Efficacy and Safety of Transdermal Fentanyl for the Treatment of Oral Mucositis Pain Caused by Chemoradiotherapy in Patients with Esophageal Squamous Cell Carcinoma

Support Care Cancer DOI 10.1007/s00520-014-2419-5

ORIGINAL ARTICLE

Efficacy and safety of transdermal fentanyl for the treatment of oral mucositis pain caused by chemoradiotherapy in patients with esophageal squamous cell carcinoma

Shao-Zhi Xing & Ying Zhang

Received: 8 February 2014 /Accepted: 25 August 2014 # Springer-Verlag Berlin Heidelberg 2014

Abstract Conclusion Transdermal fentanyl is an effective, convenient, Purpose Oral mucositis is one of the most painful side effects and well-tolerated treatment for mucositis pain caused by found in esophageal squamous cell carcinoma (ESCC) pa- chemoradiotherapy, which can improve ESCC patients’ qual- tients treated with chemoradiotherapy. The transdermal route ity of life. of administration is worthy of investigation for patients who suffer from dysphagia due to severe oral mucositis. In this Keywords Esophageal squamous cell carcinoma . phase 2 study, we investigated the efficacy and safety of Transdermal fentanyl . Chemoradiotherapy . Oral mucositis transdermal fentanyl (TDF) for mucositis pain caused by chemoradiotherapy in ESCC patients. Methods Forty-six ESCC patients who experienced moderate to severe oral mucosal pain during chemoradiotherapy re- Introduction ceived TDF for pain relief. The assessment of pain was made according to the Numeric Rating Scale (NRS). Efficacy and Esophageal cancer is a leading worldwide cause of cancer safety of TDF was collected and conducted in an open-label mortality and accounts for the sixth most common cause of fashion. The analgesic effect, quality of life, and side effects cancer-related death [1]. Concurrent chemoradiotherapy has were evaluated after the administration of transdermal fenta- already been an accepted standard treatment for patients with nyl using the paired sample Wilcoxon signed rank test. locally advanced esophageal squamous cell carcinoma Results The mucositis-induced pain disappeared in 31 (ESCC) [2–6]. However, irradiation and drugs lack specificity (67.4 %) patients during the treatment with transdermal fen- for cancer cells and thus have toxic effects on rapidly dividing tanyl with the median time of onset at day 6.6 (range 3–14). normal cells as well. Therefore, normal cells can also be The median Numeric Rating Scale (NRS) score was reduced damaged by chemoradiotherapy, which induces side effects from 6 (range 3–9) before treatment to 4.5 (range 2–9), 3 that include vomiting, diarrhea, esophagitis, renal dysfunc- (range 2–8), 2.5 (range 1–8), 2 (range 0–6),and0(range0– tion, pneumonia, and oral mucositis [7]. 4) on days 3, 6, 9, 11, and 15, respectively, after treatment Oral mucositis (OM) is one of the most painful side effects (P<0.001). The patients’ quality of life also improved signif- found in esophageal patients treated with chemoradiotherapy icantly (P<0.01). The side effects of treatment were mild and [8, 9]. The pain associated with mucositis not only affects the disappeared within several days. quality of life but also restricts food intake and may increase the cost of treatment. Furthermore, severe mucositis is often associated with infection of bacterial, viral, and mycotic ori- < * S. Z. Xing ( ) gins [10–12] and may result in higher mortality. Therefore, it Department of Oncology, School of Clinical Medicine, Binzhou Medical College, No.661, Yellow-River Second Street, is important to treat the pain from mucositis using topical 256603 Binzhou, China anesthetics or systemic analgesics because the relief of pain e-mail: [email protected] improves the patients’ quality of life and promotes food intake after chemoradiotherapy, which indirectly lowers the morbid- Y. Zh an g Department of Nutrition, School of Clinical Medicine, Binzhou ity of oral infection and shortens the duration of hospitaliza- Medical College, Binzhou, China tion [12]. Support Care Cancer

