OnabotulinumtoxinA for Treatment of FocalCancer Pain after Surgery and/or Radiationpme_1437 1..5

Shivam Mittal, MD, Duarte G. Machado, MD, andBahman Jabbari, MD

Department of Neurology, Yale University School ofMedicine, New Haven, Connecticut, USA

Reprint requests to: Shivam Mittal, MD, Department ofNeurology, Yale University School of Medicine, Room714-A, LCI Building, 15 York Street, New Haven, CT06520, USA. Tel: 203-737-2464; Fax: 203-737-1122;E-mail: shivam.mittal@yale.edu.

Disclosures: Dr. Shivam Mittal and Dr. Duarte GMachado report no disclosures.

Dr. Bahman Jabbari receives educational andresearch grants from Allergan Inc.

Abstract

Objective. To report the relief from refractory focalpost-radiation and/or postsurgical cancer pain afterlocal treatment with onabotulinumtoxinA.

Setting and Design. We studied the effect of onabo-tulinumtoxinA in seven cancer patients who suf-fered from severe focal pain (visual analog scale >5)at the site of local surgery or radiotherapy or both.OnabotulinumtoxinA (20–100 units) was injectedinto the focal pain areas (skin or muscle or both).Five of seven patients were followed beyond 1 year(1.5–5 years) with repeat treatment.

Results. All seven patients reported a significantimprovement in pain (mean drop in visual analogscale score of 5.1). They described their responseon the patient global assessment as satisfactory(two patients) or very satisfactory (five patients). Sixof seven patients found the pain relief associatedwith significant improvement in quality of life. Onepatient developed weakness of jaw muscles afterbilateral masseter injection that was not observedduring second injection (reduced dose). Improve-ments with treatment persisted with repeat injec-tions during long-term follow-up (five patients).

Conclusion. Local treatment with onabotulinum-toxinA can significantly reduce pain and improvequality of life in cancer patients suffering from painin the area of surgery and radiation and was welltolerated in cancer patients.

Key Words. OnabotulinumtoxinA; Cancer Pain;Surgery; Radiation; Visual Analog Scale; Quality ofLife

Introduction

Approximately 25% of cancer patients who undergosurgery or radiation develop postsurgical or post-radiationpain [1]. Pain occurs in many cancer-related surgeriesincluding thoracotomy, limb amputation, breast surgery ordissection of axillary, inguinal, or cervical lymph nodes[1,2]. Treatment of such cancer-related pains is difficult,and failures are common. In one study, only 25% ofpatients with postsurgical allodynia reported significantrelief after application of lidocaine patches [3]. Moderate tosevere postsurgical pain often requires opioids, whichhave abuse potential, and some cancer pain respondspoorly to opioid therapy [4]. Pain is reported in 15–30% ofpatients after radiation therapy for head and neck cancerpartly related to development of fibrosis, scar, and keloidformation [5]. Topical treatments such as trolamine, cal-endula officinalis, and hyaluronic acid application providetransient but not sustained relief [6–8]. This defines a needfor a treatment for postsurgical/post-radiation cancer painthat is effective, has a relatively low side-effect profile, andhas low risk of drug interactions.

Cognizant of the reported analgesic effects of botulinumneurotoxin (BoNT) and its low-risk profile [9–21], wetreated seven patients with focal postsurgical/post-radiotherapy cancer pain with onabotulinumtoxinA. Thepatient’s pain intensity was evaluated by visual analogscale (VAS) and by their degree of satisfaction from treat-ment with patient global assessment (PGA). In VAS, achange of two or more degrees was considered signifi-cant. For quality of life measure, we simply asked thepatient to report it as improved, not improved or wors-ened, and if improved to denote at least one major area ofimprovement. In this communication, we describe short-term and long-term response of these patients to onabo-tulinumtoxinA treatment. Table 1–3 summarize thesepatients’ demographic information, pathology, locationand type of pain, treatment dose, injected muscles, andtreatment results. In all patients, BoNT treatment wasadded to existing treatment regimen, and no change wasmade in their pharmacological treatment for pain.

Case 1

A 48-year-old male underwent laser supraglottic laryngec-tomy with bilateral neck dissections followed by chemo-therapy and radiotherapy for T2N1 squamous cellcarcinoma of the left pyriform sinus. Within weeks, after

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Pain Medicine 2012; *: **–**Wiley Periodicals, Inc.

