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New approach to relieving pain and distress during high-dose-rate intracavitary irradiation for cervical cancer
Brachytherapy 14 (2015) 642e647
New approach to relieving pain and distress during high-dose-rate intracavitary irradiation for cervical cancer Miho Watanabe Nemoto1,2,*, Natsuko Nozaki-Taguchi3, Gentaro Togasaki2, Aki Kanazawa2, Marie Kurokawa2, Rintarou Harada2, Hiroki Kobayashi1,2, Shiroh Isono3, Takashi Uno1,2 1
Department of Radiology and Radiation Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan 2 Department of Radiology, Chiba University Hospital, Chiba, Japan 3 Department of Anesthesiology, Chiba University Hospital, Chiba, Japan
ABSTRACT
BACKGROUND AND PURPOSE: To relieve the pain and distress experienced by women who undergo high-dose-rate intracavitary radiotherapy (HDR-ICRT) for cervical cancer and to improve the current status of gynecologic brachytherapy in Japan, a new intravenous anesthetic protocol involving the administration of a combination of propofol and ketamine was developed. The primary aim of this study is to investigate the efficacy and safety of this new anesthetic protocol during HDR-ICRT for cervical cancer. METHODS AND MATERIALS: All the patients who were diagnosed with cervical cancer between December 2008 and February 2011, treated with three-channel brachytherapy and subjected to the new sedation protocol, were evaluated. A visual analog scale (VAS) was used to assess the pain during brachytherapy, and we collected VAS score at the next HDR-ICRT. Toxicities were graded using the Common Toxicity Criteria, version 3. RESULTS: A total of 178 sessions of HDR-ICRT were delivered to 57 patients. The patients’ median VAS pain score was 0 (range, 0e10). The most frequent side effect was Grade 1e2 nausea, which occurred in 33 sessions (34%). However, 13 of 14 patients received concurrent cisplatin chemotherapy. None of the patients experienced Grade 3 or 4 adverse events. CONCLUSIONS: We have demonstrated that our new intravenous anesthetic protocol produces appropriate effects and can be performed by radiation oncologists who were required to finish training in basic life support and the cooperative system of emergency according to in-house guideline. Ó 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Anesthesia; Intravenous; Cervical cancer; High-dose-rate intracavitary irradiation
Introduction Intracavitary radiotherapy (ICRT) plays an important role in radiotherapy for uterine cervical cancer. ICRT exhibits a markedly enhanced curative potential in cases of carcinoma of the cervix (1). However, for many women, the diagnosis and treatment of cervical cancer are physically and emotionally debilitating. Anxiety and discomfort are widely recognized side Received 19 November 2014; received in revised form 29 March 2015; accepted 16 April 2015. * Corresponding author. Department of Radiology and Radiation Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677 Japan. Tel.: þ81-43-226-2100; fax: þ81-43226-2101. E-mail address: [email protected] (M. Watanabe Nemoto).
effects of gynecologic procedures, including simple gynecologic examinations, diagnostic tests, and treatment procedures (2). In the absence of appropriate sedation and analgesia, most patients will experience discomfort and strong pain during intracavitary brachytherapy. This can lead to problems during the procedure, such as inappropriate packing or applicator placement, which can result in an inadequate dose distribution, adverse effects on local control, and/or an increased risk of morbidities. Appropriate applicator placement must be achieved to obtain good local control, survival, and morbidity rates (3), but accurate insertion is difficult in patients who are experiencing discomfort. Thus, methods that facilitate the quick, adequate, and safe administration of anesthetic drugs, and hence, reduce the pain experienced by cervical cancer patients during brachytherapy are required. The American Brachytherapy Society recommends that conscious
1538-4721/$ - see front matter Ó 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2015.04.009
M. Watanabe Nemoto et al. / Brachytherapy 14 (2015) 642e647
sedation should be used for high-dose-rate (HDR) ICRT insertions whenever possible (4). Previous pattern of care studies unexpectedly found that in Japan many patients undergo HDR-ICRT applicator insertion without receiving any analgesic drugs (5, 6), and even when such drugs are administered, their effects are often inadequate. In the United States and Europe, most patients who undergo pelvic brachytherapy are placed under general anesthesia by anesthesiologists; thus, the co-operation of anesthesiologists is vital for such procedures (7). However, this might be hard to achieve in many Japanese facilities because of manpower shortages. Therefore, in Japan, radiation oncologists are usually required to perform certain anesthetic procedures by themselves. Under these circumstances, to relieve the pain and distress experienced by women who undergo HDR-ICRT for cervical cancer and to improve the present status of gynecologic brachytherapy in Japan, a new intravenous anesthetic protocol involving the combined use of propofol and ketamine was developed in collaboration with a boardcertificated anesthesiologist (N.N-T.). Propofol is a shortacting intravenous sedative, and ketamine is a dissociative anesthetic that has strong analgesic effects and exhibits rapid onset and recovery and a wide margin of safety. Ketamine and propofol have been successfully used in a variety of settings, including sedation for cosmetic and anorectal surgical procedures performed in office suites, pediatric hematology/oncology units, and emergency departments (7e10). Combination of propofol and ketamine was based on the opposing hemodynamic and respiratory effects of the two drugs (10), which were considered to enhance the utility of the combination; that is, to increase its safety and efficacy and allow lower doses of each drug to be used (which would reduce the risk of side effects). However, there have only been a few studies about sedation using ketamine and propofol during HDR-ICRT (2, 11, 12). The primary aim of this study is to investigate the efficacy and safety of this new intravenous anesthetic protocol during HDR intracavitary brachytherapy for cervical cancer.
