Minimally invasive treatment of peristomal metastases from gastric cancer at an ileostomy site by electrochemotherapy

Background Peristomal metastases are rare, but potentially associated with relevant morbidity. Surgical resection, followed by stoma relocation, represent the gold standard in most patients. We describe electrochemotherapy (ECT), a minimally invasive method for locally-enhancing drug delivery by means of electric pulses, as an alternative approach. Patient and methods A 49-year-old man with advanced gastric cancer developed skin metastases around an ileostomy site. The ulcerated and oozing tumor growth impaired patient’s quality of life due to continuous trouble in fitting the ostomy appliance, its poor adherence and consequent stools spillage. ECT consisted of a 20-minute course under mild general sedation. A bleomycin bolus of 15 000 IU/m2 was followed by the percutaneous application of multiple, 1.5 ms -long electric pulses by means of a needle electrode. Results Post ECT course was uneventful and the patient was discharged on the same day. After one week, tumor nodules were flattened and partial tumor regression was appreciable at one-month follow-up. More importantly, peristomal skin conditions significantly improved, thus allowing for an effective application of the ostomy appliance during the following moths, until patient’s death. Conclusions This report suggests the feasibility of ECT as a minimally invasive approach for peristomal tumors. In selected cases, ECT, by achieving a rapid tumor control, may ensure effective ostomy management and preserve patients’ quality of life.


Introduction
Despite the introduction of combined treatment strategies, gastric cancer (GC) remains one of the leading causes of cancer-related death worldwide. 1 The most common metastatic sites are lymph nodes, liver, ovary and peritoneal cavity. The oc-currence of skin metastases is a rare event, generally found at a very late stage of disease [2][3][4] and, occasionally, as the initial clinical manifestation. [5][6][7][8] Isolated superficial metastases have been also described following invasive procedures (i.e. laparoscopic surgery). 9,10 Peristomal metastases represent an even rarer, but challenging finding, due to pos-sible bowel obstruction and trouble in ostomy management. Wide local excision and stoma relocation, when feasible, represent the gold standard treatment for these patients. Unfortunately, only few of them are still considered resectable when skin metastases occur, due to disease extension and poor general conditions. Electrochemotherapy (ECT) is a minimally-invasive approach which is gaining increasing acceptance in patients with unresectable or refractory superficial metastases, thanks to its sustained antitumor activity in different tumor histotypes, rapid patient's recovery and favorable short-term outcomes. 11,12 ECT mechanism relies on the association of an anticancer agent, bleomycin (BLM) or cisplatin (CDDP), with transient tumor permeabilization by means of brief, high-voltage, electric pulses (electroporation). 13 The drug can be administered as an intravenous bolus or, alternatively, by the intratumoral route, according to disease burden. 14 Tumor electroporation is achieved by the application of suitable plate or needle electrodes. Electric pulses open multiple, reversible pores on cell membrane, throughout which an increased number of chemotherapy molecules entry into the cell and exert their selective cytotoxic activity ( Figure 1). We here report on the first case featuring ECT as an alternative treatment in a patient with symptomatic skin metastases from GC at an ileostomy site.

