- Email: [email protected]
Opioid consumption and pain in gynecological cancer patients treated with interstitial brachytherapy
Brachytherapy
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(2017)
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Opioid consumption and pain in gynecological cancer patients treated with interstitial brachytherapy Lucas C. Mendez1, Stephen Choi2, Laura D’Alimonte1, Elizabeth Barnes1, Lisa Barbera1, Eric Leung1,* 1
Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada 2 Department of Anesthesia, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
ABSTRACT
PURPOSE: Interstitial brachytherapy (ISBT) has advantages over the intracavitary techniques in the treatment of gynecological malignancies. The insertion of catheters into tumor enables higher dose conformality and normal tissue sparing. However ISBT can be associated with pain due its invasiveness. The goal of this study is to assess pain and opioid consumption of patients implanted with a perineal ISBT applicator. METHODS AND MATERIALS: Forty-eight patients were treated with ISBT from September 2014 to April 2016. Mean age was 63. Malignancies included 18 cervical cancers, 12 vaginal, 14 recurrent endometrial, and four others. Patient characteristics and technical ISBT data were collected. Opioid consumption was quantified as oral morphine equivalent per day (OMEq/day) from postimplant until removal. Pain score levels were collected by using an 11-point scoring system. RESULTS: Twenty-three patients had a single ISBT implantation, whereas 25 had a second. Twenty-eight patients required IV-patient-controlled analgesia. Mean OMEq/day for the first insertion was 55 mg. In the second insertion, an increase of 22 mg was seen ( p 5 0.0004). Patients with IV-patient-controlled analgesia had higher opioid consumption (OMEq/day 69.8 mg vs 32.1 mg, p 5 0.001) and maximum pain scores (5.5 vs 3.4, p 5 0.007) as compared with patients on oral opioids. Higher levels of pain were detected in the first hours postimplant. Previous opioids and age were associated with increased opioid consumption. CONCLUSIONS: Pain from perineal-ISBT can be managed with oral opioids in a select group of patients. For repeat insertions, there may be an increase in opioid consumption. While age and previous opioids affected opioid requirements, other factors such as number of needles and insertion depth were not associated factors. Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Interstitial brachytherapy; Gynecologic malignancy; Opioid use; Pain
Introduction Perineal-based interstitial brachytherapy (ISBT) is an effective treatment for locally advanced gynecological malignancies and has been available for decades in specialized cancer centers. The technique delivers high-dose conformal radiation and has been shown to result in Received 24 January 2017; received in revised form 1 April 2017; accepted 26 April 2017. Conflict of interest: The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. * Corresponding author. Sunnybrook Health Science Centre, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada. Tel.: 416-4803416; fax: 416-480-6002. E-mail address: [email protected] (E. Leung).
improvements in local control for bulky cervical tumors (1) and other gynecological cancers. The advantages of ISBT together with the advent of three-dimensional (3D) image-based brachytherapy have led to a growing interest in adopting this technique to improve outcomes for patients with advanced gynecological tumors. However, perineal ISBT is perceived as an invasive procedure as it involves the placement of sharp catheter needles directly through the perineum to reach the tumor and target tissue. This perception along with concerns of pain and complications have stagnated the development of expertise in this important technique. Despite its apparent invasiveness, the impact of ISBT on pain levels in patients undergoing gynecological
1538-4721/$ - see front matter Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2017.04.246
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cancer treatment has not been well-characterized. As it is generally felt that the pain experienced is significant, standard ISBT postprocedure protocols typically include patient-controlled analgesic (PCA) pumps or epidural for pain control (2). However, it is generally unknown what dosage of opioids is required postimplant or whether oral analgesics can adequately control pain for ISBT. In addition, due to the complexity of ISBT treatment, a wide variation of practice protocols exist in regard to the number of needles inserted per implant and the number of implants or fractions prescribed each treatment. These factors may affect the experience of the ISBT patient and impact the level of pain and discomfort associated with this treatment. The goal of this study is to investigate the opioid consumption and pain levels in patients treated with interstitial brachytherapy in a single-institution study. The secondary objective is to determine associated factors to opioid use in ISBT.
