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Clinical & Medical Case Reports

Case Report Volume 6 Issue 4

Successfull pain management with radiotherapy and ozone therapy in a case of metastatic, chemotherapy resistant sino-nasal mucosal malignant melanoma

Kiziltan HS,1 Ayse Gunes Bayir,2 Eris AH,1 Meryem Basibuyuk,3 Alpaslan Mayadagli,1 Adem Akcakaya,4 Fatma Betul Cakir,5 Teoman Aydin,6 Kursat Gul,7 Esra Karabal,8 Muharrem Simsek8

1Department of Radiation Oncology, Bezmialem Vakif University Medical Faculty of Medical, Turkey
2Department of Nutrition and Dietetics, Bezmialem Vakif University Faculty of Health Sciences, Turkey
3Department of Nursing, Bezmialem Vakif University Faculty of Health Sciences, Turkey
4Department of General Surgery, Bezmialem Vakif University, Faculty of Medical, Turkey
5Department of Pediatric Oncology, Bezmialem Vakif University, Faculty of Medical, Turkey
6Department of Physical Therapy and Rehabilitation, Bezmialem Vakif University, Turkey
7Department of Anestesiology and Reanimation div. of Algology, Bezmialem Vakif University, Turkey
8Department of Palliative Care Unit, Bezmialem Vakif University, Turkey

Correspondence: Huriye Şenay Kiziltan, Bezmialem Vakif University Medical Faculty of Medical, Department of Radiation Oncology, Turkey

Received: March 18, 2017 | Published: March 31, 2017

Citation: Kiziltan HS, Gunes-Bayir A, Eris AH, et al. Successfull pain management with radiotherapy and ozone therapy in a case of metastatic, chemotherapy resistant sino-nasal mucosal malignant melanoma. MOJ Clin Med Case Rep . 2017;6(4):81-83. DOI: 10.15406/mojcr.2017.06.00165

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Background: Nasal mucosal and paranasal sinus melanomas are rare tumours of head and neck region. Regional recurrence and distant metastasis are very high despite with surgery, chemotherapy, immunotherapy and radiotherapy in these tumours. Coping with pain can sometimes be quite difficult in metastatic disease.

Case: In our sino-nasal mucosal melanoma (SNMM) case, disease was progressed following chemotherapy (CT) and head and neck radiotherapy (RT), despite a full response was obtained in the primary tumour. The patients have severe pain that exacerbated even with using high dose opioids due to metastases developing in the adrenal and pancreatic regions. Ozone therapy was applied up to 2cm from the level of the umbilicus at deep as 2cm only one dose with local RT of adrenal and pancreatic regions. A complete palliation was obtained in pain and the opioids were interrupted. There was no pain in the last 3 months until death without any pain treatment.

Discussion: In our case, a full pain control was achieved with ozone therapy initiated following the progression after CT and head and neck RT.

Keywords: sinusal/sinonasal/paranasal malignant melanoma, radiotherapy, temozolomide, ozone therapy


The most common location of malignant melanoma (MM) is the head and neck region (25-30%). SNMM is a very rare and an aggressive progressive type of MM.1–3 Mucosal MM usually presents at a more advanced stage and is therefore associated with a higher mortality rate than cutaneous melanoma because of its location and rich vascularization.4,5 The best outcomes are achieved with postoperative radiotherapy in operable cases. Survival rates have been increased with the addition of radiotherapy and immunotherapy to surgery.9–12 Cisplatin, dacarbazin and vindesine combination is one of the best chemotherapy regimens in patients with metastatic disease8 In a meta-analysis, nasal mucosal melanoma had a 31% 5-year survival rate, whereas sinus melanoma patients had a 0% 5-year survival.13 Distant spread in general is associated with rapid clinical deterioration and a short survival time.25

If the cancer-related pain is not treated, it disrupts and decreases sleeping, appetite, treatment tolerance, quality of life and performance status of patients.13 Opioids usually using for severe pain despite their side effects. Cancer-related pain may be many different reasons than normal pain. The cause of cancer pain can be inflammatory, neuropathic or pain mediators.14

Palliative radiotherapy is most commonly used for pain in metastatic cancer.15 One of the factors reducing the beneficial effects of radiotherapy in rapidly growing tumors were become oxygen-starved because of a lack of sufficient vascular support. The hypoxia is an important factor in radio resistance, differentiation of tumor cells metastasis and neovascularization.16,17 Medical ozone (5% Ozone and 95%oxygen mixture) (OO)therapy which increases oxygenation on tissues can be used for treatment of inflammation, ischemic illnesses and pain palliation.18–20