Methods and materials All the patients who were diagnosed with cervical cancer between December 2008 and February 2011, treated with three-channel brachytherapy using uterine tandem and ovoid applicators and subjected to the new sedation protocol, were evaluated. Radiation was delivered using a microSelectron device (Nucletron BV, Veenendal, The Netherlands) and an iridium-192 source that demonstrated nominal activity of 10 Ci. HDR brachytherapy dosimetric planning was performed in all patients using a semiorthogonal system with a simulation box. The PLATO system was used for computerized planning (Nucletron BV, Veenendal, The Netherlands). This protocol needed the drugs (propofol and ketamine), oxygen, patient monitor
643
(electrocardiography, heart rate, blood pressure, pulse oxymetry, and respiratory rate), and patient-controlled analgesia pump (or syringe driver). Radiation oncologists and experienced nurses trained under anesthesiologists’ supervision for the first 5 patients. In our institution, radiation oncologists and nurses were required to finish training in basic life support and the cooperative system of emergency. During procedures, the trained nurses monitored the patients’ vital sign including respiratory and circulation systems. In the brachytherapy room, we prepared an emergency cart, including laryngoscope, bag valve mask, endotracheal tubes, suction machine, and resuscitation drugs. The patients’ vital signs and oxygen saturation were continuously monitored throughout the procedure by the radiation oncologists and trained nurses. Supplemental oxygen was delivered at a rate of 2 L/min via a nasal cannula to all patients during the procedure. First, we administered propofol intravenously using an i-Fusor patient-controlled analgesia pump (JMS, Tokyo, Japan) at an initial dose of 10 mg. This was then followed by a maintenance infusion, which was delivered at a dose rate of 2 mg/kg/min. About 20-mg demand boluses were limited to four per hour and subject to a 5 min lockout period. We also intravenously administered ketamine diluted in 100 mL normal saline at a dose of 1 mg/kg. When half of the ketamine had been administered, we made the patients adopt the lithotomy position. Then, when threequarters of the ketamine had been administered, we started to insert the instruments and perform the procedure. After the irradiation, a bolus of propofol was administered, and then the instruments were removed. The nurses who assisted with the procedural sedation recorded the patients’ vital signs before, during, and after the procedure. Propofol is a nonopioid and sedativeehypnotic drug. Its duration of action is approximately 6 min (9,10). Its adverse effects include hypotension and respiratory depression. However, because of propofol’s brief duration of action, such side effects generally disappear quickly and uneventfully. Propofol does not have any analgesic effects, and therefore, additional treatment with an analgesic might be necessary. Ketamine has strong analgesic effects and displays rapid onset and recovery and a wide margin of safety. Unlike general anesthetics, ketamine supports the cardiovascular system and so does not depress ventilation (10). Eastern Cooperative Oncology Group Performance Status and American Society of Anesthesiologists Physical Status Classification (Table 1) were evaluated retrospectively. Vital signs were assessed by monitoring blood pressure, heart rate, and oxygen saturation before, during, and after the brachytherapy procedure. We scored the patients’ sedation levels on the Ramsay Sedation Scale by retrospectively reviewing their nursing records (Table 2) (13). The pain experienced by the patients while they were under sedation was assessed using a questionnaire containing a visual analog scale (VAS). Toxicities were
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Table 1 ASA physical status classification system
Table 3 Patient characteristics
ASA classification Classification
Characteristics
No.
ASA I ASA II ASA III ASA IV ASA V
Total no. of patients EBRT þ HDR-ICRT HDR-ICRT alone Total no. of sessions Outpatients Age, y; median (range) FIGO stage IA IB IIA IIB III III IVA Recurrence of CIS ECOG PS, n (%) 0 1 2 3 ASA, n (%) 1 2 3 4 Weight (kg) Mean Range Height (cm) Mean Range Reproductive history Number of pregnancies Number of deliveries Nulligravida
57 56 patients 1 patient 178 22 patients, 50 sessions 59 (27e82)
Normal and healthy patient Mild systemic disturbance Moderate systemic disturbance Severe systemic disturbance that is life threatening Moribund patients who have little chance of survival with or without the operation
ASA 5 American Society of Anesthesiologists.
