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Persistent PORT-A-CATH®-Related Fistula and Fibrosis in a Breast Cancer Patient Successfully Treated With Local Ozone Application

      To the Editor:
      Persistent and delayed healing of fistulae and local infection in previously irradiated areas can increase the risk of systemic complications and complicated clinical management. Cancer patients have impaired immune systems secondary to the tumor or oncology treatments; this impairment decreases spontaneous healing. Surgical options are often associated with adverse side effects together with an increased risk of further delay in wound healing. Hyperbaric chambers have been used to treat delayed wound healing and several radiation-induced side effects.
      • Pasquier D.
      • Hoelscher T.
      • Schmutz J.
      • et al.
      Hyperbaric oxygen therapy in the treatment of radio-induced lesions in normal tissues: a literature review.
      However, this technique is cumbersome and with limited accessibility. Additionally, treatment and assessment of radiation-induced subcutaneous fibrosis has had limited success. We describe a case of a persistent fistula in a previously irradiated area, which was refractory to treatment but which was successfully treated with local ozone applications. The potential role of spectroscopy analysis imaging for objective assessment of subcutaneous fibrosis was demonstrated.

      Case

      A 46-year-old woman was admitted to our hospital for evaluation of a persistent fistula and leakage secondary to a PORT-A-CATH® (Smiths Medical, St. Paul, MN) inserted in a previously irradiated area. She had been diagnosed three years earlier with right-sided, locally advanced, breast carcinoma (infiltrating ductal carcinoma, T4bN1M0 Stage). She was treated with systemic chemotherapy (fluorouracil, epirubicin, cyclophosphamide, and docetaxel). The tumor decrease was >50% (partial response). She underwent a modified radical mastectomy followed by radiotherapy: 54 Gy at 2 Gy/day on chest wall, axillar, supra- and infraclavicular areas. Radiotherapy was well tolerated, with some areas of dermatitis Grade II. She proceeded on to hormonal therapy with tamoxifen. Local recurrence in the chest wall occurred two years after the initial diagnosis. A PORT-A-CATH® for chemotherapy administration was inserted in the right infraclavicular area, which had received the radiotherapy. Since insertion, the patient presented with a persistent subcutaneous peri-catheter fistula with continuous leakage, intermittently purulent. The catheter was removed five months later when second-line chemotherapy was concluded (13 cycles of paclitaxel, gemcitabine, and bevacizumab). Fistula and leakage continued uninterrupted during this period and persisted even after the PORT-A-CATH® was removed and several specific antibiotics were administered. The patient reported progressive subcutaneous fibrosis and a decrease in her quality of life secondary to these ongoing symptoms and moderate persistent local pain. She was admitted to our hospital for evaluation of specific treatment four months after the catheter removal (nine months after the fistula was noticeable with its accompanying leakage).
      Pretreatment physical examination revealed a hyperpigmented fibrosis plaque in the right infraclavicular area, in the catheter bed. Palpable subcutaneous induration measured 20×15 mm, with a fistulous cavity of 2 mm diameter and 25 mm depth. Leakage persisted and needed to be swabbed several times per day, every day (Fig. 1, upper left).
      Figure thumbnail gr1
      Fig. 1Details of photograph (left) and objective quantification simultaneously obtained by spectroscopy analysis using linearly polarized light (right). Black areas are with higher red cell content in the dermal micro-vascular bed; in this case related to blood-flow stasis in the fibrosis area. Upper panel: before ozone therapy. Lower panel: after ozone therapy.
      Informed consent was obtained before the commencement of treatment. Ozone therapy was done by insufflations of an O3/O2 gas mixture (100 μg/ml) through the fistulous cavity and multiple (four to six) infiltrations distributed around the fibrous induration (6–10 ml of O3/O2 gas mixture at 14 μg/ml in each infiltration point). Ozone sessions included 15 minutes of soft vacuum on the fibrosis area.
      Spectroscopy analysis was performed using a tissue viability imaging system (TiVi) (TiVi600, Wheels Bridge AB, Linköping, Sweden). It is based on linearly polarized white light, which is partly reflected by the upper layer of the skin and partly diffusely scattered in the deeper dermal layers. This technique generates an image that depends on red blood cell content in the dermal microvascular bed (depth of sampling is about 400–500 μm).
      • Henricson J.
      • Nilsson A.
      • Tesselaar E.
      • Nilsson G.
      • Sjoberg F.
      Tissue viability imaging: microvascular response to vasoactive drugs induced by iontophoresis.
      The TiVi device takes a standard photograph and automatically performs a reproducible assessment according to the signal properties analyzed. TiVi imaging was performed pre- and post-treatment with ozone.
      After two ozone insufflation treatments over two weeks, the fistulous cavity partially closed and the leakage became intermittent. Follow-up treatment was subcutaneous infiltration in the area of fibrosis alone. After the fifth session at the end of five weeks, the leakage disappeared and the fistulous cavity closed completely. The six initial sessions were one per week. The patient was living on another of the Canary Islands and to save traveling time and costs, and because there was clear objective improvement, the seventh session was two weeks later and the eighth session was one month later. Hence, after eight ozone sessions over 12 weeks, the treatment was concluded. Local pain and symptoms had noticeably decreased by the end of ozone therapy, and subcutaneous induration was lower (10×15 mm) and more superficial than initially (Fig. 1, lower left).
      Objective quantification using TiVi imaging pre- and post-treatment showed a measurable decrease in blood flow stasis in the fibrosis area (from 255±5 to 215±36 TiVi units, 19%; P<0.001), that is, blood flow in the skin in the fibrosis area was more similar to blood flow in skin areas without fibrosis. There was a similar decrease in the area of the fistulous cavity (from 335±56 to 273±37 TiVi units; P<0.001) (Fig. 1, upper and lower right).