Methods and material Cohort Forty-eight patients were treated with interstitial brachytherapy from August 2014 to April 2016 at a single institution and retrospectively reviewed. The majority of the ISBT treatments were given as a boost after EBRT for locally advanced cervical and vaginal cancers or as a salvage treatment after recurrence. Eight patients with metastatic disease or previous radiation to the pelvis received ISBT as a single-treatment modality. In general, cervix and bulky vaginal cancers were treated with two insertions, whereas more elderly and fragile patients received brachytherapy with a single insertion. Patients with recurrent endometrial cancer in the vagina were also treated with a single insertion. Implant procedure A preassessment MRI with a vaginal cylinder inserted is done 1e2 weeks before the procedure to aid in preplanning of needle depth and location. Our ISBT institutional standard is general anesthesia with intravenous induction agents (propofol) and maintenance with opioids and either propofol infusion or halogenated inhaled anesthetics. For patients with cervical cancers and an intact uterus, an intracavitary tandem is used along with a vaginal obturator. For patients with vaginal tumors, the vaginal obturator alone is used (no tandem). A disposal perineal template applicator (Best Medical Systems, Inc, Springfield VA) is placed over the obturator. With the template positioned against the perineum, plastic catheters (6F 24 cm) containing metal stylets are inserted through the template holes and obturator grooves, piercing the perineum and vagina respectively. The number, position, and depth of the inserted
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needles are based on intraprocedural physical evaluation and on preplanning based on the preassessment MRI. The mean procedure time is 75 minutes. After anesthesia recovery, patients are imaged with CT and/or MRI scans for treatment planning. For treatments completely delivered with one single insertion, the goal is to deliver 2e3 fractions of radiotherapy with a minimum 6 hours interval between each fraction. This requires another day of inpatient admission after the procedure day. After applicator insertion, treatment planning takes place while the patient is in bed with a urinary catheter in place. Subcutaneous low molecular weight heparin and antiembolic stockings are used for deep venous thrombosis prophylaxis during this period of immobilization. Low residue diet and diphenoxylate hydrochloride 2.5 mg plus atropine sulfate 0.025 mg tablets are prescribed to reduce gastro-intestinal motility while the ISBT applicator is in situ. Antiemetics and anxiolytics are provided, if necessary. The patient is turned to her side every 2 h to decrease risk of pressure ulcers. Routine vitals and pain scores are monitored. All ISBT were implanted in the early morning of day one and the majority of the applicators were removed in the following day (day 2) at late afternoon/early evening with a mean implant time of 32 hours. One patient had the applicator removed after day 2 (on day 5) due to a different fractionation schema. To address pain during the postoperative period, pain levels are scored by the nursing staff using the standardized verbal rating score for pain (VRS), an 11-point Likert scale (3, 4), every 10 minutes immediately after the procedure and then every 4 to 8 h until applicator is removed. Analgesia is prescribed in the form of oral opioids (commonly hydromorphone 4e6 mg every 2 hours) as needed or through intravenous patient-controlled analgesia pump (IV-PCA) in the recovery room after the procedure. Patients prescribed with IV-PCA also received low-dose controlled release opioids and non-opioid analgesics were not contraindicated (acetaminophen, NSAID, pregabalin). Pain pump prescription was determined by the oncologist and/or anesthetist during preoperative assessment or during the postoperative recovery period. No formal criteria was used to guide pain pump prescription, but this decision was commonly tailored by patient’s pain level throughout external radiation therapy, preprocedural anxiety level and baseline opioid consumption. The initial IV-PCA regimen prescribed was hydromorphone 0.2 mg intravenous with a lockout of 5 minutes. The PCA dose was increased, to a maximum of 0.4 mg, if the patient experienced inadequate analgesia (VRS O 5). Different opioids medications (hydromorphone, morphine, oxycodone, and fentanyl) were prescribed for pain control, in this cohort of patients. The implant removal was performed without general anesthesia or conscious sedation. Some patients requested prophylactic opioid medication before applicator removal.
L.C. Mendez et al. / Brachytherapy
In this case, analgesia was commonly given through IV minutes before applicator removal. The prescribed dose (often hydromorphone 0.2e0.4 mg) was taken into account in the calculated total quantity of opioids consumed by each patient. In most cases, this dose represented a small percentage of the patient’s total consumed opioid dose. Outcome definition The maximal VRS scores with the applicator in situ and the mean opioid consumption per day were the primary outcomes of this study. The maximum pain score was extracted from the notes taken by the nurses during the period the patient had the applicator in situ. This score was plotted to illustrate the pain dynamics during inpatient admission (morning, afternoon, overnight) for patients with all available time points recorded. Narcotic doses were converted to oral morphine equivalent dose per day (OMEq/day) (5) by using an opioid conversion scale system (6). OMEq/day was adjusted for patients’ weight (OMEq/day*Kg), since a large variation in weight was found among patients. Covariates Patient demographics (age, comorbidities, cancer primary, and baseline opioid use), target volume, and other treatment characteristics (number of brachytherapy insertions, needles, depth of insertion, and use of intracavitary tandem) were documented. Depth of needle insertion was calculated by measuring the distance from needle tip to the perineal skin in the sagittal and coronal views (Fig. 1).
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Analysis Demographic variables are described with appropriate measures of central tendency and dispersion. Paired Student t test was used to compare pain levels and opioid dose between first and second insertion unpaired Student t test was used in the pain and opioid dose comparison between groups with different analgesia strategies (oral opioids vs IV-PCA). Mixed statistical model was used to examine pain data throughout inpatient stay. Stepwise regression analysis was used to determine predictors of pain in this procedure. p value ! 0.05 was considered statistically significant.
Results Forty-eight patients treated with interstitial brachytherapy were evaluated in this study. The mean patient age was 63 years and 30 received radiation therapy as a definitive treatment for primary cervical or vaginal cancers. Fourteen patients were treated for recurrent tumors to the vagina (Table 1). The most prevalent comorbidity in this population was hypertension (20 patients), followed by diabetes mellitus (7 patients). Ten patients were on opioid therapy before the ISBT procedure and eight were routinely taking antidepressant/anxiolytic medications. Forty patients received EBRT followed by ISBT, whereas the other 8 patients were treated with ISBT alone. Twenty-five patients had two ISBT procedures 1 week apart. The median number of inserted catheters was 17 (SD 4). Typically six needles were inserted through the vaginal positions and the remaining through the perineal skin. The average maximum depth of catheter insertions was 12.8 cm (SD 1.9) (Table 1).
Fig. 1. Assessment of needle insertion depth.
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Table 1 Patient and treatment characteristics N
Age (mean) Disease Cervix primary Vaginal primary Vaginal recurrence Others Patient Hypertension Diabetes mellitus Previous opioid use Anti-depressant/anxiolytics Implant technique Number of needles Maximum depth of insertion # patients with two implants Implant total duration
63
Range 23e88
18 12 14 4
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Opioid consumption/pain
IV-PCA
Oral
p value
OMEq/day(mg) OMEq/Kg)day Max. Pain
69.8 1.14 5.5
32 0.58 3.4
0.001 0.008 0.007
OPEq 5 oral morphine equivalent; PCA 5 patient-controlled analgesia.