OO therapy can increase the sensitivity and decrease the side effects of radiotherapy causing increase in the red blood cell glycol sis rate, and the stimulation of 2,3-diphosphoglycerate.21 The cytotoxic and radiosensitive effects of OO determined to lung, breast, uterine, and ovarian cancer cells by increasing the production of interferon, tumor necrosis factor, and interleukin-2.22–25

The World Health Organization (WHO) updated pain management guidelines.26 According to these guidelines, obtained a three-stage pain management for pain of cancer. If resistance of pain available even these analgesic treatments, interventional treatment planning of pain may be a good option.27 Interventional pain management can be applied to such as joint injections, radiofrequency ablation, nerve blocks, OO injections, and cement augmentation techniques to treatment of pain which resistant to conventional management.27 OO can also reduce pain by reducing inflammation with anti-bacterial, anti-fungal and anti-viral effects.28,29 OO known to have a important role along with other standard treatments as is determined by other studies.30,31

Case report

Our case is a 54-year-old male patient who diagnosed as SNNM (Figure 1). His disease was progressed following chemotherapy (CT) and radiotherapy (RT), despite a full response was obtained in the primary tumour with RT. ECOG (Eastern Cooperative Oncology Group) performance scoring was 4, Visual Analog Scoring (VAS) was 100%. His FDG PET CT (Positron emission tomography with fluorine 18 (18F) fluorodeoxyglucose and computed tomography) images showed big tumour in the pancreas and left adrenal gland, the biggest one being 11cm.

Figure 1 Histopathological image of SNMM (HE staining 40x10).

The patient have severe pain that exacerbated even with using high dose opioids due to metastases developing in the adrenal and pancreatic regions. The palliative RT was planned with CT simulation, fraction of 250cGy with dynamic IMRT once a day and five days a week to adrenal and pancreatic regions. But After 4 fraction of RT, the pain became more severe even using opioid.

OO therapy was applied up to 2cm from the level of the umbilicus at deep as 2cm 20mcg/ml, 2ml/dose, only one dose with RT.

A complete palliation was obtained in pain and the opioids were interrupted. A new VAS was 0%. The patient's performance improved from ECOG 4 to ECOG 3 after OO with RT. There was no pain in the last 3months until death without any pain treatment.


In early stage mucosal malignant melanoma, generally, a 50-75% onset response was reported to be achieved with radiotherapy.32,33 In metastatic melanoma, 21% response was achieved with temozolomide treatment.34 In recent years, favourable results have been obtained with Src inhibitors. The Src inhibitors dasatinib and bosutinib can be used alone or with chemotherapy.35 Vemurafenib and ipilimumab are promising drugs that are recently approved for melanoma treatment.36,37 One of the most important reasons for chemo resistance in nasal mucosal malignant melanomas is the inadequacy of apoptosis; and one of the most important reasons for this is lack of oxygenation in the tumour.38 A good local control may be obtained with radiotherapy, but survival advantage has not been demonstrated with radiotherapy alone.39 In one study, Ozone was found to be more effective in tissues have intensive c-kit levels.40–42 Interestingly, over expression of c-KIT, a receptor tyrosine kinase, was reported in 39% to 88% of mucosal melanomas.43,44 This mutation was associated also with sensitivity to imatinib in vitro. The c-KIT is a key regulator of mucosal melanoma and proliferation of melanocytes.45 It has been shown to activate the intracellular signaling pathways related to tumour progression.46 Marked tumour regression was observed in metastatic mucosal melanoma with single-agent imatinib.47 These evidences may be indicates imatinib and OO probably show additive effects on melanoma for additive to CT or pain treatment in future.

OO therapy which increases oxygenation on the issues can be used for treatment of inflammation, ischemic illnesses and pain palliation.18–20 A faster and more effects can be obtained by injecting of OO into a painful spot. This is also called indirect approach or chemical acupuncture.48–49 

In our metastaticsinonasal mucosal melanoma case, disease was progressed and metastasized to pancreas and adrenal gland after CT and head and neck RT. Injection of OO treatment was applied for resistant pain despite opioids due to a big metastatic mass. It has become addicted to bedding due to lose of appetite, cachexia and severe pain complaints. The patient's performance improved from ECOG 4 to ECOG 3 after RT and OO. Although he was treated with only 1 session and 3ml injections, the pain was completely improved and opioids interrupted.

OO can help to reduce cancer related pain and other side effects and improves to overall quality of life causing decreasing of pain and side effects. There is a great need for multicenter studies for OO treatment and pain management of malign melanoma and other cancers with severe pain.



Conflict of interest

The author declares no conflict of interest.


