Phase I dose escalation study of topotecan combined with alternating schedules of paclitaxel and carboplatin in advanced solid tumors.

BACKGROUND: Combining topotecan with other cytotoxics has been problematic due to marrow suppression. A phase I trial was initiated to identify the optimal sequence and maximum-tolerated dose of topotecan in combination with paclitaxel and carboplatin. PATIENTS AND METHODS: Patients with advanced cancer and performance status ECOG < or = 2. The starting dose was paclitaxel 175 mg/m2 day 1, carboplatin AUC 6.0 day 1, and topotecan 0.5 mg/m2 daily day 1-5 (early sequence). The next course of paclitaxel and carboplatin administration was delayed to day 5 (late sequence). Treatment was repeated every three weeks. After determining maximum-tolerated dose without cytokines, granulocyte colony-stimulating factor (G-CSF) was added and further dose escalation was pursued. RESULTS: Fifty-one patients were entered; men: women ratio 30:21. Dose-limiting toxicity (DLT) for the early sequence was neutropenia at doses paclitaxel mg/m2/carboplatin AUC 5/topotecan mg/m2 (PCT) 175/5/0.75 for four to five days. DLT for the late sequence was neutropenia at PCT doses of 175/5/ 1.0 for four days. G-CSF 5 microg/kg subcutaneously starting day 6 permitted further topotecan dose escalation. After adding G-CSF, late sequence DLT was neutropenia at doses 175/5/1.25 for four days. Forty-six patients were evaluable for response and of those, there were thirteen partial responses. CONCLUSIONS: The late sequence resulted in less toxicity and was better tolerated. The early sequence maximum-tolerated dose (MTD) was 175/6/0.5 for five days. The late sequence MTD was PCT 175/5/0.75 for five days. The late sequence MTD with G-CSF was 175/5/1.0 for four days. The recommended phase II PCT dose is the late sequence 175/5/1.0 for four days with G-CSF.

Induction paclitaxel and carboplatin for patients with head and neck carcinoma. Analysis of 62 patients treated between 1994 an 1999.

BACKGROUND: After standard therapy for advanced head and neck carcinoma, 5-year survival rate is less than 50%. Our purpose was to develop a new treatment for advanced head and neck carcinoma by using preoperative chemotherapy. Long term efficacy and toxicity of induction paclitaxel and carboplatin is reported here. METHODS: Between 1994 and 1999, 62 consecutive patients with newly diagnosed head and neck carcinoma were treated with paclitaxel and carboplatin induction chemotherapy. Chemotherapy was administered every 21 days with 3 courses of paclitaxel (150-265 mg/m(2)) and carboplatin at a dose calculated using the Calvert formula area under the curve of 7.5. Patients who achieved complete or partial response at the primary received definitive radiation to the primary tumor and those with lymph node disease received neck dissection followed by radiation to the regional lymph nodes. Nonresponders received standard resection of primary tumor and draining lymph node basin followed by radiation. RESULTS: Sixty-two consecutive patients were treated. Seventy-four percent had Stage IV (according to the 5th edition of American Joint Committee on Cancer Staging manual) disease. The median duration of follow-up from initiation of chemotherapy was 64 weeks (range, 1-272 weeks). Overall complete plus partial response rate was 41 of 62 (66%). Responses were observed at all anatomic sites: oropharynx 20 of 33 (61%); hypopharynx 8 of 12 (67%); and larynx 13 of 17 (76%). Kaplan-Meier estimates of overall survival (OS), at 230 weeks, were significantly better in Stage IV oropharynx/hypopharynx responders than nonresponders (55% vs. 27%; P = 0.04). Of the variables evaluated in multivariate models, response at the primary tumor and lymph nodes were associated with improved disease free survival and OS. Organ preservation was achieved in 28 of 62 (45%) of patients at all anatomic sites: oropharynx 39%, hypopharynx 42%, larynx 59%. Seventeen of 28 (61%) patients had their primary organ site preserved for a mean duration of 78 weeks (range, 13-238 weeks). CONCLUSIONS: Induction paclitaxel and carboplatin was well tolerated. The response rate was encouraging considering most patients were Stage IV. Chemotherapy response identified a group with improved prognosis. Organ preservation was possible at all anatomic sites.

