Calvert Formula Research Articles

Concurrent chemoradiotherapy with carboplatin and uracil-f tegafur (UFT) for patients with poor performance status with locally advanced squamous cell carcinoma of the head and neck (SCCHN)

Conclusions. Concurrent chemoradiotherapy with carboplatin and uracil-f tegafur (UFT) seems to be a promising and appropriate regimen for patients with poor performance status (PS) with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Objective. We designed a regimen based on divided low-dose administration to reduce toxicity for patients with poor PS with locally advanced SCCHN. Patients and methods. Sixty-two patients with previously untreated stage III–IV SCCHN and PS of 2 or 3 were entered into this study. They received radiotherapy: 70 Gy/35 fractions. The chemotherapy consisted of a combination of carboplatin (Calvert's formula: (GFR+25)×AUC (=5)/4 mg/week; where AUC=area under the curve and GFR=glomerular filtration rate) and UFT (300 mg/day, per os). Results. The overall clinical response rate and the pathological complete response (CR) were 90% (56/62) and 61% (38/62), respectively. Grade ≥3 mucositis occurred in only 6% of patients (4/62) and grade ≥3 leukocytopenia and neutropenia occurred in only 5% (3/62).

Flat Dosing of Carboplatin Is Justified in Adult Patients with Normal Renal Function

The Calvert formula is a widely applied algorithm for the a priori dosing of carboplatin based on patients glomerular filtration rate (GFR) as accurately measured using the 51Cr-EDTA clearance. Substitution of the GFR in this formula by an estimate of creatinine clearance or GFR as calculated by formulae using serum creatinine (SCR; Cockcroft-Gault, Jelliffe, and Wright) is, however, routine clinical practice in many hospitals. The goal of this study was to validate this practice retrospectively in a large heterogeneous adult patient population. Concentration-time data of ultrafilterable platinum of 178 patients (280 courses, 3,119 samples) with different types of cancer receiving carboplatin-based chemotherapy in conventional and high doses were available. Data were described with a linear two-compartment population pharmacokinetic model. Relations between SCR-based formulae for estimating renal function and carboplatin clearance were investigated. None of the tested SCR-based estimates of renal function were relevantly related to the pharmacokinetic variables of carboplatin. Neither SCR (median, 51; range, 18-124 micromol/L) nor the estimated GFR using the three different formulae was related to carboplatin clearance. Our data do not support the application of modifications of the Calvert formula by estimating GFR from SCR in the a priori dosing of carboplatin in patients with relatively normal renal function (creatinine clearance, >50 mL/min). For targeted carboplatin exposures, the original Calvert formula, measuring GFR using the 51Cr-EDTA clearance, remains the method of choice. Alternatively, in patients with normal renal function, a flat dose based on the mean population carboplatin clearance should be administered.

Four cycles of paclitaxel and carboplatin as adjuvant treatment in early-stage ovarian cancer: a six-year experience of the Hellenic Cooperative Oncology Group

BackgroundSurgery can cure a significant percentage of ovarian carcinoma confined to the pelvis. Nevertheless, there is still a 10–50% recurrence rate. We administered paclitaxel/carboplatin as adjuvant treatment in early-stage ovarian carcinoma.MethodsPatients with stages Ia or Ib, Grade 2 or 3 and Ic to IIb (any grade) were included. Patients were treated with 4 cycles of Paclitaxel 175 mg/m2 and Carboplatin [area under the curve (AUC) 6 (Calvert Formula)] every 3 weeks.ResultsSixty-nine patients with no residual disease following cytoreductive surgery and minimal or modified surgical staging were included in this analysis. Grade 3 or 4 neutropenia occured in 29.9% of patients, while neutropenic fever was reported in 4.5%. Neurotoxicity (all Grade 1 or 2) was reported in 50% of cases. Median follow-up was 62 months. 5-year overall survival (OS) and relapse-free survival (RFS) were: 87% (95% confidence intervals [CI]: 78–96) and 79% (95% CI: 69–89), respectively. Significantly fewer patients with stages Ic-IIb and tumor grade 2 or 3 achieved a 5-year RFS than patients with only one of these two factors (73% vs 92%, p = 0.03).ConclusionPaclitaxel/Carboplatin chemotherapy is a safe and effective adjuvant treatment in early-stage ovarian carcinoma. Patients with stages Ic-IIb and tumor grade 2 or 3 may benefit from more extensive treatment.

