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Neutropenic Colitis as a Complication of High-dose Chemotherapy for Refractory Testicular Cancer
Introduction
Case Report
Discussion
References
Neutropenic Colitis as a Complication of High-dose Chemotherapy for Refractory Testicular Cancer
INTRODUCTION
High-dose chemotherapy (HDCT) combined with autologous stem-cell rescue is one of the most effective salvage therapies for refractory testicular cancer (1). The reported durable complete remission rate is about 10-20% even for the heavily pretreated and relapsed cases. However, hematological toxicity is severe and about 10% treatment-related deaths are reported (1). Here, we report our experience of neutropenic colitis as a complication of HDCT for refractory testicular cancer. Neutropenic colitis, also termed necrotizing enteropathy or typhlitis, is a serious infection that occurs in association with profound neutropenia (2). This life-threatening but generally unrecognized syndrome has been reported as a complication of hematological disease such as acute leukemia, aplastic anemia and cyclic neutropenia. Typical but non-specific clinical features are fever, watery diarrhea and diffuse crampy abdominal pain. The reported mortality rate is as high as about 21-48% in a recent review (2). Intensive medical care support including anti-endotoxin therapy was needed to manage the life-threatening condition in the present case.
CASE REPORT
A 44 year-old-man was admitted to Tsukuba University Hospital in January 1996 for treatment of non-seminomatous testicular cancer (seminoma plus choriocarcinoma). He had been treated with two different conventional-dose cisplatin-containing regimens (three courses of cisplatin, vinblastine, bleomycin and three courses of cisplatin, actinomycin D, methotrexate) for solitary metastasis in the lung at the branch hospital. He had no history of colitis before and during the conventional-dose chemotherapy. The chemotherapy induced a transient complete response; however, a newly developing lung metastasis with increasing serum [beta]-subunit of human chorionic gonadotropine level was revealed at 4 weeks after the last conventional dose chemotherapy. We elected to use the HDCT with autologous peripheral-blood stem-cell (PBSC) rescue for the treatment of this refractory case. Informed consent was obtained prior to PBSC harvest and HDCT. PBSC was collected three times by using Hemonetics V 50 during bone marrow regeneration after the last cycle of the conventional-dose chemotherapy. Additional stimulation with recombinant granulocyte colony-stimulating factor (G-CSF) at a daily dose of 5 µg/kg was performed. The chemotherapeutic regimen was according to that of the Memorial Sloan-Kettering Cancer Center (3), which consisted of total dose of 1500 mg/m2 of carboplatin, 1200 mg/m2 of etoposide and 100 mg/kg of cyclophosphamide (CPA) in one cycle. Carboplatin and etoposide were given in three divided doses on days -7, -5 and -3. CPA was given on days -5 and -3. Ciprofloxacin 600 mg orally daily and fluconasol 200 mg orally daily were administered as antibacterial and antifungal prophylaxis starting on day -3. Subsequently, 3.9 × 108 cells/kg of mononuclear cells (1.7 × 106 cells/kg of CD34-positive cells counted by a Facscan flow cytometer) were re-infused on day 0. On the same day, intravenous infusion of recombinant G-CSF at a daily dose of 5 µg/kg was started. The white blood cell (WBC) count at day 0 was 1000/mm3 and the patient was transferred to a private room with reverse isolation. Subsequently, the WBC count decreased to 200/mm3 on day 2. On the same day, mild diarrhea began with no abnormality on abdominal examination. Severe leukocytopenia with a WBC count <500/mm3 continued to day 9 as illustrated in Fig. 1. The patient's clinical course up to day 2 was almost satisfactory except for moderate nausea, appetite loss and mild vomiting, probably due to the anticancer drugs. On the next day, the patient began to complain of abdominal pain, massive watery diarrhea and vomiting, with high fever of over 39°C. Total parenteral nutrition and intravenous panipenem/betamipron, amikacin sulfate and fluconasol was started. Despite systemic antibiotic therapy, his condition deteriorated rapidly. There were decreased bowel sounds with generalized abdominal tenderness and distention. A plain abdominal radiograph on day 6 showed a nearly gas-less abdomen except for the duodenum loop as shown in Fig. 2. These abdominal X-ray findings were in sharp contrast to the marked abdominal distention revealed by physical examination. Abdominal sonography revealed echogenic thickening of the colon wall, anechogenic fluid-filled bowel and a moderate volume of ascites. A clinical diagnosis of adynamic ileus with severe enterocolitis was made and vancomycin administration from a nasogastric tube was started. Systemic vancomycin was added from the next day. Laboratory findings showed evidence of disseminated intravascular coagulation and an increase in serum creatinine and bilirubin levels during the following several days. On day 9, the urine output had decreased to below 30 ml/h. Promptly, anti-endotoxin and anti-shock therapy including direct hemoperfusion with polymyxin B-bound fibers (4) and bolus steroid administration were performed. Within a few hours from the initiation of the anti-endotoxin therapy, adequate urine output was restored. Subsequently, the patient retained an almost stable cardiovascular state. However, severe thrombocytopenia with gastrointestinal bleeding continued for the following 2 weeks, which required repeated red cell and platelet transfusions. The patient continued to be febrile, but the return of normal bowel movement was confirmed by abdominal physical examination and radiography on day 24. Antibiotics were discontinued on day 34 and the patient became afebrile. The patient made a good recovery from the infection; however, he subsequently suffered from cancer relapse with brain metastases and died 5 months later.
