness. If rigidity and guarding are present, then this may be a sign of inflammation of the peritoneum. These signs can be caused by mass effect or intestinal obstruction secondary to a tumor. For patients with abdominal, pelvic, or urinary complaints, a rectal exam should be performed. Rectal exam may be notable for an abnormal prostate, palpable masses, and fecal impaction that could be caused by infiltration of the malignancy into the rectum or mass effect causing compression of the rectum. In women, an initial pelvic exam should include bimanual palpation of the uterus, vagina, cervix, and ovaries to evaluate for masses. Primary care or gynecologists typically provide detailed pelvic and rectal exam findings before the patient presenting to the interventional pain clinic.
A comprehensive neurological exam should include deep tendon reflexes, sensory, and motor tests to further evaluate for peripheral and central nervous system involvement. Red flag symptoms, including bowel/bladder dysfunction and persistent neurological deficits, should be urgently evaluated and treated. Dermatomal mapping of pain and numbness can also be useful when determining treatment plans.
Severe pain interfering with a patient’s ability to bear weight may be indicative of a pathologic fracture. Fractures of the pelvis can be found on exam with point tenderness as well as pain with pelvic compression, thigh thrust, hip rotation, and single-leg hop. Pubic symphysis pain can occur in the anteromedial groin and presents as tenderness to palpation of the pubic symphysis or tubercle as well as pain during hip flexion with leg extension. Sacroiliac joint involvement is assessed with provocative tests including distraction, thigh thrust, compression, FABER, and Gaenslen’s test; the distraction test has the high positive predictive value of all the provocative tests.
Treatment
Malignant disease is usually accompanied by refractory and recurrent pain. Behavioral and pharmacological treatments are often first-line therapy; however, interventional options should be considered early to avoid side effects associated with systemic therapies and to provide targeted pain relief. This includes sympathetic blocks/neurolysis, neuromodulation, and intrathecal drug delivery systems.
Pharmacologic Agents
The WHO provides a stepwise approach for alleviating cancer pain through nonopioid and opioid medications. Step 1 uses nonopioids combined with adjuvant analgesics. If unable to provide adequate relief, Step 2 recommends starting a low potency opioid in addition to nonopioids and adjuvant analgesics. And Step 3 calls for higher potency opioids for severe cancer pain that is persistent and increasing.
Nonopioids medications are effective and have a relatively safe side-effect profile. The most common agents include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antidepressants, and gabapentanoids.
NSAIDs are available in many formulations. Common NSAIDs used to treat pain include ibuprofen, meloxicam, naproxen, ketorolac, and celecoxib. The mechanism of action relies on the inhibition of cyclooxygenase 1 and 2, which decreases the amount of circulating inflammatory mediators that can activate the peripheral nociceptors. The adverse effects of NSAIDs include toxicities involving the gastrointestinal, cardiovascular, hepatic, and renal systems.
Acetaminophen has been used for over 100 years. The mechanism is unclear, but its use is believed to inhibit the production of lipooxygenase and cylcooxygenase leading to a decreased amount of inflammatory mediators. It is effective for treating mild pain with a maximum dose of 4 g for ages less than 60 with no liver disease. Higher daily doses can result in hepatoxicity and are more concerning in patients with a history of liver disease, alcohol use, and hepatitis.
Corticosteroids provide analgesia primarily through the reduction of proinflammatory cytokines and eicosanoids. It also reduces tissue swelling, decreasing painful mass effects from tumor invasion. Oral dexamethasone is the preferred corticosteroid due to its high potency, long duration of action, and minimal mineralocorticoid effects. The recommended starting dose is 8 mg daily, but patients should be assessed regularly so that the lowest effective dose is prescribed. Prolong use with high doses can lead to unwanted side effects including glucose intolerance, fluid retention, sleep disturbances, delirium, osteopenia, gastric ulcers, and worsening of psychiatric conditions. These side effects can further worsen a patient’s quality of life when combined with their already existing chronic pain.
Gabapentanoids, tricyclic antidepressants, and serotonin and norepinephrine reuptake inhibitors are commonly used to treat neuropathic pain. Few trials, however, have investigated the effectiveness of these medications specifically for the treatment of neuropathic malignancy syndromes. A comparative study between gabapentin, pregabalin, and amitriptyline showed that they are individually effective for the treatment of malignant neuropathic pain. Pregabalin was shown to be more effective at decreasing burning and dysesthesias. Over 4 weeks, dosing was increased to 1800 mg/day for gabapentin, 600 mg/day for pregabalin, and 100 mg/day for amitriptyline. Side effects should be monitored during up-titration including somnolence, dizziness, altered mental status, and edema.
Opioids are still considered the mainstay treatment for moderate-to-severe cancer pain. Pure μ-agonists are preferred and most commonly used (morphine, fentanyl, hydromorphone, methadone, oxycodone, hydrocodone). It is important to recognize that individuals have varying responses to different μ-agonists, which has led practitioners to adopt opioid rotation to identify the most effective agent that minimizes side effects. Therefore, while the WHO analgesic ladder generally recommends the use of weak opioids such as tramadol and codeine for moderate pain, more potent opioids such as oxycodone or morphine at lower doses should be considered as an alternative. When starting any opioids, patients should be monitored frequently to assess for side effects and efficacy of treatment. A reasonable starting dose for patients with moderate to severe pain is 30 mg of oral morphine milligram equivalents per day. Adverse effects of opioids are well known, including nausea, sedation, constipation, respiratory depression, and neurotoxicity. If patients experience intolerable side effects or inadequate relief, opioid rotation should be considered. In these cases, the equianalgesic dose of the new opioid should be reduced by 20%–30% to account for incomplete cross-tolerance. Attention to a patient’s neuropsychological function and tolerance to side effects is essential to provide individualized therapy.