A phase II trial of paclitaxel plus carboplatin in patients with non-small cell lung cancer previously treated with chemotherapy

17103 Background: The purpose of this phase II trial was to evaluate the efficacy and toxicity of paclitaxel plus carboplatin in the treatment of advanced non-small cell lung cancer (NSCLC) previously treated with chemotherapy. Methods: Eligible patients were aged 20 to 75 years with a performance status (PS) 0 to 1, previous treatment with one or two prior chemotherapy regimen for advanced NSCLC, and adequate organ function. Paclitaxel 200 mg/m2 was infused over 3 hours, before carboplatin (area under the curve 6; Calvert formula) infused over 1 hour, once every 3 weeks for six cycles maximum. The primary endpoint of this study was response rate. Simon’s two-stage design was used to determine the sample size and the planned accrual was 30 patients. Results: Thirty patients were enrolled. Complete response was observed in one patient and partial response in eleven patients for an overall response rate of 40% (95% confidence interval: 23–59%). The median time to progression was 5 months. The median survival was 9.9 months (range, 2.5–33.8 months), and the 1-year survival rate was 46%. The hematologic toxicities were 7% for grade 4 neutropenia, 3% for grade 3 febrile neutropenia, 17% for grade 3 and 4 anemia, and 7% for grade 3 thrombocytopenia. Grade 3 non-hematologic toxicities included rash (7%), myalgia/arthralgia (3%), arrhythmia (3%), and infection (3%). There were no toxic deaths. Conclusions: The combination of paclitaxel plus carboplatin is an active and well-tolerated regimen in the treatment of patients with NSCLC previously treated with chemotherapy who have a good PS. No significant financial relationships to disclose.

High dose chemotherapy with autologous stem cell rescue (ASCR) for recurrent medulloblastoma

11507 Background: Medulloblastoma is a highly lethal disease when it recurs and very few patients survive with conventional treatment. This study evaluated the use of high-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue (ASCR) in patients with recurrent medulloblastoma. Methods: Between 8/97 and 8/05 14 patients (M/F 12/2) with recurrent medulloblastoma, aged 2 to 33 years (median, 10.5 years) at ASCR, were treated. Thirteen had relapsed after chemotherapy and craniospinal + posterior fossa irradiation and one after chemotherapy (Baby POG) at a median time of 19 months (7 to 148). One had a local relapse and 13 had dissemination at relapse (M1: 1, M2: 7 and M3: 5) Chemotherapy consisted of carboplatin 500 mg/m2 (or area under the curve = 7 mg/ml × min via Calvert formula) on days −8, −7, −6; and thiotepa 300 mg/m2 and etoposide 250 mg/m2 on days −5, −4, and −3 respectively; followed by ASCR on day 0. Results: Four patients died of treatment-related toxicities at 0, +23, +42 and +51 days post ASCR (bacterial sepsis in 2, CMV infection in 1 and CNS hemorrhage in 1). It should be remarked that all the toxic deaths were observed in patients auto grafted before October 2000. Five of 14 patients (35%) are event-free survivors at a median of 70 months post-ASCR (range: 5 to 86 months). Tumor recurred in the remaining 5 patients at a median time of 2 months post ASCR (2 to 15). All died at +23, +16, +12, +9 and +4 month post ASCR. Conclusions: Our results seem consistent with those published by Dunkel IJ (J. Clin Oncol; 16:222 - 8 1998) and argue about the efficacy of high dose chemotherapy with ASCR to provide long-term survival for some patients with recurrent medulloblastoma. No significant financial relationships to disclose.

PLEURODESIS WITH CARBOPLATIN IN ELDERLY PATIENTS WITH MALIGNANT PLEURAL EFFUSION AND LUNG ADENOCARCINOMA

PLEURODESIS WITH CARBOPLATIN IN ELDERLY PATIENTS WITH MALIGNANT PLEURAL EFFUSION AND LUNG ADENOCARCINOMA

A Phase II Randomized Study of Paclitaxel Plus Carboplatin or Cisplatin against Chemo-Naive Inoperable Non-small Cell Lung Cancer in the Elderly

