Oxaliplatin-Induced Leukocytoclastic Vasculitis under Adjuvant Chemotherapy for Colorectal Cancer: Two Cases of a Rare Adverse Event
A 75-year-old man presented with a locally advanced adenocarcinoma of the rectum (37 cm above the anal verge, endoscopically staged as uT3 uN). As he had received interstitial brachytherapy (>145 Gy) 2 years before as a treatment for prostate cancer (cT2b, cNx, cM0, Gleason score 6), the standard treatment of neoadjuvant RCT with 50.4 Gy and concomitant 5-FU (+/− oxaliplatin) was not possible. An abdomino-perineal rectum exstirpation with implantation of a descendostoma was performed to remove the rectal cancer. The histopathological work-up revealed a pT3a, pN2b (21/31), cM0, L1, V0, G3, R0 (UICC IIIB) adenocarcinoma and thus adjuvant chemotherapy was strongly suggested according to the vote of the institutional interdisciplinary tumor board.\nEight weeks after surgery, the first cycle of adjuvant chemotherapy with 5-FU, leucovorin and oxaliplatin (FOLFOX-6) was scheduled. The cycle consisted of a bimonthly regimen with intravenous oxaliplatin (80 mg/m2) and leucovorin (400 mg/m2) administered on day 1. 5-FU 2,400 mg/m2 followed on day 1 as a continuous infusion for 46 h. During the following 3 days, the patient developed fever that resolved spontaneously. Fourteen days later, the patient showed disseminated petechiae with secondary hemorrhage, along with edema on both legs and interdigital ulceration. He reported that he had experienced arthralgia in his knees and elbows 4 days after the first dose of chemotherapy. His blood count showed microcytic, hypochromic anemia, leukocytosis of 13,900/μl, elevated C-reactive protein of 90.1 mg/l, and an increase in the retention parameters (urea 25 mg/dl), indicating an affliction of the kidneys. The urine analysis was normal apart from an alkaline pH of 7.5.\nThe chemotherapy was interrupted and the patient was admitted to the Department of Dermatology. On examination, there was palpable purpura with petechial hemorrhage on the lower limb in addition to massive edema on both lower legs (fig. ). Some petechiae were also found on the lower arms and the abdomen. We suspected drug toxicity to be the cause of the skin lesions. A skin biopsy confirmed the diagnosis of leukocytoclastic vasculitis. The patient did not complain about abdominal pain and 3 tests for occult blood in the stool were negative. There was no evidence for a systemic vasculitis reaction. After 2 days, the renal parameters were rising (creatinine 1.33 mg/dl; normal range 0.5–1.0 mg/dl) and the patient developed proteinuria of 1,200 mg/day in the 24-hour urine collection. Because of the putative renal involvement, therapy with a high-dose corticosteroid (prednisolone 80 mg/day), a proton pump inhibitor (pantoprazole 40 mg/day) and osteoporosis prophylaxis (calcium carbonate and cholecalciferol 500 mg and 10 μg b.i.d., respectively) was initiated. In addition, the patient was prescribed an ACE-inhibitor (ramipril 2.5 mg/day) for renal protection.\nAn infectious origin of the leukocytoclastic vasculitis was considered implausible because there were no respective clinical symptoms and serological tests were negative for hepatitis A, B and C as well as for an infection with streptococci. The rheumatoid factors, C3c (1.37 g/l), C4 (0.25 g/l), p-ANCA-IF (<1:20), and ANA-IF (>1:80), were not elevated and no circulating immune complexes were detected.\nA punch biopsy from the active area of the frontal aspect of the right lower leg showed typical features of leukocytoclastic vasculitis (fig. ). There were lymphocytic infiltrates with numerous neutrophils as well as ‘nuclear dust’ in the higher corium, extravasated erythrocytes, focal small-vessel edema, endothelial cell swelling within the vessels and fibrinoid deposition. Direct immunofluorescence revealed IgM, IgA, C3, and fibrinogen deposition in the small vessels of the dermis.\nIn our opinion, there was strong evidence for drug-induced toxicity as the cause of the vasculitis, so chemotherapy with oxaliplatin was discontinued. The patient was treated with prednisolone at a decreasing dosage for the next 6 weeks. Under the steroid therapy, the vasculitis lesions disappeared rapidly.\nThe patient's general practitioner continuously monitored creatinine clearance and proteinuria. After 2 weeks, there was evidence of hematuria (>20 erythrocytes) and proteinuria (745 mg/l). The urine analysis showed an increase in renal parameters with creatinine 2.41mg/dl, urea 43 mg/dl, eGFR 26.3, a proteinuria of 1,800 mg/day in a 24-hour urine collection, and a creatinine clearance of 40.1 ml/min. The patient was admitted to the Department of Nephrology with the clinical diagnosis of acute renal failure, presumably as a consequence of acute glomerulonephritis. The percutaneous renal biopsy showed a focal segmental extravascular necrotizing proliferating glomerulonephritis. Because GBM-antibodies (0.4 U/ml) or cryoglobulins (<0.2%) were not detectable, the most likely cause of renal failure was a renal manifestation of the leukocytoclastic vasculitis. Under high-dose steroid therapy (prednisolone 250 mg for 3 days followed by tapered doses), the renal function improved slowly.\nUnfortunately, during further follow-up, the patient had developed tumor progression with pulmonary metastases at the 12-month follow-up visit. Consequently, a palliative regimen with FOLFIRI (5-FU, leucovorin and irinotecan) was scheduled. Under this treatment, no side effects were apparent and the metastases remained stable for 8 months. Recent MRI and CT scans revealed a progressive disease with new metastasis-like lesions in the thoracic spine and suspect lymph nodes in the retroperitoneal, iliacal and inguinal region.