Sympathetic Blocks
Superior hypogastric block, neurolysis: As previously mentioned, the superior hypogastric plexus is situated bilaterally at the level of the fifth lumbar vertebral body by the bifurcation of the common iliac vessels and receives innervation from the lumbar sympathetic chains and parasympathetic nerve fibers originating from the S2–4 nerve roots. Descending projections of the superior hypogastric plexus reach the inferior hypogastric plexus, which is located anteriorly to the sacrum and the S2–S4 foramina. The superior hypogastric plexus, inferior hypogastric plexus, and the pelvic plexus then collectively provide innervation to the pelvic viscera, including the uterus, ovary, testes, ureter, prostate, bladder, rectum, and perineum. Therefore, the superior hypogastric plexus is a popular target for treating chronic pelvic pain syndromes.
The superior hypogastric plexus is typically performed in the prone position. Under CT or fluoroscopic guidance, two needles are inserted with a paramedian approach and advanced anterolaterally until the tips sit at the anterior margin of the L5–S1 interspace. After aspiration of the needle to confirm negative intravascular injection, the injectate is given. Although providers may choose to initially perform a diagnostic block with local anesthetic, proceeding directly to a neurolytic block may be a viable alternative for patients with advanced disease. Neurolytic injections are typically done with 50%–100% ethanol or 4%–10% phenol, which causes necrotic damage to neural structures. Unlike phenol, ethanol has no local anesthetic effect and thus, it is recommended to inject local anesthetic 5 minutes before administering ethanol. A cohort study of 227 patients suffering from chronic pelvic pain associated with cancer demonstrated that superior hypogastric plexus neurolysis provided effective pain relief and a significant reduction in opioid usage in the majority of their patients.
Ganglion impar block, neurolysis: The ganglion impar, or ganglion of Walther, is a retroperitoneal structure that is anterior to the coccyx. It contains nociceptive and sympathetic fibers of the perineum, rectum, anus, distal urethra, the lower third of the vagina, vulva, and scrotum. Ganglion impar neurolysis was first described in 1990 for the treatment of pain.
There are four main techniques used to access to this structure, including the anococcygeal, coccygeus-transverse, intercoccygeal, and transcoccygeal approaches.
The transcoccygeal approach under fluoroscopy is the most popular because it allows the shortest needle trajectory while avoiding surrounding structures. Patients are placed in the prone position, and the needle is advanced through the sacrococcygeal ligament until the needle tip is anterior to the coccyx and posterior to the rectum. Contrast is used to verify correct needle placement. Diagnostic block with local anesthetic, neurolysis, cryoablation, and radiofrequency ablation of the plexus may then be performed. In a cohort of patients with perineal and pelvic cancer pain, 79% were found to have a reduction in morphine consumption 3 months following the ganglion impar block.
Neuromodulation
The first two reported spinal cord stimulators (SCS) were placed by Norman Shealy in 1967 for a patient with bronchogenic carcinoma and another for pelvic pain related to cancer. Interestingly, as the field of neuromodulation has advanced over the years, SCS devices have been used increasingly for the treatment of nonmalignant neuropathic pain and less for malignancy pain syndromes.
The mechanism of SCS is not fully understood, though Melzack and Wall’s “Gate Control” theory, has been used to describe pain perception and explain the therapeutic mechanism for SCS devices. A delta and C fibers, which carry nociceptive signals, synapse within the dorsal horn of the spinal cord. Stimulation of A beta fibers, which carry nonpainful touch signals, at the same pain-generating regions then effectively “close the gate” for pain perception by inhibiting ascending nociceptive signals. This also reduces sympathetic activity and potentiate GABA receptors leading to an overall reduction in pain.
SCS therapies can be considered for malignant pelvic pain syndromes if patients have failed conservative treatment and have a neuropathic component to their pain. Although no studies have specifically investigated the efficacy of SCS for pelvic malignancies, a recent Cochrane systemic review found in four case series totaling 92 patient with cancer pain syndromes, 80% endorsed a significant reduction in their pain, and another 50% had a reduction in opioid use.
Perioperative paresthesia mapping is typically required to determine correct lead placement for traditional dorsal column stimulation during the trial phase. The pelvis is innervated by sensory neurons from the S1–S4 nerve roots, parasympathetic neurons from S1–S4, and sympathetic nerve fibers from T10–L1 levels. Therefore, the treatment of chronic pelvic pain is aimed at these critical sites.
Dorsal root ganglion (DRG) stimulation can also be considered for these patients, which allows for focused stimulation of specific nerve roots. The number and the respective levels at which the leads are placed are dependent on the dermatomal distribution of the patient’s pain. Furthermore, this particular technology has the added benefit of utilizing less overall energy and also less risk of unwanted paresthesia with positional changes compared to dorsal column stimulators. We would recommend DRG stimulation at the upper lumbar (L1, L2) and sacral (S2) nerve roots for patients suffering from refractory pelvic pain ( Fig. 4.1 ).