20 7 10 8 17 12.8 25 32 (hours)
SD/range 4/8e26 1.9/9e19
SD 5 standard deviation.
In the first insertion of this study cohort, 28 patients received analgesia via IV-PCA and the remaining exclusively through oral route. Patients used a mean dose of 54.6 mg (SD 43; range 0e186 mg) of OMEq per day for pain control during first insertion. When adjusted for weight, this corresponded to 0.85 mg/kg (SD 0.73) of OMEq per day (Table 2). IV-PCA patients consumed over twice the amount of opioids as compared with patients receiving opioids via oral route (32 mg vs. 69.8 mg, p 5 0.001; Table 3). The mean cohort maximal VRS score was 4.7 (SD 2.5) in the first insertion. Patients with IV-PCA reported higher scores of maximum pain (5.5) in comparison to those receiving oral analgesia (3.4). This difference reached statistical significance ( p 5 0.007). Pain score dynamics after applicator insertion was plotted in 21 patients (where all time-points were available) during the first implant (Fig. 2). It is found that the highest level of pain occurs during the first few hours (day 1 morning) after applicator implant, with a subsequent progressive decrease in maximum pain score levels throughout admission. Twenty-five patients received a second-applicator insertion a week after the first procedure. For the second implant, the technique was unchanged, and there were no Table 2 Opioid consumption and pain
OMEq/day(mg) First implant Second implant OMEq/Kg)day First implant Second implant Maximal paindfirst implant Maximal paindsecond implant
(2017)
Table 3 Comparison between IV-PCA and oral opioiddfirst insertion
Patient/treatment characteristics
Opioid consumption/pain
-
Mean
SD
54.6 76.7
43 42
0.85 1.58 4.7 5.8
0.73 1.37 2.5 2.3
OPEq 5 oral morphine equivalent; SD 5 standard deviation.
differences in the number of inserted needles between both insertions ( p 5 0.37). For both groups of patients (IV-PCA and oral opioid), there was a 46% increase in consumed opioids during the second insertion as compared with the first ( p ! 0.0004). Individually, this difference for each group was upheld (oral: 31 mge56 mg of OMEq, p 5 0.002; IV-PCA: 78 mge100 mg of OMEq, p 5 0.03). Only one patient had the analgesia strategy switched from the first to the second procedure. In this case, the patient received an oral opioid regimen in the first insertion and IV-PCA in the second. Overall, a 1.1 point increase in the average maximum pain level was found in the second-applicator insertion (Table 4). This increase in pain had a trend toward statistical significance ( p 5 0.07) but was also considered moderate and did not achieve the threshold of clinical pain significance (7) (Table 4). Patient, tumor, and treatment characteristics were evaluated as predictors of opioid consumption. Previous use of opioid and age were found to be associated with OMEq/day*Kg in the stepwise regression analysis (Table 5). Number of needles and depth of insertion were not found to predictive of opioid use. Other factors evaluated and not found to be predictive include diabetes history, tumor size, cervical cancer, the use of intrauterine tandem, and ISBT as a boost treatment.
Discussion Perineal-based ISBT is a versatile technique that improves radiation dose conformality for locally advanced gynecological malignancies. Despite its availability for decades, this technique has not gained widespread adoption. Concerns regarding procedural pain and complications may contribute to a general resistance toward developing expertise in perineal ISBT. This study indicates that the maximum amount of pain experienced is moderate and a reasonable number of patients tolerate ISBT with only oral opioids prescribed for pain control. As per institutional protocol post-ISBT insertion, patients on oral opioids were prescribed dosages as ‘‘per re nata.’’ Thus, the total amount of narcotics consumed may reflect the amount of pain experienced by patients, as seen for other procedures (8). It should be noted that patients with IV-PCA pumps typically had a standing dose of oral opioids which represented 45% of the total amount of opioids used. The remaining opioid consumed through IV-
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Fig. 2. Maximum pain level throughout in hospital stay. * Statistically higher pain score levels in comparison to the other periods analyzed.
PCA represents opioid consumed ‘‘by demand,’’ similar to that of the oral opioid group. Overall, patients with gynecological malignancy treated with ISBT used an average 55 mg of OMEq/day for the first insertion procedure. Patients treated with two interstitial implants had higher levels of maximum pain for the second insertion. Opioid consumption also followed this trend, with a dose increase of roughly 50% in the second procedure in comparison to the first. This finding may be associated with a sensitization phenomenon, where a repeated pain stimuli is amplified by the nociceptive system (9). It is also possible that there is a component of a residual inflammatory process from the first applicator insertion contributing to patient’s higher consumption of opioids in the second insertion. Interestingly, patients that were treated with a pain pump reported higher levels of pain and used more opioids than those receiving analgesia orally. This finding may be due to a selection bias during high dose rate. Pain pumps were typically recommended to patients who were expected to
have poor pain control or to those who requested a pump after the procedure. It is therefore evident that not all ISBT patients require pain pumps and careful selection and screening may help identify those who can be wellcontrolled on an oral pain regimen. The American Brachytherapy Society consensus (10) in locally advanced cervical cancers presents recommendations in anesthesia and postimplant pain management. This document suggests the use of postoperative epidural analgesia, as this technique can achieve satisfactory pain control if postprocedure catheter adjustment is required. Although epidural analgesia can provide superior analgesia, particularly in opioid tolerant patients, there may be some drawbacks in the context of this clinical situation. First, VAS scores in this patient population are moderate, and in some patients, oral opioids seems to adequately manage pain from the implant in situ, as seen in this cohort. Second, given the short duration of admission (2 days) and the requirements for deep venous thrombosis prophylaxis with low molecular weight heparin, manipulation of the epidural catheter (adjustment for inadequate analgesia, removal) must be done within the guidelines of the American Society
Table 4 Opioid dose and pain comparison between fractions Opioid consumption/pain
First insertiona
Second insertion
p value
OMEq/day (mg) OMEq/Kg)day Max. Pain
52.4 0.86 4.7
76.7 1.30 5.8
0.0004 0.02 0.07
OPEq 5 oral morphine equivalent. a Comparison within 25 patients treated with two implants.
