Japanese Journal of Clinical Oncology 30:122-125 (2000)
© 2000 Foundation for Promotion of Cancer Research
Successful Initial Treatment with Weekly Etoposide, Epirubicin, Cisplatin, 5-Fluorouracil and Leucovorin Chemotherapy in Advanced Gastric Cancer Patients with Disseminated Intravascular Coagulation
1Cancer Center, Division of Gastroenterology, 2Department of Medicine, Division of General Surgery and 3Department of Surgery, Veterans General Hospital–Taipei, Taipei and 4National Yang-Ming University, School of Medicine, Taipei, Taiwan
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ABSTRACT |
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Background: Acute disseminated intravascular coagulation (DIC) is a rare but severe complication of gastric adenocarcinoma. Conventional treatments, such as fresh frozen plasma, platelet replacement and heparin injections, are disappointing. The only way to correct this fatal condition is to control the underlying cancer promptly by effective chemotherapy. Here the successful initial control of acute DIC in gastric cancer patients with weekly EEPFL chemotherapy is reported.
Methods: Advanced gastric cancer patients complicated with acute DIC were eligible. Patients were treated with weekly EEPFL therapy (etoposide 40, epirubicin 10, cisplatin 25, 5-fluorouracil 2200 and leucovorin 120 mg/m2 ). Response, survival and toxicity were evaluated.
Results: From April 1997 to April 1999, six patients were included in this study. All patients received EEPFL chemotherapy. Clinical and laboratory evidence of acute DIC stabilized quickly after starting chemotherapy. Four patients showed a partial response, one stable disease and one progressive disease. The toxicity was mild and well tolerated. Median survival was 28 weeks (12, 14, 26, 30, 30 and 32 weeks). All patients suffered from a relapse of DIC after initial successful control and died within 30 days of clinical and laboratory evidence of acute DIC relapse.
Conclusion: EEPFL therapy is an effective chemotherapy regimen for patients with advanced gastric cancer associated with acute DIC. The prognosis is poor if the DIC relapses after the initial successful control.
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INTRODUCTION |
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Acute disseminated intravascular coagulation (DIC) is a pathological syndrome in which the manifestations, such as progressive and consumptive coagulopathy with severe bleeding, are in large part a consequence of thrombin formation (1). Solid tumors such as gastrointestinal, pancreatic, liver, ovarian, breast, lung and prostatic carcinomas have been reported to induce acute DIC complication (2). The gastric cancer patient with acute DIC experiences a rare but severe complication with a fatal prognosis.
Treatment consisting of fresh frozen plasma and platelet replacement, with or without a heparin injection, had little clinical effect and patients with acute DIC died within 1–3 weeks (2–4). Although treatment of cancer-associated acute DIC is difficult, the key remains the control of the underlying cancer. Yeh and Chen (5) and Noda et al. (6) have reported successful initial treatment of gastric cancer patients with acute DIC with aggressive chemotherapy. Therefore, effective chemotherapy of the underlying cancer may play a major role in the successful initial treatment of patients with acute DIC. We have previously advanced a weekly EEPFL regimen (etoposide, epirubicin, cisplatin, 5-fluorouracil and leucovorin) as an effective regimen with tolerable toxicities in advanced gastric cancer patients (7). The high overall response rate (71%) makes the EEPFL regimen ideal for use in the critical stages of acute DIC associated with advanced gastric cancer. We report here our successful initial treatment of six patients and discuss the clinical characteristics of gastric cancer patients with acute DIC.
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PATIENTS AND METHODS |
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Patient Selection
From April 1997 to April 1999, six patients with histologically proven gastric adenocarcinoma with acute DIC were included in the study. The diagnostic criteria of acute DIC were based on evident bleeding symptoms and met at least four of a set of five conditions. The five conditions were defined as follows: thrombocytopenia (platelet count <100 000/mm3), elevated serum fibrin degradation products (FDP >20 µg/ml), prolonged porthrombin time (PT) or activated partial thromboplastin time (aPTT), decreased fibrinogen levels (<200 mg/ml) and elevated D-dimer levels (D-dimer Assay, Pacific Hemostasis, Huntersville, NC, USA). Bone marrow examinations were routinely done.
Treatment Plan
Weekly EEPFL treatment consisted of weekly etoposide 40 mg/m2 intravenous (i.v.) infusion over 30 min; weekly epirubicin 10 mg/m2 i.v. over 5 min; and cisplatin 25, 5-fluorouracil 2200 and leucovorin 120 mg/m2 given simultaneously by weekly 24-h i.v. infusion via a peripheral venous line. Once the bleeding tendency had stopped, a port-A catheter was implanted and chemotherapy was given as an outpatient regimen with a portable infusion pump (Baxter HealthCare, Deerfield, IL, USA). The dose modifications were started after six cycles of full-dose EEPFL treatment. The dose modifications were the same as described previously (7). In brief, full-dose EEPFL chemotherapy would be delivered if WBC was >2500/mm3 and platelets >75 000/mm3. Etoposide and epirubicin were omitted for WBC between 2000 and 2500/mm3. Weekly EEPFL would be delayed at least 1 week for WBC <2000/mm3 or grade 2–4 mucositis or diarrhea. Cisplatin was not given for serum creatinine >2mg/mm3. Etoposide and epirubicin were reduced by 25 or 50% for grade 3 or 4 neutropenia nadir during chemotherapy. 5-FU was reduced by 10 or 20% for grade 2 or 3 mucositis/diarrhea during chemotherapy. Weekly chemotherapy was continued until disease progression. Response, toxicities and performance status were graded according to the Eastern Cooperative Oncology Group (ECOG) criteria (8).
