Antiplatelet and Wound Healing Implications of Immunotherapy and Targeted Cancer Therapies in the Perioperative Period.

The traditional paradigm of oncologic treatment centered on cytotoxic chemotherapy has undergone tremendous advancement during the last 15 yr with the advent of immunotherapy and targeted cancer therapies. These agents, including small molecule inhibitors, monoclonal antibodies, and immune-checkpoint inhibitors, are highly specific to individual tumor characteristics and can prevent cell growth and tumorigenesis by inhibiting specific molecular targets or single oncogenes. While generally better tolerated than traditional chemotherapy, these therapies are associated with unique constellations of adverse effects. Of particular importance in the perioperative and periprocedural settings are hematologic abnormalities, particularly antiplatelet effects with increased risk of bleeding, and implications for wound healing. This narrative review discusses targeted cancer therapies and provides recommendations for physicians managing these patients' care as it relates to procedural or surgical interventions.

Dorsal Versus Ventral Intrathecal Catheter Tip Location and Effect on Dose Escalation and Opioid Use in Patients With Cancer Pain.

OBJECTIVES: In the practice of intrathecal drug delivery, consensus exists regarding the cephalad to caudad location of the catheter tip relative to dermatomal distribution of pain. However, data are lacking on the importance of dorsal vs ventral tip location relative to the spinal cord. We hypothesize that a dorsally placed catheter tip improves efficacy because of closer proximity to nociceptive pathways. MATERIALS AND METHODS: A retrospective review of 298 patients with cancer with intrathecal drug delivery systems implanted at the Huntsman Cancer Institute from May 2014 to June 2020 was performed. Patients were stratified by catheter tip location zones based on available radiographic studies. Patient-controlled intrathecal medication dose requirements and rate of change were compared with catheter zone and other variables, including the presence of adjuncts such as bupivacaine and ziconotide. RESULTS: A total of 158 patients were suitable for analysis demonstrating a dorsal tip in 63.9% (n = 101) and ventral tip in 36.1% (n = 57), with a median follow-up of 17 days (interquartile range [IQR], 10-24). There was no difference in daily dose change from implant to discharge between the dorsal group 8.2% (IQR, 0.0-41.5) and ventral group 20.8% (IQR, 0.0-66.7; p = 0.12). Daily dose change from discharge to follow-up was 2.6% (IQR, 0.0-7.1) in the dorsal group and 1.8% (IQR, 0.0-5.7) in the ventral group (p = 0.92). Catheter tip location had no impact on systemic opioid use. CONCLUSIONS: We did not find significant associations between dorsal vs ventral catheter tip location and measures of pain relief, including change in intrathecal dose or systemic opioid use.

Initial Intrathecal Dose Titration and Predictors of Early Dose Escalation in Patients With Cancer Using a 100:1 Oral to Intrathecal Morphine Conversion Ratio.

OBJECTIVE: Pain is common in patients with advanced cancer, and intrathecal drug delivery (IDD) has been successfully used for recalcitrant pain. We report on our experience using a 100:1 oral-to-intrathecal morphine conversion ratio for initial dosing and factors predictive of early dose escalation. MATERIALS AND METHODS: Retrospective review of an intrathecal drug delivery system (IDDS) data base at the Huntsman Cancer Institute-University of Utah in cancer patients initiated on IDD with morphine or hydromorphone. Demographic characteristics, preoperative opioid use, and initial and hospital discharge IDD settings were collected. RESULTS: A total of 275 patients were identified between June 2014 and May 2020. The median oral-to-intrathecal morphine conversion ratio for initial IDD dosing was 105.5:1 (interquartile range [IQR] 90-120, range 75-150). No serious adverse effects including respiratory depression or sedation were noted and the median length of stay was one night (IQR 1-2, range 1-22). Ninety-six percent of patients discontinued opioids immediately following IDDS implant. Initial IDD dosing was adequate in 42% of patients. Dose reduction was required in 4% prior to discharge due to nausea, patient request, weakness, pruritus, or urinary retention. Dose escalation was required in 54%, with a median dose increase of 66.7% (IQR 33-150%, range 5-1150%). Patients in the highest quartile of dose escalation, ≥70% between IDD initiation and discharge, had associations with younger age, higher preoperative opioid use, and inpatient status. No significant associations were found in patients who required dose reduction as compared to other patients. CONCLUSIONS: An oral-to-intrathecal morphine conversion ratio of approximately 100:1 for initiation of IDD in patients with cancer pain was safe and well tolerated and may facilitate rapid elimination of systemic opioids. Dose reduction was rare, while a majority of patients required further dose escalation prior to discharge.

