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Carboplatin may be an effective intraabdominal chemotherapeutic drug instilled immediately following surgery to remove ovarian cancer. Researchers tested the effect of intraabdominal carboplatin, Taxol, or saline solution in 70 rats after abdominal surgery in terms of adhesion formation and wound strength. None of the substances caused undue adhesion formation. Wound thickness and wound strength were significantly lower in animals receiving Taxol than in those receiving carboplatin. Carboplatin may be a more beneficial chemotherapy in humans immediately following removal of cancerous tumors than Taxol because Taxol seriously reduces white blood cell levels.

Ovarian cancer patients undergoing chemotherapy may benefit from a protein treatment that corrects chemotherapy-induced low white cell and platelet counts. Researchers injected the fusion protein PIXY321 into 34 ovarian cancer patients after the second cycle of chemotherapy with cyclophosphamide and carboplatin. The main side effects were redness and hardness at the injection site, and fatigue, fever and loss of appetite. PIXY321 treatments were not effective in increasing white blood cell and platelet counts after multiple cycles of chemotherapy. PIXY321 treatments may be safe and well tolerated by ovarian cancer patients who are also receiving cyclophosphamide and carboplatin. But they may not be able to support larger doses of chemotherapy.

Background. Hematologic toxicity of an antineoplastic drug, carboplatin, is largely dependent on its pharmacokinetics. Its therapeutic efficacy may be related to plasma drug exposure. Dosage adjustment based on isotopic determination of glomerular filtration rate has been proposed, but its ambulatory use is not yet conceivable. The dosage adjustment based on a patient's creatinine clearance relies on accurate measurement of urine volume per unit time and can be done with ease. Purpose: A population pharmacokinetics study was undertaken to determine a relationship between carboplatin clearance and patient characteristics. A predictive formula was derived that was then prospectively evaluated, and its outcome was compared with that obtained by other methods available to predict carboplatin clearance. Methods: Plasma carboplatin pharmacokinetics determined as ultrafilterable platinum in 70 patients (age range, 23-84 years) treated with different combination regimens that included carboplatin at doses ranging from 184 mg to 950 mg (1-hour intravenous infusion) for various tumor types. Data were analyzed using the nonlinear mixed effects model (NONMEM). The data from 34 patients (46 cycles) were utilized to derive the most predictive formula. The reliability of the formula was subsequently evaluated by analyzing the data obtained from 36 other patients (43 cycles). Results: Carboplatin clearance (mL/min) was found to be best predicted by the following formula: 0.134 . weight + [218 . weight . (1 - 0.00457 . age) . (1 - 0.314 . sex)]/creatinine expressed in micromolar concentration (with weight in kg, age in years, and sex = 0 if male and sex = 1 if female). Prospectively, this formula predicted the carboplatin clearance with good precision (median absolute percent error of 10% [range, 0% to 30%]) and minimal bias (median percent error of 2% [range, -25% to 30%]). This method of prediction was as accurate as the one derived from the measurement of glomerular filtration rate following the injection of 51 chromium-EDTA. Conclusion: This formula for the determination of carboplatin clearance can permit individualized determination of carboplatin dosage in adults by simply multiplying the calculated carboplatin clearance by the area under the curve for the desired dosage administration.

Background. Chemotherapy remains inadequate for patients with carcinoid tumors, islet cell tumors, and medullary carcinomas of the thyroid. Carboplatin has shown activity in oat cell carcinoma of the lung, another tumor of neuroectodermal origin. Methods. Forty-two patients with advanced APUD tumors (20 carcinoid tumors, 9 islet cell carcinomas, 5 medullary carcinomas of the thyroid, and 9 neuroendocrine tumors of unknown primary site) were treated with carboplatin in a Phase II study. Results. Carboplatin was inactive in carcinoid and islet cell tumors, with 0 of 20 and 0 of 9 patients responding, respectively. Of the 41 total patients evaluable for response, only 2 (5%) achieved a partial response. Both of these responding patients had neuroendocrine tumors of unknown primary site. No complete responses were seen. Toxicities were those previously noted with carboplatin, with myelosuppression, particularly thrombocytopenia, being dose limiting. Conclusions. Carboplatin is inactive in carcinoid tumors and did not show evidence of activity in islet cell tumors. Further investigations are needed to identify active agents in the treatment of neuroendocrine malignancies.