Systemic analgesics, including opioids, are clinically used University, PR China, from October 2010 to December forpainmanagementinmostpatientswithsevereOM.How- 2012. It was designed to collect information on efficacy and ever, these agents have significant side effects and efficacy can safety in a clinical setting and was conducted in an open-label vary by medication, dose, and route of administration. Patient- fashion. The baseline assessment of pain was made according controlled analgesia (PCA) with systemic morphine is the to the Numeric Rating Scale (NRS), with “0” indicating “no gold standard for the treatment of severe oral mucositis [13]; pain,”“10” indicating “worst pain,”“1–3” indicating mild however, continuous venous access is inconvenient for pa- pain that did not interfere with sleep, “4–6” indicating mod- tients and a potential source of infectious complications. Fur- erate pain that interfered with sleep, and NRS scales ≥7 thermore, there is no evidence that PCA is better than contin- indicating severe pain with severe sleep interference. Consec- uous infusion method for controlling pain; however, less utive ESCC patients with painful mucositis of grade >1, opiate was used per hour, and duration of pain was shorter, according to the National Cancer Institute Common Toxicity for PCA [14]. The administration of morphine sulfate extend- Criteria (NCI CTC 3.0) [27], caused by concurrent chemora- ed release capsules via gastrostomy was reviewed in a popu- diotherapy was enrolled in this study. Written informed con- lation of H&N cancer patients. While these studies suggested sents were obtained from all the patients in accordance with effective pain relief, no guideline was possible due to insuffi- the regulations of Institutional Review Boards (IRBs). With a cient evidence [15]. However, although the use of oral opioid two-sided alpha error of 0.05 and a power of 0.90 to detect a analgesics has been reported, their effects are affected by true response probability of 30 %, 18 patients were entered in ingestion; therefore, they cannot be widely used clinically the first stage; if 3 or more patients responded, the trial entered [12, 16, 17]. the second stage and another 18 patients were recruited. The The ability of any drug to achieve consistent drug levels in upper limit of second-stage rejection was 7 responses ob- the blood and the brain could, in theory, lead to better control served out of 36 patients enrolled. of cancer pain. Since that, various different drugs with Content validity of the scale was assessed by the following morphine-like actions have been produced for treating experts: two head nurses of the department of oncology, one cancer-related pain, one of which is transdermal fentanyl. specialty nurse of the department of radiotherapy, and one Due to its rapid onset and short duration of action, fentanyl specialty-attending physician in the department of esophageal is used as a transdermal patch that delivers a steady continuous radiotherapy; all four experts above are responsible for data dose of medication [18, 19]. Fentanyl is approximately 100 collection, and one oncology nurse and two nursing instruc- times more potent in analgesic activity than morphine. Several tors with many years of teaching experience and had received studies have evaluated transdermal fentanyl for the manage- >2 years of training in psychological counseling. ment of pain due to OM secondary to standard-dose chemotherapy or high-dose chemotherapy prior to hematopoietic stem cell transplant (HSCT) [20–22]. It also relieves the need Inclusion and exclusion criteria to take medicines several times a day, as patches can often last for several days before changing [23]. Transdermal fentanyl Inclusion criteria has been recommended for the management of chronic cancer pain [24–26]; however, there have been relatively few reports ESCC patients with painful mucositis (pain score ≥4 using the evaluating the effectiveness of transdermal fentanyl for the NRS [22] or mucositis grade >1 according to the NCI CTC treatment of oral mucositis pain caused by chemoradiothera- [27]) which was caused by chemoradiotherapy were included py. The transdermal route of administration is non-invasive, so in this study. it is especially valuable for patients who suffer from dysphagia due to severe oral mucositis. Exclusion criteria In this study, we designed an open-label, prospective, single-center phase 2 study to evaluate the efficacy and safety The exclusion criteria have been previously described [20]. of transdermal fentanyl for the treatment of oral mucositis pain Patients with a history of opioid abuse, known allergy or caused by concurrent chemoradiotherapy in ESCC patients. hypersensitivity to fentanyl, or dysfunction of major organs Our study showed that transdermal fentanyl was an effective, such as hepatic insufficiency (AST, ALT >200 U), renal convenient, and well-tolerated treatment for this type of pain. failure (creatinine >2.5 mg/dl), heart or respiratory failure, and severe mental illness (defined by the American Psychiat- ric Association: schizophrenia, schizoaffective disorder, bipo- Patients and methods lar disorder, major depression, panic disorder, obsessive- compulsive disorder, and autism as assessed by a clinician) This phase 2 study was conducted in the Department of [28] were excluded from this study. Moreover, all patients Oncology, the Affiliated Hospital of Binzhou Medical were not concomitantly using other analgesics and also not Support Care Cancer receiving medications used for antidepressants, antianxiety, The analgesic efficacy was evaluated by comparing the and/or antineuroleptics which may have an influence on pain scores of NRS before and after treatment with the ratings. transdermal fentanyl patch. Pain was measured by the patients once a day (1 day before, during, and after treatment) at rest using NRS scales [30]. The scores for quality of life (e.g., appetite, mental status, sleep, Chemoradiotherapy regimens fatigue, and daily life) were determined by EORTC QLQ-C30 (questionnaire 11, 13, 18, 26, 27) [32]. The After completion of diagnostic workup, all patients received EORTC QLQ-C30 questionnaires were sent to all pa- the same therapeutic regimens. Chemotherapy with PF (cis- tients and were all recorded before the treatment with platin/5-fluorouracil) regimen and radiotherapy were started the transdermal fentanyl patch then 2, 6, and 10 days on the same day. The initial radiotherapy volume included the later. Safety assessments included evaluation of adverse primary tumor with a radial margin of 1.5 cm and a proximal events (anxiety, muscle aches, back pain, joint pain, and distal margin of 3–4 cm and enlarged lymph nodes. Two- diarrhea, tachycardia, tachypnea, fever, anorexia, nausea, dimensional or three-dimensional treatment plans using CT vomiting, irritability, shivering, stomach cramps, insom- scans were done. A total radiation dose of 60–70 Gy (1.8– nia, and weakness), vital signs (blood pressure, pulse, 2 Gy/fraction, 5 days a week) was delivered with the three- respiratory rate, and body temperature), and standard field technique. laboratory tests (complete blood count, serum biochem- Concurrent chemotherapy regimens consisted of cisplatin ical analysis, excrement, and urine analysis). Adverse (80 mg/m2 day 1) with 5-fluorouracil (3 g/m2 days 1 to 2). events were recorded during the period of treatment Two cycles of chemotherapy were done during radiotherapy at with the transdermal fentanyl patch, and the skin was 4-week intervals. examined for local reaction during treatment and after the removal of the fentanyl patch.