Case report
A 49-year-old man with peritoneal carcinomatosis from GC, who previously required the construction of an end-ileostomy due to bowel obstruction, presented with multiple peristomal metastases that were confluent in a 10 x 10 cm area on the abdominal wall ( Figure 2). In 2008 the patient was diagnosed with stage IV GC with peritoneal dissemination. He received 3 cycles of epirubicin, oxaliplatin and 5-fluorouracil, before undergoing total gastrectomy, D2 lymphadenectomy, distal pancreatectomy and splenectomy. Histopathological examination was T4aN3aM1, signet ring cells, HER2 negative, gastric adenocarcinoma. Additional 5 cycles of adjuvant chemotherapy were administered after surgical treatment. In April 2010, chemotherapy with epirubicin, oxaliplatin and 5-fluorouracil was started and then shifted to docetaxel, cisplatin plus 5-fluorouracil. In September 2011, an ileostomy was created in the lower right abdominal quadrant in order to palliate the progressively worsening symptoms of bowel obstruction. Third line monochemotherapy with irinotecan was ongoing at the time of our first evaluation, on October 2011. Given patient's low performance status according to the Eastern Cooperative Oncology Group scale, peritonectomy associated with intraperitoneal chemotherapy was deemed contraindicated. On the other hand, peristomal tumor growth was highly symptomatic, since cutaneous metastases caused a continuous burning sensation that was exacerbated by the contact with liquid and slightly caustic stools at the ileostomy site. Moreover, tumor nodules were oozing and partially bleeding and the abundant exudate engendered continuous troubles in ileostomy management, due to difficult application of the pouching bag. At physical examination, ileostomy outer mucosa appeared macroscopically normal ( Figure 2B). Mild stricture was present, but repetitive manual expansions maintained its patency and digital exploration was negative for tumor infiltration. ECT was offered with a palliative intent to improve diseaserelated complaints and everyday ileostomy management. The patient signed an informed consent. Tumor nodules are briefly exposed to a train of eight consecutive, high voltage (1000 V/cm), square-wave, 100-ms electric pulses, delivered at a repetition frequency of 5000 Hz by means of a needle electrode inserted into tumor tissue and connected to a pulse generator. As a consequence, transient pores open on the cell membrane and enable bleomycin concentration and entrapment, thus increasing its cytotoxic activity.
ECT procedure lasted 20 min and was performed under mild general sedation ( Figure 3A). Tumor site was rinsed and prepared with sterile drapes; a silicon tube was placed into the ileostomy in order to drain stools and keep the operative field clean. ( Figure 3B) Chemotherapy consisted of an intravenous bolus of BLM (15 000 IU/m 2 ). After 8 minutes, necessary for drug biodistribution in accordance with the European Standard Operating Procedures on Electrochemotherapy (ESOPE) 15 , electric pulses were delivered by percutaneously inserting a 2-cm long needle electrode into skin nodules ( Figure 3C). The electrode is composed of seven metal needles arranged in an hexagonal fashion ( Figure 1) and is maneuvered by means of an handle connected to an electric pulse generator (Cliniporator TM , Igea, Modena, Italy) ( Figure 3A). Complete tumor coverage was achieved by means of multiple electrode placements delivering a 1.5 ms -long electric pulse. At the end of the procedure, local toxicity consisted of slight skin marks at the site of electrode insertion ( Figure 3D). There was no sign of bleeding, rather the thicker portion of the tumor turned to a bluish coloration due to local vasoconstriction ( Figure 3D). After treatment, electroporated skin was carefully cleaned and covered with a healing powder ( Figure 4A). Moreover, a custom-sized hydrocolloid dressing (DuoDERM ® , ConvaTech, Inc.) was applied over the ECT field ( Figure 4B) and the space between ileostomy and peristomal skin was sealed by means of a stoma paste (Stomahesive ® Paste, ConvaTech, Inc.) in order to prevent stools leakage over inflamed tissues ( Figure 3C). Additionally, a silicon catheter was placed into the stoma in order to drain stools directly into the ostomy bag (Figure 4 C,D). The postoperative course was uneventful and the patient was discharged on the same day with the prescription for a course of metronidazole plus ciprofloxacin prophylactic therapy. After one week, tumor nodules were significantly flattened ( Figure 5A). Skin care consisted of hydrocolloid dressing application combined with stools deviation by means of a silicon tube ( Figure 5B). After three weeks, physical examination showed a normal appearing stoma with adjacent mild erythema and partially necrotic skin from the 12-o'clock to the 7-o'clock position ( Figure 5C). Tumor nodules were partially regressed and electroporated skin was healing and dry, thus allowing for easy application and effective sealing of the ostomy flange and pouching bag ( Figure 5D). The ileostomy function remained normal throughout this period and no sign of infection was present. In January 2011, one moth after treatment, the patient returned to the outpatient clinic for a minor surgical debridement, during which the necrotic crusts were removed, leaving an underlying intact tissue that was suitable for the application of the ostomy flange. The ileostomy maintained its patency and, importantly, the adherence of the stoma appliance was preserved during the following four months, until patient's death.