graded using the Common Toxicity Criteria, version 3, developed by the National Cancer Institute. Results The patients’ characteristics are presented in Table 3. A total of 178 sessions of HDR-ICRT were delivered to 57 patients. Twenty-two patients (50 sessions) were treated on an outpatient basis. The clinical stage of the patients’ disease according to the International Federation of Gynecology and Obstetrics criteria was as follows: IB, 6 patients; IIA, 12 patients; IIB, 20 patients; IIIA, 2 patients; IIIB, 15 patients; IVA, 1 patient; and recurrence of carcinoma in situ, 1 patient. Most patients had Eastern Cooperative Oncology Group Performance Status of !2 (90%) and American Society of Anesthesiologists Physical Status Classification scores of 1 or 2 (83%). One hundred seventy-eight questionnaires were sent out, and 74 responses were received. The patients’ VAS pain scores are shown in Fig. 1 and Table 4. The median VAS pain score was 0 (range, 0e10). The median VAS pain scores of the parous and nulliparous women were 0 (range, 0e7) and 7 (range, 0e10), respectively. The median VAS pain score of the nulligravida women was significantly higher than that of the parous women according to the Student’s t test ( p ! 0.05). We received the answer ‘‘satisfied’’ from 35 procedures (47%) and ‘‘very satisfied’’ from 25 procedures (34%). In 60 procedures (81%), patients were satisfied with the results of this new protocol. We also received the answer ‘‘remember very well’’ in 15 procedures (20%), ‘‘remember’’ in 34 procedures (46%), and ‘‘don’t remember at all’’ in 25 procedures (34%). The Ramsay Sedation Scale scores obtained when the patients were in the lithotomy position were used to evaluate the induction time (Table 5). Level 2e3 sedation, which was considered to be an appropriate degree of sedation, was Table 2 Ramsay sedation scale (13) Level Level Level Level Level
Response 1 2 3 4
Level 5 Level 6
Patient is anxious and agitated or restless, or both Patient is co-operative, oriented, and tranquil Patient responds to commands only Patient exhibits a brisk response to light glabellar tapping or loud auditory stimuli Patient exhibits a sluggish response to light glabellar tapping or loud auditory stimuli Patient exhibits no response
0 6 12 20 2 15 1 1 33 (55.9) 20 (34.5) 3 (5.2) 2 (3.4) 31 (54.4) 16 (28.1) 9 (15.8) 1 (1.8) 49.6 29.6e116.8 153.2 138.7e167.0 0e8 (mean, 3) 0e4 (mean, 2) 7 patients
EBRT 5 external beam radiation therapy; HDR-ICRT 5 high-doserate intracavitary radiotherapy; FIGO 5 International Federation of Gynecology and Obstetrics; CIS 5 carcinoma in situ; ECOG PS 5 Eastern Cooperative Oncology Group Performance Status; ASA 5 American Society of Anesthesiologists.
achieved in 136 sessions (76.4%). The period from the start of the infusion to the insertion of the instruments lasted about 10 min in most sessions. Table 6 lists the frequencies and degree of the side effects caused by sedation. The most frequent side effect was Grade 1e2 nausea, which occurred in 33 sessions (34%). However, 13 of 14 patients received concurrent cisplatin chemotherapy and complained of nausea and vomiting before the start of the HDR-ICRT. None of the patients experienced Grade 3 or 4 adverse events although some patients experienced mild hypertension. These side effects were temporary and self-limiting and did not require specific medical interventions. Discussion The considerable discomfort experienced by patients during HDR-ICRT for cervical cancer has various causes.
M. Watanabe Nemoto et al. / Brachytherapy 14 (2015) 642e647
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Table 5 Ramsay sedation scale scores obtained while the patients were in the lithotomy position Sedation level
No. of sessions
Level Level Level Level Level Level
2 sessions 33 sessions 103 sessions 40 sessions 0 sessions 0 sessions
1 2 3 4 5 6
The presence of applicator rods in the body of the uterus stimulates sympathetic autonomic afferents, which enter the spinal cord at the Th10eL1 level. This produces poorly localized central and lower abdominal pain (cramping) in addition to nausea and vomiting. Distention of the cervix and upper vagina stimulates parasympathetic autonomic afferents from the pelvic splanchnic nerves (S2eS4), resulting in low back pain. In addition, vaginal packing stimulates somatic afferents via the pudendal nerves (S2eS4) (7). There are a number of ways to relieve the pain and distress caused by HDR-ICRT. General anesthesia is one option. General anesthesia enables good pain control; however, it requires airway management and strict monitoring of vital signs by anesthesiologists. In Japan, general anesthesia is not feasible because of the shortage of anesthesiologists. In addition, the use of general anesthesia makes it difficult to perform ICRT on an outpatient basis. Paracervical block of the cervix is the most commonly used form of local anesthesia for minor gynecologic procedures. Cooper et al. (14) conducted a systematic review to determine the effects of the various local anesthetic techniques used for controlling pain during outpatient hysteroscopy procedures and concluded that paracervical
local anesthetic injections are a good pain control method for patients who undergo such procedures. However, there is some doubt as to whether it is appropriate to regularly administer paracervical local anesthetic injections to cancer patients. As an alternative, Chen et al. (15) investigated the efficacy and safety of lidocaine spray. Although lidocaine spray was found to be safe, its effects were inadequate; that is, the patients who underwent brachytherapy sessions for cervical cancer in which local lidocaine spray was used exhibited a mean VAS pain score of 49.1 24.1. Osmotic dilators (laminaria type) have been used for the gradual nontraumatic dilation of the cervical canal in various intrauterine procedures. Mayr et al. (16) described the use of laminaria dilators for brachytherapy in gynecologic cancer patients in which general/regional anesthesia was not used. The discomfort experienced by the patients was minimal in all cases. However, most of the patients received opioids, paracervical block, and midazolam. Only three of the 13 sessions did not involve sedation. Although it might be true that the use of laminaria dilators reduces the discomfort caused by dilating the cervix and upper vagina, discomfort can still be caused by vaginal packing. Lumbar and epidural blocks are popular in many obstetric units as they provide excellent pain control; however, there are some problems associated with the use of lumbar and epidural blocks during HDR-ICRT. Lumbar blocks are not suitable for outpatients because they can cause lower leg numbness and paralysis. In addition, headaches, low blood pressure, nausea, and vomiting can occur as complications. Moreover, radiation oncologists are unfamiliar with the procedures associated with lumbar and epidural blocks. Therefore, as mentioned previously, each method of inducing anesthesia has advantages and disadvantages.