Table 5 Predictors of OMEq/Kg)day Predictors investigated Age Previous use of opioid
Regression coefficient 0.02 0.64
OPEq 5 oral morphine equivalent.
Standard error
p value
0.006 0.25
0.007 0.01
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of Regional Anesthesia to minimize the risk of spinal hematoma, a catastrophic outcome (11). Accounting for these practice guidelines along with the ability to urinate after the regression of the epidural analgesia (urinary retention is a known minor complication) provide logistical and safety challenges that potentially could delay discharge. In short, the benefits of epidural analgesia in this clinical context, while present in terms of reduced opioid consumption over a short period of time, may be overshadowed by the risks of the procedure itself and the attendant effects on patient flow. A common belief surrounding the perineal ISBT technique is that the greater number of needles used for the implant and the deeper the needles are inserted, the more pain experienced by the patient. An exploratory analysis was performed to determine if the needles or other patient and tumor factors are predictors of opioid use. Both number and depth of needles were not found to be predictive of opioid use. Tumor size and type were also not predictive in this cohort. However, age and previous use of opioids were found to be negative and positive predictors of OMEq/day*Kg, demonstrating the consistency of this data with published evidence. Previous use of opioids is a well-known factor for hyperalgesia or opioid tolerance as suggested by Chu et al. (12) and this seems to be also consistent in ISBT patients. Age was found to have an inverse correlation with dose as older patients used less opioid. This is also consistent with postsurgical pain data that show that younger patients require higher doses of opioid in the first 24 hours immediately after the surgery (13). All patients except one had the applicator in situ for less than 2 days (approximately 32 hours). Only one patient in this cohort had the applicator in place for over 48 hours and was an inpatient for 5 days due to logistical reasons for avoiding subsequent insertions. However, the results of this study may be applicable to patients treated in institutions with longer inpatient stay protocols and with higher number of fractions per procedure, as no incremental pain was noticed with time (Fig. 2). The highest level of pain was usually recorded in the first hours after the ISBT procedure. This may represent the period of time when the anesthetic medications from the procedure become metabolized and adequate levels of postprocedure opioids have not yet been administered. Proactive pain management in this period may be essential at improving pain management protocols in this scenario. This study has limitations. First, procedure discomfort was estimated through opioid consumption and patient reported pain. No data were collected in regard to patient well-being, anxiety, and distress levels. A prospective validated questionnaire may be useful in helping answer deeper questions in regard to the ISBT experience (14). Another limitation relates to the systematic but irregular time assessment of pain monitored by nursing. Maximum pain levels reflected in this study were not at a common time-point among all patients. Nevertheless, in 21 patients, an extensive pain registration was available throughout inpatient
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stay enabling the construction of a pain score-level curve after ISBT procedure. It should also be noted that the mechanisms of pain in perineal ISBT may differ to that of intracavitary/interstitial applicators. Although both techniques may use vaginal needles, they have other important differences including perineal needles or vaginal packing, which likely cause pain through different mechanisms. Finally, although factors that determine which patients consume more opioids for ISBT were found, this does not directly assess which patients would benefit from a pain pump vs. oral medications as this study was not designed to directly assess this endpoint. However, these factors may help identify which patients require a proactive pain management strategy, and the incorporation of an IV pain pump may help in these scenarios.
Conclusion Patients treated with perineal-ISBT have a moderate level of pain that commonly reaches its highest intensity during the first few hours after ISBT implant and can be managed adequately with opioid analgesics. Not all patients require IV-PCA for adequate pain control and some can be managed appropriately with oral medications. A second ISBT implant procedure is associated with increased opioid consumption as compared with the first. The number of needles used in the procedure and the depth of needle insertions are not associated with the amount of opioid consumed by the patient. Previous opioid use and age were found to be predictors of opioid consumption, similar to data for postsurgical patients.
References [1] Mendez LC, Weiss Y, D’Souza D, et al. Three-dimensional-guided perineal-based interstitial brachytherapy in cervical cancer: a systematic review of technique, local control and toxicities. Radiother Oncol 2017;123:312e318. [2] Michalek-Sauberer A, Kozek-Langenecker S, Heinzl H, et al. Median effective local anesthetic doses of plain bupivacaine and ropivacaine for spinal anesthesia administered via a spinal catheter for brachytherapy of the lower abdomen. Reg Anesth Pain Med 2008;33:4e9. [3] McCaffery M, Beebe A. Pain: Clinical manual for nursing practice. St. Louis, MO: Mosby; 1989. [4] Breivik EK, Bjornsson GA, Skovlund E. A comparison of pain rating scales by sampling from clinical trial data. Clin J Pain 2000;16: 22e28. [5] Svendsen K, Borchgrevink P, Fredheim O, et al. Choosing the unit of measurement counts: the use of oral morphine equivalents in studies of opioid consumptions is a useful addition to defined daily doses. Palliat Med 2011;25:725e732. [6] Alberta hospice palliative care resource manual. Second edition;. Available at: http://www.palliative.org/NewPC/_pdfs/education/ACB %20Hospice%20Palliative%20Manual.pdf. [7] Todd KH, Funk JP. The minimum clinically important difference in physician-assigned visual analog pain scores. Acad Emerg Med 1996;3:142e146.
