Calvert Formula Research Articles

Multimodal treatment for glassy cell carcinoma of the uterine cervix

Glassy cell carcinoma of the uterine cervix is a rare form of cervical cancer that is characterized by aggressiveness and poor prognosis because of its rapid growth, its frequent distant metastases, and its relative resistance to conventional treatment modalities including surgery, radiotherapy, and chemotherapy. We report here a case of glassy cell carcinoma of the uterine cervix that was successfully treated with radical surgery followed by radiation therapy and combination chemotherapy with paclitaxel and carboplatin. A 30-year-old primigravid Japanese woman was admitted to our hospital to be treated for stage IIb uterine cervical cancer. She was treated with radical hysterectomy with pelvic and paraaortic lymphadenectomy. The pathological diagnosis of the surgical specimen was glassy cell carcinoma of the uterine cervix with metastases to the right obturator lymph nodes and left external iliac lymph nodes. The surgical staging of the disease was pT2b, pN1, and pM0. Subsequently, she was treated using conventional radiation therapy (50Gy by whole pelvic radiation) and six courses of tri-weekly chemotherapy with paclitaxel (180 mg/m(2)) and carboplatin (area under the curve of 6.0 mg min/mL calculated using the Calvert formula). The patient is alive, without evidence of recurrence, 30 months following the surgery. It is suggested that multimodal therapy with radical surgery, radiation, and combined chemotherapy should be used to treat glassy cell carcinoma of the uterine cervix. Our multimodal treatment protocol may be one of the treatment options for this aggressive disease.

Evaluation of renal function and carboplatin clearance in Japanese cancer patients

2556 Background: There is a close relationship between carboplatin clearance and glomerular filtration rate (GFR). Calvert developed the following formula for the dosing of carboplatin: dose (mg) = target area under the concentration versus time curve (AUC, mg ml-1 min) × [GFR (ml min-1) + 25]. However, this formula has not been evaluated in Japanese population. In this study, we prospectively evaluated renal function and carboplatin clearance in Japanese cancer patients. Methods: GFR was measured by inulin clearance before chemotherapy. The dose of carboplatin was determined by Calvert's formula using adjusted 24-h creatinine clearance (Ccr) by adding 0.2 (mg dl-1) to serum creatinine. A pharmacokinetic study was performed during the first cycle of the chemotherapy. Blood samples were obtained at 10 points within 24 hours. The observed AUC of carboplatin and the observed carboplatin clearance were calculated. Results: Inulin clearance was estimated in 28 cancer patients. Estimation of renal function with adjusted 24-h Ccr and estimated GFR equation (eGFR) were unbiased [mean prediction error (MPE) = -2.3%, 5.2% respectively] and acceptably precise [root mean squared error (RMSE) = 23.7%, 25.7% respectively], whereas non-adjusted Ccr and the Cockcroft-Gault equation overestimated GFR (MPE = 24.2%, 12.5% and RMSE = 37.2%, 32.7% respectively). Observed carboplatin clearance was proportional to GFR in range of renal function in this study (r = 0.903) and we verified the linearity. Non-renal clearance of carboplatin in Japanese cancer patients was 5.6 (ml min-1). Conclusions: 24-h Ccr adjusted by adding 0.2 (mg dl-1) to serum creatinine and eGFR were useful in assessing renal function for carboplatin dosing. It was suggested that non-renal clearance of carboplatin in Japanese cancer patients was less than 25 (ml min-1). No significant financial relationships to disclose.

Paclitaxel (T), ifosfamide (I), and carboplatin (Cb) (TICb) combination chemotherapy in advanced uterine and adnexal malignant mixed mullerian tumors (MMMTs)

5517 Background: Malignant mixed mullerian tumors (MMMTs) of the uterus and adnexa represent aggressive gynecologic malignancies with a high rate of locoregional and distant failure. For that reason we evaluated the TICb combination in patients with advanced MMMTs. Methods: Patients with advanced MMMTs [stages III-IV and relapses after surgery (Sx)±RT], WHO-PS 0–2, no prior chemotherapy, unimpaired hematopoietic/organ function were eligible. Chemotherapy was administered as follows; T: 175 mg/m2 d1, I: 2.0 g/m2/d-d1+2, and Cb at a target AUC = 5 (according to creatinine clearance based on Calvert's formula) on d2 after I. G-CSF was administered from day 3–7. Results: Thirty-two patients with MMMTs of the uterus (n = 28), tubes (n = 2), or ovary (n = 2) have entered so far and all are evaluable for response and toxicity: median age = 61 (45–72), PS = 1 (0–1), stages; III = 18 (56%), IV = 14 (44%), histologies were; with homologous sarcoma component: 21, with heterologous component: 11. Prior treatment for locoregional disease included Sx: 23, Sx+RT: 9. Disease sites at diagnosis included: pelvic disease 12; pelvic/paraortic lymph nodes 14; peritoneal implants 16; liver 4; lung nodules 9; bone metastases 1; malignant pleural effusion 4. Responses were as follows: 21/32 (66%) evaluable patients responded, with 9 complete responses (CR) and 12 partial responses (PR), while 8 had stable disease (SD), and 3 developed progressive disease (PD). The median response duration was 8 mo (4–28), median time-to-progression (TTP) 12.5mo (4–26), while median overall survival (OS) has not been reached yet since most patients receive second-line therapy. Grade (Gr) 3/4 toxicities included: neutropenia 18/32 (56%)-with 11 developing Gr4 (≤7 days) and 19% of patients at least one episode of febrile neutropenia managed successfully by broad spectrum antibiotics, thrombocytopenia Gr3: 5/32 (16%) and Gr4 3/32 (9%), no Gr3 neuropathy, Gr1 CNS toxicity in 1, no renal toxicity, 15 Gr2 myalgias, and 4 Gr3 vomiting. Conclusions: In the present study, it appears that the TICb combination, yielded important activity with acceptable toxicity in females with advanced MMMTs. No significant financial relationships to disclose.