Paclitaxel plus carboplatin (CAR) or cisplatin (CIS) has shown activity in the treatment of advanced non-small cell lung cancer (NSCLC). Our aim was to determine whether paclitaxel plus platinum is an appropriate regimen for chemo-naïve NSCLC in patients aged 70 years or older. Patients were randomized into paclitaxel plus CAR or paclitaxel plus CIS treatment arms. Treatment consisted of paclitaxel 160 mg/m and carboplatin at AUC = 6 (predicted using measured clearances and the Calvert formula) IV infusion on day 1 every 3 weeks, or paclitaxel 160 mg/m and cisplatin 60 mg/m IV on day 1 every 3 weeks. In total, 81 patients were enrolled from September 2000 to February 2005, including 40 who received CAR treatment and 41 who received CIS treatment. In all, 152 cycles of CAR (median, four cycles per patient) and 172 cycles of CIS (median, four cycles per patient) were given. Each arm had one complete response and 15 partial responses to the treatment, with overall response rates of 40% and 39%, respectively. Myelosuppression was mild in both arms, and there was no statistical difference between the two arms. Alopecia (P < 0.001), peripheral neuropathy (P = 0.017), and fatigue (P < 0.001) were more severe in the CIS treatment arm than in the CAR treatment arm. Median time to disease progression was 6.6 months in the CAR arm and 6.9 months in the CIS arm. Median survival time was 10.3 months in the CAR arm and 10.5 months in the CIS arm. In conclusion, paclitaxel plus CAR or CIS treatment is feasible in elderly patients and has similar activity. However, paclitaxel plus CAR had less non-hematological toxicity than paclitaxel plus CIS.

Pilot phase II study of weekly chemotherapy with paclitaxel and carboplatin for refractory or relapsed small-cell lung cancer

The safety and efficacy of weekly chemotherapy with paclitaxel and carboplatin for the treatment of patients with refractory or relapsed small-cell lung cancer (SCLC) were evaluated. Paclitaxel (100 mg/m(2)) and carboplatin (with a target area under the concentration versus time curve of 2 mg min/ml using the Calvert formula) were administered to patients with previously- treated SCLC on days 1 and 8 at every 3-4 weeks. A total of 29 patients (pts) [male/female, 26/3 pts; median age 62.7 years (43-74); performance status 0/1/2, 9/10/10 pts] were enrolled between March 2000 and June 2002. The mean number of cycles administered per pt was 3 (1-7). The overall response rate was 69% (95% confidence interval 52-86%), and 83% (15/18) in sensitive pts and 45% (5/11) in refractory pts (P<0.01). The overall median survival time was 29.6 weeks with a 1-year survival rate of 37% [34.1 weeks in sensitive pts and 23.1 weeks in refractory pts (P=0.085), 46.9 weeks in PS 0-1 and 16.3 weeks in PS 2 (P<0.001)]. The median time to progressive disease was 16.4 weeks [21.7 weeks in sensitive pts and 15.3 weeks in refractory pts (P=0.32)]. Hematologic toxicities observed included grade >or=3 neutropenia in 55%, grade >or=3 anemia in 36%, and grade >or=3 thrombocytopenia in 3%. Non-hematologic toxicities were mild except for grade 3 diarrhea in three pts and grade 3 pneumonitis in one pt. Weekly chemotherapy with paclitaxel and carboplatin was well- tolerated and gave a high-response rate in pts with refractory or relapsed small-cell lung cancer.

Evaluation of Calvert's Formula for Dosage Adjustment of Carboplatin in Japanese Patients with Hormone Refractory Prostate Cancer

For hormone refractory prostate carcinoma, a combination therapy of paclitaxel and carboplatin is used to expect life extension. We investigated the pharmacokinetics of carboplatin in Japanese prostate cancer patients (n=10, 55-72 years), and evaluated the usefulness of Calvert's formula in the individualized dosing adjustment. They were intravenously administered carboplatin (area under the free plasma concentration versus time curve (AUC)=5 mg.min/ml), following the intravenous administration of paclitaxel (175 mg/m(2)). The dosage of carboplatin for each patient was determined with Calvert's formula using individual creatinine clearance values. Plasma concentration of total platinum was measured sequentially and the pharmacokinetic parameters of carboplatin were determined in each patient. Plasma concentration of total carboplatin after intravenous infusion well fitted the two-compartment model. Carboplatin clearance was 62.0+/-12.7 ml/min (mean+/-S.D.), and linearly related to the individual creatinine clearance (r(2)=0.64, p<0.01). The actual AUC for total carboplatin was 8.20+/-1.11 mg.min/ml, and its inter-individual variability was decreased to 65% of that in carboplatin clearance, indicating the effectiveness of Calvert's formula for dosage adjustment of carboplatin. Leucopenia of grade 4 according to the National Cancer Institute's Common Toxicity Criteria was found in one patient, but no patient demonstrated thrombocytopenia. In conclusion, determining carboplatin dosage based on Calvert's formula decreased the inter-individual variability in the actual AUC compared with that in the carboplatin clearance, and a target AUC of 5 mg.min/ml of carboplatin was comparatively safe for Japanese patients with prostate cancer.