L.C. Mendez et al. / Brachytherapy [8] Bot A, Bekkers S, Arnstein P, et al. Opioid use after fracture surgery correlates with pain intensity and satisfaction with pain relief. Clin Orthop Relat Res 2014;472:2542e2549. [9] Latremoliere A, Woolf C. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 2009;10:895e 926. [10] Viswanathan A, Thomadsen BAmerican Brachytherapy Society Cervical Cancer Recommendations Committee. American Brachytherapy Society consensus guidelines for locally advanced carcinoma of the cervix. Part I: general principles. Brachytherapy 2012;11:33e46.
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[11] Horlocker T, Wedel D, Rowlingson J, et al. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and pain medicine evidence-based guidelines (Third edition). Reg Anesth Pain Med 2010;35:64e101. [12] Chu L, Clark D, Angst M. Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: a preliminary prospective study. J Pain 2006;7:43e48. [13] Macintyre P, Jarvis D. Age is the best predictor of postoperative morphine requirements. Pain 1996;64:357e364. [14] Melzack R. The McGill Pain questionnaire: major properties and scoring methods. Pain 1975;1:277e299.
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Opioid consumption and pain in gynecological cancer patients treated with interstitial brachytherapy Lucas C. Mendez1, Stephen Choi2, Laura D’Alimonte1, Elizabeth Barnes1, Lisa Barbera1, Eric Leung1,* 1
Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada 2 Department of Anesthesia, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
ABSTRACT
PURPOSE: Interstitial brachytherapy (ISBT) has advantages over the intracavitary techniques in the treatment of gynecological malignancies. The insertion of catheters into tumor enables higher dose conformality and normal tissue sparing. However ISBT can be associated with pain due its invasiveness. The goal of this study is to assess pain and opioid consumption of patients implanted with a perineal ISBT applicator. METHODS AND MATERIALS: Forty-eight patients were treated with ISBT from September 2014 to April 2016. Mean age was 63. Malignancies included 18 cervical cancers, 12 vaginal, 14 recurrent endometrial, and four others. Patient characteristics and technical ISBT data were collected. Opioid consumption was quantified as oral morphine equivalent per day (OMEq/day) from postimplant until removal. Pain score levels were collected by using an 11-point scoring system. RESULTS: Twenty-three patients had a single ISBT implantation, whereas 25 had a second. Twenty-eight patients required IV-patient-controlled analgesia. Mean OMEq/day for the first insertion was 55 mg. In the second insertion, an increase of 22 mg was seen ( p 5 0.0004). Patients with IV-patient-controlled analgesia had higher opioid consumption (OMEq/day 69.8 mg vs 32.1 mg, p 5 0.001) and maximum pain scores (5.5 vs 3.4, p 5 0.007) as compared with patients on oral opioids. Higher levels of pain were detected in the first hours postimplant. Previous opioids and age were associated with increased opioid consumption. CONCLUSIONS: Pain from perineal-ISBT can be managed with oral opioids in a select group of patients. For repeat insertions, there may be an increase in opioid consumption. While age and previous opioids affected opioid requirements, other factors such as number of needles and insertion depth were not associated factors. Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Interstitial brachytherapy; Gynecologic malignancy; Opioid use; Pain
Introduction Perineal-based interstitial brachytherapy (ISBT) is an effective treatment for locally advanced gynecological malignancies and has been available for decades in specialized cancer centers. The technique delivers high-dose conformal radiation and has been shown to result in Received 24 January 2017; received in revised form 1 April 2017; accepted 26 April 2017. Conflict of interest: The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. * Corresponding author. Sunnybrook Health Science Centre, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada. Tel.: 416-4803416; fax: 416-480-6002. E-mail address: [email protected] (E. Leung).
improvements in local control for bulky cervical tumors (1) and other gynecological cancers. The advantages of ISBT together with the advent of three-dimensional (3D) image-based brachytherapy have led to a growing interest in adopting this technique to improve outcomes for patients with advanced gynecological tumors. However, perineal ISBT is perceived as an invasive procedure as it involves the placement of sharp catheter needles directly through the perineum to reach the tumor and target tissue. This perception along with concerns of pain and complications have stagnated the development of expertise in this important technique. Despite its apparent invasiveness, the impact of ISBT on pain levels in patients undergoing gynecological
1538-4721/$ - see front matter Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2017.04.246
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cancer treatment has not been well-characterized. As it is generally felt that the pain experienced is significant, standard ISBT postprocedure protocols typically include patient-controlled analgesic (PCA) pumps or epidural for pain control (2). However, it is generally unknown what dosage of opioids is required postimplant or whether oral analgesics can adequately control pain for ISBT. In addition, due to the complexity of ISBT treatment, a wide variation of practice protocols exist in regard to the number of needles inserted per implant and the number of implants or fractions prescribed each treatment. These factors may affect the experience of the ISBT patient and impact the level of pain and discomfort associated with this treatment. The goal of this study is to investigate the opioid consumption and pain levels in patients treated with interstitial brachytherapy in a single-institution study. The secondary objective is to determine associated factors to opioid use in ISBT.