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RESULTS |
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Between May 1997 and May 1999, six patients were diagnosed with poorly differentiated adenocarcinoma of the stomach combined with acute DIC. There were five men and one woman, with a median age of 38 years (range 36–71 years). All patients had an ECOG performance status score of 3. One patient had had previous gastrectomy. No patient had had previous chemotherapy. Peritoneum, bone, lung and liver metastases were noted in five, three, two and two patients, respectively. Multiple ecchymoses and upper gastrointestinal tract bleeding were noted in five and four patients, respectively. The abnormal blood and serum biochemical data indicating acute DIC together with the diagnosis are illustrated in Table 1. All patients needed an initial blood transfusion and platelet supplement to maintain hemodynamic stabilization, and also to correct the bleeding tendency. All patients received weekly EEPFL chemotherapy and the patients’ platelet count normalized (>130 000/mm3) after a median five-cycle treatment (range 4–7 cycles). Most of the laboratory evidence of acute DIC gradually resolved within six cycles of weekly EEPFL chemotherapy. One patient suffered from a high-dose 5-fluorouracil-related encephalopathy, although the consciousness cleared after supportive treatment. After nutrition supplements, the high-dose 5-fluorouracil-related encephalopathy did not recur in following chemotherapies (9). The clinical conditions of the remaining five patients improved dramatically and bleeding stopped.
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All patients were evaluated for response and survival (Table 2). There was no complete response in any patient and partial response (PR) in four (66.6%), stable disease (SD) in one (16.6%) and progressive disease (PD) in one (16.6%) patient were observed. The toxicity was mild and well tolerated. The performance status was improved from score 3 to score 0–1 in all patients. The median time to PR was 10 weeks (9, 10, 10 and12 weeks, respectively). The median response duration of PR was 11 weeks (10, 10, 12 and 18 weeks, respectively). The DIC-free survival of these six patients was 8, 12, 24, 24, 28 and 28 weeks and the overall survival was 12, 14, 26, 30, 30 and 32 weeks, respectively. No patient is alive at the time of writing. Patients experienced a relapse of acute DIC symptoms after disease progression was noted. All patients died within 30 days of DIC symptoms recurring.
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Discussion |
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The prognosis for a cancer patient who develops acute DIC is grave and most patients die within 1–3 weeks (2–4). Treatment in the form of blood transfusions and platelet replacement, with or without heparin therapy, is always disappointing. The regimen in Yeh and Chen’s study (5) consisted of a weekly 24 h infusion of high-dose 5-fluorouracil (5-FU) 2600 mg/m2 and leucovorin 300 mg/m2. Noda et al. (6) employed a regimen of sequential methotrexate and 5-fluorouracil (MTX-5FU). Both studies reported successful initial treatment with aggressive chemotherapy that prolongs survival in advanced gastric cancer patients with acute DIC. In our study, we were successful in controlling acute DIC after aggressive chemotherapy. Therefore, effective chemotherapy may be the only way to control acute DIC and to correct thrombocytopenia and the bleeding tendency. Out of interest, these three reports all used a weekly 5-FU-based chemotherapeutic regimen (5–7).
Predicting the development of acute DIC in a patient with gastric cancer is difficult. Petechiae, ecchymoses and mucosal or gastrointestinal bleeding are the most common symptoms. Thrombocytopenia, anemia, elevated serum lactate dehydrogenase, increased total bilirubin and indirect hyperbilirubinemia should lead a physician to consider acute DIC in differential diagnoses. Prolonged prothrombin time, activated partial thromboplastin time, low fibrinogen level and elevated fibrinogen degradation products can confirm the diagnosis of acute DIC.
The pathogenesis of DIC in patients with malignancies, such as prostate, colon, breast and non-small cell lung cancers, may be due to tumor cells expressing urokinase-type plasminogen activators (u-PA) (10). In our previous report, the plasma plasminogen activator inhibitor-1 was significantly higher and plasma u-PA significantly lower in patients with gastric cancer than in those patients with benign ulcers (11). The relationship between tumor tissue u-PA and acute DIC is still unclear. Whether gastric cancer patients with acute DIC have higher u-PA expression needs further investigation.
Effective chemotherapy for the underlying cancer is the key to successful initial treatment of patients with acute DIC. The weekly EEPFL regimen has been proven to have high response rates and minimal toxicity in advanced gastric cancer patients (7). Therefore, we chose the weekly EEPFL regimen to treat these gravely afflicted patients. In our study, six patients received weekly EEPFL therapy. Their platelet counts gradually increased and the bleeding tendency eventually stabilized. Only one patient developed unusual high-dose 5-fluorouracil-related hyperammonemia and encephlopathy. After nutritional support, this patient was able to tolerate high-dose 5-FU base chemotherapy with a good objective response and died 7 months later. DIC symptoms eventually recurred in all patients in association with tumor progression. In all cases mortality resulted within 30 days of the recurrence of DIC. The efficacy of salvage chemotherapy with newly developed anticancer agents, such as gemcitabine or taxane, is unknown and can be tried in the future.
In conclusion, we advocate that weekly EEPFL therapy is an effective initial treatment for advanced gastric cancer patients with acute DIC. Once DIC recurs after initial control, prognosis is grave.
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FOOTNOTES |
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+ For reprints and all correspondence: Yee Chao, Cancer Center, Veterans General Hospital–Taipei, No 201, Section 2, Shih-Pai road, Taipei, 112, Taiwan. E-mail: chaoy@vghtpe.gov.tw
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REFERENCES |
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Received September 30, 1999; accepted December 28, 1999.
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