POLSKI PRZEGLĄD CHIRURGICZNY 2014, 86, 2, 94–96
10.2478/pjs-2014-0017
CASE REPORTS
Multiple colon perforation as a fatal complication during treatment of metastatic melanoma with ipilimumab – case report Paweł Dilling1, Jakub Walczak1, Paweł Pikiel1, Wiesław J. Kruszewski1,2 Department of Surgical Oncology, Gdynia Oncology Center, Maritime Hospital in Gdynia1 Kierownik: prof. dr hab. W. J. Kruszewski Division of Propedeutics of Oncology, Medical University in Gdańsk2 Kierownik: prof. dr hab. W. J. Kruszewski Ipilimumab, an anticancer drug, is an anti-CTLA4 monoclonal antibody. It is used in treatment of disseminated melanoma. Therapy is associated with high risk of complications. One of the most serious, although one of the rarest is perforation of gastrointestinal tract. In this case report we describe a 52-year old male, with disseminated melanoma with unknown starting point, treated with antiCTLA4 monoclonal antibody. After 3rd dose of drug administration, bloody diarrhea and acute abdominal pain occurred as a symptom of gastrointestinal perforation. A single perforation was sutured during laparotomy. Symptoms of acute abdomen returned after 10 days. Pus-faecalperitonitis, symptoms of necro-hemorrhagic colitis and multilocal perforation of the colon were found during relaparotomy. Pancolectomy with end ileostomy was performed. Few hours since relaparotomy pacient died due to multiple organ failure. The purpose of this case report is to draw attention to a risk of multilocal colon perforation in patient treated with ipilumumab. Key words: melanoma, ipilimumab, anti-CTLA4, complications
Ipilimumab belongs to the group of cancer drugs which use the antigen-antibody reaction. The active drug substance is the antiCTLA4 monoclonal antibody directed against the CD152 receptor located on the surface of T lymphocytes mediating the inhibition of lymphocyte T activation (1). The administration of ipilimumab promotes the activation of T lymphocytes towards proliferation. Thus, arising lymphocytic infiltrations in the vicinity of the tumor increase the chance of tumor cell apoptosis. The efficacy of anti-CTLA4 was confirmed in case of patients with advanced melanoma, and introduced into the treatment of the abovementioned disease. The recommended therapeutic schedule consists in the intravenous dosage of 3 mg/kg/ body weight, once every 3 weeks in four doses. Ipilimumab therapy might
be responsible for the development of complications, such as reduction of appetite, nausea, vomiting, enteritis, diarrhea, rash presence, pruritis, fever, and others (1-5). The most severe complications, although rare, include gastrointestinal perforation, septic shock, Guillain-Barré syndrome, hepatic and renal failure. As a result, each of these complications lead to patient death. According to recent analysis of ongoing clinical trials with a dose of 10 mg/kg/body weight, one may come to the conclusion that increased drug doses increase the risk of complications (6, 7). Case report In November, 2011, a 52-year old man observed enlarged lymph nodes in his left
Brought to you by | Cambridge University Library Authenticated Download Date | 9/13/15 3:21 AM
Multiple colon perforation as a fatal complication during treatment of metastatic melanoma with ipilimumab
armpit. The lymph nodes were collected for histopathological analysis, which supplemented by immunohistochemical analysis revealed the presence of melanoma metastases. The primary lesion was not found. Over time, peripheral lymphadenopathy was observed. The PET-CT examination performed in May, 2012 revealed the presence of generalized malignancy in the chest, abdomen, and pelvis. Neoplastic lymphadenopathy predominated, the liver was free of secondary lesions. In June, 2012 imaging examinations showed the presence of a metastatic lesion located in the VIII hepatic segment. The patient received ipilimumab therapy. Since treatment was held under a clinical trial regimen the dose of the drug was concealed. After the third dose of the drug the patient complained of hemorrhagic diarrhea. The patient developed an acute abdomen as a symptom of gastrointestinal perforation and ensuing peritonitis. Laparotomy was performed at the Department of Surgery, county hospital, with suturing of the perforated bowel. After stabilization of the general condition the patient was transferred to the Department of Surgical Oncology, Gdynia Oncology Center for the treatment of systemic therapy complications. Steroid therapy was initiated. Ipilimumab was not administered. Ten days after laparotomy the patient was transferred to the Department of Surgery, Gdynia Oncology Center with clinical symptoms of diffuse peritonitis, as a consequence of gastrointestinal perforation, and presence of left pleural cavity fluid. Ad hoc laboratory and imaging diagnostics confirmed the clinical diagnosis and the patients’ severe condition. Alkalosis dominated. Laboratory results were as follows: CRP – 41.4, hemoglobin – 10.5 g/dl, hematocrite – 35%. After decompression of the left pleural cavity, 800 ml
95
of a serous-hemorrhagic content was obtained. Emergency laparotomy was performed demonstrating fecal-purulent peritonitis, necrotic colitis, and multifocal colon perforation. Colectomy was performed with end ileostomy. The patient was transferred to the ICU with symptoms of septic shock, where he died several hours later, due to multiorgan failure. The histopathological examination revealed the presence of multifocal deep ulcerations with the development of fissures penetrating into the muscular layer (fig. 1). In 35% of patients treated by means of anti-CTLA4, one may observe the occurrence of complications. Death, due to gastrointestinal perforation is observed in less than 1% of patients (4). Despite the incidence of complications, including those that are lifethreatening, such as multifocal colon perforation, ipilimumab remains a useful drug possibly prolonging the life of patients diagnosed with advanced melanoma (6, 7). Our observation confirmed the advisability of emergency clinical surveillance, considering a patient with colitis and perforation, as potential fatal complications during ipilimumab therapy.