Table 4 Visual analog scale pain scores
Table 6 Adverse effects experienced during sedation
Fig. 1. Histogram of the patients’ visual analog scale pain scores during high-dose-rate intracavitary radiotherapy.
Visual analog scale Median Range Total number of patients )
Nulliparous women
Parous women
Total
Adverse event
Grade 1
Grade 2
$Grade 3
Total
7) 0e10 4
0) 0e8 21
0 0e10 25
Hypoxia Hypertension Nausea and vomiting
0 11 (11%) 17 (18%)
7 (7%) 0 14 (14%)
0 0 0
7 (7%) 11 (11%) 33 (34%)a
p ! 0.05 according to the Student’s t test.
a Adverse events were graded according to the Common Terminology Criteria for Adverse Events (version 3).
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There are three key criteria that anesthetic techniques that are used during HDR-ICRT should meet. First, they should provide an adequate level of sedation while minimizing pain and anxiety during the procedure and cause minimal side effects when the drugs are discontinued. Second, they should be safe enough to allow procedures to be performed on an outpatient basis without any requirement for special equipment. Third, they should be easy enough for radiation oncologists to perform by themselves. We consider that a combination of propofol and ketamine meets these conditions. Our new intravenous anesthetic protocol provided adequate pain control (Table 4) and an appropriate degree of sedation (Table 5), which only took about 10 min to achieve in most sessions. Grade 1e2 adverse events, which were temporary and self-limiting and did not require any special interventions, occurred in 34% of sessions. None of the patients experienced Grade 3 or 4 adverse events (Table 6). In addition, our anesthetic protocol can be performed by radiation oncologists. As a result, it has been routinely used at our hospital since 2011. To the best of our knowledge, this is the first study to investigate practical anesthetic protocols for use during HDR-ICRT in Japan. Sedation during HDR-ICRT has been underused in Japan because of the shortage of anesthesiologists. The Japanese Patterns of Care Study found that among the examined patients who underwent brachytherapy, 199 (51%) received no sedation, 107 (28%) received nonsteroidal anti-inflammatory drugs (orally/rectally administered), 29 (7%) received conscious sedation, and only 2 patients received general/spinal anesthesia (5). On the other hand, in Western countries, few studies have directly compared the efficacy or toxicity of the various anesthetic methods that can be used for HDR brachytherapy, mainly because of the widespread use of general anesthesia. However, there were some cases in which our new protocol did not provide adequate pain control, for example, in nulliparous women. The frequency of cervical cancer among young patients has been increasing, and further research is needed to improve the pain control strategies for such patients. We should acknowledge the limitations of our study. Retrospective toxicity reporting is not ideal, and we consider that the results of retrospective reports should always be prospectively confirmed. In addition, we did not attempt to evaluate other outcomes, such as applicator position or the extent of vaginal packing, and our sedation protocol might have resulted in better positioning and/or packing. We consider that use of these drugs is useful and safe because we have taken measures to ensure the safety. We trained under anesthesiologists’ supervision for the first 5 patients and were required to finish training in basic life support and the cooperative system of emergency with
anesthesiology and critical care according to in-house guideline. Also this protocol needed experienced nurses and equipment, including patient monitor and an emergency cart. However, there is certainly the potential lifethreatening risk unless sufficient safety precautions are taken. Thus, it seems better to consider carefully whether to use these drugs depending on the resources and safety system of each facility.
Conclusion In conclusion, this is the first study to investigate the efficacy and safety of a new intravenous anesthetic protocol for use during HDR brachytherapy for cervical cancer. We have demonstrated not only that the protocol is practical but also that it provides adequate and quick pain relief in daily practice. Further research is needed to improve the pain control strategies for certain groups of patients, especially nulliparous women, and the present status of gynecologic brachytherapy in Japan.
Acknowledgment This work was supported by JSPS KAKENHI (grant number, 25861073).
References [1] Landoni F, Maneo A, Colombo A, et al. Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical cancer. Lancet 1997;350:535e540. [2] Kwekkeboom KL, Dendaas NR, Straub M, et al. Patterns of pain and distress during high-dose-rate intracavity brachytherapy for cervical cancer. J Support Oncol 2009;7:108e114. [3] Corn BW, Hanlon AL, Pajak TF, et al. Technically accurate intracavitary insertions improve pelvic control and survival among patients with locally advanced carcinoma of the uterine cervix. Gynecol Oncol 1994;53:294e300. [4] Nag S, Erickson B, Thomadsen B, et al. The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys 2000;48: 201e211. [5] Toita T, Nakamura K, Uno T, et al. Radiotherapy for uterine cervical cancer: Results of the 1995-1997 patterns of care process survey in Japan. Jpn J Clin Oncol 2005;35:139e148. [6] Toita T, Kodaira T, Shinoda A, et al. Patterns of radiotherapy practice for patients with cervical cancer (1999-2001): Patterns of care study in Japan. Int J Radiat Oncol Biol Phys 2008;70:788e794. [7] Smith MD. Analgesia for pelvic brachytherapy. Br J Anaesth 2002; 88:270e276. [8] Borker A, Ambulkar I, Gopal R, et al. Safe and efficacious use of procedural sedation and analgesia by non-anesthesiologists in a pediatric hematology-oncology unit. Indian Pediatr 2006;43: 309e314. [9] Willman EV, Andolfatto G. A prospective evaluation of ‘‘ketofol’’ (ketamine/propofol combination) for procedural sedation and analgesia in the emergency department. Ann Emerg Med 2007;49: 23e30.