Erythropoietin reduces anemia and transfusions: A randomized trial with or without erythropoietin during chemotherapy.

BACKGROUND: Anemia has been reported to develop during preoperative chemotherapy with paclitaxel and carboplatin. The use of recombinant human erythropoietin (EPO) has been shown to reduce anemia and subsequent packed red blood cell transfusions. The current study is a report of a Phase III, prospective, randomized trial with or without EPO that confirms the original observations of less anemia and fewer transfusions in those patients randomized to receive EPO concurrently with paclitaxel and carboplatin. METHODS: Thirty patients with advanced head and neck or lung carcinoma were treated with 2 courses of paclitaxel, 230 mg/m(2), and carboplatin, 7.5 mg/mL/minute, repeated every 21 days. The treatment group was comprised of 15 patients randomized to receive concurrent EPO, 150 U/kg, 3 times per week; in patients deemed nonresponsive the dose was increased to 300 U/kg and 450 U/kg in subsequent courses. The control group was comprised of 15 patients randomized not to receive EPO. RESULTS: Twenty-seven patients were evaluable. After 2 courses of chemotherapy the mean hemoglobin decrease was 1.2 g/dL in the EPO group versus 2.8 g/dL in the control group (P = 0.037). There was a highly significant decrease in hemoglobin over time in patients who did not receive EPO (P = 0.008). After 4 courses of chemotherapy, fewer patients were transfused in the EPO arm: 2 of 13 (15%) in the EPO treatment group versus 5 of 14 (36%) in the control group. CONCLUSIONS: There was significantly less anemia and transfusions were reduced by 50% in patients randomized to receive EPO during chemotherapy with paclitaxel and carboplatin.

Cimetidine therapy for recalcitrant warts in adults: is it any better than placebo?

Three open-label, uncontrolled studies have documented successful treatment of warts with cimetidine, whereas two placebo-controlled, double-blind studies and two open-label comparative trials have failed to demonstrate efficacy. This double-blind, placebo-controlled study was designed with stringent enrollment and outcome criteria to minimize the confounding issue of spontaneous remission. Efficacy was not statistically superior to that of placebo, but a trend toward efficacy was suggested for younger subjects.

Ototoxicity associated with vinblastine.

OBJECTIVE: To describe a patient with ototoxicity associated with vinblastine chemotherapy. CASE SUMMARY: A 29-year-old white man with recurrent Hodgkin's disease received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy once every two weeks for 12 cycles. He reported tinnitus after each treatment, with an onset of about six hours and a duration of seven to 10 days. This interfered with reading, watching television, and general concentration. Symptoms returned to baseline prior to the beginning of each subsequent cycle. Audiograms performed before and after several cycles showed mild sensorineural hearing loss in the high-decibel range, but no loss of speech recognition. DISCUSSION: No reported cases of ototoxicity or tinnitus from ABVD were found. All concomitant medications were eliminated as possible causes either due to lack of temporal association with the symptoms or no reports of ototoxicity in the literature. Vincristine, a more commonly used vinca alkaloid very similar to vinblastine, was noted to have caused several cases of sensorineural hearing loss. CONCLUSIONS: This case suggests that vinblastine may cause ototoxicity.

A phase II evaluation of pentoxifylline combined with radiation in the treatment of brain metastases.

Pentoxifylline (PTX) has pharmacological properties that suggest potential utility as a radiation sensitizer, and preclinical animal studies have been promising. In a non-randomized phase II trial, we used PTX plus standard-dose external-beam whole-brain radiation treatment (WBRT) in patients with brain metastases. Seventeen patients were entered; 14 received both WBRT and PTX and were considered evaluable. Nine of the 14 completed treatment. Analyzing data on all 14 evaluable patients according to intent to treat, median survival time was 33 days, comparable to published data from historical controls. PTX toxicity was not a common cause of patient dropout, supporting higher PTX doses in future trials.

