An evaluation of the policy of routine treatment of advanced epithelial ovarian carcinoma by debulking surgery and combined platinum-cyclophosphamide chemotherapy in Singapore

This is an outcome study of a management protocol for patients with FIGO stage III and IV epithelial ovarian cancer treated by debulking surgery and combined platinum and cyclophosphamide chemotherapy. The aim of the study was to determine if the experience of clinical trials could be reproduced in a routine clinical practice in an Asian population. Of the entire group of 62 patients, 50 (80.6%) had the tumor debulked: 26 optimally and 24 suboptimally. Twelve patients had a biopsy of the tumor only. Thirty patients had a histologic grade 3 tumor. Fifty-two (83.9%) patients received the combined platinum-cyclophosphamide chemotherapy. Of these, 49 were assessable for response, and the overall response rate was 49.0%, with 20.4% complete and 28.6% partial response. The overall 5-year survival was 6.8% and the disease-free survival was 4.7% for the entire cohort. The platinum-cyclophosphamide chemotherapy responders showed a significantly better 5-year survival rate of 29.5%, compared to no survival beyond 42 months among the non-responders. Apart from nausea, vomiting and alopecia, the other toxicities of chemotherapy were mild and mostly hematological. These results showed that the management protocol of debulking surgery and combined platinum-cyclophosphamide chemotherapy could be applied routinely in more than 80% of patients with advanced epithelial ovarian cancer. Although the chemotherapy response rate was lower in this clinical study compared to other clinical trials, the overall benefit on survival appeared to be similar. It is concluded that advanced epithelial ovarian carcinoma should continue to be treated actively with debulking surgery followed by combined platinum-cyclophosphamide chemotherapy.     

Fever and neutropenia in children with cancer: diagnostic parameters at presentation

We evaluated 91 episodes of fever in 46 profoundly neutropenic children with cancer, in a search for any symptom, sign or laboratory test that would serve to identify patients with septicemia and differentiate them from those in no immediate need of prompt antimicrobial therapy. Seventeen episodes (19%) were bacteremias, 59 (64%) were suspected septic infections, 9 (10%) were focal bacterial infections and 6 (7%) proved not to be bacterial infections. We were unable to detect any parameter, either on admission or after two days of antimicrobial therapy (except for blood culture findings), that would be helpful in differentiating bacteremia from an episode not of bacterial origin. We focused on serum levels of C reactive protein and found them unreliable on an individual level. Prompt institution of antimicrobial therapy at the occurrence of fever results in low mortality, but does not allow assignment of cases to different categories.     

Infections in acute leukemia: an analysis of 240 febrile episodes

Infections are the major cause of morbidity and mortality in acute leukemia patients. Case records of 91 consecutive patients (AML-48, ALL-40, RAEB-t/AML-3) treated between January 1997 and July 1999 were studied to determine the type, frequency and severity of infections. Patients' median age was 36 y (range 6–66) and male to female ratio was 2.5:1. A total of 240 febrile episodes were recorded; of them, 162 were associated with neutropenia (absolute neutrophil count, ANC<500/mm³) and 78 were without neutropenia. Among the neutropenic episodes, an infectious etiology could be documented in 52%; the remainder (485) were defined as isolated febrile episodes. Chest was the most common site of infection (35.7%) followed by skin, soft tissue (13%), GIT (7%) and genitourinary tract (6%) infections in order of decreasing frequency. Microbiologically, gram positive organisms (staphylococcus aureus, coagulase negativestaphylococcus, streptococcus, enterococcus) were the most common isolates (52.8%) followed by gram negative organisms (E. coli, klebsiella, pseudomonas) in 42.8% of isolates. Two patients had pulmonary tuberculosis and three patients had fungal infections (candida—2,aspergillus—1). Among non-neutropenic patients, infection could be documented in 36%; the remaining 64% were isolated febrile episodes. Gram negative infections were documented in 50%, gram positive in 305 and fungal infections (candia—4,aspergillus—1,mucormycosis—1) in 20% of them. A combination of third generation cephalosporin and an aminoglycoside were used in 79% of episodes initially; a combination of a newer, penicillin and aminoglycoside (4.6%), double betalactums (4.1%), oral, antibiotics (9.8%) and others were used in the remaining episodes. Fever resolved in 38%, of episodes using the above combinations; in the remainder second line antibiotics (mainly vancomycin) and antifungals (amphotericin-B) were added empirically or depending on culture and sensitivity. In 52.5% of episodes fever resolved after addition of second line antibiotics and antifungals. 11 of 91 patients died of infectious complications in this study. There is a need for improvised diagnostic tests to detect infections early, as well as for new therapies to overcome antimicrobial resistance.     