M. Watanabe Nemoto et al. / Brachytherapy 14 (2015) 642e647 [10] Arora S. Combining ketamine and propofol (‘‘ketofol’’) for emergency department procedural sedation and analgesia: A review. West J Emerg Med 2008;9:20e23. [11] Lim KHC, Lu JJ, Wynne CJ, et al. A study of complications arising from different methods of anesthesia used in high-dose-rate brachytherapy for cervical cancer. Am J Clin Oncol 2004;27: 449e451. [12] Benrath J, Kozek-Langenecker S, H€upfl M, et al. Anaesthesia for brachytherapyd51/2 yr of experience in 1622 procedures. Br J Anaesth 2006;96:195e200.
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[13] Ramsay MA, Savege TM, Simpson BR, et al. Controlled sedation with alphaxalone-alphadolone. Br Med J 1974;2:656e659. [14] Cooper NAM, Khan KS, Clark TJ. Local anaesthesia for pain control during outpatient hysteroscopy: Systematic review and meta-analysis. BMJ 2010;340:c1130. [15] Chen HC, Leung SW, Wang CJ, et al. Local vaginal anesthesia during high-dose-rate intracavitary brachytherapy for cervical cancer. Int J Radiat Oncol Biol Phys 1998;42:541e544. [16] Mayr NA, Sorosky JI, Zhen W, et al. The use of laminarias for osmotic dilation of the cervix in gynecological brachytherapy applications. Int J Radiat Oncol Biol Phys 1998;42:1049e1053.
New approach to relieving pain and distress during high-dose-rate intracavitary irradiation for cervical cancer Miho Watanabe Nemoto1,2,*, Natsuko Nozaki-Taguchi3, Gentaro Togasaki2, Aki Kanazawa2, Marie Kurokawa2, Rintarou Harada2, Hiroki Kobayashi1,2, Shiroh Isono3, Takashi Uno1,2 1
Department of Radiology and Radiation Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan 2 Department of Radiology, Chiba University Hospital, Chiba, Japan 3 Department of Anesthesiology, Chiba University Hospital, Chiba, Japan
ABSTRACT
BACKGROUND AND PURPOSE: To relieve the pain and distress experienced by women who undergo high-dose-rate intracavitary radiotherapy (HDR-ICRT) for cervical cancer and to improve the current status of gynecologic brachytherapy in Japan, a new intravenous anesthetic protocol involving the administration of a combination of propofol and ketamine was developed. The primary aim of this study is to investigate the efficacy and safety of this new anesthetic protocol during HDR-ICRT for cervical cancer. METHODS AND MATERIALS: All the patients who were diagnosed with cervical cancer between December 2008 and February 2011, treated with three-channel brachytherapy and subjected to the new sedation protocol, were evaluated. A visual analog scale (VAS) was used to assess the pain during brachytherapy, and we collected VAS score at the next HDR-ICRT. Toxicities were graded using the Common Toxicity Criteria, version 3. RESULTS: A total of 178 sessions of HDR-ICRT were delivered to 57 patients. The patients’ median VAS pain score was 0 (range, 0e10). The most frequent side effect was Grade 1e2 nausea, which occurred in 33 sessions (34%). However, 13 of 14 patients received concurrent cisplatin chemotherapy. None of the patients experienced Grade 3 or 4 adverse events. CONCLUSIONS: We have demonstrated that our new intravenous anesthetic protocol produces appropriate effects and can be performed by radiation oncologists who were required to finish training in basic life support and the cooperative system of emergency according to in-house guideline. Ó 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Anesthesia; Intravenous; Cervical cancer; High-dose-rate intracavitary irradiation
Introduction Intracavitary radiotherapy (ICRT) plays an important role in radiotherapy for uterine cervical cancer. ICRT exhibits a markedly enhanced curative potential in cases of carcinoma of the cervix (1). However, for many women, the diagnosis and treatment of cervical cancer are physically and emotionally debilitating. Anxiety and discomfort are widely recognized side Received 19 November 2014; received in revised form 29 March 2015; accepted 16 April 2015. * Corresponding author. Department of Radiology and Radiation Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677 Japan. Tel.: þ81-43-226-2100; fax: þ81-43226-2101. E-mail address: [email protected] (M. Watanabe Nemoto).