Figure 1. Clinical course of the present case. Figure 2. Plain abdominal radiograph on day 6. An abdominal X-ray showed a nearly gas-less abdomen except for segmental dilatation of the duodenum loop. At this time, physical abdominal examination revealed marked abdominal distention. All antibiotics used in the present case were started before bacteriological confirmation. The specific organism contributing to the septicemia is unclear, because repeated blood cultures failed to detect any organism. Stool culture at the onset of symptoms showed yeast which suggested the presence of Candida. Stool assay for Clostridium difficile toxin was negative. Two different organisms were repeatedly detected during the febrile period, Enterococcus faesium from the gastric juice and methicillin-resistant Staphylococcus aureus from the sputum. Both strains showed high resistance to various antibiotics except vancomycin.
DISCUSSION
Neutropenic colitis is thought to be developed by several mechanisms, including suppression of local or systemic immune response, physical damage to bowel mucosa induced by anti-cancer drugs and abnormal gut flora (2). Ettighausen (2) pointed out that neutropenic colitis represents a pathological syndrome rather than a discrete disease. Starnes et al. (5) used the term neutropenic enteropathy to describe a similar condition. Pathological features of the affected bowel include mucosal and transmural edema, hemorrhage, ulceration and mucosal or transmural necrosis with perforation (2). A number of enteric organisms including Escherichia, Pseudomonas, Klebsiella and Candida have been reported as pathogenic organisms in this syndrome (2,6). Typical but non-specific clinical features are fever, watery diarrhea and diffuse crampy abdominal pain in the setting of severe neutropenia. There is no specific laboratory or radiological findings for establishing early and definite diagnosis. Detection of colonic wall thickening by abdominal sonography or CT scan is considered to be helpful for suggesting the progression of the syndrome (7). The reported mortality rate is as high as about 21-48% in a recent review. There is still some controversy in the management of neutropenic colitis, namely conservative therapy or surgical therapy. Generally, continued intestinal bleeding after recovery of myelosuppression and free intraperitoneal perforation are considered as absolute indications for operation. In the present case, we chose conservative therapy based on the reasons that (1) anti-endotoxin and anti-shock therapy was effective in stabilizing the cardiovascular state, (2) there was no evidence of free intraperitoneal perforation and (3) ultrasonography suggested that a broad range of the colon and small bowel was involved.
Neutropenic colitis has been widely reported as a complication of leukemia and other hematological diseases. In contrast, the development of this complication in patients receiving chemotherapy for solid cancer is rare, with only sporadic reports in the literature (8-10). Although a broad spectrum of chemotherapy regimen has been used in solid cancer cases, the common denominator in all cases was neutropenia (10). HDCT combined with autologous stem-cell rescue is one of the most effective salvage therapies for refractory testicular cancer (1). The reported durable complete remission rate is about 10-20% even for heavily pretreated and relapsed cases. However, severe myelosuppression is still unavoidable in HDCT despite recent improvements in supporting care (11,12). Gastrointestinal complications such as diarrhea, probably due to drug-induced bowel mucosal damage, are also frequently seen in HDCT (11,12). In the present case, diarrhea started at day 2 of HDCT (5 days after the last injection of anti-cancer drugs). Since the onset of gastrointestinal symptoms was relatively early, the drug-induced mucosal damage might have been responsible for the early symptoms. However, subsequent rapid deterioration of the general condition with the development of adynamic ileus is not usually seen in HDCT for testicular cancer. Although diagnosis by pathological examination or CT scan could not be made, the clinical features were compatible with those of reported cases in the literature. In the present case, neutropenic colitis was thought to be precipitated by several mechanisms, including drug-induced mucosal damage, severe neutropenia and opportunistic infection under prophylactic antibacterial and antifugal medication.
In conclusion, the present case indicates that neutropenic colitis may occur in patients receiving HDCT for solid cancer. Hence the frequency of this severe complication can be expected to increase as increasing numbers of patients with solid cancers are subjected to HDCT. Prompt recognition of the predicting signs such as massive watery diarrhea, development of adynamic ileus and thickened colon wall is a key to appropriate management of this serious complication.
References
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Copyright©Japanese Journal of Clinical Oncology, 1998.
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E.-I. Takaoka, K. Kawai, S. Ando, T. Shimazui, and H. Akaza
Neutropenic Colitis during Standard Dose Combination Chemotherapy with Nedaplatin and Irinotecan for Testicular Cancer
Jpn. J. Clin. Oncol.,
January 1, 2006;
36(1):
60 - 63.
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