Study procedures and TDF administration Statistical analysis Transdermal fentanyl (Duragesic, Janssen, Johnson & John- son, USA) was administered at a rate of 25 μg/h for the Data were analyzed using SPSS (version 13.0). The paired patients with an NRS ≥4[22], including patients who were sample Wilcoxon signed rank test was used to evaluate dif- naive to opioids [29, 30]. The application site for the patch ferences before and after treatment. A P value <0.05 was (upper torso) was examined and was free of any skin irritation. considered significant. The onset of pain-relieving effect is delayed for about 8–12 h after the application of transdermal fentanyl, so intravenous (IV) or subcutaneous (SC) morphine was given to relieve the Results pain during that period. Patches were usually replaced every 72 h [31]. The dose of transdermal fentanyl was adjusted after Patient characteristics the first 24 h according to the degree of mucositis-related pain until the pain was controlled and the score was ≤3ontheNRS. The clinicopathological characteristics of the 46 ESCC pa- The dose of transdermal fentanyl was increased by 25-μg/h tients with pain from oral mucositis are summarized in Table 1. increments. Severe breakthrough pain was managed with IV The ratio of male (n=34) to female (n=12) patients was 2.8:1. or SC morphine. At the same time, all subjects with oral The median age was 56.3 (range 42–72) years. According to mucositis were routinely treated with oral hygiene (oral rinses the 6th edition of the TNM classification of the International with normal saline, etc.) and antiviral, antibacterial, or anti- Union Against Cancer (UICC, 2002), 5 patients were classi- fungal (including topical oral rinses) agents. fied into stage II, 27 cases were stage III, and 14 cases were stage IV. All patients received the same regimen of concurrent chemoradiotherapy described above. Thirty-nine patients re- Criteria for efficacy and safety ceived a total dose of 60 Gy; the other 7 cases received 62– 70 Gy. All patients did not receive any other antitumor All patients had a physical examination and routine laboratory treatments. tests before treatment was initiated. All of the patients No patient received oral or slow-release opioid analgesics underwent oral examination by the same clinician who before the treatment with transdermal fentanyl. Three patients assessed the degree of oral mucositis using the NCI CTC on (6.5 %) were given mild opioids (such as codeine). Twelve the first day of cytotoxic therapy then daily for about 3 weeks. patients (26.1 %) were given non-opioid analgesics (such as, Support Care Cancer