Background. To reduce the side effects of cisplatin-based combination chemotherapy, the activity of carboplatinum was evaluated in patients with advanced seminoma. Methods. Forty-two evaluable patients with advanced seminoma (defined as abdominal lymph nodes > 5 cm or supradiaphragmatic or visceral disease) received single-agent carboplatinum at a dose of 400 mg/[m.sup.2] intravenously every 4 weeks for a maximum of six cycles. The median follow-up was 31 months (18-67 months). Results. Thirty patients (71%) achieved a complete remission (CR; 21 chemotherapy alone, 9 with additional surgery), 8 patients (19%) a partial remission (PR), and 4 patients had disease progression (10%). Patients with metastases confined to the lymph nodes had a significantly higher remission rate than patients with visceral metastases (97% versus 50%; P < 0.002). Elevation of lactate dehydrogenase or human chorionic gonadotropin before radiation therapy had no influence on response rate. Eight patients have relapsed (five from CR and three from PR). All 12 patients failing carboplatinum therapy received cisplatin-based combination regimens. Ten patients achieved a stable favorable response (eight CR, two PR), whereas two patients died of their disease. Currently, 30 patients (71%) are continuously free from progression (25 CR, 5 PR), and 40 patients are alive (survival 93%). Toxicity was mild with no neurotoxicity or nephrotoxicity. Conclusions. The use of up-front carboplatinum therapy appears not to compromise the ultimate curability of patients with advanced seminoma. Randomized trials, however, will have to demonstrate the effectiveness of carboplatinum with regard to survival, and help to identify prognostic subgroups of patients who require up-front cisplatinum-based combination chemotherapy.

Background. Cisplatin and its analogue carboplatin have been shown to cause dose-dependent growth inhibition throughout a wide dose range in the ovarian cancer cell lines OVCAR-3, 2780, HTB-77, and CRL-1572 tested. Cisplatin was 30 times more effective than carboplatin. The combination of both substances led to a less-than-synergistic effect, as was revealed by an isobologram in the OVCAR-3 cell line. Because of the different toxicity pattern, cisplatin and carboplatin theoretically are ideal candidates for combination chemotherapy in platinum-sensitive tumors. Methods. In a Phase 11 study, the efficacy, the toxicity profile, and the feasibility of combining both substances were assessed in 20 previously untreated patients with ovarian cancer. The regimen consisted of carboplatin (300 Mg/[m.sup.2]) on day 1, followed by cisplatin (100 mg/[m.sup.2]) on day 2 every 4 weeks. Results. A total of 81 cycles were administered (median, 4 cycles; range, 1-6 cycles); four patients experienced complete remission and three experienced clinical partial remissions. Limiting toxicities were thrombocytopenia, leukopenia, and ototoxicity. The mean ([+ or -] standard deviation [SD]) carboplatin and cisplatin dose intensities (DI) reached during the first four cycles of therapy were 58 Mg/[m.sup.2]/week ([+ or -] 18 Mg/[m.sup.2]/week) and 21 mg/[m.sup.2]/ week ([+ or -] 7 mg/[m.sup.2]/week), respectively, which corresponded closely to the projected DI of 75 and 25 mg/[m.sup.2]/ week, respectively. Based on the equivalence ratio of 4:1, the DI of carboplatin has been converted into the respective cisplatin DI, resulting in a total DI estimate. The overall DI of 37 mg/[m.sup.2]/week ([+ or -] 14 mg/[m.sup.2]/week) was close to the projected one of 44 mg/[m.sup.2]/week. Conclusions. Combining cisplatin with carboplatin was found to represent a feasible and efficacious therapeutic strategy for increasing platinum dose intensity. Cancer 1993; 71:3082-90.

Background. This study compared the efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) alone or in combination with peripheral blood-derived hematopoietic progenitor cells (PBP) as support for patients receiving high-dose chemotherapy and assessed the adequacy of these strategies as alternatives to autologous bone marrow rescue. Methods. The authors studied patients with metastatic breast carcinoma who had a major response to conventional chemotherapy or had achieved a complete remission by surgical resection of all known metastases. They were treated with carboplatin 1500 mg/[m.sup.2], etoposide 1200 mg/[m.sup.2], and cyclophosphamide 5.0g/[m.sup.2]. Before this high-dose chemotherapy, the patients had been randomly assigned to one of two hematopoietic support strategies: GM-CSF alone (Group 1) or GM-CSF-primed PBP and GM-CSF (Group 2). Autologous bone marrow was harvested from all patients for use only in the event of persistent pancytopenia with marrow aplasia on day 15. Results. A total of 18 patients were treated. Randomization was halted after the initial 10 patients because of the significant advantages for patients in Group 2 in comparison with those in Group 1 in regard to (1) the median number of days to absolute neutrophil count 0.5 x [10.sup.9]/l (12 versus 21) and platelet count to 50 x [10.sup.9]/1 (13 versus 23), (2) platelet transfusions (3 versus 15.5), and (3) episodes of neutropenic sepsis (0 versus 4, respectively). One patient in Group 1 died from treatment-related complications. All patients in Group 1 required bone marrow reinfusion. No patient in Group 2 required bone marrow reinfusion, and no early mortality was observed in this group. Eight subsequent patients were treated with PBP and GM-CSF (Group 3). This group was more heavily pretreated than Groups 1 or 2 and had a slower hematologic recovery than Group 2. However, none of these patients required bone marrow reinfusion. The four patients in Group 1 that did not have early bone marrow rescue all had neutrophil counts of 0.0 on day 15. For Groups 2 and 3, the neutrophil counts on day 15 ranged from 0.3-2.1 x [10.sup.9]/1 (median, 1.9) and from 0.2-2.1 x [10.sup.9]/1 (median 0.6), respectively. Conclusions. The use of PBP plus GM-CSF accelerated hematologic recovery after this chemotherapeutic regimen compared with GM-CSF alone; there were reduced morbidity and platelet transfusion requirements. Recovery was sufficiently rapid that PBP were an acceptable alternative to autologous bone marrow transplantation in patients receiving high-dose carboplatin, etoposide, and cyclophosphamide. Cancer 1993; 71:2515-21.