1

the neck surgery and radiotherapy, the patient developedintense pain around the area of the surgical scar affectingthe upper part of the left sternocleidomastoid muscle(SCM) radiating sharply to the neighboring regions. Therewas no significant pain relief from fentanyl 25 mcg/h patchand hydromorphone 2 mg tabs PRN. On examination, theupper one third of the SCM was indurated along thesurgical scar; the lower part of the muscle was partiallyremoved. Injection of onabotulinumtoxinA into the affectedareas resulted in significant improvement of pain andquality of life. The improvement continued over 24 monthsof follow-up, during which he had reinjection every3 months.

Case 2

A 69-year-old female with stage 4 non-small cell carci-noma of the lungs with metastasis to bone (femur andpetrous bone) and brain underwent multiple courses ofchemotherapy and radiation therapy. She complained ofjaw stiffness, inability to open the mouth fully, and severepain in attempting to open the mouth over the right mas-seter. The problem reached the point that she refrainedfrom eating. Her medications included oxycodone 10 mgtwice daily and fentanyl 25 mcg patch every 72 hours.Injection of onabotulinumtoxinA into the masseter andtemporalis muscles improved the pain and decreased thetone of masseters for 2 months. She received onabotuli-numtoxinA treatment every 2–3 months, and she was ableto eat for up to 1.5 months after each treatment.Increased dosage and bilateral injections were necessaryto maintain improvement of symptoms (Table 2) with morefrequent injections often every 2 months. Eventually, shegained weight and was less depressed, but she died 18months later due to complication of her cancer.

Case 3

A 54-year-old male with left tonsillar cancer developedsevere painful spasms of the jaw muscles during mouthopening and eating 6 months following surgical resectionand radiation therapy. This eventually spread to left side ofher neck with subsequent excruciating pain. Treatmentwith baclofen and acetaminophen-oxycodone (percocet)failed to control the painful spasms. We injected 60 unitsof onabotulinumtoxinA into each masseter muscle. Hereported significant relief after the first injection (1 monthpain free, next 1.5 months mild pain). The second treat-ment after 3 months extended the pain-free interval to2 months and resulted in improvement in his quality of life.

Case 4

A 29-year-old male with a grade 3 pontine astrocytomaexperienced painful spasms of the muscles affecting neckand shoulder muscles 6 months following radiationtherapy. He tried tizanidine 2 mg tablets three times a dayfor the spasms, but it did not have any improvement.Administration of onabotulinumtoxinA into affectedregions (Table 2) resulted in marked improvement of pain.A repeat injection at 3 months had the same effect.Ta

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Case 5

A 50-year-old female with adenocarcinoma of the breastunderwent left mastectomy and reconstructive surgery. Afew weeks later, she developed deep pain in the left axilla,preventing her from functioning during the day and attain-ing comfortable sleep at night. She had tried opioids withno significant pain relief. On palpation, the muscles aroundand deep in the left axilla were tender and indurated.Intermittent muscle spasms could be felt in the axillaryregion. Intramuscular administration of onabotulinum-toxinA resulted in significant pain relief. She reported con-tinued responsiveness over the next 2 years while beingreinjected every 3 months.

Case 6

A 54-year-old male with nasopharyngeal carcinoma hadsevere painful spasms of masseter muscles after heunderwent 2 years of radiation therapy. He also developedsensory loss over the chin extending to mid and lower face

extending to the tragus bilaterally. On examination,opening of the mouth causes severe discomfort. Therewere florid fasciculations over both masseter muscles.Treatment with celecoxib 200 mg and tizanidine 2 mg didnot ease the symptoms. The injection of onabotulinum-toxinA into masseter muscles results in marked pain relief,and it stopped the fasciculations. He reported continuedresponsiveness over the next 17 months while beinginjected every 5 months.

Case 7

A 56-year-old male underwent radiotherapy and surgicalresection of the tumor at the base of his tongue andvarious right-sided neck and pharyngeal muscles. Afterthe surgery, he experienced “tightening” and “pulling” atthe base of his tongue, which impaired his speech andswallowing. The patient suffered from moderate to severepain in the left-upper cervical and occipital area, whichworsened when he tried to turn his head to the left side.Treatment with a variety of analgesic drugs failed to relievepain. Administration of onabotulinumtoxinA into the neckand shoulder muscles resulted in marked improvement ofsymptoms. Improvement continued after each injectionand over the 5 years of follow-up.