Phase III Study by the Norwegian Lung Cancer Study Group: Pemetrexed Plus Carboplatin Compared With Gemcitabine Plus Carboplatin As First-Line Chemotherapy in Advanced Non–Small-Cell Lung Cancer

PURPOSE To compare pemetrexed/carboplatin with a standard regimen as first-line therapy in advanced non-small-cell lung cancer NSCLC. PATIENTS AND METHODS Patients with stage IIIB or IV NSCLC and performance status of 0 to 2 were randomly assigned to receive pemetrexed 500 mg/m(2) plus carboplatin area under the curve (AUC) = 5 (Calvert's formula) on day 1 or gemcitabine 1,000 mg/m(2) on days 1 and 8 plus carboplatin AUC = 5 on day 1 every 3 weeks for up to four cycles. The primary end point was health-related quality of life (HRQoL) defined as global quality of life, nausea/vomiting, dyspnea, and fatigue reported on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and the lung cancer-specific module LC13 during the first 20 weeks. Secondary end points were overall survival and toxicity. Results Four hundred thirty-six eligible patients were enrolled from April 2005 to July 2006. Patients who completed the baseline questionnaire were analyzed for HRQoL (n = 427), and those who received > or = one cycle of chemotherapy were analyzed for toxicity (n = 423). Compliance of HRQoL questionnaires was 87%. There were no significant differences for the primary HRQoL end points or in overall survival between the two treatment arms (pemetrexed/carboplatin, 7.3 months; gemcitabine/carboplatin, 7.0 months; P = .63). The patients who received gemcitabine/carboplatin had more grade 3 to 4 hematologic toxicity than patients who received pemetrexed/carboplatin, including leukopenia (46% v 23%, respectively; P < .001), neutropenia (51% v 40%, respectively; P = .024), and thrombocytopenia (56% v 24%, respectively; P < .001). More patients on the gemcitabine/carboplatin arm received transfusions of RBCs and platelets, whereas the frequencies of neutropenic infections and thrombocytopenic bleedings were similar on both arms. CONCLUSION Pemetrexed/carboplatin provides similar HRQoL and survival when compared with gemcitabine/carboplatin with less hematologic toxicity and less need for supportive care.

Outcome of patients with recurrent medulloblastoma or central nervous system germinoma treated with low dose continuous intravenous etoposide along with dose‐intensive chemotherapy followed by autologous hematopoietic stem cell rescue

Adults and children with recurrent malignant central nervous system (CNS) tumors have a poor prognosis despite high dose chemotherapy with a conventional stem cell rescue regimen. In this study we evaluated the results of low dose, continuous infusion etoposide over 21 days added to a conventional high-dose regimen of carboplatin and thiotepa in eight patients with relapsed pediatric CNS tumors. Patients with high risk CNS tumors were treated with etoposide 25 mg/m(2)/day by continuous intravenous (IV) infusion from day -22 to day -2, carboplatin 667 mg/m(2)/dose IV (or area under the curve = 9 mg/ml/min according to the Calvert formula on days -8, -7, and -6, and thiotepa 300 mg/m(2)/dose IV on days -5, -4, and -3, followed by autologous hematopoietic stem cell rescue on day 0. Eight adults and children, with a mean age of 12.9 years (age range 5.6-27.8 years), with relapsed primary CNS tumors (metastatic medulloblastoma (7), germinoma (1)), were enrolled. The mean survival post-transplant was 4.8+ years, (range 8-160+ months). The 2- and 5-year overall survival rates were 75% and 50% respectively. None of the survivors required additional salvage irradiation. The strategy of low dose chronic exposure to a topoisomerase inhibitor along with ablative carboplatin and thiotepa with stem cell rescue showed promising survival outcomes in these relapsed patients. This treatment strategy deserves further evaluation in a larger group of high-risk or relapsed primary CNS tumors.