Background. Ifosfamide and carboplatin are agents that have completed Phase I studies using a continuous infusion schedule for as long as 14 days. The in vitro compatibility of the two drugs allows for the simultaneous administration in an admixture, and a pilot study was undertaken to determine the feasibility and tolerability of the infusion schedule for the combination. Methods. Ifosfamide at 500 mg/[M.sup.2]/day and carboplatin at 15 or 20 mg/[M.sup.2]/day were administered for 14-day cycles repeated at 28 days in 29 patients, with a total of 60 courses administered. Results. Total cumulative dose per cycle was: ifosfamide 7.0 g/[M.sup.2] and carboplatin 210-280 Mg/[M.sup.2]. Hematuria developed in five patients, four of whom had prior urologic disease, severe thrombocytopenia, or pelvic radiation. In all patients, the hematuria was transient and inconsequential despite the absence of mesna. Grade 3 or 4 leukopenia was observed in eight patients with or without thrombocytopenia and delayed subsequent treatment cycles. Thrombocytopenia was less frequent (Grade 3, 2 patients: Grade 4, 1 patient). No significant episodes of sepsis or hemorrhage were noted. Anemia requiring transfusion developed in 12 of 29 patients. Twenty-one of the 29 patients had received prior chemotherapy. Five of seven previously untreated patients with non-small cell lung cancer achieved a complete (1) or partial (4) response. Conclusions. A continuous 14-day infusion of ifosfamide admixed with carboplatin is feasible in an ambulatory setting with no need for adding mesna for urologic protection and full dosage administration for each agent. Phase 2 studies in non-small cell lung cancer would be reasonable at the optimal doses of ifosfamide 500 Mg/[M.sup.2]/ day and carboplatin 15 mg/[M.sup.2]/day, and the potential exists for the introduction of additional agents, such as etoposide. Cancer 1993; 71:2072-5.

Background. New salvage chemotherapy is needed for metastatic breast cancer. Cisplatin and VP-16 have activity but considerable toxicity. Methods. This study determines the response rate, response duration, and toxicity of a combination chemotherapy regimen of the better-tolerated carboplatin plus VP-16 in a group of patients with metastatic breast cancer and only one prior exposure to cytotoxic chemotherapy. Results. Twenty-three patients received an average of 2.8 courses of treatment before a lack of response or progression of disease was noticed. Four patients had evidence of rapidly progressive disease or early death and received only one course. No complete responses occurred, but three patients (13%) experienced partial responses. Mean response duration was 5 months. Metastatic disease which responded included lung, lymph node, and chest wall sites. Toxicity was mainly myelosuppression with 57% of patients having grade 3-4 neutropenia or thrombocytopenia. Two patients (8%) had significant infection with neutropenia requiring hospitalization but no toxic deaths occurred. Conclusions. Carboplatin and VP-16 at this dose and schedule was a reasonably well-tolerated regimen with only modest activity in metastatic breast cancer as second-line cytotoxic chemotherapy.

Background. For advanced colorectal carcinoma, 5-fluorouracil (5-FU)-leucovorin is the best therapy available. To improve results, a variety of drugs were added, including cisplatin (CDDP), sometimes with controversial results. The combination of CDDP and etoposide (VP-16) has shown synergistic activity in other settings. Although VP-16 alone is considered rather inactive in colorectal carcinoma, the authors believed it was appropriate to evaluate the combination of VP-16 and carboplatin (CBDCA) in this disease because the newer platinum analogue CBDCA has more limited side effects than the parent compound. Methods. Twenty-eight patients with advanced colorectal carcinoma were treated with CBDCA (200 mg/[m.sup.2], days 1-3) and VP-16 (100 mg/[m.sup.2], days 1-5). Cycles were repeated every 4 weeks. All patients received at least two cycles (median, six cycles; range, two to eight cycles). Results. There were three complete responses and four partial responses. The median duration of response was 35 weeks (range, 25-84 weeks). The median time to tumor progression was 23 weeks (range, 9-84 weeks). The median survival time was 49 weeks (range, 9-151+ weeks). Toxic effects generally were assessed as mild, with no Grade 4 (Eastern Cooperative Oncology Group classification) toxic effects observed during this study. Conclusions. Response rate and toxic effects observed during this study warrant additional studies comparing this regimen with 5-FU-based regimens in advanced colorectal carcinoma. Cancer 1993; 71:2706-8.