Discussion

BoNTs are now used for treatment of a number of humanpain syndromes. Animal data have provided evidence fora variety of mechanisms to explain BoNTs’ analgesiceffects. These include inhibiting the release of pain trans-mitters; glutamate, substance P, cacitonin-gene-relatedpeptide and proinflammatory agents like prostaglandins,bradykinin, histamine and cyclooxygenase from the nerveendings and sensory ganglia [9,10]. In humans, local injec-tion of BoNT A and B reduce pain in a large number ofpain syndromes, including pain of cervical dystonia,chronic migraine, post-herpetic and post-traumatic neu-ralgia, diabetic allodynia, plantar faciitis, chronic lateralepicondylitis, piriformis syndrome, painful knee osteoar-thritis, refractory painful total knee arthroplasty, andchronic low back pain [11–24].

Using efficacy guidelines of American Academy of Neu-rology [25], the efficacy of BoNT is established (Level Aevidence—two or more class I studies) in certain painfulconditions: chronic migraine, cervical dystonia, andchronic lateral epicondylitis. Following the positive resultsof the two large multicentric randomized controlledstudies (PREEMPT I and II), Food and Drug Administrationapproved the treatment of chronic migraine with BoNT.Each study had a 24-week blinded arm followed by a32-week open arm. PREEMT 2 met its primary (decreasein number of headache days at 24 weeks) and secondaryoutcomes at all time points [13,14]. The change in head-ache days was 9 for onabotulinumtoxinA vs 6.7 for theplacebo (P < 0.001). The pooled data of the two studiesalso showed significant change from the baseline in favorof onabotulinumtoxinA in all primary and secondaryparameters. Neck pain is often the most disabling

Table 2 Summary of botulinum toxin treatment

Patient Muscles Injected

InitialDose(U)

ChangedDose (U)

TotalDose(U)

1 Left SCM 60 80 200Left trapezius 60 80Left scalene 40

2 Right masseter 50 70 140Left masseter — 30Right temporalis 20Left temporalis 20

3 Left masseter 50 100Right masseter 50

4 Left splenius capitis 40 300Left trapezius 40Left SCM 20Left levator scapulae 40Left platysma 20Right splenius 40Right trapezius 40Right SCM 20Right levator scapulae 40

5 Left teres major 60 200Left latissimus dorsi 60Left pectoralis major 80

6 Left masseter 65 50 150Right masseter 65 50Left anterior temporal 25Right anterior temporal 25

7 Right trapezius 20 100Right upper SCM 60Right platysma 20

OnabotulinumtoxinA injections were done with a dilution of100 unit/cc, using 3/4 inch and 27.5-gauge needle.SCM = Sternocleidomastoid.

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OnabotulinumtoxinA for Treatment of Focal Cancer Pain

symptom experienced by a majority of the patients withcervical dystonia (68–75%). Eight class I studies (fourusing BoNT type A and four using type B) evaluated theeffects of BoNT treatment on pain in cervical dystoniapatients. The results uniformly showed significant reduc-tion of neck pain (P < 0.05) after BoNT type A or B injec-tions [12,15]. Three class I studies [12,16] assessed theefficacy of onabotulinumtoxinA in chronic lateral epi-condylitis using VAS for pain intensity and patient satis-faction at different time points (2–12 weeks) [12,19]. Allthree studies reported significant reduction of pain anddescribed patient satisfaction with treatment (P < 0.003to <0.001).

BoNT-A is probably effective (level B evidence, one class Ior two class II studies) in painful conditions like post-herpetic and post-traumatic neuralgia with allodynia,plantar fasciitis, piriformis syndrome and total knee arthro-plasty (each one class I study) [12,16,18,20,23]. Otherpainful conditions like allodynia of diabetic neuropathy,chronic low back pain, knee osteoarthritis, anterior kneepain with vastus lateralis imbalance, and pelvic pain havelevel C evidence (possibly effective and may be used atthe discretion of the clinician) [12,17,22,24].

