Continuous subcutaneous administration of mesna to prevent ifosfamide-induced hemorrhagic cystitis.

Hemorrhagic cystitis is a major potential toxicity of ifosfamide that can be prevented by administering mesna along with the cytotoxic agent. Mesna is generally administered by the intravenous route, although experience with oral delivery of the drug has increased. The continuous subcutaneous administration of mesna has the advantage of not requiring intravenous access. In addition, subcutaneous delivery of the neutralizing agent will not be associated with the risk of inadequate urinary mesna concentrations, such as in a patient taking oral mesna who experiences severe ifosfamide-induced emesis and is unable to absorb the drug. Limited clinical experience with continuous subcutaneous mesna administration suggests it is a safe, practical, and economic method of drug delivery that permits ifosfamide to be administered successfully in the outpatient setting.

An effective and more convenient drug regimen for prophylaxis against paclitaxel-associated hypersensitivity reactions.

"Standard" prophylaxis for paclitaxel-associated hypersensitivity reactions has included the systemic administration of H1 and H2 histamine antagonists, along with oral dexamethasone taken both the night prior to, and the morning of, each paclitaxel treatment. To improve patient convenience and compliance with steroid delivery, the Gynecologic Cancer Program of the Cleveland Clinic Foundation has treated patients with an all-intravenous prophylaxis regimen (diphenhydramine 50 mg, famotidine 20 mg, dexamethasone 20 mg) given 30 min prior to paclitaxel (without any earlier oral steroid dosing). To date, we have treated more than 200 patients who received all courses of paclitaxel with this simplified prophylactic regimen, of whom approximately 9% developed hypersensitivity reactions (major or minor). This incidence is comparable to our previously reported experience with hypersensitivity reactions in a similar number of patients receiving the standard prophylaxis (including oral dexamethasone) with their initial course of paclitaxel, and subsequent cycles employing this all-intravenous program. We conclude that this "modified" regimen for paclitaxel-associated hypersensitivity reactions (with all drugs administered approximately 30 min prior to the delivery of paclitaxel) is as effective as, and more convenient than, the standard regimen, and avoids delaying chemotherapy as a result of a patient failing to remember to take one or both oral steroid doses.

Low-dose intravenous ondansetron (8 mg) plus dexamethasone: an effective regimen for the control of carboplatin-induced emesis.

Twenty-nine patients with gynecologic malignancies were treated with a fixed low dose of intravenous ondansetron (8 mg) plus dexamethasone (20 mg) in an effort to develop an effective and less expensive antiemetic regimen for the control of carboplatin-induced emesis. Twenty-six (90%) of the women participating in this trial experienced complete control of both acute nausea and vomiting (developing within the first 24 h after chemotherapy administration), while 27 (93%) patients exhibited either complete or major control (< or = 2 episodes of vomiting, < or = 5 episodes of retching, minimal interference with eating) of emesis. On the basis of our experience in this trial, we conclude that the combination of low dose (8 mg) intravenous ondansetron plus dexamethasone is a well-tolerated and highly cost-effective antiemetic strategy for individuals receiving carboplatin-based chemotherapy.

Experience with prophylactic oral ciprofloxacin in gynecological cancer patients developing severe chemotherapy-induced neutropenia.

The development of significant neutropenia is a relatively frequent complication of cytotoxic chemotherapy of malignant disease. In an effort to develop a cost-effective management strategy to prevent serious infectious events associated with severe chemotherapy-induced neutropenia, patients treated in the Gynecological Oncology Program of the Cleveland Clinic Taussig Cancer Center have been administered ciprofloxacin, a potent broad-spectrum antibiotic, 500 mg orally twice a day, beginning at the time of documentation of grade 4 neutropenia. The antibiotic is continued until granulocyte recovery. A total of 44 patients (57 treatment courses) have been treated in this manner. There have been no complications of therapy and no episodes of subsequent infections due to ciprofloxacin-resistant organisms. Two patients required hospital admission following the development of significant fever, despite the use of ciprofloxacin. While these results are encouraging and suggest that the use of prophylactic ciprofloxacin is a highly cost-effective management approach in this setting, randomized controlled trials are necessary to define the ultimate benefit of this clinical strategy.

Prevention and management of antineoplastic-induced hypersensitivity reactions.

Acute hypersensitivity reactions (HSRs) are an unpredictable and potentially catastrophic complication of treatment with chemotherapeutic agents. Reactions may affect any organ system in the body and range widely in severity from mild pruritus to systemic anaphylaxis. Certain classes of chemotherapeutic agents, such as the taxanes, platinum compounds, asparaginases, and epipodophyllotoxins are commonly associated with HSRs. The clinical characteristics of these high risk agents with respect to HSRs are discussed in this review. Protocols to prevent or reduce the severity of these reactions have been developed, but despite these attempts, HSRs will still happen. Should a reaction occur, it is imperative that it be recognised quickly in order to minimise exposure to the inciting agent and implement appropriate therapeutic and supportive measures. When a patient becomes sensitised to a chemotherapeutic agent, avoidance of re-exposure is the mainstay of future prevention. For sensitised patients who have derived clinically meaningful benefit from a particular agent, however, continuation of treatment with the agent is desirable. Options may include attempting a trial of desensitisation or treatment with a related compound. Virtually all patients demonstrating HSRs to paclitaxel and docetaxel are able to successfully tolerate re-treatment following discontinuation and administration of diphenhydramine and hydrocortisone. Re-treatment has generally been less successful with platinum compounds. with recurrent HSRs occurring in up to 50% of patients following desensitisation protocols. Patients sensitised to asparaginase are often able to tolerate the alternative preparations, Erwinia carotovora asparaginase or polyethylene glycol-modified Escherichia coli asparaginase. There is very little experience with re-treatment following sensitisation to the epipodophyllotoxins. As re-treatment may have serious consequences, careful consideration of the risks and benefits of these strategies is imperative when deciding among these options.