First-line treatment of ovarian/tubal/peritoneal cancer FIGO stage IIB-IV with paclitaxel/carboplatin with or without epirubicin (TEC vs TC). A gynecologic cancer intergroup study of the NSGO, EORTC GCG, and NCIC CTG. Results on progression-free survival

Adding anthracyclin to conventional platinum-based chemotherapy of ovarian cancer has been found to improve survival. The aim of this study was to evaluate the effect on survival on adding epirubicin to the standard treatment with carboplatin and paclitaxel. Between March 1999 and August 2001, 887 patients with epithelial ovarian, tubal, or peritoneal cancer FIGO stage IIB–IV were enrolled. They were randomized to receive six to nine cycles of paclitaxel (175 mg/m2, 3 h iv) followed by carboplatin (AUC 5, Calvert formula) with or without epirubicin (75 mg/m2 iv prior to paclitaxel) on a 3-weekly schedule. The primary end point was progression-free survival, and 542 progression events were required to detect a hazard ratio of 0.786 or less. Patient characteristics were similar across the treatment arms. Residual disease less than 1 cm at surgery with no measurable disease before chemotherapy was reported in 328 patients (37%), with 159 in the TEC arm and 169 in the TC arm. A total of 63 patients had to be withdrawn from the study: 20 due to ineligibility, 32 due to hypersensitivity reaction to paclitaxel during the first or second course, and 11 due to withdrawal of informed consent, leaving 824 patients for the survival analysis. The median follow-up is 30 months for patients still alive. Progressive disease has been reported for 573 patients, and 326 have died. In the total group of patients, the median time to progression was 17.2 months in the TEC arm and 16.3 in the TC arm (P = 0.99). In the group with residual tumor of 1 cm or less, the median time to progression was 24.7 months in the TEC arm and 24.4 months in the TC arm (P = 0.94). In patients with more than 1 cm of residual tumor, the median time to progression in the TEC arm was 14.6 months and 13.8 months in the TC arm (P = 0.75). The median overall survival has not yet been reached. The addition of epirubicin to the standard carboplatin and paclitaxel treatment did not improve progression-free survival. The evaluation of effect on long-term survival awaits further follow-up.

Epirubicin/paclitaxel/carboplatin (TEC) vs paclitaxel/carboplatin (TC) in first-line treatment of ovarian cancer FIGO stages IIB-IV. Results of a randomized AGO-GINECO GCIG Intergroup phase III trial

A randomized phase III trial was conducted in patients with advanced ovarian cancer FIGO IIB–IV in order to determine whether epirubicin (E) in addition to paclitaxel (T) and carboplatin (C) will increase survival in comparison to TC alone. The rationale of this study was based not only on the evidence of activity of free and liposomal anthracylins in patients who have been pretreated with the platinum–paclitaxel regimen but also on the evidence of meta-analyses performed before the taxane era of a 7% improvement in survival when doxorubicin was added as the third agent in first-line treatment (Ovarian Cancer Meta-analysis Project. J Clin Oncol 1991;9:1668–74). In addition, there were some reports suggesting a synergistic activity between paclitaxel and anthracylins (Ray-Coquard I et al. Gynecol Oncol 2003;88:351–7) in patients with ovarian cancer in relapse. Between November 1997 and February 2000, 1282 patients were randomized to receive six cycles of either T 175 mg/m2 3 h iv + C area under curve 5 (according to the Calvert formula) + E 60 mg/m2 iv (TEC) or TC at same doses, both in 3-week intervals. Patients were stratified per centre and into one of two strata according to FIGO stage and residual tumor size: stratum I includes patients with FIGO IIB–IIIC and residual tumor ≤1 cm and stratum II patients with FIGO IIB–IIIC and residual tumor >1 cm or FIGO IV. The primary end point was overall survival (OS). Secondary end points included toxicity, response to treatment, quality of life, and progression-free survival (PFS). Median follow-up at the time of analysis was 51.9 months. The whole population is available for PFS and OS analysis. A total of 1264 patients received at least one cycle of treatment and are evaluable for toxicity. Patient characteristics are well balanced between the two arms with respect to median age, performance status, FIGO stage, histology, and stratification, with less than one third of the patients suboptimally debulked. The three-drug combination induced a markedly higher myelotoxicity resulting in increased demand on supportive care. Grade 3/4 febrile neutropenia occurred in 5.5% patients in TEC and in 1.3% patients in TC (P

