Cixutumumab-Associated Pancolitis in a Patient With Prostate Cancer

New therapies for cancer have emerged as we have gained better understanding of the molecular mechanisms that underlie those diseases. Several types of tumors, including prostate cancer (PC), overexpress the insulin-like growth factor 1 receptor (IGF1R).1 The antitumor effect of IGF1R inhibition has been noted in both in vitro and in vivo models of PC.2,3 Several different agents, including such monoclonal antibodies as IMC-A12 (cixutumumab), have been developed as antagonists to IGF1R.4-6 Because of its antitumor activity in tumor cell models, cixutumumab has advanced into clinical studies.7 Recent phase I and II studies in patients with various cancers showed that this agent is well tolerated and without unreasonable side effects. We describe here, to our best knowledge, the first case of a patient with PC who developed pancolitis while participating in a clinical trial of cixutumumab. Case Report A 53-year-old white man was seen by a local physician for musculoskeletal pain in the lower back and neck ultimately resulting in upper-extremity weakness. Further evaluation, including a prostate biopsy performed in March 2007, revealed Gleason score 9 (4+5) prostatic adenocarcinoma. At that time, his prostate-specific antigen (PSA) concentration was 953 ng/mL, a bone scan showed diffuse bony metastasis, and computed tomography (CT) scanning revealed retroperitoneal and pelvic lymphadenopathy. That same month, the patient sought evaluation at The University of Texas MD Anderson Cancer Center for further care. Here, he was initially treated with androgen-ablation therapy, including bicalutamide and leuprolide acetate, which yielded a transient favorable response. His PSA decreased to a nadir of 0.4 ng/mL. Nine months later, his PSA concentration was 0.7 ng/mL, so bicalutamide treatment was stopped. In another 6 months, his PSA had increased to 4.9 ng/mL, and his testosterone concentration was 22 nmol/L. The staging workup identified progressive bony metastasis involving the spine, ribs, hemipelvis, scapula, and proximal femurs. The patient agreed to participate in a randomized phase II clinical trial of docetaxel and dasatinib. He was given two cycles of docetaxel (75 mg/m2 intravenously [IV] every 3 weeks), dasatinib (100 mg orally [PO] once daily for 14 days), and prednisone (5 mg PO twice daily). He developed nausea (grade 1) and diarrhea (grade 1) during this treatment. Two months later, he was hospitalized for Aspergillus pneumonia, withdrawn from the study, and treated with voriconazole. His subsequent PSA concentration was 1.5 ng/mL. Within 3 months after that, his PSA was 5.8 ng/mL, so treatment was restarted with docetaxel (75 mg/m2 IV every 3 weeks). He underwent a total of six cycles, but 5 months later, his PSA concentration had increased further, to 7.7 ng/mL. After 2 more months, with his PSA concentration still increasing, he agreed to participate in a randomized phase II clinical trial testing either cixutumumab (IMC-A12) or ramucirumab (IMC-1121B) plus mitoxantrone and prednisone. His PSA was 17.4 ng/mL at enrollment. He was randomized to treatment with cixutumumab (6 mg/kg IV weekly), mitoxantrone (12 mg/m2 IV every 3 weeks), and prednisone (5 mg PO twice daily). After 3 months on that regimen, his left ventricular ejection fraction decreased, but the measure returned to normal 5 months after the mitoxantrone was discontinued. He received a total of 32 cycles of cixutumumab plus prednisone according to the study protocol and experienced a favorable response, with a PSA nadir of 1.6 ng/mL. Although the patient had tolerated the treatment, afterward he was hospitalized with abdominal pain, severe watery diarrhea, dehydration, and malnutrition. Cixutumumab and prednisone were discontinued. Abdominal CT scanning revealed thickening of the ascending, transverse, and descending colon walls with minimal stranding of the adjacent fat, suggestive of pancolitis (Figure 1A). Stool cultures and Clostridium difficile toxin tests revealed no pathogenic colonization. Figure 1 (A) Computed tomography of the abdomen revealed thickening of the ascending (arrow on right), transverse, and descending (arrow on left) colon walls with minimal stranding of the adjacent fat. (B) Colonoscopy revealed extensive ulceration in the cecum. ... He was treated with piperacillin–tazobactam and metronidazole for a week. Colonoscopy revealed pancolitis with extensive ulceration in the cecum (Figure 1B). Multiple biopsy specimens from the right, transverse, and rectosigmoid colon showed markedly increased lymphoplasmacytic infiltration of the lamina propria and submucosa (Figure 2A), neutrophilic inflammation with cryptitis and crypt abscess formation (Figure 2B), and focal granuloma in the lamina propria (Figure 2C). No viral inclusions or microorganisms were identified on Gomori's methenamine silver and acid-fast staining. Immunohistochemical staining for CD3 (Figure 2D) and CD20 revealed the lymphoplasmacytic infiltration of the lamina propria. Immunohistochemical staining for IGF1R detected no evidence of the receptor. Figure 2 Representative micrographs of colonic biopsies. (A) Markedly increased lymphoplasmacytic infiltration of the lamina propria and submucosa (arrows) (original magnification ×40); (B) neutrophilic inflammation with cryptitis and abscess formation ... On the basis of those findings, a diagnosis of autoimmune colitis was made, so methylprednisolone treatment (125 mg IV every 6 hours) was begun. The diarrhea subsided, and the patient's nutritional status improved quickly. His preadmission prealbumin concentration of 5.5 mg/mL had improved to 15.2 mg/dL at his discharge, and he was given a tapering dose of prednisone for 4 weeks. At his first follow-up visit 2 months after his hospitalization for the colitis, his diarrheal symptoms had resolved, his appetite had improved, and he had gained weight. At another follow-up visit 2 months later, his PSA concentration was 28.5 mg/dL. Treatment with abiraterone acetate (1 g PO daily) plus prednisone (5 mg PO twice daily) was initiated, and his PSA level decreased to 10.2 mg/dL within the next month. On his last clinical follow-up in December 2011, he was still alive and well. However, in January 2012, the patient died from a cause not directly related to his prostate cancer or treatment.