Discussion
Peristomal tumors represent a rare late complication of surgery for gastrointestinal cancers [16][17][18] and inflammatory bowel diseases. [19][20][21][22] Sporadically, peristomal metastases have been reported also in patients with head and neck 23,24 and genitourinary tumors. 25 Besides harboring the risk of possible stoma obstruction, these lesions may interfere with peristomal skin care and application of the pouching systems. In patients with bowel deviation, all the conditions that produce a less than perfect adhesion of the stoma appliance may cause direct contact between stools and peristomal skin, thus affecting patient's quality of life. 26,27 In fact, even minor consequences, such as peristomal dermatitis, need extra medical care that may significantly impair ostomy everyday management, patients' autonomy and ultimately increase the costs of the procedure. 27,29 Wide local resection followed by stoma resiting, when feasible, represent the only potential effective treatment for peristomal metastases. Unfortunately, in our patient en bloc resection of the stoma together with surrounding soft tissues would have require abdominal wall repair by means of a complex reconstructive technique (i.e. long groin flap, anterolateral thigh flap or latissimus dorsi flap) that would have been likely associated with relevant morbidity in a patient with peritoneal carcinomatosis and poor general conditions. On the contrary, ECT procedure proved feasible and well tolerated. It ensured rapid local tumor control thus proving effective in palliating disease-related complaints. A single course of treatment led to an appreciable flattening of peristomal tumor nodules. As a result, the improved peristomal skin conditions allowed for the effective application of ileostomy bag and prevented stools spillage on the abdominal wall.
Since local inflammatory reaction and soft tissue ulceration are possible side effects of ECT application 30,31 , one challenging aspect was played by peristomal skin protection from the ileostomy outflow. Our management strategy aimed at separating the electroporated skin from stools. For this purpose, a smooth silicon drain was placed into the ileostomy during the procedure and the first postoperative course. Moreover, a hydrocolloid dressing proved to be an effective barrier and a reliable support for the flange of the pouching system.
It is not clear to us why, despite the rapid and homogeneous tumor response after one week ( Figure 4A), afterwards local response was rather inhomogeneous and some portions of the tumor were clearly necrotic, while others not ( Figure 4C). Although BLM was given intravenously, in accordance with ESOPE guidelines 14 which recommend systemic drug administration in case of multiple or large tumors, the irregular tumor vascularization and consequent inhomogeneous drug distribution could explain the jeopardized response to treatment in our patient.  ECT has been recognized as a safe and effective option for patients with superficially disseminated metastases, mainly from malignant melanoma and breast cancer. 30,31 Interestingly, several other tumor histotypes seem to be sensitive to electroporationdriven chemotherapy, thus potentially expanding the number of eligible patients. 11 If its efficacy and feasibility will be further confirmed, ECT could represent not only a valuable palliative option for peristomal metastases, but also an effective treatment for those patients with primary skin / soft tissue tumors arising at any ostomy site. Although rare, the occurrence of peristomal primary tumors have been described, especially in the setting of colorectal cancer or inflammatory bowel diseases (Table 1). [32][33][34][35][36][37][38] Waiting for more evidence, in our opinion some precautions should be taken when applying ECT to peristomal lesions. First, since some peristomal tumors may represent metachronous intestinal cancers, which are not amenable with current ECT equipment (due to feasibility of electrode application and possible damage to intestinal wall), preoperative clinical or endoscopic evaluation seems mandatory. Second, electrode insertion should be extremely careful and possibly image-guided, in order to avoid direct physical damage or late cytotoxic effects to the stoma. Finally, the assistance of an ostomy nursing staff represent a precious support to ensure adequate skin care and pouching system management.
In conclusion, we applied, for the first time, ECT in a very rare, but morbid condition such as skin tumor infiltration from GC at an ileostomy site. A single 20-minute treatment course led to rapid