Chemo-Radiation Therapy for Locally Advanced Rectal Cancer in a Patient Affected by Hereditary Angioedema

Acta Medica Mediterranea, 2014, 30: 1245

CHEMO-RADIATION THERAPY FOR LOCALLY ADVANCED RECTAL CANCER IN A PATIENT AFFECTED BY HEREDITARY ANGIOEDEMA. A CASE REPORT AND A LITERATURE REVIEW

TOLU BARBARA*, PONTI ELISABETTA*, LANCIA ANDREA*, BRUNI CLAUDIA*, CICCHETTI SARA*, MURGIA ALESSANDRA*, DI CRISTINO DANIELA*, MORELLI PASQUALE*, TERENZI SARA*, PIETRASANTA FRANCA^, SANTONI RICCARDO* * M.D. of Radiation Therapy Unit, Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology and Radiotherapy, University of Tor Vergata, Rome, Italy. ^RN, MSN of Radiation Therapy Unit, Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology and Radiotherapy, University of Tor Vergata, Rome, Italy

ABSTRACT

Angioedema is a rare disorder caused by C1 inhibitor deficiency that may be either hereditary or acquired. We report a case about a 42-year-old male who was referred to our Centre of Radiotherapy with the diagnosis of a locally advanced rectal carcinoma and Hereditary Angioedema. Preoperative chemo-radiotherapy was proposed during our gastro-enteric tumour board and the rheumatologist gave no absolute contraindication to chemo-radiotherapy ensuring that the patient was instructed to control angioedema attacks by self-administering C1 inhibitor concentrate. A Total Fractionated Dose of 54 Gy was delivered to the target volume (45 Gy to the whole pelvis and a boost dose of 9 Gy to the rectal volume only) with 1.8 Gy daily fractions, in association with continual infusion of 5-fluorouracil (300 mg/mq) five days per week. The treatment was well tolerated; the patient presented only G1 gastrointestinal toxicity according to RTOG/EORTC score criteria with no angioedema attacks during treatment. Severe abdominal cramps, associated with bowel sounds, diffuse abdominal pain and nausea were referred by the patient a week after completion of treatment. Complete symptom remission appeared after self-administering C1 inhibitor concentrate. To our knowledge, this is the only patient described in literature who completed chemo-radiotherapy in the presence of a life threatening condition such as Hereditary Angioedema is. It is interesting to notice that even though no data exist about the use of radiotherapy on the pelvis in patients affected by Hereditary Angioedema this treatment modality seems to be safe even when associated with chemotherapy.

Key words: Hereditary Angioedema, Rectal Cancer, Chemo-radiotherapy, Gastro-intestinal toxicity. Received May 18, 2014; Accepted September 02, 2014

Introduction of functional C1 inhibitor and C4 levels. Attenuated androgens, anti-fibrinolytics, and C1 inhibitor con- Angioedema caused by C1 inhibitor deficien- centrate (C1INH) are used for long-term and pre- cy is a rare disorder that may be either hereditary or procedure prophylaxis, but have significant draw- acquired, the latter being mainly associated with backs. C1 inhibitor concentrate and fresh frozen lymphoproliferative disorders(1). Hereditary plasma are available for acute intervention(2). angioedema (HAE) is an autosomal-dominant defi- Limited experience is reported in literature about ciency of C1 inhibitor (a serpin inhibitor of the association between this syndrome and malig- kallikrein, C1r, C1s, factor XII, and plasmin). nant tumors requiring aggressive treatments with Quantitative or qualitative deficiency of C1 relevant side effects. Our aim is to report about a inhibitor leads to the generation of vasoactive medi- patient who underwent chemo-radiotherapy treat- ators, most likely bradykinin. The clinical syn- ment (CHT-RT) for a locally advanced rectal carci- drome consists in repeated bouts of non-pruritic noma in the presence of HAE. This is to contribute edema of the face, larynx, extremities, and intesti- to a better knowledge of the possibility to safely nal viscera. Hereditary angioedema is often misdi- treat these patients affected by life-threatening agnosed and poorly treated; diagnosis requires care- pathologies. ful medical and family history and the measurement 1246 Tolu Barbara, Ponti Elisabetta et Al