1148 POSTER A phase I-II study of imatinib mesylate (Glivec) in combination with irinotecan (CPT-11) in patients with relapsed or refractory small cell lung cancer (SCLC)

We examined the safety and efficacy of the combination of irinotecan plus carboplatin in patients with refractory or relapsed small cell lung cancer (SCLC). Patients with previously treated SCLC were eligible. Patients were treated every 3 weeks with carboplatin (with a target area under the concentration versus time curve of 5 mg min/ml using the Calvert formula on day 1) plus irinotecan (50 mg/m2 on days 1 and 8). From May 2000 to January 2002, 24 patients were eligible. None of the 22 patients achieved a complete response, but 15 achieved a partial response with an overall response rate of 68.2% (95% confidence interval, 45.1–86.1%). In 13 patients with sensitive disease, the response rate was 92.3% (95% confidence interval, 64.0–99.8%). The median survival time (MST) was 194 days (range 27–605 days). The MST did not differ significantly between patients with sensitive disease (245 days) and those with refractory disease (194 days, P=0.88). One patient died of treatment-related sepsis. Grade 3–4 hematologic toxicities included leukopenia in 58% of patients, neutropenia in 63%, thrombocytopenia in 58%, and anemia in 67%. Grade 3 diarrhea developed in 21% of patients and grade 3–4 infection in 13%. No patients had grade 4 diarrhea or grade 3–4 nausea and vomiting. This regimen is effective and well tolerated in patients with relapsed or refractory SCLC. However, the search for even more active regimens should be continued.

Prospective evaluation of carboplatin AUC dosing in patients with a BMI ≥27 or Cachexia

When determining the carboplatin dosage from the Calvert formula, there are a lack of data when evaluating patients with cachexia or body mass index (BMI)>or=27. If the Cockcroft and Gault (C-G) creatinine clearance (CrCl) equation is utilized and substituted for glomerular filtration rate in the Calvert formula, the chance for inaccurate dosing occurs especially in these populations. Therefore, the purpose of this study is to evaluate and compare the target carboplatin area under the concentration (AUC) with the actual AUC achieved in cachectic or BMI>or=27 patients. In a prospective manner, we evaluated 19 patients with a BMI>or=27 and nine cachectic patients. In the C-G equation to determine creatinine clearance, the adjusted body weight was used for BMI>or=27 patients and serum creatinine value of 70.7 microM (0.8 mg/dl) for the cachectic patients. The carboplatin dose was calculated, administered to the patients, and subsequent carboplatin blood samples were obtained for pharmacokinetic determination. Once the AUC was determined, the results were compared with the expected outcomes from the modified C-G CrCl equation for the Calvert formula, Chatelut and Bénézet equations. The results demonstrated that the modified C-G CrCl equation for the Calvert formula had less bias and more precision than using actual weight in the C-G CrCl equation or using the Chatelut and Bénézet equations. Using the actual weight in overweight and especially obese patients and using a serum creatinine<70.7 microM in cachectic patients will lead to overestimation of the carboplatin clearance and thus AUC.

Methotrexate-Paclitaxel-Epirubicin-Carboplatin (M-TEC) Combination Chemotherapy in Patients with Advanced Bladder Cancer: An Open Label Phase II Study

The present phase II study aimed to define the application of a novel regimen incorporating methotrexate, paclitaxel, epirubicin, and carboplatin (M-TEC) in advanced bladder cancer, essentially as an M-VAC-like regimen, by substitution of cisplatin by carboplatin, doxorubicin by epirubicin and vinblastine by paclitaxel.Forty patients with advanced bladder cancer entered the study; 34 males/6 females, median age: 68 (range, 59-76), median PS (Karnovsky): 80, without receiving prior chemotherapy. Disease extention was as follows; 11/40 had local recurrence, 6/40 liver metastases, 14/40 lung metastases, bone and Iymph node 8/40, bones-Iymph node-lung metastases 4, lymph node and liver 4/40, lymph node-Iiver and lung metastases 2/40. Drug schedule and doses were as follows: paclitaxel 180 mg/m2, carboplatin AUC=5 (according to creatinine clearance, based on Calvert's formula), and epirubicin 40 mg/m2 were administered during day 1, whereas methotrexate 30 mg/m2 and epirubicin 40 mg/m2 were administered on day 14.All patients were evaluable for response with 24/40 responding [response rate (RR) 60%]; 10/40 (25%) CR, 14/40 (35%) PR, 9/40 (22.5%) SD, and 7/40 (17.5%) PD. Symptomatic improvement was observed in 50% of patients. The median duration of response was 22 (14-32) weeks, median time-to-progression (TTP) 33 (12-44) weeks, and median survival was 56 (20-84) weeks. Toxicity was well accepted and was mainly neutropenia >grade 3: 17%, anemia >grade 3: 16%, thrombocytopenia >grade 2: 6%, nausea & vomiting mainly >grade2: 31%, according to the administered chemotherapy cycles, whereas fatigue grade 2-3: 19%, neurotoxicity grade 1-2 13% of patients, and alopecia grade 2 was observed in all patients.The present pilot study indicates the feasibility of the M-TEC combination for bladder cancer with acceptable toxicity.