Fig. 1
REFERENCES 1. Bugelski PJ, Martin PL: Concordance of preclinical and clinical pharmacology and toxicology of therapeutic monoclonal antibodies and fusion proteins: cell surface targets. Br J Pharmacol 2012; 166(3): 823-46 2. Lyall A, Vargas HA, Carvajal RD et al.: Ipilimumab-induced colitis on FDG PET/CT. Clin Nucl Med. 2012; 37(6): 629-30.
3. Johnston RL, Lutzky J, A Chodhry et al.: Cytotoxic T-lymphocyte-associated antigen 4 antibodyinduced colitis and its management with infliximab. Dig Dis Sci 2009; 54(11): 2538-40. 4. Minor D, Chin K, Kashani-Sabet M: Infliximab in the treatment of anti-CTLA4 antibody (Ipilimumab) induced immune-related colitis. Cancer Biother Radiopharm 2009; 24(3): 321-25.
Brought to you by | Cambridge University Library Authenticated Download Date | 9/13/15 3:21 AM
96
P. Dilling et al.
5. Koch Ch, Paetzold S, Trojan J: Enetrocolitis in a patient being treated with ipilimumab for metastatic melanoma. Gastroenterology 2012; 143(2): 298, 504-05. 6. Jeter JM, Cranmer LD, Marsh EM: Ipilimumab pharmocotherapy in patients with metastatic
melanoma. Clin Med Insights Oncol 2012; 6: 27586. 7. Beck KE, Blanfield JA, Tran KQ et al.: Enerocolitis in patiens with cancer after anibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J ClinOncol 2006; 24(15): 2283-89.
Received: 4.03.2013 r. Adress correspondence: 81-519 Gdynia, ul. Powstania Styczniowego 1 e-mail: [email protected]
Brought to you by | Cambridge University Library Authenticated Download Date | 9/13/15 3:21 AM
10.2478/pjs-2014-0017
CASE REPORTS
Multiple colon perforation as a fatal complication during treatment of metastatic melanoma with ipilimumab – case report Paweł Dilling1, Jakub Walczak1, Paweł Pikiel1, Wiesław J. Kruszewski1,2 Department of Surgical Oncology, Gdynia Oncology Center, Maritime Hospital in Gdynia1 Kierownik: prof. dr hab. W. J. Kruszewski Division of Propedeutics of Oncology, Medical University in Gdańsk2 Kierownik: prof. dr hab. W. J. Kruszewski Ipilimumab, an anticancer drug, is an anti-CTLA4 monoclonal antibody. It is used in treatment of disseminated melanoma. Therapy is associated with high risk of complications. One of the most serious, although one of the rarest is perforation of gastrointestinal tract. In this case report we describe a 52-year old male, with disseminated melanoma with unknown starting point, treated with antiCTLA4 monoclonal antibody. After 3rd dose of drug administration, bloody diarrhea and acute abdominal pain occurred as a symptom of gastrointestinal perforation. A single perforation was sutured during laparotomy. Symptoms of acute abdomen returned after 10 days. Pus-faecalperitonitis, symptoms of necro-hemorrhagic colitis and multilocal perforation of the colon were found during relaparotomy. Pancolectomy with end ileostomy was performed. Few hours since relaparotomy pacient died due to multiple organ failure. The purpose of this case report is to draw attention to a risk of multilocal colon perforation in patient treated with ipilumumab. Key words: melanoma, ipilimumab, anti-CTLA4, complications
Ipilimumab belongs to the group of cancer drugs which use the antigen-antibody reaction. The active drug substance is the antiCTLA4 monoclonal antibody directed against the CD152 receptor located on the surface of T lymphocytes mediating the inhibition of lymphocyte T activation (1). The administration of ipilimumab promotes the activation of T lymphocytes towards proliferation. Thus, arising lymphocytic infiltrations in the vicinity of the tumor increase the chance of tumor cell apoptosis. The efficacy of anti-CTLA4 was confirmed in case of patients with advanced melanoma, and introduced into the treatment of the abovementioned disease. The recommended therapeutic schedule consists in the intravenous dosage of 3 mg/kg/ body weight, once every 3 weeks in four doses. Ipilimumab therapy might
be responsible for the development of complications, such as reduction of appetite, nausea, vomiting, enteritis, diarrhea, rash presence, pruritis, fever, and others (1-5). The most severe complications, although rare, include gastrointestinal perforation, septic shock, Guillain-Barré syndrome, hepatic and renal failure. As a result, each of these complications lead to patient death. According to recent analysis of ongoing clinical trials with a dose of 10 mg/kg/body weight, one may come to the conclusion that increased drug doses increase the risk of complications (6, 7). Case report In November, 2011, a 52-year old man observed enlarged lymph nodes in his left