effects of gynecologic procedures, including simple gynecologic examinations, diagnostic tests, and treatment procedures (2). In the absence of appropriate sedation and analgesia, most patients will experience discomfort and strong pain during intracavitary brachytherapy. This can lead to problems during the procedure, such as inappropriate packing or applicator placement, which can result in an inadequate dose distribution, adverse effects on local control, and/or an increased risk of morbidities. Appropriate applicator placement must be achieved to obtain good local control, survival, and morbidity rates (3), but accurate insertion is difficult in patients who are experiencing discomfort. Thus, methods that facilitate the quick, adequate, and safe administration of anesthetic drugs, and hence, reduce the pain experienced by cervical cancer patients during brachytherapy are required. The American Brachytherapy Society recommends that conscious
1538-4721/$ - see front matter Ó 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2015.04.009
M. Watanabe Nemoto et al. / Brachytherapy 14 (2015) 642e647
sedation should be used for high-dose-rate (HDR) ICRT insertions whenever possible (4). Previous pattern of care studies unexpectedly found that in Japan many patients undergo HDR-ICRT applicator insertion without receiving any analgesic drugs (5, 6), and even when such drugs are administered, their effects are often inadequate. In the United States and Europe, most patients who undergo pelvic brachytherapy are placed under general anesthesia by anesthesiologists; thus, the co-operation of anesthesiologists is vital for such procedures (7). However, this might be hard to achieve in many Japanese facilities because of manpower shortages. Therefore, in Japan, radiation oncologists are usually required to perform certain anesthetic procedures by themselves. Under these circumstances, to relieve the pain and distress experienced by women who undergo HDR-ICRT for cervical cancer and to improve the present status of gynecologic brachytherapy in Japan, a new intravenous anesthetic protocol involving the combined use of propofol and ketamine was developed in collaboration with a boardcertificated anesthesiologist (N.N-T.). Propofol is a shortacting intravenous sedative, and ketamine is a dissociative anesthetic that has strong analgesic effects and exhibits rapid onset and recovery and a wide margin of safety. Ketamine and propofol have been successfully used in a variety of settings, including sedation for cosmetic and anorectal surgical procedures performed in office suites, pediatric hematology/oncology units, and emergency departments (7e10). Combination of propofol and ketamine was based on the opposing hemodynamic and respiratory effects of the two drugs (10), which were considered to enhance the utility of the combination; that is, to increase its safety and efficacy and allow lower doses of each drug to be used (which would reduce the risk of side effects). However, there have only been a few studies about sedation using ketamine and propofol during HDR-ICRT (2, 11, 12). The primary aim of this study is to investigate the efficacy and safety of this new intravenous anesthetic protocol during HDR intracavitary brachytherapy for cervical cancer.
Methods and materials All the patients who were diagnosed with cervical cancer between December 2008 and February 2011, treated with three-channel brachytherapy using uterine tandem and ovoid applicators and subjected to the new sedation protocol, were evaluated. Radiation was delivered using a microSelectron device (Nucletron BV, Veenendal, The Netherlands) and an iridium-192 source that demonstrated nominal activity of 10 Ci. HDR brachytherapy dosimetric planning was performed in all patients using a semiorthogonal system with a simulation box. The PLATO system was used for computerized planning (Nucletron BV, Veenendal, The Netherlands). This protocol needed the drugs (propofol and ketamine), oxygen, patient monitor
643
(electrocardiography, heart rate, blood pressure, pulse oxymetry, and respiratory rate), and patient-controlled analgesia pump (or syringe driver). Radiation oncologists and experienced nurses trained under anesthesiologists’ supervision for the first 5 patients. In our institution, radiation oncologists and nurses were required to finish training in basic life support and the cooperative system of emergency. During procedures, the trained nurses monitored the patients’ vital sign including respiratory and circulation systems. In the brachytherapy room, we prepared an emergency cart, including laryngoscope, bag valve mask, endotracheal tubes, suction machine, and resuscitation drugs. The patients’ vital signs and oxygen saturation were continuously monitored throughout the procedure by the radiation oncologists and trained nurses. Supplemental oxygen was delivered at a rate of 2 L/min via a nasal cannula to all patients during the procedure. First, we administered propofol intravenously using an i-Fusor patient-controlled analgesia pump (JMS, Tokyo, Japan) at an initial dose of 10 mg. This was then followed by a maintenance infusion, which was delivered at a dose rate of 2 mg/kg/min. About 20-mg demand boluses were limited to four per hour and subject to a 5 min lockout period. We also intravenously administered ketamine diluted in 100 mL normal saline at a dose of 1 mg/kg. When half of the ketamine had been administered, we made the patients adopt the lithotomy position. Then, when threequarters of the ketamine had been administered, we started to insert the instruments and perform the procedure. After the irradiation, a bolus of propofol was administered, and then the instruments were removed. The nurses who assisted with the procedural sedation recorded the patients’ vital signs before, during, and after the procedure. Propofol is a nonopioid and sedativeehypnotic drug. Its duration of action is approximately 6 min (9,10). Its adverse effects include hypotension and respiratory depression. However, because of propofol’s brief duration of action, such side effects generally disappear quickly and uneventfully. Propofol does not have any analgesic effects, and therefore, additional treatment with an analgesic might be necessary. Ketamine has strong analgesic effects and displays rapid onset and recovery and a wide margin of safety. Unlike general anesthetics, ketamine supports the cardiovascular system and so does not depress ventilation (10). Eastern Cooperative Oncology Group Performance Status and American Society of Anesthesiologists Physical Status Classification (Table 1) were evaluated retrospectively. Vital signs were assessed by monitoring blood pressure, heart rate, and oxygen saturation before, during, and after the brachytherapy procedure. We scored the patients’ sedation levels on the Ramsay Sedation Scale by retrospectively reviewing their nursing records (Table 2) (13). The pain experienced by the patients while they were under sedation was assessed using a questionnaire containing a visual analog scale (VAS). Toxicities were
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Table 1 ASA physical status classification system
Table 3 Patient characteristics
ASA classification Classification
Characteristics
No.