Case presentation only G1 gastrointestinal toxicity according to RTOG/EORTC toxicity criteria score with no We report about the case of a 42-year-old male angioedema attacks during treatment. Severe who was referred to our Centre of Radiotherapy abdominal cramps, associated with bowel sounds, with the diagnosis of a rectal carcinoma and diffuse abdominal pain and nausea were referred by Hereditary Angioedema (HAE) which was diag- the patient a week after completion of CHT-RT nosed when he was 12. His past medical history treatment disappearing after self-administering was significant for asthma, hypertension, left varic- C1INH with complete symptom remission. ocele and hydrocele. In October 2012 he presented A CT scan and a rectal ultrasound endoscopy intermittent rectal bleeding and in March 2013 he were obtained showing a considerable downsizing underwent colonoscopy demonstrating an ulcerated, in spite of the fact that ultra-sound staging didn’t exophytic rectal lesion, pathology showing an ade- change (uT3 uN-). nocarcinoma. A lesion at 1 cm from the anal verge Eight weeks after the end of chemo-radiation extending cranio-caudally for 10 cm and infiltrating the patient underwent surgery with total mesorectal all mucosal layers, reaching the perivisceral fat excision (TME) and pathology demonstrated a with small perirectal nodes was demonstrated on poorly differentiated adenocarcinoma of the rectum rectal ultrasound-endoscopy. Loco-regional staging with mucinous aspects. Final stage was ypT3 ypN0 was usT3 N+. No distant metastases were detected G3. Eight cycles of chemotherapy using at total body computed tomography (CT). Oxaliplatin, 5-FU and folinic acid were adminis- Preoperative CHT-RT was proposed during our gas- tered postoperatively. Patient is disease free one tro-enteric tumour board; the rheumatologist fol- year after completion of treatment. lowing the patient was involved and gave no absolute contraindication to CHT-RT ensuring that Discussion the patient was instructed to control any angioedema attack by self-administering C1INH. Literature reports only few cases of patients Prophylaxis with androgens and/or tranexamic acid affected by angioedema and treated for a neoplasm was also suggested. The risks related to the chemo- and, to our knowledge, only one case affected by radiation therapy treatment were widely explained HAE and treated with concurrent CHT-RT for can- to the patient who accepted and signed a written cer by Kasamatsu et al. in Japan. They reported consent form. He underwent a planning CT scan about a 69-year-old man affected by HAE and lung (GE LightSpeed® Scanner, GE Healthcare cancer who developed acute attacks of angioedema Diagnostic Imaging Slough, UK) of the abdomen during chemotherapy. Attacks were managed by and pelvis region in prone position at 5 mm thick- self-administration of C1INH and for this reason ness and the images were transferred to the Precise danazol was given during concurrent CHT-RT pre- Plan Treatment Planning System (Elekta Oncology venting further occurrence of angioedema attacks(3). Systems, Crawley, UK) where Clinical Target Christie D.R.H. et al.(4) described the associa- Volume (CTV) and organs at risk (OAR) were tion between HAE and breast cancer in a family in defined. CTV was delineated as the rectal lesion which diseases coexisted. Only a member of this including pelvic nodes. OAR were bladder, bowel family underwent surgery followed by adjuvant and femoral heads. Planning Target Volume (PTV) chemotherapy. She was given a course of radiation was obtained adding 5 mm all around the CTV. A therapy in association with danazol without devel- Total Fractionated Dose of 54 Gy was delivered to oping severe reactions or any angioedema attack. the target volume (45 Gy to the whole pelvis and a The association of rectal carcinoma and boost dose of 9 Gy to the rectal volume only) with Acquired Angioedema (AAE) has been described 1.8 Gy daily fractions. High energy photons (10 and by Cohen et al.(5). The patient was treated with 15 MV) were used to deliver, 5 days per week, the danazol, he underwent surgery and developed only prescribed dose using a commercial Linac one episode of laryngeal edema after surgery. He (Standard Elekta Precise®) in association with con- was negative for local recurrence or distant metas- tinuous infusion of 5-Fluorouracile (5-FU) (300 tases at follow-up. mg/mq). The treatment was well tolerated, blood In spite of the lack of correlation between samples were obtained regularly during treatment HAE and cancer, an association between AAE and and resulted unremarkable; the patient presented immunoproliferative disorders (non Hodgkin’s lym- Chemo-radiation therapy for locally advanced rectal cancer in a patient affected by Hereditary Angioedema... 