Japanese Journal of Clinical Oncology 30:401-405 (2000)
© 2000 Foundation for Promotion of Cancer Research
Bacterial Meningitis Observed in a Phase I Trial of Vinorelbine, Cisplatin and Thoracic Radiotherapy for Non-small Cell Lung Cancer: Report of a Case and Discussion on Dose-limiting Toxicity
Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONCASE REPORTLITERATURE REVIEWDISCUSSIONAcknowledgmentsREFERENCES |
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Although neutropenia increases the risk of life-threatening infections, bacterial meningitis is rarely encountered as a complication during cancer chemotherapy in adults with a solid tumor. A 66-year-old male with adenosquamous carcinoma of the lung, cT2N3M0, stage IIIB, was enrolled in a phase I trial of chemoradiotherapy and treated with cisplatin 80 mg/m2 (122 mg/body) on day 1, vinorelbine 20 mg/m2 (32 mg/body) on days 1 and 8 and thoracic radiotherapy 30 Gy/15 fractions, beginning on day 2, with dexamethasone administered for antiemesis at a dose of 16 mg on day 1, 8 mg on days 2 and 3, 4 mg on day 4 and 2 mg on day 5. The patient developed headache and fever on day 6 of the second cycle of the treatment and bacterial meningitis was diagnosed based on the findings of consciousness disturbance, an elevated peripheral blood leukocyte count and numerous leukocytes in the cerebrospinal fluid. In spite of the doctor’s delay in establishing the exact diagnosis, the bacterial meningitis in this case was successfully treated with intensive antibiotic therapy. This life-threatening complication, equivalent to a grade 4 non-hematological adverse reaction, was not counted as dose-limiting toxicity in the current phase I trial, because there are only a few reports of bacterial meningitis associated with cancer chemotherapy and it developed in this case without any associated decrease in the peripheral blood leukocyte count.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCASE REPORTLITERATURE REVIEWDISCUSSIONAcknowledgmentsREFERENCES |
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Bacterial meningitis in adults remains a serious infection with an overall fatality rate of 25%, which has not varied over 27 years (1). Although patients with severe neutropenia are at an increased risk of developing life-threatening bacterial infections, meningitis in adults with cancer is extremely rare, except in patients with hematological malignancies who are receiving high-dose chemotherapy with or without stem cell transplantation (2–6) and in nasopharyngeal carcinoma patients with direct invasion of the meninges (7).
Dose-limiting toxicity (DLT) is the principal factor to establish the maximum tolerated dose in phase I or dose-escalation studies. Dose escalation is stopped if the incidence of DLT exceeds a certain percentage, usually 33% in phase I trials of antineoplastic drugs (8). Whether DLT should include any life-threatening adverse events associated with the treatment or be limited to specific toxicity related to the treatment has not yet been clearly defined.
We report a case of bacterial meningitis observed in a combination phase I trial and we clarify the characteristics of this serious infection in patients with solid tumors by a literature review. We then discuss whether or not this complication in this specific case should be counted as a DLT.
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CASE REPORT |
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TOPABSTRACTINTRODUCTIONCASE REPORTLITERATURE REVIEWDISCUSSIONAcknowledgmentsREFERENCES |
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A 66-year-old male was referred to the National Cancer Center Hospital with a nodular shadow in the right lower lung field detected during a health examination in July 1999. He had been well, without any symptoms. His past history was unremarkable. He was diagnosed as having adenosquamous carcinoma of the lung, cT2N3M0, stage IIIB and was registered for a phase I trial of vinorelbine, cisplatin and thoracic radiotherapy for locally advanced non-small cell lung cancer, which was approved by the Institutional Review Board of National Cancer Center in September 1999. The patient received the first cycle of chemoradiotherapy between October 19 and November 10, consisting of cisplatin 80 mg/m2 (122 mg/body) on day 1, vinorelbine 20 mg/m2 (32 mg/body) on days 1 and 8 and thoracic radiotherapy 30 Gy/15 fractions beginning on day 2. For antiemesis, dexamethasone was administered at a dose of 16 mg on day 1, 8 mg on days 2 and 3, 4 mg on day 4 and 2 mg on day 5. Grade 4 neutropenia developed, that lasted for 3 days starting from day 20, but without any associated fever or infection during the first cycle of chemotherapy. Chest X-ray films showed that the primary tumor was decreased in size. The second cycle of the treatment was begun on November 16.