Methods and material Cohort Forty-eight patients were treated with interstitial brachytherapy from August 2014 to April 2016 at a single institution and retrospectively reviewed. The majority of the ISBT treatments were given as a boost after EBRT for locally advanced cervical and vaginal cancers or as a salvage treatment after recurrence. Eight patients with metastatic disease or previous radiation to the pelvis received ISBT as a single-treatment modality. In general, cervix and bulky vaginal cancers were treated with two insertions, whereas more elderly and fragile patients received brachytherapy with a single insertion. Patients with recurrent endometrial cancer in the vagina were also treated with a single insertion. Implant procedure A preassessment MRI with a vaginal cylinder inserted is done 1e2 weeks before the procedure to aid in preplanning of needle depth and location. Our ISBT institutional standard is general anesthesia with intravenous induction agents (propofol) and maintenance with opioids and either propofol infusion or halogenated inhaled anesthetics. For patients with cervical cancers and an intact uterus, an intracavitary tandem is used along with a vaginal obturator. For patients with vaginal tumors, the vaginal obturator alone is used (no tandem). A disposal perineal template applicator (Best Medical Systems, Inc, Springfield VA) is placed over the obturator. With the template positioned against the perineum, plastic catheters (6F 24 cm) containing metal stylets are inserted through the template holes and obturator grooves, piercing the perineum and vagina respectively. The number, position, and depth of the inserted
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needles are based on intraprocedural physical evaluation and on preplanning based on the preassessment MRI. The mean procedure time is 75 minutes. After anesthesia recovery, patients are imaged with CT and/or MRI scans for treatment planning. For treatments completely delivered with one single insertion, the goal is to deliver 2e3 fractions of radiotherapy with a minimum 6 hours interval between each fraction. This requires another day of inpatient admission after the procedure day. After applicator insertion, treatment planning takes place while the patient is in bed with a urinary catheter in place. Subcutaneous low molecular weight heparin and antiembolic stockings are used for deep venous thrombosis prophylaxis during this period of immobilization. Low residue diet and diphenoxylate hydrochloride 2.5 mg plus atropine sulfate 0.025 mg tablets are prescribed to reduce gastro-intestinal motility while the ISBT applicator is in situ. Antiemetics and anxiolytics are provided, if necessary. The patient is turned to her side every 2 h to decrease risk of pressure ulcers. Routine vitals and pain scores are monitored. All ISBT were implanted in the early morning of day one and the majority of the applicators were removed in the following day (day 2) at late afternoon/early evening with a mean implant time of 32 hours. One patient had the applicator removed after day 2 (on day 5) due to a different fractionation schema. To address pain during the postoperative period, pain levels are scored by the nursing staff using the standardized verbal rating score for pain (VRS), an 11-point Likert scale (3, 4), every 10 minutes immediately after the procedure and then every 4 to 8 h until applicator is removed. Analgesia is prescribed in the form of oral opioids (commonly hydromorphone 4e6 mg every 2 hours) as needed or through intravenous patient-controlled analgesia pump (IV-PCA) in the recovery room after the procedure. Patients prescribed with IV-PCA also received low-dose controlled release opioids and non-opioid analgesics were not contraindicated (acetaminophen, NSAID, pregabalin). Pain pump prescription was determined by the oncologist and/or anesthetist during preoperative assessment or during the postoperative recovery period. No formal criteria was used to guide pain pump prescription, but this decision was commonly tailored by patient’s pain level throughout external radiation therapy, preprocedural anxiety level and baseline opioid consumption. The initial IV-PCA regimen prescribed was hydromorphone 0.2 mg intravenous with a lockout of 5 minutes. The PCA dose was increased, to a maximum of 0.4 mg, if the patient experienced inadequate analgesia (VRS O 5). Different opioids medications (hydromorphone, morphine, oxycodone, and fentanyl) were prescribed for pain control, in this cohort of patients. The implant removal was performed without general anesthesia or conscious sedation. Some patients requested prophylactic opioid medication before applicator removal.
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In this case, analgesia was commonly given through IV minutes before applicator removal. The prescribed dose (often hydromorphone 0.2e0.4 mg) was taken into account in the calculated total quantity of opioids consumed by each patient. In most cases, this dose represented a small percentage of the patient’s total consumed opioid dose. Outcome definition The maximal VRS scores with the applicator in situ and the mean opioid consumption per day were the primary outcomes of this study. The maximum pain score was extracted from the notes taken by the nurses during the period the patient had the applicator in situ. This score was plotted to illustrate the pain dynamics during inpatient admission (morning, afternoon, overnight) for patients with all available time points recorded. Narcotic doses were converted to oral morphine equivalent dose per day (OMEq/day) (5) by using an opioid conversion scale system (6). OMEq/day was adjusted for patients’ weight (OMEq/day*Kg), since a large variation in weight was found among patients. Covariates Patient demographics (age, comorbidities, cancer primary, and baseline opioid use), target volume, and other treatment characteristics (number of brachytherapy insertions, needles, depth of insertion, and use of intracavitary tandem) were documented. Depth of needle insertion was calculated by measuring the distance from needle tip to the perineal skin in the sagittal and coronal views (Fig. 1).
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Analysis Demographic variables are described with appropriate measures of central tendency and dispersion. Paired Student t test was used to compare pain levels and opioid dose between first and second insertion unpaired Student t test was used in the pain and opioid dose comparison between groups with different analgesia strategies (oral opioids vs IV-PCA). Mixed statistical model was used to examine pain data throughout inpatient stay. Stepwise regression analysis was used to determine predictors of pain in this procedure. p value ! 0.05 was considered statistically significant.