Table 1 Clinicopatholo- gical characteristics of 46 Characteristics Number (%) (n=46) ESCC patients Age (years)a ≤55 21 (45.7) >55 25 (54.3) Gender Male 34 (73.9) Female 12 (26.1) Location Cervical 19 (41.3) Thoracic 27 (58.7) WHO grade G1 6 (13.0) Fig. 1 Changes of median NRS score after treatment of transdermal G2 19 (41.3) fentanyl G3-4 21 (45.7) Tumor sizeb opioids nor mouth wash relieved the patients’ pain. One ≤6 cm 26 (56.5) patient (2.2 %) did not use any analgesics. No patient was >6 cm 20 (43.5) excluded from the response assessment. Tstatus T2–3 30 (65.2) The onset of oral mucositis T4 16(34.8) N status The median time of the onset of moderate oral mucositis was N0 15 (32.6) day 7 (range 3–16) after chemoradiotherapy. Among the N1 31 (67.4) patients with moderate mucositis pain, the median time of M status ESCC esophageal squa- onset was day 8 after conventional chemoradiotherapy (range mous cell carcinoma, M0 22 (47.8) 3–17). The median time of the onset of severe oral mucositis WHO World Health M1-lymc 24 (52.2) (NCI CTC grade 3–4) was day 9 (range 5–19). Among the Organization Clinical stage patients with severe mucositis pain, the median time of onset a Mean age II 5 (10.9) was day 10 after conventional chemoradiotherapy (range 5– b Mean tumor size III 15 (32.6) 20). The number of patients with grade 4 mucositis was 12 out c Distant lymph node IV 26 (56.5) of 46 (26.1 %). metastases

Response to transdermal fentanyl non-steroidal anti-inflammatory drugs and others). Thirty (65.2 %) were given mouth wash (such as 0.5 % lidocaine The duration of the study was 15 days, and the total duration or other non-analgesic mouth wash). However, neither mild of the transdermal fentanyl treatment was a median of 8.5

Table 2 Median NRS scores after treatment with fentanyl transdermal system and the non-parameter test of the median NRS scores before and after treatment

Duration of Median Non-parameter test of the median treatment NRS scores NRS scores before and after treatment (days) (range) ZPvalue

0a 6.0 (3–9) 34.5(2–9) 4.43 <0.001 63.0(2–8) 4.36 <0.001 92.5(1–8) 4.11 <0.001 11 2.0 (0–6) 3.76 <0.001 15 0.0 (0–4) 2.59 <0.001 Fig. 2 Changes of median mucositis grade after treatment of transdermal a Before treatment fentanyl Support Care Cancer

Table 3 Comparison of life quality indices pre- and post-treatment of fentanyl transdermal

Life items Pre-treatment Post-treatment (median 95 % CI) Z P value (median 95 % CI) 3 days 6 days 9 days 11 days 15 days

Appetite 4.0 (3.12–3.76) 4.0 (3.21–3.87) 3.6 (3.03–3.78) 3.1 (2.61–3.39) 2.5 (2.13–3.06) 2.0 (1.56–2.43) 3.72 <0.001 Mental status 4.0 (3.43–3.98) 3.8 (3.32–3.82) 3.2 (2.83–3.37) 2.8 (2.32–3.04) 2.3 (2.02–2.87) 2.0 (1.96–2.76) 3.89 <0.001 Sleep 4.0 (3.29–3.56) 3.5 (3.17–3.62) 3.0 (2.87–3.41) 2.8 (2.76–3.32) 2.4 (1.97–2.68) 2.0 (1.76–2.57) 4.25 <0.001 Fatigue 4.0 (3.51–3.78) 3.9 (3.39–3.71) 3.6 (3.23–3.68) 3.4 (3.03–3.52) 3.2 (2.79–3.35) 3.0 (2.31–2.85) 3.28 <0.001 Daily life 4.0 (3.29–3.66) 3.8 (3.16–3.56) 3.2 (2.89–3.47) 2.9 (2.53–3.23) 2.5 (2.16–3.07) 2.0 (1.82–2.39) 3.83 <0.001