The Effect of Measured Radiotherapy Dose on Intrathecal Drug Delivery System Function.

OBJECTIVES: Radiation therapy (RT) and intrathecal drug delivery systems (IDDS) are often used concurrently to optimize pain management in patients with cancer. Concern remains among clinicians regarding the potential for IDDS malfunction in the setting of RT. Here we assessed the frequency of IDDS malfunction in a large cohort of patients treated with RT. MATERIALS AND METHODS: Cancer patients with IDDS and subsequent RT at our institution from 2011 to 2019 were eligible for this study. Patients were excluded in the rare event that their IDDS was managed by an outside clinic and follow-up documentation was unavailable. Eighty-eight patients aged 22-88 years old (43% female, 57% male) representing 106 separate courses of RT were retrospectively identified. Patients received varying levels of radiation for treatment of cancer and cumulative dose to the IDDS was calculated. IDDS interrogation was subsequently performed by a pain specialist. Malfunction was recorded as deviation from the expected drug volume and/or device errors reported upon interrogation as defined by the manufacturer. RESULTS: Total measured RT dose to the IDDS ranged from 0 to 18.0 Gy (median = 0.2 Gy) with median dose of 0.04 Gy/fraction (range, 0-3.2 Gy/fraction). Ten pumps received a total dose >2 Gy and three received ≥5 Gy. Eighty-two percentage of patients had follow-up with a pain specialist for IDDS interrogation and all patients underwent follow-up with a healthcare provider following RT. There were zero incidences of IDDS malfunction related to RT. No patient had clinical evidence of radiation related pump malfunction at subsequent encounters. CONCLUSIONS: We found no evidence that RT in patients with IDDS led to device failure or dysfunction. While radiation oncologists and pain specialists should coordinate patient care, it does not appear that RT dose impacts the function of the IDDS to warrant significant clinical concern.

The Rate of Infectious Complications After Intrathecal Drug Delivery System Implant for Cancer-Related Pain Is Low Despite Frequent Concurrent Anticancer Treatment or Leukopenia.

BACKGROUND: The efficacy of intrathecal drug delivery (IDD) for cancer-related pain is well established. Cancer therapies are often associated with immunosuppression and increased risk of infection, and the rate of infection after intrathecal drug delivery system (IDDS) implant in cancer patients has been reported as 2.4%-6.3%. Our objective is to report on the rate of surgical site infections (SSI) in patients implanted with IDDS for cancer-related pain and to provide a data-driven discussion on the relationship between antineoplastic treatment, leukopenia, and other clinical or demographic characteristics and SSI. METHODS: Following local institutional review board approval, we conducted a retrospective chart review of IDDS implants from May 2014 through December 2018. Data collected included demographic data, health status, prophylactic antibiotic administration, surgery duration, presence of leukopenia (white blood cell [WBC] count of <4.0 K/µL) or moderate neutropenia (absolute neutrophil count [ANC] of <1000/µL) within the 30 days before IDDS implant, and details of antineoplastic treatment or systemic corticosteroid use in the perioperative period. This information was assessed in relation to SSI incidence up to 6 months following implant. RESULTS: Two hundred seventeen IDDS implants were identified. A majority of patients (79.3%) received ≥1 form of antineoplastic therapy within 30 days before or after implant, and 42.4% received multiple forms of antineoplastic therapy. Therapies included chemotherapy in 46.5%, immunotherapy in 28.6%, systemic steroids in 32.3%, and radiation therapy in 28.1%. One-quarter of patients (25.8%) were leukopenic within 30 days before implant, with 3.2% having moderate neutropenia. There were 2 infectious complications representing an infection rate of 0.9% (95% CI, 0.1%-3.3%), with limited shared characteristics between those experiencing SSI. CONCLUSIONS: SSI risk after IDDS placement for cancer pain is low, despite frequent concurrent antineoplastic therapy and leukopenia in the perioperative period. Concomitant cancer therapies should not be a barrier to the implementation of IDD for cancer pain.