1247 phoma and Chronic Lymphocytic Leukaemia) has cannot comment on the possibility to extend these been described(6-9). conclusions to all of the patients with such a diag- As few data exist in literature about concurrent nosis including those with the acquired form which diagnosis of HAE with a tumour requiring concomi- seems to be more common. tant CHT-RT no specific conclusions about safety of these associated treatments have been stated. To our knowledge this is the only patient recently described in literature and treated with References concomitant CHT-RT for locally advanced rectal carcinoma with an associated diagnosis of HAE. 1) Collard HR, Schwarz MI. Diffuse alveolar hemor1) , Luengo O, Nogueiras C, Labrador-Horrillo M, Muñoz As HAE represents a potentially life threaten- E, López A, Cardona V. Acquired angioedema associat- ing clinical condition characterized by acute and ed with hereditary angioedema due to C1 inhibitor unexpected onset of symptoms caused by different deficiency. J Investig Allergol Clin Immunol. 2008; kind of triggers, we were concerned about the pos- 18(2): 126-30. sibility to safely deliver our treatment in the pres- 2) Bracho FA. Hereditary angioedema. Curr Opin Hematol. 2005 Nov; 12(6): 493-8 ence of such a situation. One of our main concern 3) Kasamatsu Y, Nakayama I, Kobayashi T. A case of lung was that the patient was alone in the treatment cancer with hereditary angioedema treated effectively room. In the case of an angioedema attack occur- by chemo-radiotherapy with C1 esterase inhibitor con- ring during treatment delivery he could not move. A centrate and danazol. Nihon Kokyuki Gakkai Zasshi 2004; 42(5): 435-9 (in Japanese). latent period of about 20-30 seconds is necessary to 4) Christie DRH, Kirk JA, Clarke CL, Boyages J. give access to the treatment room to give medica- Association of hereditary angioedema and hereditary tion to the patient and this represents an obstacle in breast cancer. Cancer Genet Cytogenet. 1997 Jun; case of an emergency. Moreover, we instructed the 95(2): 159-62. patient about the danger related to movement dur- 5) Cohen SH, Koethe SM, Kozin F, Rodey G, Arkins JA, Fink JN. Acquired angioedema associated with rectal ing treatment for radioprotection safety. carcinoma and its response to danazol therapy. J Another point of concern was the fact that Allergy Clin Immunol. 1978 Oct; 62(4): 217-21. most of the symptoms of HAE are gastrointestinal 6) Healy C1, Abuzakouk M, Feighery C, Flint S. Acquired disorders that may be relevant when undergoing angioedema in non-Hodgkin's lymphoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007 May; radiotherapy on the pelvis, especially when it is 103(5): 29-32. associated with a phase-specific anti-metabolite like 7) Jung M, Rice L. “Surgical” abdomen in a patient with 5-FU, which presents gastrointestinal toxicity as the chronic lymphocytic leukemia: a case of acquired most frequent side effect(4). For this reason, in order angioedema. J Gastrointest Surg 2011; 15: 2262- to further decrease radiation therapy-related adverse 2266N. 8) Mohyuddin GR, Rabinowitz I. A patient with chronic effects, we instructed the patient to follow a diet lymphocytic leukemia and acquired angioedema: cor- regimen which we recommend to all of the patients relation of clinical and biochemical response to CLL undergoing treatments on the abdomen and pelvis. therapy. Ecancer 2013; 7: 292. Following all these recommendations and 9) Lam DH, Levy NB, Nickerson JM, Gruenberg DA, Lansigan F. Acquired angioedema and marginal zone instructions the patient completed the treatment lymphoma. JCO 2012; 30(16): 151-153. without toxicity related to CHT-RT. It is remarkable that during the course of irradiation he did not develop any angioedema attack reporting only an episode of severe abdominal cramps, bowel sounds and nausea occurring a week after the end of treatment. We report this limited experience of us in the treatment of a severe pathology as a locally advanced rectal tumour is in the presence of a life ______threatening condition like HAE. This is to testify Correspoding author that an internationally accepted protocol as preoper- BARBARA TOLU M.D. ative CHT-RT treatment for locally advanced rectal Radiotherapy Unit, Tor Vergata University Hospital Viale Oxford 81 cancer may be safely delivered at least in patients 00133 Rome affected by HAE. Due to this limited experience we (Italy)