Difference of carboplatin clearance estimated by the Cockroft–Gault, Jelliffe, Modified-Jelliffe, Wright or Chatelut formula

Objective. Although the Calvert formula is the standard method to calculate the dose of carboplatin, there is no consensus how to determine the glomerular filtration rate (GFR) without using [ 51Cr]-ethylenediamine tetraacetic acid ( 51Cr-EDTA). Creatinine clearance (Ccr), calculated using the Cockroft–Gault, Jelliffe, Modified-Jelliffe or Wright formulae, has been used as a substitute for the GFR. In addition to these four formulae, the Chatelut formula has been proposed as a way to calculate carboplatin clearance. Among these formulae, Jelliffe formula does not include body surface area (BSA) or body weight to adjust the body size and thus may have greater bias than the other four formulae in estimating carboplatin clearance. The purpose of this study is to evaluate if these five formulae could equally estimate the carboplatin clearance. Methods. Carboplatin clearance was estimated in 253 patients with gynecologic cancer who received carboplatin-based chemotherapy between January 1996 and August 2004. Ccr was estimated using the Cockroft–Gault, Jelliffe, Modified-Jelliffe or Wright formulae. Carboplatin clearance was also calculated directly by using the Chatelut formula. The five estimations of carboplatin clearance were compared with each other using the post-hoc Wilcoxon signed rank test. The median percent error (MPE) and the median absolute percent error (MAPE) were evaluated by comparing carboplatin clearance. The relationships between BSA and ratios of estimated carboplatin clearance (Jelliffe/Cockroft–Gault, Jelliffe/Modified-Jelliffe, Jelliffe/Wright, Jelliffe/Chatelut) were evaluated by using simple regression. Results. The estimated carboplatin clearances were: Cockroft–Gault formula, 109.8 ± 28.4; Jelliffe formula, 128.5 ± 28.2; Modified-Jelliffe formula, 110.8 ± 25.7; Wright formula, 112.2 ± 24.3; Chatelut formula, 114.1 ± 33.0. A statistically significant difference was observed between carboplatin clearance calculated using Jelliffe formula and that given by each of the other four formulae. Comparing the results of the Cockroft–Gault formula with the Jellife, Modified-Jelliffe, Wright and Chatelut formulae yielded MPEs of +19%, +2%, +3% and +3% and MAPEs of 27%, 5%, 6% and 6%, respectively. There was a significant correlation between BSA and ratio of estimated carboplatin clearance (Jelliffe/Cockroft–Gault, Jelliffe/Modified-Jelliffe, Jelliffe/Wright, Jelliffe/Chatelut), with Pearson correlation coefficients of 0.928, 0.847, 0.965 and 0.839 respectively. As the BSA of patient became smaller, the differences between the carboplatin clearance calculated by the Jelliffe formula from other four formulas became larger. Conclusions. Estimates of carboplatin clearance calculated by the Jelliffe formula tend to have greater positive bias compared to the other four formulae, particularly when the BSA of the patient is small. In order to conduct collaborative international studies, it may be necessary to standardize the formula used to estimate carboplatin clearance to perform international collaboration studies.

Phase II trial of gemcitabine (G), carboplatin (C) and bexarotene (B) in patients (pts) with newly diagnosed, locally-advanced or metastatic non-small cell carcinoma of the lung (NSCLC)