Results Forty-eight patients treated with interstitial brachytherapy were evaluated in this study. The mean patient age was 63 years and 30 received radiation therapy as a definitive treatment for primary cervical or vaginal cancers. Fourteen patients were treated for recurrent tumors to the vagina (Table 1). The most prevalent comorbidity in this population was hypertension (20 patients), followed by diabetes mellitus (7 patients). Ten patients were on opioid therapy before the ISBT procedure and eight were routinely taking antidepressant/anxiolytic medications. Forty patients received EBRT followed by ISBT, whereas the other 8 patients were treated with ISBT alone. Twenty-five patients had two ISBT procedures 1 week apart. The median number of inserted catheters was 17 (SD 4). Typically six needles were inserted through the vaginal positions and the remaining through the perineal skin. The average maximum depth of catheter insertions was 12.8 cm (SD 1.9) (Table 1).
Fig. 1. Assessment of needle insertion depth.
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Table 1 Patient and treatment characteristics N
Age (mean) Disease Cervix primary Vaginal primary Vaginal recurrence Others Patient Hypertension Diabetes mellitus Previous opioid use Anti-depressant/anxiolytics Implant technique Number of needles Maximum depth of insertion # patients with two implants Implant total duration
63
Range 23e88
18 12 14 4
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Opioid consumption/pain
IV-PCA
Oral
p value
OMEq/day(mg) OMEq/Kg)day Max. Pain
69.8 1.14 5.5
32 0.58 3.4
0.001 0.008 0.007
OPEq 5 oral morphine equivalent; PCA 5 patient-controlled analgesia.
20 7 10 8 17 12.8 25 32 (hours)
SD/range 4/8e26 1.9/9e19
SD 5 standard deviation.
In the first insertion of this study cohort, 28 patients received analgesia via IV-PCA and the remaining exclusively through oral route. Patients used a mean dose of 54.6 mg (SD 43; range 0e186 mg) of OMEq per day for pain control during first insertion. When adjusted for weight, this corresponded to 0.85 mg/kg (SD 0.73) of OMEq per day (Table 2). IV-PCA patients consumed over twice the amount of opioids as compared with patients receiving opioids via oral route (32 mg vs. 69.8 mg, p 5 0.001; Table 3). The mean cohort maximal VRS score was 4.7 (SD 2.5) in the first insertion. Patients with IV-PCA reported higher scores of maximum pain (5.5) in comparison to those receiving oral analgesia (3.4). This difference reached statistical significance ( p 5 0.007). Pain score dynamics after applicator insertion was plotted in 21 patients (where all time-points were available) during the first implant (Fig. 2). It is found that the highest level of pain occurs during the first few hours (day 1 morning) after applicator implant, with a subsequent progressive decrease in maximum pain score levels throughout admission. Twenty-five patients received a second-applicator insertion a week after the first procedure. For the second implant, the technique was unchanged, and there were no Table 2 Opioid consumption and pain
OMEq/day(mg) First implant Second implant OMEq/Kg)day First implant Second implant Maximal paindfirst implant Maximal paindsecond implant
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Table 3 Comparison between IV-PCA and oral opioiddfirst insertion
Patient/treatment characteristics
Opioid consumption/pain
-
Mean
SD
54.6 76.7
43 42
0.85 1.58 4.7 5.8
0.73 1.37 2.5 2.3
OPEq 5 oral morphine equivalent; SD 5 standard deviation.
differences in the number of inserted needles between both insertions ( p 5 0.37). For both groups of patients (IV-PCA and oral opioid), there was a 46% increase in consumed opioids during the second insertion as compared with the first ( p ! 0.0004). Individually, this difference for each group was upheld (oral: 31 mge56 mg of OMEq, p 5 0.002; IV-PCA: 78 mge100 mg of OMEq, p 5 0.03). Only one patient had the analgesia strategy switched from the first to the second procedure. In this case, the patient received an oral opioid regimen in the first insertion and IV-PCA in the second. Overall, a 1.1 point increase in the average maximum pain level was found in the second-applicator insertion (Table 4). This increase in pain had a trend toward statistical significance ( p 5 0.07) but was also considered moderate and did not achieve the threshold of clinical pain significance (7) (Table 4). Patient, tumor, and treatment characteristics were evaluated as predictors of opioid consumption. Previous use of opioid and age were found to be associated with OMEq/day*Kg in the stepwise regression analysis (Table 5). Number of needles and depth of insertion were not found to predictive of opioid use. Other factors evaluated and not found to be predictive include diabetes history, tumor size, cervical cancer, the use of intrauterine tandem, and ISBT as a boost treatment.
Discussion Perineal-based ISBT is a versatile technique that improves radiation dose conformality for locally advanced gynecological malignancies. Despite its availability for decades, this technique has not gained widespread adoption. Concerns regarding procedural pain and complications may contribute to a general resistance toward developing expertise in perineal ISBT. This study indicates that the maximum amount of pain experienced is moderate and a reasonable number of patients tolerate ISBT with only oral opioids prescribed for pain control. As per institutional protocol post-ISBT insertion, patients on oral opioids were prescribed dosages as ‘‘per re nata.’’ Thus, the total amount of narcotics consumed may reflect the amount of pain experienced by patients, as seen for other procedures (8). It should be noted that patients with IV-PCA pumps typically had a standing dose of oral opioids which represented 45% of the total amount of opioids used. The remaining opioid consumed through IV-
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Fig. 2. Maximum pain level throughout in hospital stay. * Statistically higher pain score levels in comparison to the other periods analyzed.