A phase I report of paclitaxel dose escalation combined with a fixed dose of carboplatin in the treatment of head and neck carcinoma.

BACKGROUND: Standard therapy for advanced head and neck carcinoma is surgery and radiation, and the subsequent 5-year survival with this treatment has been less than 50%. New combined modality treatment strategies are being tested to improve survival. New chemotherapy combinations are being developed and administered simultaneously with, or sequenced with, radiation and surgery. This article reports the Phase I results of administering paclitaxel and carboplatin preoperatively. The authors' objective was to develop an outpatient chemotherapy that would downstage tumors and allow organ preservation with equal or improved survival as compared with standard therapy. METHODS: Thirty-six patients with untreated Stage III/IV head and neck carcinoma were treated and were evaluable for toxicity. All patients had lesions that were measurable in perpendicular planes. A nonrandomized, Phase I design was used, according to which cohorts of patients were treated every 21 days with escalating doses of paclitaxel (150-265 mg/m2) given as a 3-hour infusion immediately preceding carboplatin. Premedication was used to avoid acute hypersensitivity reactions. Carboplatin was administered intravenously over 1 hour at a constant dose calculated with the Calvert formula (area under the curve, 7.5). RESULTS: The dose-limiting toxicities were neuropathy and thrombocytopenia at a paclitaxel dose of 265 mg/m2. Neutropenic fever was observed in 30% of patients at a paclitaxel dose of 250-265 mg/m2. Other observed adverse effects included pruritus, myalgia, arthralgia, alopecia, nausea, and vomiting. CONCLUSIONS: Toxicity was acceptable. The maximum tolerated dose of paclitaxel was 230 mg/m2 without hematopoietic growth factor, or 250 mg/m2 with hematopoietic growth factor, the carboplatin dose held constant, calculated at area under the curve of 7.5. Phase II studies of this combination are warranted in the treatment of these carcinomas.

Erythropoietin reduces anemia and transfusions after chemotherapy with paclitaxel and carboplatin.

BACKGROUND: The authors report on anemia observed during preoperative paclitaxel and carboplatin chemotherapy in patients with advanced head and neck carcinoma and discuss how the use of recombinant human erythropoietin (r-HuEPO) ameliorates this anemia, reducing the need for subsequent packed red blood cell (PRBC) transfusions. METHODS: Response to r-HuEPO was defined as reduced hemoglobin fall during preoperative chemotherapy and reduced transfusion requirements during surgery. Thirty-six patients with advanced head and neck carcinoma were evaluable after treatment with preoperative chemotherapy using paclitaxel and carboplatin. Group 1 was comprised of 14 patients who empirically received r-HuEPO at a dose of 150 U/kg 3 times per week for 3 weeks; in patients deemed nonresponders, the dose was increased to 300 U/kg and 450 U/kg in the subsequent courses. Group 2 was comprised of 22 patients who did not receive r-HuEPO. RESULTS: During preoperative chemotherapy, the mean hemoglobin fall was 0.5 g/dL in Group 1 (P = 0.40). In Group 2 there was a statistically significant mean hemoglobin fall of 3.3 g/dL (P < 0.0001). There was also a nonstatistically significant trend toward fewer PRBC transfusions: none of 14 patients (0%) in Group 1 versus 4 of 22 patients (18%) in Group 2 (P = 0.141). CONCLUSIONS: A significant fall in hemoglobin and an increase in the need for transfusions were observed in head and neck carcinoma patients receiving carboplatin and paclitaxel chemotherapy prior to surgery. Empiric r-HuEPO therapy appeared to prevent anemia and reduced the need for PRBC transfusions.

Antifungal effects of yeast-derived rhu-GM-CSF in patients receiving high-dose chemotherapy given with or without autologous stem cell transplantation: a retrospective analysis.