      Comment

      Subcutaneous PORT-A-CATH®s are widely used to facilitate chemotherapy administration. Anatomically, the placement is technically easier and with lower risk in the right rather than left infraclavicular area. However, irradiated areas have an increased risk of delayed healing and morbidity after local invasive procedures. Often, it is not necessary to administer special pharmacotherapeutic agents but, occasionally, delayed healing can be persistent and debilitating. As with other refractory radiation-related side effects, the most used nonsurgical approach is treatment with hyperbaric chambers.
      • Pasquier D.
      • Hoelscher T.
      • Schmutz J.
      • et al.
      Hyperbaric oxygen therapy in the treatment of radio-induced lesions in normal tissues: a literature review.
      However, the accessibility of the equipment is limited and was unavailable in our center. The surgical approach for this problem should include block resection of the fibrotic area within the widely irradiated area. Often the consequence is increased morbidity and potential risk of further delay in wound healing.
      Our patient was referred to our hospital for ozone therapy because of our previous experience in treating side effects of oncology therapy.
      • Clavo B.
      • Gutierrez D.
      • Martin D.
      • et al.
      Intravesical ozone therapy for progressive radiation-induced hematuria.
      • Clavo B.
      • Suarez G.
      • Aguilar Y.
      • et al.
      Syndrome of brain ischemia and hypometabolism treated by ozone therapy.
      We have described the effect of this technique in improving blood flow
      • Clavo B.
      • Suarez G.
      • Aguilar Y.
      • et al.
      Syndrome of brain ischemia and hypometabolism treated by ozone therapy.
      • Clavo B.
      • Catala L.
      • Perez J.L.
      • Rodriguez V.
      • Robaina F.
      Ozone therapy on cerebral blood flow: a preliminary report.
      and tissue oxygenation,
      • Clavo B.
      • Perez J.L.
      • Lopez L.
      • et al.
      Effect of ozone therapy on muscle oxygenation.
      both of which are decreased in radiation-induced fibrosis. Additionally, the antimicrobial properties of ozone augur well for complementary management of the documented infection associated with drained fluid.
      • Valacchi G.
      • Fortino V.
      • Bocci V.
      The dual action of ozone on the skin.
      • Bocci V.
      • Borrelli E.
      • Travagli V.
      • Zanardi I.
      The ozone paradox: ozone is a strong oxidant as well as a medical drug.
      Based on the mechanism of action of different treatments proposed for radiation-related fistula/fibrosis,
      • Delanian S.
      • Lefaix J.L.
      Current management for late normal tissue injury: radiation-induced fibrosis and necrosis.
      other properties ascribed to ozone therapy can be of additional clinical value, such as immunomodulation,
      • Bocci V.
      • Borrelli E.
      • Travagli V.
      • Zanardi I.
      The ozone paradox: ozone is a strong oxidant as well as a medical drug.
      anti-inflammatory effects through phospholipase A2 decrease,
      • Barber E.
      • Menendez S.
      • Leon O.S.
      • et al.
      Prevention of renal injury after induction of ozone tolerance in rats submitted to warm ischaemia.
      and an enhanced antioxidant system.
      • Bocci V.
      • Borrelli E.
      • Travagli V.
      • Zanardi I.
      The ozone paradox: ozone is a strong oxidant as well as a medical drug.
      • Barber E.
      • Menendez S.
      • Leon O.S.
      • et al.
      Prevention of renal injury after induction of ozone tolerance in rats submitted to warm ischaemia.
      In our patient, physical examination (palpation) showed a decrease in the surface dimension of fibrosis and the level of induration. However, these assessments often seem imprecise and subjective. TiVi (Fig. 1, upper and lower right) is noninvasive and highly reproducible. In our patient, changes measured with this technique pre- and post-ozone treatment provided more objective assessment of the changes than palpation, that is, decrease in thickness and dimensions of the induration/fibrosis area.
      In conclusion, management of refractory fistulae and fibrosis in previously irradiated areas can be difficult. Local treatment with ozone can be easy and effective especially when more standard treatments are unsuccessful or are not available. Tissue viability imaging using linearly polarized light can be a very useful tool for objective assessment and follow-up of fibrosis.

      Disclosures and Acknowledgments

      Research activity related to this work was supported, in part, by the I3SNS Program from the Instituto de Salud Carlos III (INT07/030 for BC and INT 07/172 for NS), Madrid, Spain. The ozone therapy device, Ozonosan Alpha-plus®, was provided by Dr. Hänsler GmbH (Iffezheim, Germany). Editorial assistance was provided by Dr. Peter R. Turner of t-SciMed (Reus, Spain). The authors declare no conflicts of interest.

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      Linked Article

      • Ozone Therapy in the Management of Enterocutaneous Fistulas Resulting from Postsurgery Abdominal/Pelvic Mesh Placement
        Journal of Pain and Symptom ManagementVol. 43Issue 4
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          To replace part of the abdominal wall, or for wound closure without tension postsurgery, either polypropylene or expanded polytetrafluoroethylene mesh is commonly used. These synthetic materials are useful but, owing to the variety and complexity of complications, long-term problems are common.1–3 Severe infections associated with mesh extrusion and enterocutaneous fistulas are fairly frequent drawbacks and are difficult to manage without mesh removal. However, de novo abdominal-pelvic surgery for mesh removal can be high risk in older patients or in those with comorbidities.
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