Prospective Association of Serum Opioid Levels and Clinical Outcomes in Patients With Cancer Pain Treated With Intrathecal Opioid Therapy.

BACKGROUND: Opioids remain the mainstay of cancer pain management but are associated with systemic toxicity. In refractory cancer pain, intrathecal therapy (ITT) is associated with improved pain control, reduced systemic side effects, and improved survival. It has been assumed that ITT decreases systemic serum opioid levels and their associated toxicity, but there are limited data to support this assumption. This study hypothesizes that serum opioid levels decrease with ITT. Secondary objectives include comparative measures of pain, bowel function, and other cancer-related symptoms. METHODS: Fifty-one cancer patients undergoing ITT for cancer pain were recruited in a prospective observational study. Daily oral morphine equivalency (OME) dose, serum opioid levels, Brief Pain Inventory (BPI), MD Anderson Symptom Inventory (MDASI), and a constipation questionnaire were obtained at the time of implant, and 4 and 8 weeks postoperatively. RESULTS: Average baseline daily OME was 375 mg (median, 240; interquartile range, 150-405; range, 0-3160), mean serum morphine concentration was 53.7 ng/mL (n = 17), and mean oxycodone concentration was 73.7 ng/mL (n = 20). At 4 weeks, 87.5% of patients had discontinued non-IT opioids, and 53% had undetectable (<2 ng/mL) serum opioid concentrations. At 8 weeks, 92% remained off all non-IT opioids and 59% had undetectable serum opioid levels. IT morphine doses >4.2 mg/d were invariably associated with detectable serum levels; with doses <4.2 mg, morphine was undetectable in 80% of subjects. IT hydromorphone doses >6.8 mg/d were detectable in the serum. Using linear mixed model analyses, there were statistically significant decreases in the mean "worst pain," "average pain," and MD Anderson symptom severity and interference scores at 4 and 8 weeks. This change was independent of serum opioid levels; when analyzed separately, there was no difference in the pain scores of subjects with detectable serum opioid levels compared to those with undetectable levels at 4 and 8 weeks. Constipation ranked as "quite a bit" or "very much" decreased from 58.7% to 19.2% of subjects at week 4 (P < .001) and to 37.5% at 8 weeks (P = .23). A very low complication rate was observed. CONCLUSIONS: ITT for cancer pain was associated with a marked reduction in serum opioid concentrations, with the majority of patients having undetectable serum levels. Reducing serum opioid concentrations in cancer patients may have implications with respect to restoring bowel function, improving fatigue, and promoting the integrity of antitumor immune function and warrants further study.

Initiation of Intrathecal Drug Delivery Dramatically Reduces Systemic Opioid Use in Patients With Advanced Cancer.

