INSULIN POTENTIATION THERAPY COMBINED WITH ULTRASONIC ASSISTANT CHEMOTHERAPY OF TONGUE TUMOURS A CASE REPORT Dr. Christo Damyanov, Dr. Ivan Maslev, Dr. Desislava Gerasimova, Dr. Veselinka Yankova, Dr. Vladislav Tashev Medical Center of Integrative Medicine, Sofia, Bulgaria

TONGUE CANCER The average age of tongue cancer patients is 61, the diagnosed cases represent about 25 per cent of the oral cavity tumors. Total survival rate of the patients for 5 and 10 years is 61 and 51 percent respectively. Mortality from the disease has not significantly changed during the last 40 years. Annually in Europe there die about 8,000 tongue cancer patients. The main reason for the increased mortality is the late cancer diagnosis. In the early stages treatment is operative (partial glossectomy) while in the advanced stages the combined treatment includes surgery, radiotherapy and chemotherapy. The problems of the late stage treatment are the increased recurrent rate, the seriously compromised quality of life and the reduced survival rate. In the current report we present a case from our practice of loco- regional advanced tongue tumor treated with IPTLD in combination with local chemotherapy and ultrasonic irradiation.

A CASE REPORT A 60-year-old man of was admitted for treatment progressively complaining of speech and eating disturbances, a swelling and ulceration on the left halve of the tongue. For these complaints he consulted in Oral and Maxillofacial surgery department on December 2011, following which a biopsy was performed with a histological result – a squamous cell carcinoma. The case was considered as a locally advanced tumor and radical surgical treatment was proposed or radio and chemotherapy, which were declined by the patient.

EXAMINATION BEFORE TREATMENT Tumor nodular lesion and ulceration in the left side of the tongue with a diameter 4/3 cm. Submandibulary to the left a lymph node palpitated of about 2,5 cm in size. PET/CT (01.2012) A metabolically active tumor process in the area of the tongue, without defining the size due to available artifacts in the oral cavity (teeth dentures). Dissemination of the process in the left submental lymph node 17 mm size, submandibular lymph nodes of 14 and 11 mm sizes as well as other two behind the left sternocleidomastoid muscle of 14 and 12 mm sizes.

Macroscopic findings before treatment

TREATMENT IPT treatment with Cisplatin/5-FU (Four IPT applications) Alternating treatment with a new chemotherapy scheme: Epirubicin, Methotrexat, Carboplatin in four consecutive applications, once a week. Length one scan treatment – 4 applications in every 5 days interval, then sustaining treatment in gradual increasing intervals (four applications in 10 days, 2, 3 and more weeks). In the interval an vitamin therapy, immune therapy and ozone therapy. IPT therapy was combined with a local DMSO and 5-FU application and a local ultrasonic (sonodynamic) treatment of the tongue and left cervical area two time weekly.

ULTRASOUND DEVICE The ultrasonic treatment (1 watt/cm2 and frequency 1 Mhz) is applied ten minutes after the local 5-Fu application with a duration 10 minutes.

RESULTS In the course of the treatment the patient’s complaints of speech and eating disturbances phased out. The Beretta symptomatic index of 12 points went down to 1 point. Right now the patient is stabilized and with a totally restored to a working capacity. Treatment continues to the present. Examination after the treatment: a tumor nodular lesion and ulceration in the left side of the tongue with a diameter about 15 mm. Submandibulary to the left a lymph node palpitated of about 5 mm in size. Control investigation with MRI (03.2012): A slight asymmetry of the tongue. With the applied native and post contrast MRI techniques also including dynamic evaluations could not categorically verify the tumor formation in the tongue. The lesions described in the lymph nods from the preceding PET/CT underwent a negative development in quantity.

Macroscopic findings 1 months after treatment RESULTS Macroscopic findings 1 months after treatment

2 months after treatment RESULTS Macroscopic findings 2 months after treatment Macroscopic findings 3 months after treatment

SIDE EFFECTS No serious side effects were observed excluding increasingly growing thrombocytopenia of up to 76 g/l which was medically treated. Following the treatment the thrombocytes values steadied within 112- 118 g/l. The thrombocytopenia was explained by the available hypersplenism before the treatment and a side effect of the chemotherapy applied.

DISCUSSION Searching for a possibility of lowering the side effects from the treatment and maintaining the functional capacities of the tongue, we applied a combined treatment on a patient with a locally advanced tongue tumor who had declined conventional treatment. Treatment started by an IPTLD combined with Cisplatin/5-FU. Aiming at increasing the local anti tumor effect, after the third application the chemotherapy scheme was changed and the treatment included a local chemotherapy with a 20 percent solution of 5-Fluorouacil in DMSO and ultrasonic therapy of the tongue lesion in the left cervical area. The ultrasonic treatment (1 watt/cm2 and frequency of 1 Mhz) is applied ten minutes after the local 5-FU application with a duration of 10 minutes. The local treatment is applied at the same time with IPTLD as well as in the interval of twice weekly.

DISCUSSION DMSO The idea of applying locally a 5-FU dissolved in DMSO is based on experimental and clinical researches demonstrating the potentiation effect of the organic solvent DMSO on the chemotherapy. On 1968 it was discovered that dimethyl sulfoxide (DMSO) had a very high affinity for cancer cells so DMSO targeted cancer cells. DMSO could bind to other substances, and still target cancer cells. It would bind to certain types of molecules, and then DRAG these molecules inside cancer cells. In later studies DMSO was found to bind to Adriamycin, Cisplatin, 5 Fluorouracil, Methotrexate, and others.

DISCUSSION Resistance to chemotherapy is the important reason for treatment failure in patients with cancer. Current methods which focus on the identification of more selective and potent drug resistance reversing agents are not satisfying. It is an urgent need for development of new approaches to overcoming drug resistance. The use of low power ultrasound in cancer therapy is a developing field. Recently, it was found that some anticancer drugs, upon ultrasonic irradiation, could create active oxygen species and effectively destruct cancer cells. This means that, in addition to cytotoxicity, these chemotherapeutic agents may be used as sonosensitizers and kill cancer cells by another mechanism. Moreover, local hyperthermia induced by ultrasound could enhance drug cytotoxicity. For the unique advantage of ultrasound, which are quite different from current therapy, we hypothesize that ultrasound assistant chemotherapy may be a new strategy to block drug resistance, which might enhance the efficacy of chemotherapeutic drugs, and reduce undesired side effects. Med Hypotheses. 2009 Oct;73(4):526-7. Epub 2009 Jul 1. Ultrasound assistant chemotherapy may be a novel modality for solid tumors HuiXuan Pan, XiaoPeng Ma MingZhong Li., JunZhang Chen, Hong Jiang, Summary Department of Medicine, Clinic Medical College of Yangtze University, Jingzhou 434000, China.

CONCLUSION In the presented case, complementing the standard IPT with local chemotherapy and sonodynamic therapy demonstrates an increased therapeutic efficiency and alludes to potential possibilities for the successful combination of IPTLD with other methods in the treatment of metastatic tumors.