Systemic fungal infections (SFI) in patients receiving high-dose chemotherapy (HDC) are a frequent cause of morbidity and mortality. Preclinical studies have reported augmented antifungal activity of monocytes, macrophage cells, and neutrophils exposed to certain colony-stimulating factors (CSF), including GM-CSF. We conducted a retrospective descriptive epidemiologic study to examine the characteristics of 145 consecutive patients receiving HDC administered with or without autologous stem cell transplantation (ASCT) and who subsequently received either GM-CSF and G-CSF, G-CSF alone, GM-CSF +/- IL-3 or no CSF. The analysis of this patient population sought to define the incidence of SFI and its relationship to therapy with monocyte/macrophage-stimulating (MMS group) cytokines (GM-CSF and G-CSF; GM-CSF +/- IL-3) or to cytokines which do not result in monocyte/macrophage stimulation (NMMS group, G-CSF alone or no CSF). Risk factors for the development of SFI were balanced between the MMS (n = 70) and NMMS (n = 75) groups. Two patients (2.9%) in the MMS and nine patients (12%) in the NMMS groups developed SFI. The risk ratio for developing SFI in the NMMS group compared to the MMS group was 4.20 (P = 0.023). This relationship was confounded, however, by the diagnosis of hematologic tumor or solid tumor (RR = 3.15, P = 0.082). SFI was the primary cause or major contributing factor in five of the 10 total deaths in our study population. Four SFI-related deaths occurred in the NMMS group and one SFI-related death occurred in the MMS group. Our data suggest a protective role for GM-CSF, IL-3 or other MMS cytokines in preventing SFI in patients receiving HDC. This should be further investigated as a potential complementary approach to conventional strategies in antifungal prophylaxis for patients receiving HDC.

Quality-assurance testing of staff pharmacists handling cytotoxic agents.

Competency-based simulation testing was used to improve staff pharmacists' handling of cytotoxic agents. Pharmacists were asked to prepare a simulated liquid cytotoxic agent (fluorescein sodium 0.5 mg/ml.) according to the pharmacy service standard operating procedures. Participants were observed throughout the preparation to assess proper safety and aseptic technique, waste disposal, and labeling. Ultraviolet light was used to assess surface contamination. After the test, errors were discussed with each participant. All participants then received scheduled annual training on preparation of cytotoxic agents, and they took the simulation test again three months later. Thirteen staff members completed all testing. Simulation test scores improved from 61% to 84%. Evidence of surface contamination was found for 92% of these pharmacists during the pretest and only 23% during the posttest. Written test scores improved, but not significantly, from 85% to 89%. Each simulation and feedback session took 30 minutes. Simulation testing significantly improved competence in preparation of cytotoxic agents.

Safe handling of antineoplastic drugs.

Managers should be aware of the hazardous properties of antineoplastic drugs and of the procedures and equipment commonly recommended to provide a safe working environment for employees, patients, and visitors. Compliance with the many published guidelines should help ensure passage of the inevitable Occupational Safety and Health Administration (OSHA) or Joint Commission inspection. Acute and chronic toxicities of the antineoplastic drugs, the potential for exposure in the workplace, and the basic guidelines for safe handling of these agents are reviewed.

IR-192, low dose rate endobronchial brachytherapy in the treatment of malignant airway obstruction.

PURPOSE: To assess the value of low-dose-rate endobronchial brachytherapy in the treatment of malignant airway obstruction. METHODS AND MATERIALS: Between September 1986 and April 1989, 39 patients with malignant airway obstruction had 49 catheter placements for an afterloading, low-dose-rate Ir-192 endobronchial brachytherapy. A flexible fiberoptic bronchoscope with fluoroscopic guidance was used for positioning. Thirty-eight of 39 (97%) patients completed the prescribed treatments. Ninety-seven percent had received previous external radiation in doses ranging from 36-60 Gy. One patient had metastatic renal cell carcinoma; the remainder had recurrent lung cancer. Endobronchial laser treatments were given to three patients 2-3 weeks prior to endobronchial brachytherapy. All patients were followed until death. The median dose delivered in 48 of the 49 placements was 20 Gy at 1 cm. RESULTS: Follow-up bronchoscopy was performed in 28 (72%) of 39 patients. Of these, 13 (46%) had a complete response, 12 (43%) had a partial response, and 3 (17%) had a minor response. Dyspnea improved in 30 of 37 patients (82%); hemoptysis in 17 of 19 patients (89%); cough in 31 of 39 patients (79%); and postobstructive pneumonia in 21 of 23 patients (92%). The median survival for the entire group was 5 months (range 1-31 months). CONCLUSION: This technique is simple, well-tolerated and offered significant palliation.