Cancer chemotherapeutic agents.

Clinicians, in general, must understand the causes, methods of prevention, management principles, and complications of cancer therapy. They must recognize that patients with cancer require multidisciplinary treatment and coordination of care. The oncologist who manages the patient's care must involve the oral health care provider before the initiation of chemotherapy. The oral health care provider must recognize that cancer chemotherapeutic agents are not selectively tumoricidal and may produce adverse effects by direct toxicity at the cellular level or indirectly, characterized by myeloimmunosuppression, and has the obligation to deliver quality care, competently and timely before, during, and after cancer chemotherapy.

Limits to the "benefits" from our oncologic interventions: a case report.

PURPOSE: The aim of this study was to discuss the potential implications of prolonged and aggressive treatment of long-term survivors of ovarian cancer. METHODS: A case report of a patient with ovarian cancer extensively treated with platinum-based chemotherapy and aggressive surgery is presented. RESULTS: A woman with a >15-year history of ovarian cancer experienced severe neurotoxicity (peripheral neuropathy, hearing loss), underwent aggressive resection of asymptomatic and long-standing metastatic disease in the liver (with tumor recurrence <1 year after surgery), and subsequently died of secondary acute leukemia. CONCLUSION: It is critical that oncologists remember that the theoretical benefits of available anti-neoplastic interventions must be carefully and constantly weighted against the potential harm they may cause.

Nephrotoxicity of high-dose intracavitary cisplatin with intravenous thiosulfate protection.

Sodium thiosulfate has been shown experimentally to protect against cisplatin-induced renal insufficiency by inactivating the nephrotoxic as well as cytotoxic properties of the agent. However, significant plasma levels of 'active' cisplatin have been demonstrated following high-dose intracavitary cisplatin administration with simultaneous intravenous thiosulfate delivery. At the UCSD Cancer Center 131 patients have been treated with a total of 485 courses (median per patient, 3; range 1-18) of intrapleural or intraperitoneal cisplatin with intravenous thiosulfate protection. Seventy-six patients (58%) had previously been treated with intravenous cisplatin. A total of 14 courses (2.9%) of intracavitary therapy were complicated by a serum creatinine rise to greater than 1.5 mg% which, in all but three cases, returned to the normal range within 1 month following treatment. All but one patient demonstrating clinical evidence of nephrotoxicity had been heavily pretreated with cisplatin. We conclude that thiosulfate can protect against clinically significant cisplatin-induced nephrotoxicity by cisplatin delivered in high doses via the intracavitary route.

Low-dose oral granisetron (1 mg) plus intravenous dexamethasone: efficacy in gynecologic cancer patients receiving carboplatin-based chemotherapy.

OBJECTIVE: The objective of this study was to determine the efficacy of a low-dose oral granisetron plus intravenous dexamethasone prophylactic antiemetic regimen in patients receiving carboplatin-based chemotherapy. PATIENTS AND METHODS: Patients with gynecologic malignancies being treated with either single-agent carboplatin or a carboplatin-paclitaxel regimen received a single 1-mg oral dose of granisetron 30 min prior to chemotherapy plus intravenous dexamethasone (20 mg) as prophylaxis for emesis. Patients either had not previously been treated with chemotherapy or had not received any cytotoxic drugs for >/=4 months prior to study entry. Effectiveness was evaluated based on the degree of control of nausea and vomiting during the 24 h following treatment. RESULTS: Of the 32 patients participating in this phase 2 trial, only 2 (6%) experienced any degree of nausea or vomiting within the first 24 h of chemotherapy administration. Both of these individuals had carcinomatosis and were experiencing emesis prior to chemotherapy. One patient developed mild delayed nausea >24 h after treatment. No major or minor toxic effects of the antiemetic regimen observed. CONCLUSION: A 1-mg dose of oral granisetron plus intravenous dexamethasone (20 mg) is a safe, effective, and relatively inexpensive prophylactic antiemetic regimen for patients receiving single-agent carboplatin or combination carboplatin-paclitaxel chemotherapy.

Control of carboplatin-induced emesis with a fixed low dose of granisetron (0.5 mg) plus dexamethasone.