ASA I ASA II ASA III ASA IV ASA V
Total no. of patients EBRT þ HDR-ICRT HDR-ICRT alone Total no. of sessions Outpatients Age, y; median (range) FIGO stage IA IB IIA IIB III III IVA Recurrence of CIS ECOG PS, n (%) 0 1 2 3 ASA, n (%) 1 2 3 4 Weight (kg) Mean Range Height (cm) Mean Range Reproductive history Number of pregnancies Number of deliveries Nulligravida
57 56 patients 1 patient 178 22 patients, 50 sessions 59 (27e82)
Normal and healthy patient Mild systemic disturbance Moderate systemic disturbance Severe systemic disturbance that is life threatening Moribund patients who have little chance of survival with or without the operation
ASA 5 American Society of Anesthesiologists.
graded using the Common Toxicity Criteria, version 3, developed by the National Cancer Institute. Results The patients’ characteristics are presented in Table 3. A total of 178 sessions of HDR-ICRT were delivered to 57 patients. Twenty-two patients (50 sessions) were treated on an outpatient basis. The clinical stage of the patients’ disease according to the International Federation of Gynecology and Obstetrics criteria was as follows: IB, 6 patients; IIA, 12 patients; IIB, 20 patients; IIIA, 2 patients; IIIB, 15 patients; IVA, 1 patient; and recurrence of carcinoma in situ, 1 patient. Most patients had Eastern Cooperative Oncology Group Performance Status of !2 (90%) and American Society of Anesthesiologists Physical Status Classification scores of 1 or 2 (83%). One hundred seventy-eight questionnaires were sent out, and 74 responses were received. The patients’ VAS pain scores are shown in Fig. 1 and Table 4. The median VAS pain score was 0 (range, 0e10). The median VAS pain scores of the parous and nulliparous women were 0 (range, 0e7) and 7 (range, 0e10), respectively. The median VAS pain score of the nulligravida women was significantly higher than that of the parous women according to the Student’s t test ( p ! 0.05). We received the answer ‘‘satisfied’’ from 35 procedures (47%) and ‘‘very satisfied’’ from 25 procedures (34%). In 60 procedures (81%), patients were satisfied with the results of this new protocol. We also received the answer ‘‘remember very well’’ in 15 procedures (20%), ‘‘remember’’ in 34 procedures (46%), and ‘‘don’t remember at all’’ in 25 procedures (34%). The Ramsay Sedation Scale scores obtained when the patients were in the lithotomy position were used to evaluate the induction time (Table 5). Level 2e3 sedation, which was considered to be an appropriate degree of sedation, was Table 2 Ramsay sedation scale (13) Level Level Level Level Level
Response 1 2 3 4
Level 5 Level 6
Patient is anxious and agitated or restless, or both Patient is co-operative, oriented, and tranquil Patient responds to commands only Patient exhibits a brisk response to light glabellar tapping or loud auditory stimuli Patient exhibits a sluggish response to light glabellar tapping or loud auditory stimuli Patient exhibits no response
0 6 12 20 2 15 1 1 33 (55.9) 20 (34.5) 3 (5.2) 2 (3.4) 31 (54.4) 16 (28.1) 9 (15.8) 1 (1.8) 49.6 29.6e116.8 153.2 138.7e167.0 0e8 (mean, 3) 0e4 (mean, 2) 7 patients
EBRT 5 external beam radiation therapy; HDR-ICRT 5 high-doserate intracavitary radiotherapy; FIGO 5 International Federation of Gynecology and Obstetrics; CIS 5 carcinoma in situ; ECOG PS 5 Eastern Cooperative Oncology Group Performance Status; ASA 5 American Society of Anesthesiologists.
achieved in 136 sessions (76.4%). The period from the start of the infusion to the insertion of the instruments lasted about 10 min in most sessions. Table 6 lists the frequencies and degree of the side effects caused by sedation. The most frequent side effect was Grade 1e2 nausea, which occurred in 33 sessions (34%). However, 13 of 14 patients received concurrent cisplatin chemotherapy and complained of nausea and vomiting before the start of the HDR-ICRT. None of the patients experienced Grade 3 or 4 adverse events although some patients experienced mild hypertension. These side effects were temporary and self-limiting and did not require specific medical interventions. Discussion The considerable discomfort experienced by patients during HDR-ICRT for cervical cancer has various causes.