  1. McKinnon JG, Kokal WA, Neifeld JP, et al. Natural history and treatment of mucosal melanoma. J Surg Oncol. 1989;41(4):222–225.
  2. Batsakis JG. Pathology of tumours of the nasal cavity and paranasal sinuses and neck cancer. Philadelphia, WB Saunders Company; 1999. p. 522–539.
  3. Huang SF, Liao CT, Kan CR, et al. Primary mucosal melanoma of the nasal cavity and paranasal sinuses:12 years of experience. J Otolaryngology. 2007;36(2):124–129.
  4. Goldman JA, Lawson W, Zak FG. The presence of melanocytes in the human larynx. Laryngoscope. 1972;82(5):824–835.
  5. Lund VJ, Howard DJ, Harding L, et al. Management options and survival in malignant melanoma of the sinonasal mucosa. Laryngoscope. 1999;109(2 pt 1):208–211.
  6. Kharoubi S. Malignant melanoma of nasal fossae:clinical and therapeutic considerations about three cases. Cancer Radiother. 2005;9(2):99–103.
  7. Khademi B, Bahranifard H, Nasrollahi H, et al. Primary mucosal melanoma of the sinonasal tract: report of 18 patients and analysis of 1077 patients in the literature. Braz J Otorhinolaryngol. 2011;7(1):58–64.
  8. Guzzo M, Grandi C, Licitra L, et al. Mucosal malignant melanoma of head and neck: forty–eight cases treated at Istituto Nazionale Tumori of Milan. Eur J Surg Oncol. 1993;19(4):316–319.
  9. Ulutin C, Güden M, Pak Y. Local control of mucosal malignant melanoma after combined treatment (surgery and postoperative Radiotherapy); a case presentation. J Med Sci. 2002;22(2):200–202.
  10. Ishihara K, Yamazaki N, Asano K. Chemotherapy of malignant melanoma. Gan To Kagaku Ryoho. 1993;20(10):1287–1292.
  11. Rapini RP, Golitz LE, Greer RO Jr, et al. Primary malignant melanoma of the oral cavity. A review of 177 cases. Cancer. 1985;55(77):1543–1551.
  12. Balch CM, Buzaid AC, Soong SJ, et al. Final version of the American joint committee on cancer staging system for cutaneous melanoma. J Clin Oncol. 2001;19(16):3635–3648.
  13. Pergolizzi JV, Gharibo C, Ho KY. Treatment considerations for cancer pain: a global perspective. Pain Pract. 2015;15(8):778–792.
  14. Schmidt BL. The Neurobiology of Cancer Pain. Neuroscientist. 2014;20(5):546–562.
  15. Hoegler D. Radiotherapy for palliation of symptoms in incurable cancer. Curr Probl Cancer. 1997;21(3):129–183.
  16. Brahimi–Horn C, Berra E, Pouysségur J. Hypoxia: the tumor’s gateway to progression along the angiogenic pathway. Int Rev Cytol. 2005;242:157–213.
  17. Subarsky P, Hill RP. The hypoxic tumour microenvironment and metastatic progression. Clin Exp Metastasis. 2003;20(3):237–250.
  18. Maffei RM, Maffei LM. Ozone therapy in the treatment of some strictly neurologic pathology. Int J Ozone Ther. 2013;12(1):16–24.
  19. Zaky S, Kamel SE, Hassan MS, et al. Preliminary results of ozone therapy as a possible treatment for patients with chronic hepatitis C. J Altern Complement Med. 2011;17(3):259–263.
  20. Kızıltan HŞ, Bayir AG, Yucesan G, et al. Medical ozone and radiotherapy in a peritoneal, Erlich–ascites, tumor–cell model. Altern Ther Health Med. 2015;21(2):24–29.
  21. Clavo B, Pérez JL, López L, et al. Ozone therapy for tumor oxygenation:a pilot study. Evid Based Complement Alternat Med. 2004;1(1):93–98.
  22. Bocci V, Luzzi E, Corradeschi F, et al. Studies on the biological effects of ozone, VI: production of transforming growth factor 1 by human blood after ozone treatment. J Biol Regul Homeost Agents. 1994;8(4):108–112.
  23. Bucci B, Cannizzaro A, Brunetti E, et al. Ozone treatment inhibits proliferation in human neuroblastoma SK–N–SH cells. Rivista Italiana di. Ossigeno–Ozonoterapia. 2006;5:85–92.
  24. Karlic H, Kucera H, Metka M, et al. Effect of ozone and ionizing radiation on an in vitro model—a pilot study of 4 gynecologic tumors[in German]. Strahlenther Onkol. 1987;163(1):37–42.
  25. Sweet F, Kao MS, Lee SC, et al. Ozone selectively inhibits growth of human cancer cells. Science. 1980;209(4459):931–933.