The clinical course of the meningitis in our patient is summarized in Table 1 and Fig. 1. Headache and fever appeared on November 21 and consciousness disturbance developed the following morning without any findings indicative of the infectious focus. Amikacin 100 mg and panipenem 1 g were administered at 09:00, as delirium was suspected at this time to be caused by sepsis. The diagnosis of bacterial meningitis was made at 15:30 based on the findings of numerous cells and an elevated protein concentration in the cerebrospinal fluid (CSF). Ampicillin/sulbactam and panipenem at doses of 12 and 2 g per day, respectively, were started on November 23. Granulocyte colony-stimulating factor was administered prophylactically for 3 days to avoid severe leukocytopenia. After about 1 week, the patient improved and became afebrile and fully alert. This combination of antibiotics was continued empirically for 2 weeks, because cultures and Gram’s staining of the CSF and blood yielded no pathogens. After additional therapy with ampicillin/sulbactum and cefpirome for 17 days, all antibiotics were discontinued.
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MRI scanning of the brain on December 10 disclosed multiple brain metastases. Whole brain irradiation was delivered at a total dose of 45 Gy/18 fractions. The patient was discharged on February 18, 2000, without any symptoms suggestive of infection or progression of lung cancer.
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LITERATURE REVIEW |
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TOPABSTRACTINTRODUCTIONCASE REPORTLITERATURE REVIEWDISCUSSIONAcknowledgmentsREFERENCES |
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Manual and Medline searches using the key words ‘meningitis/bacterial in MeSH’ and ‘neoplasms in MeSH’ yielded eight cases of bacterial meningitis associated with solid tumors (9–14). The clinical characteristics in these cases and in the present case (total nine cases) are summarized in Table 2. Bacterial meningitis developed during chemotherapy and radiotherapy in only four and three cases, respectively, but all the cases except one were under steroid administration. The peripheral blood leukocyte count was normal or elevated in all the cases.
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To identify the incidence of bacterial meningitis in patients who receive vinorelbine, a Medline search limited to the English language literature and clinical trials using the key word ‘vinorelbine’ was performed. In total, 7829 patients who received vinorelbine with or without other cytotoxic agents in 149 trials were identified. Of these, 49.5% had developed grade 3 or 4 neutropenia, 6.7% had developed grade 3 or 4 infection and 1.1% died of toxicity, but none developed bacterial meningitis.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONCASE REPORTLITERATURE REVIEWDISCUSSIONAcknowledgmentsREFERENCES |
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Bacterial meningitis is a serious infection associated with a high mortality and requires prompt diagnosis and antimicrobial therapy (15). Dexamethasone for antiemesis might be related to the development of the complication in this case, although steroid therapy is a standard treatment of cisplatin-induced acute and delayed emesis and no case of bacterial meningitis was noted even when higher dose of dexamethasone was administered during chemotherapy (16). Lack of signs of meningeal irritation such as neck stiffness and Kernig’s sign in the current case, which could be due to the dexamethasone administration, was the reason for the doctor’s delay in establishing the exact diagnosis. Detection of the pathogen is extremely important for the selection of antibiotics and prediction of prognosis (15). Gram’s staining and cultures of the CSF were negative in this case, mainly because the CSF samples were obtained 4 h after the initial dose of antibiotics.
The antibiotics administered initially in this case were amikacin and panipenem, since the delirium was suspected to be caused by sepsis at this stage. The empirical selection of antibiotics for bacterial meningitis should be high-dose ampicillin combined with cefotaxime or ceftriaxone (15). Recent randomized trials showed that carbapenem was as effective as the aforementioned combination for bacterial meningitis in adults (17). In addition, carbapenem is effective against Listeria monocytogenes (18), which is a relatively common pathogen causing meningitis in patients with solid tumors (Table 2). Thus, we started our patient on high-dose ampicillin/sulbactam and panipenem therapy. Because the serum CRP levels did not decrease to the normal range, we replaced panipenem with cefpirome, a third-generation cephalosporin which accumulates at high concentrations in the CSF both in patients with purulent meningitis (19) and in those with non-inflamed meninges (20). The bacterial meningitis in the present case was successfully treated with this regimen.