CI confidence interval

(range 3–15) days. The total amount of transdermal fentanyl treatment (Table 3). However, oral mucositis was not released administered per person was a median of two patches (range before and after TDF treatment (Table 4). 1–9) at 25 μg/h. Subcutaneous morphine was administered only once for breakthrough pain in 18 patients (39.1 %). Side effects Seven (15.2 %) patients required an escalated dose of transdermal fentanyl at 50 μg/h. Seven patients (15.2 %) reported nausea and vomiting, six Before treatment with the transdermal fentanyl patch, patients (13.0 %) developed dizziness, five patients (10.9 %) 54.3 % (25/46) of the patients suffered from moderate muco- reported stomach discomfort, and four patients (8.7 %) report- sitis pain and 45.7 % (21/32) had severe pain. The median ed constipation. All symptoms were mild and disappeared NRS score was 6 (range 3–9). There was a significant differ- within several days after proper management. Symptoms of ence (Wilcoxon’s test, P<0.001) in the median NRS scores neither drug withdrawal nor drug dependence were observed. before and after treatment when analyzed using the non- Definition of drug withdrawal or drug dependence of fentanyl parameter test, as shown in Table 2. The median time for the was elaborated as previously described [33], including anxi- NRS scores to decrease to ≤3 was 4.2 days (range 2–15) after ety, muscle aches, back pain, joint pain, diarrhea, tachycardia, beginning treatment with transdermal fentanyl. The tachypnea, fever, tearing from eyes, rhinorrhea, sneezing fits, mucositis-induced pain disappeared in 31 (31/46, 67.4 %) chills, sweating, yawning, anorexia, nausea, vomiting, a feel- patients during the treatment with transdermal fentanyl with ing of hair standing on end, nervousness, irritability, shivering, the median time of onset at day 6.6 (range 3–14). stomach cramps, insomnia, weakness. No patient abandoned Changes in the NRS score and grade of mucositis after the drug because of fentanyl toxicity. No severe side effects treatment with the fentanyl transdermal system are presented were observed. in Figs. 1 and 2. The efficacy of transdermal fentanyl was evaluated beginning after 24 h of treatment. The NRS scores decreased rapidly to ≤2duringdays2–6 then gradually de- clined further. The median grades of mucositis were 3, 2.5, 2, Discussion 1, and 0 before treatment and at 3, 6, 9, 11, and 15 days after treatment, respectively. Oral mucositis (OM) causes spontaneous pain, odynophagia, The patients’ quality of life was improved significantly and dry mouth [34], which substantially reduce oral food because of the relief of pain after the administration of trans- intake, commonly resulting in malnutrition and weight loss. dermal fentanyl. There were significant differences Furthermore, pain from oral mucositis may have on the mor- (Wilcoxon’stest,P<0.001) between the indices of quality of tality of the individual as there are times when the limiting life, such as appetite, mental status, sleep, fatigue, and daily factor to the proper protocol for chemoradiotherapy is compro- life, before treatment and at 3, 6, 9, 11, and 15 days after mised due to this pain [35, 36]. Although chemoradiotherapy

Table 4 Comparison of oral mucositis indices pre- and post-treatment of fentanyl transdermal

Pre-treatment Post-treatment (median 95 % CI) ZPvalue (median 95 % CI) 3 days 6 days 9 days 11 days 15 days

Oral mucositis 3.4 (2.83–3.84) 3.4 (2.46–3.66) 3.5 (2.87–3.67) 3.4 (2.52–3.62) 3.6 (2.11–3.77) 3.6 (2.82–2.69) 9.13 0.892

CI confidence interval Support Care Cancer for ESCC can be beneficial, pain, eating disturbances, and the in addition to TDF. Nevertheless, our findings provide pre- resulting discontinuation of treatment caused by treatment af- liminary support for the hypothesis that transdermal fentanyl fect the patient psychologically. Thus, pain control during is efficacious and safe for the management of pain from chemoradiotherapy for esophageal carcinoma is an important mucositis of ESCC patients. aspect of treatment. In spite of diverse methods to prevent or In conclusion, despite the small number of ESCC patients reduce chemoradiotherapy-induced painful mucositis [37], with painful mucositis available and the non-blinded and non- there is no standard recommendation for its management. randomized nature of this study, our findings nonetheless In the present study, our results add to the evidence that demonstrated that transdermal fentanyl was effective in transdermal fentanyl can be effective in the management of treating pain from oral mucositis caused by chemoradiother- pain from oral mucositis, showing a reduction in patients’ pain apy. Treatment using transdermal fentanyl is convenient, well scores to ≤3 after 4.2 days of treatment. Sufficient analgesia tolerated with mild toxicity, and capable of improving pa- was achieved in most patients (84.8 %) with a dose of 25 μg/h. tients’ quality of life. Adoseof50μg/h was sufficient to control mucositis pain in the other 7 (15.2 %) patients. The patients’ quality of life was improved significantly after treatment (P<0.001). Moreover, Conflicts of interest There are no any actual or potential conflicts of topical transdermal fentanyl had an additional clinical advan- interest that exist. tage in these patients with painful mucositis who all suffered from dysphagia. Relieving the pain helped the patients to take oral nourishment promptly, improving their nutritional status References and dental hygiene. There have been relatively few reports evaluating the effi- 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) – cacy of transdermal fentanyl for the treatment of pain from Global cancer statistics. CA Cancer J Clin 61(2):69 90. doi:10.3322/ caac.20107 oral mucositis. Kim et al. [22]publishedareportontheuseof 2. D’Journo XB, Thomas PA (2014) Current management of esopha- transdermal fentanyl for the treatment of a cohort of 22 pa- geal cancer. 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