Brought to you by | Cambridge University Library Authenticated Download Date | 9/13/15 3:21 AM
Multiple colon perforation as a fatal complication during treatment of metastatic melanoma with ipilimumab
armpit. The lymph nodes were collected for histopathological analysis, which supplemented by immunohistochemical analysis revealed the presence of melanoma metastases. The primary lesion was not found. Over time, peripheral lymphadenopathy was observed. The PET-CT examination performed in May, 2012 revealed the presence of generalized malignancy in the chest, abdomen, and pelvis. Neoplastic lymphadenopathy predominated, the liver was free of secondary lesions. In June, 2012 imaging examinations showed the presence of a metastatic lesion located in the VIII hepatic segment. The patient received ipilimumab therapy. Since treatment was held under a clinical trial regimen the dose of the drug was concealed. After the third dose of the drug the patient complained of hemorrhagic diarrhea. The patient developed an acute abdomen as a symptom of gastrointestinal perforation and ensuing peritonitis. Laparotomy was performed at the Department of Surgery, county hospital, with suturing of the perforated bowel. After stabilization of the general condition the patient was transferred to the Department of Surgical Oncology, Gdynia Oncology Center for the treatment of systemic therapy complications. Steroid therapy was initiated. Ipilimumab was not administered. Ten days after laparotomy the patient was transferred to the Department of Surgery, Gdynia Oncology Center with clinical symptoms of diffuse peritonitis, as a consequence of gastrointestinal perforation, and presence of left pleural cavity fluid. Ad hoc laboratory and imaging diagnostics confirmed the clinical diagnosis and the patients’ severe condition. Alkalosis dominated. Laboratory results were as follows: CRP – 41.4, hemoglobin – 10.5 g/dl, hematocrite – 35%. After decompression of the left pleural cavity, 800 ml
95
of a serous-hemorrhagic content was obtained. Emergency laparotomy was performed demonstrating fecal-purulent peritonitis, necrotic colitis, and multifocal colon perforation. Colectomy was performed with end ileostomy. The patient was transferred to the ICU with symptoms of septic shock, where he died several hours later, due to multiorgan failure. The histopathological examination revealed the presence of multifocal deep ulcerations with the development of fissures penetrating into the muscular layer (fig. 1). In 35% of patients treated by means of anti-CTLA4, one may observe the occurrence of complications. Death, due to gastrointestinal perforation is observed in less than 1% of patients (4). Despite the incidence of complications, including those that are lifethreatening, such as multifocal colon perforation, ipilimumab remains a useful drug possibly prolonging the life of patients diagnosed with advanced melanoma (6, 7). Our observation confirmed the advisability of emergency clinical surveillance, considering a patient with colitis and perforation, as potential fatal complications during ipilimumab therapy.
Fig. 1
REFERENCES 1. Bugelski PJ, Martin PL: Concordance of preclinical and clinical pharmacology and toxicology of therapeutic monoclonal antibodies and fusion proteins: cell surface targets. Br J Pharmacol 2012; 166(3): 823-46 2. Lyall A, Vargas HA, Carvajal RD et al.: Ipilimumab-induced colitis on FDG PET/CT. Clin Nucl Med. 2012; 37(6): 629-30.
3. Johnston RL, Lutzky J, A Chodhry et al.: Cytotoxic T-lymphocyte-associated antigen 4 antibodyinduced colitis and its management with infliximab. Dig Dis Sci 2009; 54(11): 2538-40. 4. Minor D, Chin K, Kashani-Sabet M: Infliximab in the treatment of anti-CTLA4 antibody (Ipilimumab) induced immune-related colitis. Cancer Biother Radiopharm 2009; 24(3): 321-25.
Brought to you by | Cambridge University Library Authenticated Download Date | 9/13/15 3:21 AM
96
P. Dilling et al.
5. Koch Ch, Paetzold S, Trojan J: Enetrocolitis in a patient being treated with ipilimumab for metastatic melanoma. Gastroenterology 2012; 143(2): 298, 504-05. 6. Jeter JM, Cranmer LD, Marsh EM: Ipilimumab pharmocotherapy in patients with metastatic
melanoma. Clin Med Insights Oncol 2012; 6: 27586. 7. Beck KE, Blanfield JA, Tran KQ et al.: Enerocolitis in patiens with cancer after anibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J ClinOncol 2006; 24(15): 2283-89.
Received: 4.03.2013 r. Adress correspondence: 81-519 Gdynia, ul. Powstania Styczniowego 1 e-mail: [email protected]
Brought to you by | Cambridge University Library Authenticated Download Date | 9/13/15 3:21 AM