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Table 5 Ramsay sedation scale scores obtained while the patients were in the lithotomy position Sedation level
No. of sessions
Level Level Level Level Level Level
2 sessions 33 sessions 103 sessions 40 sessions 0 sessions 0 sessions
1 2 3 4 5 6
The presence of applicator rods in the body of the uterus stimulates sympathetic autonomic afferents, which enter the spinal cord at the Th10eL1 level. This produces poorly localized central and lower abdominal pain (cramping) in addition to nausea and vomiting. Distention of the cervix and upper vagina stimulates parasympathetic autonomic afferents from the pelvic splanchnic nerves (S2eS4), resulting in low back pain. In addition, vaginal packing stimulates somatic afferents via the pudendal nerves (S2eS4) (7). There are a number of ways to relieve the pain and distress caused by HDR-ICRT. General anesthesia is one option. General anesthesia enables good pain control; however, it requires airway management and strict monitoring of vital signs by anesthesiologists. In Japan, general anesthesia is not feasible because of the shortage of anesthesiologists. In addition, the use of general anesthesia makes it difficult to perform ICRT on an outpatient basis. Paracervical block of the cervix is the most commonly used form of local anesthesia for minor gynecologic procedures. Cooper et al. (14) conducted a systematic review to determine the effects of the various local anesthetic techniques used for controlling pain during outpatient hysteroscopy procedures and concluded that paracervical
local anesthetic injections are a good pain control method for patients who undergo such procedures. However, there is some doubt as to whether it is appropriate to regularly administer paracervical local anesthetic injections to cancer patients. As an alternative, Chen et al. (15) investigated the efficacy and safety of lidocaine spray. Although lidocaine spray was found to be safe, its effects were inadequate; that is, the patients who underwent brachytherapy sessions for cervical cancer in which local lidocaine spray was used exhibited a mean VAS pain score of 49.1 24.1. Osmotic dilators (laminaria type) have been used for the gradual nontraumatic dilation of the cervical canal in various intrauterine procedures. Mayr et al. (16) described the use of laminaria dilators for brachytherapy in gynecologic cancer patients in which general/regional anesthesia was not used. The discomfort experienced by the patients was minimal in all cases. However, most of the patients received opioids, paracervical block, and midazolam. Only three of the 13 sessions did not involve sedation. Although it might be true that the use of laminaria dilators reduces the discomfort caused by dilating the cervix and upper vagina, discomfort can still be caused by vaginal packing. Lumbar and epidural blocks are popular in many obstetric units as they provide excellent pain control; however, there are some problems associated with the use of lumbar and epidural blocks during HDR-ICRT. Lumbar blocks are not suitable for outpatients because they can cause lower leg numbness and paralysis. In addition, headaches, low blood pressure, nausea, and vomiting can occur as complications. Moreover, radiation oncologists are unfamiliar with the procedures associated with lumbar and epidural blocks. Therefore, as mentioned previously, each method of inducing anesthesia has advantages and disadvantages.
Table 4 Visual analog scale pain scores
Table 6 Adverse effects experienced during sedation
Fig. 1. Histogram of the patients’ visual analog scale pain scores during high-dose-rate intracavitary radiotherapy.
Visual analog scale Median Range Total number of patients )
Nulliparous women
Parous women
Total
Adverse event
Grade 1
Grade 2
$Grade 3
Total
7) 0e10 4
0) 0e8 21
0 0e10 25
Hypoxia Hypertension Nausea and vomiting
0 11 (11%) 17 (18%)
7 (7%) 0 14 (14%)
0 0 0
7 (7%) 11 (11%) 33 (34%)a
p ! 0.05 according to the Student’s t test.
a Adverse events were graded according to the Common Terminology Criteria for Adverse Events (version 3).
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There are three key criteria that anesthetic techniques that are used during HDR-ICRT should meet. First, they should provide an adequate level of sedation while minimizing pain and anxiety during the procedure and cause minimal side effects when the drugs are discontinued. Second, they should be safe enough to allow procedures to be performed on an outpatient basis without any requirement for special equipment. Third, they should be easy enough for radiation oncologists to perform by themselves. We consider that a combination of propofol and ketamine meets these conditions. Our new intravenous anesthetic protocol provided adequate pain control (Table 4) and an appropriate degree of sedation (Table 5), which only took about 10 min to achieve in most sessions. Grade 1e2 adverse events, which were temporary and self-limiting and did not require any special interventions, occurred in 34% of sessions. None of the patients experienced Grade 3 or 4 adverse events (Table 6). In addition, our anesthetic protocol can be performed by radiation oncologists. As a result, it has been routinely used at our hospital since 2011. To the best of our knowledge, this is the first study to investigate practical anesthetic protocols for use during HDR-ICRT in Japan. Sedation during HDR-ICRT has been underused in Japan because of the shortage of anesthesiologists. The Japanese Patterns of Care Study found that among the examined patients who underwent brachytherapy, 199 (51%) received no sedation, 107 (28%) received nonsteroidal anti-inflammatory drugs (orally/rectally administered), 29 (7%) received conscious sedation, and only 2 patients received general/spinal anesthesia (5). On the other hand, in Western countries, few studies have directly compared the efficacy or toxicity of the various anesthetic methods that can be used for HDR brachytherapy, mainly because of the widespread use of general anesthesia. However, there were some cases in which our new protocol did not provide adequate pain control, for example, in nulliparous women. The frequency of cervical cancer among young patients has been increasing, and further research is needed to improve the pain control strategies for such patients. We should acknowledge the limitations of our study. Retrospective toxicity reporting is not ideal, and we consider that the results of retrospective reports should always be prospectively confirmed. In addition, we did not attempt to evaluate other outcomes, such as applicator position or the extent of vaginal packing, and our sedation protocol might have resulted in better positioning and/or packing. We consider that use of these drugs is useful and safe because we have taken measures to ensure the safety. We trained under anesthesiologists’ supervision for the first 5 patients and were required to finish training in basic life support and the cooperative system of emergency with
anesthesiology and critical care according to in-house guideline. Also this protocol needed experienced nurses and equipment, including patient monitor and an emergency cart. However, there is certainly the potential lifethreatening risk unless sufficient safety precautions are taken. Thus, it seems better to consider carefully whether to use these drugs depending on the resources and safety system of each facility.
Conclusion In conclusion, this is the first study to investigate the efficacy and safety of a new intravenous anesthetic protocol for use during HDR brachytherapy for cervical cancer. We have demonstrated not only that the protocol is practical but also that it provides adequate and quick pain relief in daily practice. Further research is needed to improve the pain control strategies for certain groups of patients, especially nulliparous women, and the present status of gynecologic brachytherapy in Japan.
Acknowledgment This work was supported by JSPS KAKENHI (grant number, 25861073).
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