Evaluation of severity, attribution of causality and expectedness of an adverse event occurring in a clinical trial is important to determine the further course of treatment of the patient, the way of reporting the event and whether to continue the trial (21,22). Bacterial meningitis is clearly a life-threatening infection and therefore is equivalent to grade 4 toxicity in the module of infection without neutropenia according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0 (23). Attribution of causality is a critical and often difficult step in evaluating an adverse event to ensure that treatment-related conditions are distinguished from disease-related conditions or accidental complications (21). The attribution is graded into five categories, definite, probable, possible, unlikely and unrelated (21). Although treatment with cytotoxic drugs may increase the risk of severe infections, the attribution of bacterial meningitis in the present case is considered to correspond to unlikely (the relationship of the adverse event to the investigational agent is doubtful), because there are only a few reports of bacterial meningitis associated with cancer chemotherapy and the infection in this case developed without an associated decrease in the peripheral blood leukocyte count; however, a relationship between this adverse event and the treatment can still not be ruled out. Thus, bacterial meningitis should be considered to be an adverse (drug) reaction (22). The expectedness of an adverse reaction is critical to make investigators, clinicians and other involved personnel aware of new important information on the drug reactions (22). An adverse reaction, the nature or severity of which is not consistent with the relevant source documents, is defined as unexpected in the guideline of the International Conference on Harmonization (22). We considered the bacterial meningitis in this case to be an unexpected serious adverse reaction and therefore reported its occurrence to the Independent Data Monitoring Committee (IDMC) on November 24.
Whether bacterial meningitis should be counted as DLT or not is another contentious issue. Determination of DLT is considered to require higher grade attribution of causality, when the maximum tolerated dose and recommended dose for subsequent studies are established based on the incidence of the DLT. The term toxicity is generally used for an adverse event that is possibly, probably or definitely related to the agent or treatment (20). In the NCI-CTC manual (21), ‘The definition of DLT is determined by the individual protocol, not CTC. Although it would be convenient to assume that all Grade 3 adverse events represent DLT, this is not appropriate’. We think that DLT should include only the toxicity that is related to escalation of the agent dose in the study or toxicity that is specifically related to the treatment. We received a comment from the Independent Data Monitoring Committee that the bacterial meningitis in our case might not be specifically related to the treatment, but to the patient, and that it was appropriate to include another patient in the trial to assess the drug toxicity. Based on the aforementioned discussion, we concluded that bacterial meningitis in this case was a serious adverse reaction but did not take it into consideration for the decision as to whether or not the dose of vinorelbine should be escalated and whether or not the trial should be continued.
In conclusion, bacterial meningitis occurring as a complication during cancer chemotherapy in our patient with a solid tumor was considered to be an unexpected serious adverse reaction with the causal attribution of unlikely. This extremely rare adverse reaction was reported to the IDMC, but not considered as DLT in the current combination phase I trial.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONCASE REPORTLITERATURE REVIEWDISCUSSIONAcknowledgmentsREFERENCES |
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This work was supported in part by Grants-in-Aid for Cancer Research from the Ministry of Health and Welfare of Japan. We thank Miss Miki Fukutani and Miss Hiroko Matsumoto for their compilation of the toxicity data of cytotoxic agents from the literature and drug companies.
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FOOTNOTES |
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+ For reprints and all correspondence: Ikuo Sekine, Medical Oncology Division, National Cancer Center Hospital, Tsukiji 1–1, Chuo-ku 5-chome, Tokyo 104-0045, Japan. E-mail: isekine@gan2.ncc.go.jp
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REFERENCES |
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TOPABSTRACTINTRODUCTIONCASE REPORTLITERATURE REVIEWDISCUSSIONAcknowledgmentsREFERENCES |
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Received March 28, 2000; accepted June 21, 2000.
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