European journal of cancer & clinical oncology最新文献

With the advent of new chemotherapeutic agents, and their well-known side effect of emesis, the need for a greater facility with anti-emetics has emerged. As well as the common problem of chemotherapy-induced emesis, other problems have become apparent such as delayed emesis and anticipatory emesis. The control of such emetic problems may be affected by certain patient characteristics, such as a history of chronic high alcohol intake, and age. Blockade of the different types of neuroreceptors can lead to effective emetic control. Dopamine receptor blockers such as the phenothiazines, butyrophenones and substituted benzamides have been among the most effective agents. However, newer agents, such as ondansetron, which specifically bind to serotonin receptors, may preserve the anti-emetic efficacy of the dopamine-blockers, but without the associated extrapyramidal side effects of these agents.

Ondansetron is a 5-HT3 receptor antagonist which has shown activity in the prevention of nausea and vomiting resulting from cytotoxic therapy. This paper describes the results of studies evaluating the efficacy of oral ondansetron in controlling radiation-induced emesis. Initial non-randomised studies showed that doses of 4 mg q.d.s. or 8 mg t.d.s. of ondansetron achieved complete or major control of vomiting in 77-91% of patients and mild or absence of nausea in 72-77% following single exposure high-dose (8-10 Gy) radiotherapy to the upper abdomen. A subsequent double-blind, prospective, randomised trial compared ondansetron 8 mg t.d.s. with metoclopramide 10 mg t.d.s. in the prevention of emesis following single radiation doses of 8-10 Gy to the upper abdomen. On the day of radiotherapy, ondansetron achieved significantly greater control of vomiting and retching (P less than 0.001) and nausea (P = 0.001) than metoclopramide. An advantage for ondansetron was also seen on days 2 and 3 after irradiation, although this did not reach a statistically significant level. Only two patients, out of 154, in all the studies experienced side effects attributable to ondansetron: one developed headache and the other experienced headache and vertigo. These studies show that ondansetron is a safe drug, with activity in the prevention of radiation-induced emesis and significantly greater efficacy than metoclopramide in the control of nausea and vomiting following single exposure upper abdominal high-dose radiotherapy.

The metabolism of ondansetron has been studied in rat, dog and man. In laboratory animals absorption of the compound across the gastrointestinal tract is rapid and extensive, but due to high first-pass metabolism, the oral systemic bioavailability is low (less than 10%). The high systemic clearance of ondansetron results in a very short half-life in rat and dog. The renal clearance of ondansetron is low, indicating that the major route of systemic clearance is by metabolism. Routes of excretion of drug-related material differ between laboratory animals and man - the major route in the rat and dog is via the bile, while in man the predominant route is via the urine. However, the routes of metabolism are qualitatively similar in all species, indicating that the species used in toxicological testing of ondansetron were appropriate.

Febrile episodes during chemotherapy-induced neutropenia are a frequent cause of morbidity and mortality in cancer patients. Empiric antibiotic therapy commencing at the onset of fever is selected according to three principles: intravenous therapy is used to rapidly achieve bactericidal serum levels, antibiotics with appropriate antibacterial spectra are required, and combinations of antibiotics have been preferred for their synergistic activity. Initial empiric monotherapy with single antibiotics such as imipenem which have a sufficiently broad antibacterial spectrum in their own right are potentially as efficacious as conventional combination therapies. Granulocytopenic periods complicated by fever are significantly longer in patients receiving chemotherapy for leukaemia than in patients undergoing treatment for lymphoma and solid tumours. However, defervescence of fever following commencement of antibiotic therapy occurs equally rapidly in these three groups. The persistent granulocytopenia leaves leukaemic patients at greatest risk of breakthrough or second infections. These patients therefore appear to be the most likely to benefit from the clinical use of haemopoietic growth factors such as granulocyte and granulocyte-macrophage colony-stimulating factor.

Patients undergoing intensive antileukemic chemotherapy and profound granulocytopenia are susceptible to overwhelming infections, particularly those arising from disease- and therapy-related gastrointestinal tract damage. We have previously demonstrated that the ability to suppress bacterial colonization of this site with oral norfloxacin prophylaxis (400 mg every 12 h) affects the incidence and distribution of aerobic gram-negative bacterial infections and the overall management of infectious complications in this patient population. We have now determined the broad impact of continuous, long-term use of oral norfloxacin on aerobic gram-negative bacterial infection and colonization, overall management of presumed and documented infections during marrow aplasia and emergence of clinically significant antibiotic resistant pathogens during intensive antileukemic chemotherapy. Oral norfloxacin prophylaxis administered throughout the course of induced granulocytopenia continues to afford effective protection by suppressing the development of aerobic gram-negative infections, particularly those arising from the gastrointestinal tract, and preventing the acquisition or emergence of multiply resistant pathogens. A long-range effect of norfloxacin on pathogens colonizing the respiratory tract is also detected, with inhibition of acquired drug resistance occurring at that site as well. For these reasons, norfloxacin continues to be an excellent agent for oral prophylactic use in this patient population.

Bone marrow transplants experience severe immuno-deficiency as a consequence of pretransplant radiation and chemotherapy, transient granulocytopenia before marrow engraftment, and post-transplant prevention and treatment of graft-versus-host disease with immuno-suppressive agents. During periods of granulocytopenia, chemoprophylaxis with the oral fluorinated quinolones can prevent colonization and infection with gram-negative bacilli, is better tolerated than oral non-absorbable antibiotics or trimethoprim-sulfamethoxazole and is more cost-effective than laminar-air-flow isolation or prophylactic granulocyte transfusions. Antifungal prophylaxis with oral nystatin, ketoconazole or amphotericin B, however, has not been consistently effective; empiric intravenous amphotericin B therapy is still the most reliable way to prevent fatal fungal infections. Following marrow engraftment, cytomegalovirus infection and interstitial pneumonia can be prevented in cytomegalovirus-seronegative patients by the use of cytomegalovirus-seronegative blood products and cytomegalovirus immune globulin. In cytomegalovirus-seropositive patients, prophylactic DHPG (ganciclovir) is currently being evaluated in a controlled clinical trial. Herpes simplex and varicella-zoster infections can be treated effectively with intravenous acyclovir, but routine acyclovir prophylaxis is not cost-effective. Trimethoprim-sulfamethoxazole is used for prophylaxis of Pneumocystis carinii pneumonia and may be continued in patients with chronic graft-versus-host disease for prevention of late post-transplant bacterial infections.

Norfloxacin has been compared to placebo (136 patients), sulfamethoxazole plus trimethoprim (SXT, 72 patients) and oral vancomycin plus colistin (V/C, 61 patients) for the prevention of alimentary tract-associated infections during and after induction chemotherapy. These patients were evaluated for the safety and tolerability of each regimen by clinical and laboratory means. Most neutropenics involved, regardless of the regimen, experienced at least one adverse experience. The majority were felt to be unrelated to prophylactic study drug therapy. Of 139 patients who received norfloxacin, only two had drug-related adverse experiences, compared to two of 35 receiving SXT, five of 28 for VC, and none of 67 receiving placebo. In evaluating adverse experiences considered possibly drug related, 19 occurred on norfloxacin compared to 13 for placebo. Among neurologic adverse experiences, only one possibly related to norfloxacin occurred (confusion), while three occurred on placebo (confusion, decreased auditory acuity and hallucinations). Generally, no significant differences were seen between any of the regimens except for a higher frequency of diarrhea in those receiving V/C.