  26. World health organization. Cancer Pain Relief with a Guide to Opioid Availability. 2nd ed. Geneva, Switzerland; 1996.
  27. Meuser T, Pietruck C, Radbruch L, et al. Symptoms during cancer pain treatment following WHO–guidelines:a longitudinal follow–up study of symptom prevalence, severity and etiology. Pain. 2001;93(3):247–257.
  28. Elvis AM, Ekta JS. Ozone therapy: a clinical review. J Nat Sci Biol Med. 2011;2(1):66–70.
  29. Bocci V. The clinical application of ozone therapy. In: Ozone BA, editor. A New Medical Drug. Amsterdam, The Netherlands: Springer; 2005. p. 97–226.
  30. Borrelli E, De Monte A, Bocci V. Oxygen ozone therapy in the integrated treatment of chronic ulcer:a case series report. International Journal of Recent Scientific Research. 2015;6:4132–4136.
  31. De Monte A, Gori C. Major ozonated autohaemotherapy in the treatment of limb ulcers not responding to conventional therapy. International Journal of Ozone Therapy. 2011;10(2):85–98.
  32. Gilligan D, Slevin NJ. Radical radiotherapy for 28cases of mucosal melanoma in nasal cavity and sinuses. Br J Radiol. 1991;64(768):1147–1150.  
  33. Harwood AR, Cummings BJ. Radiotherapy for mucosal melanomas. Int J Radiat Oncol Biol Phys. 1982;8:1121–1126.
  34. Bleehen NM, Newlands ES, Lee SM, et al. Cancer Research Campaign phase II trial of temozolomide in metastatic melanoma. J Clin Oncol. 1995;13:910–913.
  35. Homsi J, Cubitt CL, Zhang S, et al. Src activation in melanoma and Src inhibitors as therapeutic agents in melanoma. Melanoma Res. 2009;19(3):167–175.
  36. Papadatos–Pastos D, Januszewski A, Dalgleish A. Revisiting the role of systemic therapies in patients with metastatic melanoma to the CNS. Expert Rev Anticancer Ther. 2013;13(5):559–567.
  37. Balakan O, Süner A, Yiğiter R, et al. Long–term survival in metastatic malignant melanoma: ipilimumab followed by vemurafenib in a patient with brain metastasis. Intern Med. 2012;51(19):2819–2823.
  38. Kızıltan HŞ, Kanser, Belirtiler, et al. Edit: Dikmen M. Elit Kültür Yayın. 2010;440:80–85.
  39. Mihajlovic M, Vlajkovic S, Jovanovic P, et al. Primary mucosal melanomas: a comprehensive review. Int J Clin Exp Pathol. 2012;5(8):739–753.
  40. Rivera RS, Nagatsuka H, Gunduz M, et al. C–kit protein expression correlated with activating mutations in KIT gene in oral mucosal melanoma. Virchows Arch. 2008;452(1):27–32.
  41. Di Filippo C, Luongo M, Marfella R, et al. Oxygen/ozone protects the heart from acute myocardial infarction through local increase of eNOS activity and endothelial progenitor cells recruitment. Naunyn Schmiedebergs Arch Pharmacol. 2010;382(3):287–291.
  42. Montgomery E, Voltaggio L, Vieth M. Inflammation, malignancy and immunology in gastrointestinal spindle cell tumors: what is beyond GIST? Pathologe. 2014;35 Suppl 2:207–213.
  43. Antonescu CR, Busam KJ, Francone TD, et al. L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition. Int J Cancer. 2007;121:257–264.
  44. Ali S. Role of c–kit/SCF in cause and treatment of gastrointestinal stromal tumours (GIST). Gene. 2007;401(1–2):38–45.
  45. Nelson JD, Cameron JD. The conjunctiva: Anatomy and physiology. In: Krachmer JH, et al. editors. Cornea. 2nd ed. Vol. 1 Philadelphia: Elsevier Mosby; 2005. p. 37–43.
  46. Lutzky J, Bauer J, Bastian BC. Dose–dependent, complete response to imatinib of a metastatic mucosal melanoma with a K642E KIT mutation. Pigment Cell Melanoma Res. 2008;21:492–493.
  47. Bocci V. Oxygen–Ozone Therapy: A Critical Evaluation. Dordrecht: Kluwer Academic; 2002.
  48. Siemsen CH. Ozon–Anwendung bei akuten und chronischen Gelenker–krankungen [Ozone use in acute and chronic joint diseases] In: Beck EG, et al. editors. Ozon–Handbuch: Grundlagen, Prävention, Therapie [Ozone handbook: basics, prevention, therapy] Landsberg. Ecome: German; 1995. p. V–9.2.1–9.2.14.
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