In this study, we have put forward the use of BoNT inanother important pain disorder, namely focal pain incancer patients following surgery or radiation. All of ourpatients reported pain relief after this treatment with amean change in VAS of 5.1, and “satisfactory” or “verysatisfactory” response on PGA. Six of seven patientsreported a significant improvement in their quality of life(Table 3). Dysphagia and dry mouth may occur in patientsafter BoNT injections into cervical muscles (up to 19%reported in cervical dystonia). This could be a concern forpatients with cervical or oropharyngeal cancer who aremore prone to develop dysphagia. None of our patients,however, reported dry mouth or dysphagia. This mighthave been related to relatively small dose of BoNT admin-istered to anterior neck muscles.

A limited literature reports in efficacy of BoNT treatment inlocal cancer pain. A recent study of 15 patients with rectalcancer, who after endorectal brachytherapy developed

acute radiation proctitis (ARP), reported significantimprovement in ARP symptoms of anal pain and bowelurgency after local injection (peri-annally) of 100 units ofonabotulinumtoxinA [26]. The patients also demonstratedbetter compliance and minimum side effects when com-pared with oral, rectal, or intravenous administration ofdrugs. In a case series of six patients who developedsevere neck spasms and pain after receiving radiotherapyfor oropharyngeal carcinoma, two thirds (four of five) hadsignificant relief from the neck pain after injecting averagedose of 22 units of BoNT-A into the affected SCM muscle[27]. Hartl et al. [28] reported on 19 patients with signifi-cant jaw pain and trismus after radiation therapy fororopharyngeal cancer. OnabotulinumtoxinA injections (50units per muscle) into both masseters resulted in signifi-cant improvement in jaw pain but did not improve trismus.

In conclusion, our results add to and agree with emergingliterature that local injection of onabotulinumtoxinA cansignificantly reduce focal pain of cancer patients at the siteof surgery or radiation therapy. We have further demon-strated sustenance of the response to BoNT A in thispopulation beyond 1 year of follow-up. Treatment withonabotulinumtoxinA in our observation and that of othersis safe in cancer patients. Further studies are necessaryfor this indication of BoNT therapy that can improve thequality of life of cancer patients.

References1 Kanner RM, Foley KM. Patterns of narcotic drug use in

a cancer pain clinic. Ann N Y Acad Sci 1981;362:161–72.

2 Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgi-cal pain: Risk factors and prevention. Lancet2006;367:1618–25.

3 Fleming JA, O’Connor BD. Use of lidocaine patchesfor neuropathic pain in a comprehensive cancercentre. Pain Res Manag 2009;14(5):381–8.

4 Ballantyne JC, Mao J. Opioid therapy for chronic pain.N Engl J Med 2003;349:1943–53.

Table 3 Treatment outcome and follow-up in cancer patients after BoNT treatment

Patient

VAS Score

PGA Quality of Life Follow UpBeforeBoNT

AfterBoNT

1 8 1 VS Disabling pain stopped 3 years2 6 1 VS Eating became possible 1.5 years3 6 1 VS Eating improved substantially 6 months4 7 2 S Easier to drive without pain while neck turns 6 months5 6 1 VS Able to move the left arm without significant pain 2 years6 6 0 VS Improved swallowing 1.5 years7 5 2 S improvement of articulation 5 years

BoNT = botulinum neurotoxin; PGA = patient global assessment; VAS = visual analog scale; S = satisfactory; VS = very satisfactory.

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5 List MA, Bilir SP. Functional outcomes in head andneck cancer. Semin Radiat Oncol 2004;14:178–89.

6 Chargari C, Fromantin I, Kirova YM. Importance oflocal skin treatments during radiotherapy for preven-tion and treatment of radio-induced epithelitis. CancerRadiother 2009;13:259–66.

7 Fisher J, Scott C, Stevens R, et al. Randomized phaseIII study comparing best supportive care to Biafine asa prophylactic agent for radiation-induced skin toxicityfor women undergoing breast irradiation: RadiationTherapy Oncology Group [RTOG] 97–13. Int J RadiatOncol Biol Phys 2000;48:1307–10.

8 Kirova YM, Fromantin I, De Rycke Y, et al. Can wedecrease the skin reaction in breast cancer patientsusing hyaluronic acid during radiation therapy-resultsof phase III randomised trial. Radiother Oncol2011;100:205–9.