7308 Background: The current standard of care for unresectable NSCLC is platinum-based chemotherapy. There is no benefit to adding together 3 or more cytotoxic agents, but adding a biologic agent may improve response rates and survival. B, a retinoic acid X-receptor agonist, is a differentiating agent with antineoplastic activity. Recent data suggests that the addition of B to platinum-based therapy may increase response rates and survival in NSCLC. Due to the poor outcome in this disease, we are studying a combination of G, C, and B as front-line therapy. Methods: Eligibility criteria includes histologically diagnosed NSCLC stage IIIB/IV; Karnofsky PS 70–100%; age ≥ 18, adequate bone marrow, renal and hepatic function, and written informed consent. Pts receive G, 1 g/m2 days 1 and 8 with C, AUC 5 (Calvert formula) on day 8. B, 400mg/m2 PO QD in divided doses is given days 1–28 of each treatment cycle. Pts may receive up to 6 cycles of chemotherapy or 2 cycles after CR achieved. Tumor restaging is performed every 2 cycles of therapy, in the absence of obvious rapid disease progression. Results: 19 pts have been enrolled; 10 males, 9 females; median age is 63.5 years (range 30–85 years). 2 pts had protocol violations (prior chemotherapy (1); small cell cancer on further pathologic evaluation (1)). A median of 2 cycles has been delivered (range 1–6). To date, the overall PR rate is 23.5% (4/17); 2 have had SD (1 progressed by cycle 4), for an overall clinical benefit rate of 35%. One is too early to evaluate. 18 pts to date are evaluable for toxicity. Thus far, the mean TTP is 68 days, and the mean OS is 142 days. The therapy has been well-tolerated with 7 pts experiencing Grade 2–3 myelosuppression (no febrile neutropenia), and 3 pts experiencing Grade 3–4 nausea and emesis. There have been no significant B-related adverse events. Conclusions: The addition of the differentiating agent B to a regimen of G and C is tolerable and active. In contrast to other studies, our early results suggest that the addition of B at this dose and schedule may add little to the clinical benefit observed with this regimen. Accrual continues in an effort to better define response rate and duration. No significant financial relationships to disclose.

Paclitaxel/carboplatin (TC) vs. paclitaxel/carboplatin followed by topotecan (TOP) in first-line treatment of advanced ovarian cancer. Mature results of a Gynecologic Cancer Intergroup phase III trial of the AGO OVAR and GINECO

LBA5007 Background: A randomized phase III trial was performed in patients (pts) with advanced ovarian cancer (OC) to determine the role of Top in first line treatment. The sequential manner was chosen to incorporate Top as a non cross resistant third drug to TC by avoiding the toxicity of a simultaneous triple drug regimen. Methods: Between 12/1999 and 03/2002 1,308 pts with previously untreated OC with FIGO stages IIb-IV were randomized to receive 6 cycles of Paclitaxel (175 mg/m2 3h iv) and Carboplatin (AUC 5, Calvert formula) (TC) followed by either no further therapy (n=650) or 4 cycles of Topotecan (1.25 mg/m2 iv d1–5) (Top) (n=658) on a 3 weekly schedule. The primary endpoint was overall survival (OS). This study was designed to show an increase in 3 year survival of 8% with a power of 0.8 using a log-rank test with alpha set to 0.05. Therefore 541 events are necessary. Results: Overall, 9417 treatment cycles were administered, 5535 in the TC-Top arm and 3882 in the TC arm. During treatment with TC, there was no significant difference in Grade (G) 3/4 hematologic and non-hematologic toxicity between both study arms. The median doses of TC were given as scheduled, as were the median intervals between therapy courses. 78% of pts who were randomized for Top received Top. The median number of Top courses was 4.0. Median Top dose/course/day for all courses was 1.25 mg/m2. Top myelotoxicity resulted in treatment delays of at least 7 days in 10.6% of courses. G 3/4 anemia occured in 6.4% of all Top courses, thrombocytopenia in 10.6% and neutropenia in 57.0%. However, this was of minimal clinical relevance in terms of febrile neutropenia (1.0%) or infections (0.9%). Response data were available from 141 and 143 pts with measurable disease in the TC and TC-Top arm. There was no statistically significant difference in CR and PR between treatment arms (76.2% for TC vs. 68.1% for TC-Top, p= n.s). Conclusions: The necessary events for OS are awaited within the next couple of weeks. The final efficacy analysis reporting on OS will be done in February 2005. Results will be submitted as late breaking abstract. No significant financial relationships to disclose.

Phase II Trial of Weekly Paclitaxel and Carboplatin Chemotherapy in Patients with Advanced Transitional Cell Cancer