OBJECTIVES: Pain is common in cancer, affecting more than 70% of patients with advanced disease. Intrathecal drug delivery systems (IDDS) are a well-established treatment for patients with refractory cancer pain, improving pain control and reducing associated side effects. To date, details of systemic opioid use before and after IDDS implant have not been reported. MATERIALS AND METHODS: We conducted a retrospective review of patients at Huntsman Cancer Institute-University of Utah treated with IDDS for cancer pain from May 2014 to May 2018. Oral, transdermal, and parenteral opioid use before IDDS implant was compared to use 30 days postoperatively. RESULTS: A total of 173 patients were included, 93% with stage IV disease. The pre-implant median daily oral morphine equivalent (OME) was 240 mg (interquartile range 130-390, range 0-2616 mg). OME doses >200 mg/day were required by 57% of patients, and >500 mg OME by 19% of patients. The post-implant median OME was 0 mg (interquartile range 0-0, range 0-480 mg) and 82.6% of patients discontinued systemic opioids completely. 11.0% of patients used <100 mg OME, and only 1.7% of patients used >200 mg OME. Mean OME decreased by 94% following IDDS implant (p < 0.0001) and all patients who continued to use systemic opioids required a lower OME compared to pre-implant. CONCLUSIONS: In the largest cohort of patients with advanced cancer and refractory pain treated with IDDS, implantation was associated with a dramatic reduction in systemic opioid use 30 days postoperatively, with a large majority of patients discontinuing systemic opioids. Those patients that continued systemic opioids utilized significantly lower doses as compared to their pre-implant dose.

Adult Cancer Pain, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology.

In recent years, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Adult Cancer Pain have undergone substantial revisions focusing on the appropriate and safe prescription of opioid analgesics, optimization of nonopioid analgesics and adjuvant medications, and integration of nonpharmacologic methods of cancer pain management. This selection highlights some of these changes, covering topics on management of adult cancer pain including pharmacologic interventions, nonpharmacologic interventions, and treatment of specific cancer pain syndromes. The complete version of the NCCN Guidelines for Adult Cancer Pain addresses additional aspects of this topic, including pathophysiologic classification of cancer pain syndromes, comprehensive pain assessment, management of pain crisis, ongoing care for cancer pain, pain in cancer survivors, and specialty consultations.

Tertiary Care Clinical Experience with Intravenous Lidocaine Infusions for the Treatment of Chronic Pain.

Objective: To evaluate the safety of and long-term pain relief due to intravenous lidocaine infusion for the treatment of chronic pain in a tertiary pain management clinic. Design: Retrospective chart review. Methods: Medical records were reviewed from 233 adult chronic pain patients who underwent one to three lidocaine infusions. The initial lidocaine challenge consisted of 1,000 mg/h administered intravenously for up to 30 minutes until infusion was complete, full pain resolution, the patient requested to stop, side effects (SEs) became intolerable, and/or if there were any safety concerns. Subsequent infusions were tailored to patient response. Data reviewed included pain diagnosis, lidocaine dose, SEs, and duration of pain relief documented at a follow-up visit. Results: Patients primarily had neuropathic pain (80%), were 94% white, 58% were female, and there was an average pain duration of 7.9 years. SEs were usually mild and transient, including perioral tingling, dizziness, tinnitus, and nausea/vomiting, and they were uncommon after the initial infusion. Overall, 41% of patients showed long-lasting pain relief, with positive response to the initial infusion associated with receiving and benefitting from subsequent infusions. Benefit by pain diagnoses varied from 32% to 58%. Conclusions: Our retrospective study in a heterogeneous population with chronic pain suggests that intravenous lidocaine is a safe treatment. Data also suggest long-term pain relief in a significant proportion of patients. Additional study is important in order to delineate patient selection, determine optimal dosing and treatment frequency, assess pain reduction and duration, and treatment cost-effectiveness.

Controversies in intrathecal drug delivery for cancer pain.

Pain and suffering related to cancer are challenging issues that continue to deserve consideration for treatment optimization. Advances in analgesic management and control of the underlying cancer have improved symptom management, yet many patients still suffer from uncontrolled pain. Intrathecal drug delivery has an established role in the management of refractory cancer pain, but there are significant knowledge gaps in our understanding and application of this therapy. This review addresses several areas of controversy, including the importance of intrathecal catheter tip location, the necessity of an intrathecal trial and the role of intrathecal ziconotide and local anesthetics. In each area, the evidence is discussed, with an emphasis on presenting practical clinical guidance and highlighting deficiencies in our knowledge that are worthy of future investigation.

Migration of Epidural Leads During Spinal Cord Stimulator Trials.