9 Cui M, Khanijou S, Rubino J, Aoki KR. Subcutaneousadministration of botulinum toxin A reduces formalin-induced pain. Pain 2001;107:125–33.

10 Marinelli S, Luvisetto S, Cobianchi S, et al. Botulinumneurotoxin type A counteracts neuropathic pain andfacilitates functional recovery after peripheral nerveinjury in animal models. Neuroscience 2010;171:316–28.

11 Jabbari B. Botulinum neurotoxins in the treatment ofrefractory pain. Nat Clin Pract Neurol 2008;4:676–85.

12 Jabbari B, Machado D. Treatment of refractory painwith botulinum toxins—An evidence-based review.Pain Med 2011;12:1594–606.

13 Aurora SK, Dodick DW, Turkel CC. Onabotulinum-toxinA for treatment of chronic migraine: Results fromthe double-blind, randomized, placebo-controlledphase of the PREEMPT 1 trial. Cephalalgia 2010;30:793–803.

14 Diener HC, Dodick DW, Aurora SK, et al. Onabotuli-numtoxinA for treatment of chronic migraine: Resultsfrom the double blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia2010;30:804–14.

15 Lew MF, Chinnaponse R, Zhang Y, Corliss M.RimabotulinumtoxinB effects on pain associated withcervical dystonia: Results of placebo and comparator-controlled studies. Int J Neurosci 2010;120:298–300.

16 Ranoux D, Attal N, Morain F, Bouhassira D. Botulinumtoxin type A induces direct analgesic effects in chronicneuropathic pain. Ann Neurol 2008;64:274–83.

17 Yuan RY, Sheu JJ, Yu JM, et al. Botulinum toxin fordiabetic neuropathic pain: A randomized double-blindcrossover trial. Neurology 2009;72:1473–8.

18 Babbock MS, Foster L, Pasquina P, Jabbari B.Treatment of pain attributed to plantar faciitis withbotulinum toxin A: A short term, randomized, placebo-controlled, double blind study. Am J Phys MedRehabil 2005;84:649–54.

19 Wong SM, Hui AC, Tong PY, et al. Treatment of lateralepicondylitis with botulinum toxin: A randomized,double-blind, placebo-controlled trial. Ann Intern Med2005;143:793–7.

20 Childers MK, Wilson DJ, Gnatz SM, Conway RR,Sherman AK. Botulinum toxin type A use in piriformismuscle syndrome: A pilot study. Am J Phys MedRehabil 2002;81:751–9.

21 Fishman LM, Anderson C, Rosner B. BOTOX andphysical therapy in the treatment of piriformis syn-drome. Am J Phys Med Rehabil 2002;81:936–42.

22 Boon AJ, Smith J, Dahm DL, et al. Efficacy of intra-articular botulinum toxin type A in painful kneeosteoarthritis: A pilot study. PM R 2010;2:268–76.

23 Singh JA, Mahowald ML, Noorbaloochi SJ. Intraar-ticular botulinum toxin a for refractory painful total kneearthroplasty: A randomized controlled trial. J Rheuma-tol 2010;37:2377–86.

24 Foster L, Clapp L, Erickson M, Jabbari B. Botulinumtoxin A and chronic low back pain: A randomized,double-blind study. Neurology 2001;56:1290–3.

25 French J, Gronseth G. Lost in a jungle of evidence: Weneed a compass. Neurology 2008;71:1634–38.

26 Vuong R, Waschke K, Niazi T, et al. The value ofBotox-A in acute radiation proctitis: Results from aphase I/II study using a three-dimensional scoringsystem. Int J Radiat Oncol Biol Phys 2011;80:1505–11.

27 Van Daele DJ, Finnegan EM, Rodnitzky RL, et al. Headand neck muscle spasm after radiotherapy-management with botulinum toxin a injection. ArchOtolaryngol Head Neck Surg 2002;128:956–59.

28 Hartl DM, Cohen M, Julieron M, et al. Botulinum toxinfor radiation-induced facial pain and trismus. Otolaryn-gol Head Neck Surg 2008;138:459–63.

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OnabotulinumtoxinA for Treatment of Focal Cancer Pain