Objective: We investigated the efficacy and toxicity of a first-line combination chemotherapy using weekly paclitaxel and carboplatin in patients with metastatic transitional cell cancer (TCC). Patients and methods: Thirty-three patients with advanced measurable TCC of the urothelium were entered onto this trial. Patients were treated once weekly with a combination therapy of paclitaxel (100 mg/m 2) and carboplatin (AUC 2, according to the Calvert formula). Therapy courses were administered for six consecutive weeks. After two cycles, a re-staging was carried out to evaluate response. Results: Objective response rate was 57.6% with 6 complete (18.2%) and 13 partial remissions (39.4%). Seven patients had stable disease (21.2%) and 7 patients had progressed at the first evaluation of response (21.2%). Median progression-free interval and median survival was 6.5 (1–35) and 12 (2.5–58) months, respectively. Toxicity was moderate and manageable with grade 3 and 4 neutropenia in 8 patients (24%), but no case of neutropenic fever. Other hematological grade 3 toxicities occurred in 9 patients (27%) and grade 3 peripheral neuropathy in 2 patients (6%). There was no treatment-related death. Dose reduction or short delay of treatment was necessary in 3 patients. Conclusions: Combination therapy using weekly paclitaxel and carboplatin was active in patients with advanced TCC and adverse prognostic features. The weekly dosing used in this trial warrants further investigation as an alternative first-line approach in patients with poor renal reserve and/or performance status or as a second-line management of advanced TCC.

Combination chemotherapy with docetaxel and CBDCA in previously untreated advanced non-small-cell lung cancer

7244 Background: This study was conducted to prospectively evaluate the efficacy and toxicity of combination chemotherapy with docetaxel (60 mg/m2) and carboplatin (CBDCA), which was determined by body surface area (300 mg/m2) rather than AUC, in patients with previously untreated advanced (stage IIIB and IV) non-small-cell lung cancer (NSCLC). Methods: Docetaxel 60 mg/m2 was administered intravenously over 3 hours followed by CBDCA 300 mg/m2 over 2 hours on day 1. This treatment cycle was repeated every 3–4 weeks until the patients showed disease progression or refused further treatment. Results: Twenty-one patients were eligible for the treatment. Fourteen patients (66.7%) had adenocarcinoma, three (14.3%) squamous cell carcinoma, and four (19%) large-cell carcinoma or unspecified NSCLC. The median number of cycles was four (range, 2 to 12). The median AUC as calculated by Calvert's formula, using the measured creatinine clearance as GFR, was 4.4 (range, 2.8 to 6.1). Fourteen patients had a major objective response (66.7%; 95% confidence interval, 43.0–85.4%). The median progression free survival was 226 days (range, 59 to 388 days), that for adenocarcinoma patients 257 days (59 to 388 days), and that for non-adenocarcinoma patients 127 days (66 to 198 days). The overall median survival time was 454 days (range, 52 to 823 days), that for adenocarcinoma patients 537 days (67 to 823 days), and that for non-adenocarcinoma patients 193 days (52 to 266 days). The 1-year survival rate was 58.5%. The major toxicity was neutropenia. Grade 3 or 4 neutropenia occurred in 17 patients (81.0%). Conclusions: This regimen shows significant antitumor activity and outcomes. No significant financial relationships to disclose.

Combination chemotherapy with docetaxel and CBDCA in previously untreated advanced non-small-cell lung cancer

7244 Background: This study was conducted to prospectively evaluate the efficacy and toxicity of combination chemotherapy with docetaxel (60 mg/m2) and carboplatin (CBDCA), which was determined by body surface area (300 mg/m2) rather than AUC, in patients with previously untreated advanced (stage IIIB and IV) non-small-cell lung cancer (NSCLC). Methods: Docetaxel 60 mg/m2 was administered intravenously over 3 hours followed by CBDCA 300 mg/m2 over 2 hours on day 1. This treatment cycle was repeated every 3–4 weeks until the patients showed disease progression or refused further treatment. Results: Twenty-one patients were eligible for the treatment. Fourteen patients (66.7%) had adenocarcinoma, three (14.3%) squamous cell carcinoma, and four (19%) large-cell carcinoma or unspecified NSCLC. The median number of cycles was four (range, 2 to 12). The median AUC as calculated by Calvert's formula, using the measured creatinine clearance as GFR, was 4.4 (range, 2.8 to 6.1). Fourteen patients had a major objective response (66.7%; 95% confidence interval, 43.0–85.4%). The median progression free survival was 226 days (range, 59 to 388 days), that for adenocarcinoma patients 257 days (59 to 388 days), and that for non-adenocarcinoma patients 127 days (66 to 198 days). The overall median survival time was 454 days (range, 52 to 823 days), that for adenocarcinoma patients 537 days (67 to 823 days), and that for non-adenocarcinoma patients 193 days (52 to 266 days). The 1-year survival rate was 58.5%. The major toxicity was neutropenia. Grade 3 or 4 neutropenia occurred in 17 patients (81.0%). Conclusions: This regimen shows significant antitumor activity and outcomes. No significant financial relationships to disclose.