Objective: Lead migration is the most commonly reported complication of spinal cord stimulation (SCS) procedures and lead migration during trials of SCS can compromise both the success of the trial as well as the efficacy of subsequent implantation. Our objective was to examine the incidence and degree of intra-trial SCS lead migration and our hypothesis was that there would be a higher rate of significant radiographic lead migration during SCS trial than what has been previously published for permanently implanted leads. Materials and Methods: We retrospectively assessed the radiographic location of SCS leads on final fluoroscopic imaging at the time of trial lead placement compared to thoracic radiographs obtained at the end of the SCS trial to quantify the rate and degree of migration during the trial. Thirty-five patients were included in the study with 69 leads assessed for radiographic degree of migration. The majority of patients were trialed utilizing paresthesia-free systems (57%) and the most common indication was for post-laminectomy syndrome (57%). Results: In our series of 35 patients, on average there was 28 mm or 1.17 vertebral body levels of migration. No statistically significant correlation was found between fixation technique, physician experience, device manufacturer, patient age, sex, height or BMI and likelihood of significant radiographic migration. Conclusion: In our study, lead migration appears to be a more significant occurrence during SCS trial than previously reported. Intra-trial migration presents a significant challenge for clinical care and examination of risk factors for migration and techniques for prevention are warranted.

Quantitative Assessment of the Incidence of Persistent Orthostatic Hemodynamic Changes After Celiac Plexus Neurolysis: A Prospective Case Series.

Celiac plexus neurolysis has been associated with orthostatic hypotension but has not been quantified prospectively or evaluated for persistence after the immediate postprocedural period. Our objective was to quantify persistent hemodynamic changes induced by celiac plexus neurolysis. In this case series of 16 patients with cancer, 8 (50%) had orthostatic hypotension alone, 3 (18.75%) developed an exaggerated postural heart rate increase (>30 beats per min), and 1 (6.25%) had both orthostatic hypotension and an increased heart rate. While the analgesic benefit of celiac plexus neurolysis is clear, the observed hemodynamic changes may be poorly tolerated in some individuals.

An exploratory study Evaluating the impact of opioid and non-opioid pain medications on serum/plasma free testosterone and free estradiol concentrations.

Chronic use of opioid medications has been reported to cause altered sexual function. It is not known if non-opioid pain medications have similar effects. Assessment of this effect through the measurement of concentrations of free hormones is limited. Positivity of opioid medications (hydrocodone, oxycodone, morphine, methadone, tramadol and fentanyl) and non-opioid pain medications (gabapentin or pregabalin) in human serum and plasma samples from adult men and women were evaluated for association with concentrations of free testosterone (fTe) and free estradiol (fE2) measured using equilibrium dialysis-liquid chromatography-tandem mass spectrometry methods. Lower concentrations of fTe (p = 0.0253) were observed in samples positive for the hydrocodone, oxycodone and morphine group compared to age matched controls. The presence of methadone, tramadol, fentanyl and pregabalin had no effect on fTe. When compared with age-matched controls, women between 48-55 years of age showed reduced fE2 concentrations in samples positive for tramadol, fentanyl and gabapentin (p = 0.0243, 0.0045 and 0.0050, respectively). Particular opioid medications such as methadone, tramadol or fentanyl and non-opioid medications such as pregabalin or gabapentin may offer advantages over opioid medications for treating pain with fewer endocrinologic side effects. Measurement of free hormones in pain medication users could be important in determining their association with sexual function. Copyright © 2017 John Wiley & Sons, Ltd.

Interventional Treatments of Cancer Pain.

Pain is a significant burden for patients with cancer and is particularly prevalent among those with advanced cancer. Appropriate interventional cancer pain therapies complement conventional pain management by reducing the need for systemic opioid therapy and its associated toxicity; however, these therapies are often underutilized. This article reviews techniques, indications, complications, and outcomes of the most common interventional approaches for the management of cancer-related pain. These approaches include intrathecal drug delivery, vertebral augmentation, neurolysis of the celiac, superior hypogastric and ganglion impar plexus', image-guided tumor ablation, and other less commonly performed but potentially beneficial interventions.