PCA represents opioid consumed ‘‘by demand,’’ similar to that of the oral opioid group. Overall, patients with gynecological malignancy treated with ISBT used an average 55 mg of OMEq/day for the first insertion procedure. Patients treated with two interstitial implants had higher levels of maximum pain for the second insertion. Opioid consumption also followed this trend, with a dose increase of roughly 50% in the second procedure in comparison to the first. This finding may be associated with a sensitization phenomenon, where a repeated pain stimuli is amplified by the nociceptive system (9). It is also possible that there is a component of a residual inflammatory process from the first applicator insertion contributing to patient’s higher consumption of opioids in the second insertion. Interestingly, patients that were treated with a pain pump reported higher levels of pain and used more opioids than those receiving analgesia orally. This finding may be due to a selection bias during high dose rate. Pain pumps were typically recommended to patients who were expected to
have poor pain control or to those who requested a pump after the procedure. It is therefore evident that not all ISBT patients require pain pumps and careful selection and screening may help identify those who can be wellcontrolled on an oral pain regimen. The American Brachytherapy Society consensus (10) in locally advanced cervical cancers presents recommendations in anesthesia and postimplant pain management. This document suggests the use of postoperative epidural analgesia, as this technique can achieve satisfactory pain control if postprocedure catheter adjustment is required. Although epidural analgesia can provide superior analgesia, particularly in opioid tolerant patients, there may be some drawbacks in the context of this clinical situation. First, VAS scores in this patient population are moderate, and in some patients, oral opioids seems to adequately manage pain from the implant in situ, as seen in this cohort. Second, given the short duration of admission (2 days) and the requirements for deep venous thrombosis prophylaxis with low molecular weight heparin, manipulation of the epidural catheter (adjustment for inadequate analgesia, removal) must be done within the guidelines of the American Society
Table 4 Opioid dose and pain comparison between fractions Opioid consumption/pain
First insertiona
Second insertion
p value
OMEq/day (mg) OMEq/Kg)day Max. Pain
52.4 0.86 4.7
76.7 1.30 5.8
0.0004 0.02 0.07
OPEq 5 oral morphine equivalent. a Comparison within 25 patients treated with two implants.
Table 5 Predictors of OMEq/Kg)day Predictors investigated Age Previous use of opioid
Regression coefficient 0.02 0.64
OPEq 5 oral morphine equivalent.
Standard error
p value
0.006 0.25
0.007 0.01
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of Regional Anesthesia to minimize the risk of spinal hematoma, a catastrophic outcome (11). Accounting for these practice guidelines along with the ability to urinate after the regression of the epidural analgesia (urinary retention is a known minor complication) provide logistical and safety challenges that potentially could delay discharge. In short, the benefits of epidural analgesia in this clinical context, while present in terms of reduced opioid consumption over a short period of time, may be overshadowed by the risks of the procedure itself and the attendant effects on patient flow. A common belief surrounding the perineal ISBT technique is that the greater number of needles used for the implant and the deeper the needles are inserted, the more pain experienced by the patient. An exploratory analysis was performed to determine if the needles or other patient and tumor factors are predictors of opioid use. Both number and depth of needles were not found to be predictive of opioid use. Tumor size and type were also not predictive in this cohort. However, age and previous use of opioids were found to be negative and positive predictors of OMEq/day*Kg, demonstrating the consistency of this data with published evidence. Previous use of opioids is a well-known factor for hyperalgesia or opioid tolerance as suggested by Chu et al. (12) and this seems to be also consistent in ISBT patients. Age was found to have an inverse correlation with dose as older patients used less opioid. This is also consistent with postsurgical pain data that show that younger patients require higher doses of opioid in the first 24 hours immediately after the surgery (13). All patients except one had the applicator in situ for less than 2 days (approximately 32 hours). Only one patient in this cohort had the applicator in place for over 48 hours and was an inpatient for 5 days due to logistical reasons for avoiding subsequent insertions. However, the results of this study may be applicable to patients treated in institutions with longer inpatient stay protocols and with higher number of fractions per procedure, as no incremental pain was noticed with time (Fig. 2). The highest level of pain was usually recorded in the first hours after the ISBT procedure. This may represent the period of time when the anesthetic medications from the procedure become metabolized and adequate levels of postprocedure opioids have not yet been administered. Proactive pain management in this period may be essential at improving pain management protocols in this scenario. This study has limitations. First, procedure discomfort was estimated through opioid consumption and patient reported pain. No data were collected in regard to patient well-being, anxiety, and distress levels. A prospective validated questionnaire may be useful in helping answer deeper questions in regard to the ISBT experience (14). Another limitation relates to the systematic but irregular time assessment of pain monitored by nursing. Maximum pain levels reflected in this study were not at a common time-point among all patients. Nevertheless, in 21 patients, an extensive pain registration was available throughout inpatient
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stay enabling the construction of a pain score-level curve after ISBT procedure. It should also be noted that the mechanisms of pain in perineal ISBT may differ to that of intracavitary/interstitial applicators. Although both techniques may use vaginal needles, they have other important differences including perineal needles or vaginal packing, which likely cause pain through different mechanisms. Finally, although factors that determine which patients consume more opioids for ISBT were found, this does not directly assess which patients would benefit from a pain pump vs. oral medications as this study was not designed to directly assess this endpoint. However, these factors may help identify which patients require a proactive pain management strategy, and the incorporation of an IV pain pump may help in these scenarios.
Conclusion Patients treated with perineal-ISBT have a moderate level of pain that commonly reaches its highest intensity during the first few hours after ISBT implant and can be managed adequately with opioid analgesics. Not all patients require IV-PCA for adequate pain control and some can be managed appropriately with oral medications. A second ISBT implant procedure is associated with increased opioid consumption as compared with the first. The number of needles used in the procedure and the depth of needle insertions are not associated with the amount of opioid consumed by the patient. Previous opioid use and age were found to be predictors of opioid consumption, similar to data for postsurgical patients.
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