Chemo-irradiation induced aortoesophageal fistula.

A patient with squamous cell carcinoma of the esophagus developed fatal aortoesophageal (AE) fistula following a preoperative course of combined chemotherapy plus radiation therapy. This is the first reported case of AE fistula following preoperative chemoradiotherapy. This complication is potentially correctable if suspected early, since the massive hemorrhage characteristic of AE fistula is usually preceded by an initial sentinel hemorrhage. The cause of this complication is not clear, but it may be due to inflammation of the vasa vasorum with necrosis of the aortic wall. The concomitant use of fluorouracil and cisplatin with radiation therapy acts as a radiosensitizer and may have potentiated the radiation effect on the aortic wall.

Dose-response relationship to dacarbazine demonstrated in a patient with malignant melanoma.

Dacarbazine has shown the most consistent activity of any single chemotherapeutic agent in patients with metastatic melanoma. While the overall rate is 21%, responses fall to less than 10% when hepatic metastases are present. We report a patient with malignant melanoma metastatic to the liver in whom an apparent dose-response relationship to dacarbazine was demonstrated. His liver metastases responded to hepatic artery infusion, progressed with systemic iv therapy, and responded upon reinstitution of hepatic artery infusion.

Vinblastine-associated pulmonary toxicity in patients receiving combination therapy with mitomycin and cisplatin.

Two of 33 patients entered in a local pilot study of mitomycin, vinblastine, and cisplatin for non-small cell lung cancer developed vinblastine-associated pulmonary toxicity. As with other reports of vinca alkaloid-related pulmonary toxicity, the regimen included mitomycin. Based on these cases and others previously reported, the incidence of abrupt pulmonary toxicity following vinca alkaloid administration as part of mitomycin/vinca alkaloid combination appears to be three to six percent. Suggestions for management are given.

Lack of effect of vitamin E therapy on the anemia of patients receiving hemodialysis.

We conducted a prospective, randomized, double-blind therapeutic trial of vitamin E as an erythropoietic agent in a group of patients with chronic renal failure who were undergoing chronic hemodialysis. Sixteen patients received 400 IU of vitamin E (d-alpha-tocopheryl acetate) by mouth twice daily and 19 patients received a placebo twice daily for 20 wk. The serum vitamin E concentration increased from 1.3 to 2.6 mg/dl in the treated group and decreased from 1.3 to 1.1 in the placebo group. For the treated group the initial hematocrit was 24.8 +/- 3.0 (mean +/- SD) and the final hematocrit was 25.8 +/- 3.8. For the placebo group the initial hematocrit was 24.9 +/- 3.0 and the final hematocrit was 23.5 +/- 2.7. The treated group received a total of 40 blood transfusions, and the placebo group received a total of 35 blood transfusions. Thus, vitamin E had no effect on the anemia or transfusion requirements of patients undergoing chronic hemodialysis for chronic renal failure.

Developing guidelines for working with antineoplastic drugs.

The potentially hazardous properties of antineoplastic drugs and problems associated with the admixture and administration of injectable antineoplastics are reviewed. The mutagenicity of anticancer drugs, carcinogenicity testing in animals, carcinogenicity of antineoplastic agents in humans, and federal regulation of carcinogens are discussed. Concern in the literature regarding the handling of antineoplastic drugs in reviewed briefly, and guidelines for proper handling are suggested. Local hospital guidelines on the handling of antineoplastic drug products should be designed to protect health-care workers from unnecessary exposure to potential carcinogens.