Steroid responsive cyclical neutropenia

Summary A 19-year old girl with severe cyclical neutropenia associated with life-threatening infection and who responded dramatically to the administration of oral prednisolone is described. During reduction and eventual cessation of steroid therapy normal or near normal neutrophil counts have been maintained, and there has been parallel improvement in clinical well-being. Prior to therapy and at a time of peak blood neutrophil count low numbers of granulocyte-macrophage progenitor cells (CFU-C) were found in the patient's bone marrow, and her lymphocytes co-cultured with normal marrow failed to show the inhibitory effect normally seen with normal lymphocytes.The findings in this patient are compared with those in the two other cases where cyclical neutropenia has been shown to respond to steroids.     

Granulopoiesis in the Neutropenia of Negroes

A number of reports have shown that the peripheral blood neutrophil count in many negroes is considerably lower than in white populations. This neutropenia has been ascribed previously to both genetic and nutritional causes. We have studied bone marrow reserve function and myelopoiesis in 3 negroes with neutropenia, and found these to be normal.     

OUTBREAK OF CO-TRIMOXAZOLE- and GENTAMICIN-RESISTANT KLEBSIELLA AEROGENES BACTEREMIA IN NEUTROPENIC PATIENTS RECEIVING ORAL CO-TRIMOXAZOLE PROPHYLAXIS

Over a five-day period, three neutropenic patients developed bacteremia with an identical strain of Klebsiella aerogenes (serotype K16) resistant to co-trimoxazole and gentamicin. All three patients had received prophylaxis with oral co-trimoxazole before the onset of bacteremia. This report outlines some of the problems associated with co-trimoxazole prophylaxis. (Aust NZ J Med 1983; 13: 636–638.)     

Flucloxacillin associated neutropenia in children treated for bone and joint infections

OBJECTIVE: This report describes episodes of acute neutropenia associated with flucloxacillin use in children treated for bone and joint infections. METHODS: A retrospective chart audit was performed on eight children who developed neutropenia when treated with flucloxacillin. RESULTS: Eight children (aged 1 month to 13 years) had a diagnosis of neutropenia attributed to treatment with flucloxacillin, seven of whom received parenteral therapy. The time to onset of neutropenia averaged 27 days, with neutrophil counts returning to normal limits in all patients after 2 to 9 days. Two children were asymptomatic when the neutropenia was detected. The average flucloxacillin dose used was 65% (range 20-100%) of the recommended maximum dose. CONCLUSIONS: These cases suggest that flucloxacillin should be used with greater caution and guidelines for dosing and clinical monitoring (regular neutrophil counts) need to be reassessed, despite none of these patients experiencing serious sequelae.     

Application of the CFU-GM assay to predict acute drug-induced neutropenia: an international blind trial to validate a prediction model for the maximum tolerated dose (MTD) of myelosuppressive xenobiotics.

In a previous study of prevalidation, a standard operating procedure (SOP) for two independent in vitro tests (human and mouse) had been developed, to evaluate the potential hematotoxicity of xenobiotics from their direct and the adverse effects on granulocyte-macrophages (CFU-GM). A predictive model to calculate the human maximum tolerated dose (MTD) was set up, by adjusting a mouse-derived MTD for the differential interspecies sensitivity. In this paper, we describe an international blind trial designed to apply this model to the clinical neutropenia, by testing 20 drugs, including 14 antineoplastics (Cytosar-U, 5-Fluorouracil, Myleran, Thioguanine, Fludarabine, Bleomycin, Methotrexate, Gemcitabine, Carmustine, Etoposide, Teniposide, Cytoxan, Taxol, Adriamycin); two antivirals (Retrovir, Zovirax,); three drugs for other therapeutic indications (Cyclosporin, Thorazine, Indocin); and one pesticide (Lindane). The results confirmed that the SOP developed generates reproducible IC90 values with both human and murine GM-CFU. For 10 drugs (Adriamycin, Bleomycin, Etoposide, Fludarabine, 5-Fluorouracil, Myleran, Taxol, Teniposide, Thioguanine, and Thorazine), IC90 values were found within the range of the actual drug doses tested (defined as the actual IC90). For the other 10 drugs (Carmustine, Cyclosporin, Cytosar-U, Cytoxan, Gemcitabine, Indocin, Lindane, Methotrexate, Retrovir, and Zovirax) extrapolation on the regression curve out of the range of the actual doses tested was required to derive IC90 values (extrapolated IC90). The model correctly predicted the human MTD for 10 drugs out of 10 that had "actual IC90 values" and 7 drugs out of 10 for those having only an extrapolated IC90. Two of the incorrect predictions (Gemcitabine and Zovirax) were within 6-fold of the correct MTD, instead of the 4-fold range required by the model, whereas the prediction with Cytosar-U was approximately 10-fold in error. A possible explanation for the failure in the prediction of these three drugs, which are pyrimidine analogs, is discussed. We concluded that our model correctly predicted the human MTD for 20 drugs out of 23, since the other three drugs (Topotecan, PZA, and Flavopiridol) were tested in the prevalidation study. The high percentage of predicitivity (87%), as well as the reproducibility of the SOP testing, confirm that the model can be considered scientifically validated in this study, suggesting promising applications to other areas of research in developing validated hematotoxicological in vitro methods.