In an effort to develop a cost-effective antiemetic regimen for carboplatin-based chemotherapy, we examined a fixed (0.5 mg) low dose of granisetron (a new 5-HT3 (serotonin) antagonist) plus dexamethasone (20 mg) in 23 patients with gynecologic malignancies receiving this antineoplastic drug. Nineteen (83%) patients experienced complete control of acute emesis (nausea and vomiting) while 22 (96%) individuals demonstrated complete or major control (< or = 2 episodes of vomiting, < or = 5 episodes of retching, minimal interference with eating) of emetic events. We conclude that this fixed low-dose granisetron plus dexamethasone regimen is a safe, convenient, and cost-effective antiemetic program for individuals receiving carboplatin-based chemotherapy.

Declining CA-125 in an ovarian cancer patient with progression of measurable disease: a rational hypothesis for discordant results.

OBJECTIVES: While a declining CA-125 has been demonstrated to be a useful indicator of response to chemotherapy in ovarian cancer, occasional patients will demonstrate discordant results between the level of this antigen and changes in the size of measurable tumor masses. CASE: The patient was seen in the Gynecologic Oncology Program of the Cleveland Clinic Taussig Cancer Center. RESULTS: This patient exhibited a "major response" by CA-125 criteria, significant shrinkage of multiple peritoneal and perirectal implants, but clear progression of a pelvic side wall mass. The discordant results in this case are likely an example of a "mixed response" to the chemotherapy regimen, with the declining CA-125 corresponding to shrinkage of the responding tumor cell population. CONCLUSION: An evaluation of changes in both the serum CA-125 level and measurable masses may represent a more complete analysis of the status of disease in an individual with ovarian cancer.

The antiemetic efficacy of oral ondansetron plus intravenous dexamethasone in patients with gynecologic malignancies receiving carboplatin-based chemotherapy.

PURPOSE: The purpose of this study was to develop a cost-effective prophylactic antiemetic regimen for the prevention of carboplatin-induced emesis. METHODS: Patients being treated in the Gynecologic Cancer Program of the Cleveland Clinic Taussig Cancer Center with a carboplatin-based chemotherapy regimen received a prophylactic antiemetic program consisting of a single dose of oral ondansetron (16 mg) plus intravenous dexamethasone (20 mg) approximately 30 min prior to chemotherapy. Evaluation of the effectiveness of this antiemetic regimen was performed during a single treatment course. RESULTS: A total of 27 patients (median age, 62; range, 41-83) participated in this phase 2 trial. Three patients received single-agent carboplatin, and 24 were treated with either a carboplatin/paclitaxel or carboplatin/docetaxel regimen. The carboplatin AUC dosing level was 4, 5, or 6 in 6, 5, and 16 individuals, respectively. No patient developed vomiting; 2 (7%) individuals experienced nausea during the 24-h period following chemotherapy administration. CONCLUSION: The combination of a single dose of oral ondansetron (16 mg) plus intravenous dexamethasone (20 mg) is an effective prophylactic antiemetic regimen for patients receiving carboplatin-based chemotherapy.

The use of recombinant human erythropoietin to prevent carboplatin-induced anemia.

Anemia is a frequent and potentially serious toxicity associated with the use of carboplatin, particularly when this agent is administered in the salvage setting. In an effort to evaluate a possible role for human erythropoietin (rh-E) in preventing or minimizing carboplatin-induced anemia we analyzed the impact of the agent on anemia and transfusion requirements of women with ovarian cancer who were treated on one of two nonrandomized trials employing identical second-line carboplatin-based intraperitoneal regimens, with the only difference in the regimens being the addition of rh-E (Study 1, without rh-E; Study 2, with rh-E). There was a statistically significant difference in the incidence of documented nadir hemoglobin levels of < 9 g/dl (Study 1, 60%; Study 2, 13%; P < 0.005) and < 8 g/dl (Study 1, 33%; Study 3, 6%; P < 0.05). We also observed a threefold reduction in transfusion requirements with the use of rh-E (Study 1, 23%; Study 2, 6%), but this difference was not statistically significant with the limited sample size evaluated. In this nonrandomized comparison of two identical chemotherapy programs we have demonstrated that rh-E significantly reduced the incidence and severity of anemia associated with carboplatin-based chemotherapy. A randomized trial examining the potential impact of rh-E on carboplatin-induced anemia and transfusion requirements is warranted.

Intraperitoneal Taxol (paclitaxel) in the management of ovarian cancer.

In an effort to examine the safety and pharmacology of the intraperitoneal (i.p.) delivery of paclitaxel, 25 patients (24 with ovarian cancer) were treated in a phase I dose escalation trial. The drug was administered in normal saline every 3 to 4 weeks, starting at a dose of 25 mg/m2. The dose-limiting toxicity at doses at or above 175 mg/m2 was abdominal pain. A 3-log pharmacokinetic advantage for peritoneal cavity exposure to paclitaxel, compared with the systemic compartment, was observed. High levels of drug persisted within the cavity for longer than 48 hours following a single treatment. In addition, significant paclitaxel concentrations were found in the systemic compartment after i.p. treatment, despite the pharmacokinetic advantage demonstrated for cavity exposure. Several patients exhibited clinical and laboratory evidence of an antitumor response. On the basis of these data, further exploration of a potential role for i.p. paclitaxel in the management of ovarian cancer appears justified.