Dose Individualization Can Minimize Nephrotoxicity due to Carboplatin Therapy in Patients With Ovarian Cancer

Carboplatin (Carbo-Pt), an alkylating agent cleared from the plasma through glomerular filtration, is commonly used for the treatment of ovarian cancer. When administered at high dosage or to patients with reduced renal function, Carbo-Pt may be nephrotoxic. The dose of Carbo-Pt is calculated with Calvert formula, using the value of 24-hour creatinine clearance (24h Ccr) as an estimate of glomerular filtration rate (GFR). The aim of this study was to evaluate the possibility of individualizing the dose of Carbo-Pt using an alternative method to estimate GFR, based on body composition analysis, and then to assess the nephrotoxicity of Carbo-Pt therapy individualized with this new method. First, we evaluated the agreement between GFR (renal clearance of diethylene triamine pentaacetic acid (99mTc-DTPA)), 24h Ccr, and the new estimate of GFR (BCMGFR) calculated on the basis of individual values of body cell mass (BCM) and plasma creatinine. BCMGFR gave a better estimate of GFR than 24h Ccr. Then, we evaluated the nephrotoxicity of a combination chemotherapy based on Carbo-Pt (AUC(5-6)) in 23 patients affected by ovarian cancer. The dose of Carbo-Pt was adjusted to residual renal function of patients, evaluated as BCMGFR. No case of acute renal failure was observed with this treatment regimen. Urinary excretion of proteins (albumin, beta2-microglobulin, and retinol-binding protein) and tubular enzymes, measured as markers of tubular damage, increased significantly and transiently only in the first days after chemotherapy, whereas no evidence of chronic nephrotoxic effect was documented. Dose individualization, using the value of BCMGFR, may minimize nephrotoxicity due to Carbo-Pt therapy.

A Phase I and Pharmacokinetic Study of Ixabepilone in Combination with Carboplatin in Patients with Advanced Solid Malignancies

To determine the recommended phase II dose of combination ixabepilone plus carboplatin based on the maximum tolerated dose, pharmacokinetics, optimum schedule, and safety. Patients with advanced solid malignancies were treated with escalating doses of carboplatin plus ixabepilone administered on day 1 (schedule A) or days 1 and 8 (schedule B) of a 21-day cycle. Blood was sampled during cycle 1 for pharmacokinetic analysis of ixabepilone (both schedules) and carboplatin (schedule B). Fifty-two patients were treated with ixabepilone doses ranging from 30 to 50 mg/m2 per 21-day cycle plus carboplatin area under curve (AUC) 5 or 6 (Calvert formula). On schedule A (ixabepilone 40 mg/m2 over 1 hour plus carboplatin AUC 6), 2 of 2 patients experienced dose-limiting toxicity (DLT). On schedule B (ixabepilone 25 mg/m2 over 1 hour on days 1 and 8 plus carboplatin AUC 6), 3 of 3 patients experienced DLT. DLT was myelosuppression; however, cumulative sensory neuropathy limited extended dosing on schedule A. Ixabepilone and carboplatin pharmacokinetics were similar to those using either drug as monotherapy, indicating an absence of pharmacokinetic drug interactions. Based on DLTs and tolerability with repeated dosing, the recommended doses were 30 mg/m2 ixabepilone (1-hour infusion) d1 q3w plus carboplatin AUC 6 (schedule A) and 20 mg/m2 ixabepilone (1 hour infusion) d1, d8 q3w plus carboplatin AUC 6 (schedule B). Data from the present study show the feasibility and tolerability of combination ixabepilone plus carboplatin, with ixabepilone administered on day 1 or on days 1 and 8 on a 21-day cycle.

Evaluation of carboplatin dosage based on 4-variable modification of diet in renal disease equation

Traditionally, carboplatin dosage is based on the Calvert formula. Glomerular filtration rate (GFR) and creatinine clearance (CrCl) are often used interchangeably in this formula. The modification of diet in renal disease (MDRD) equation is now routinely available to estimate GFR (eGFR). We performed a retrospective analysis of carboplatin dosage in our institute. Calvert formula derived carboplatin dose using eGFR calculated from the MDRD equation was compared to estimated CrCl from the Cockcroft-Gault and Jelliffe equations. Ninety-two carboplatin treatment episodes were recorded. eGFR and CrCl correlated reasonably well with a correlation coefficient (r) of 0.88. The correlation was weakest at lower levels of serum creatinine. Correcting eGFR for body surface area resulted in a tighter correlation (r = 0.94). The MDRD derived eGFR is readily available and may prove very useful in calculating carboplatin dosage for patients with impaired renal function.

Carboplatin dosing in overweight and obese patients with normal renal function, does weight matter?

The purpose of this study was to determine the potential utility of alternative weight descriptors in the Cockcroft-Gault equation to more accurately predict carboplatin clearance in underweight, normal weight, overweight and obese patients. Clearance values obtained from individual fits using NONMEM were compared to predicted carboplatin clearances calculated using the modified Calvert formula in which creatinine clearance was calculated with the Cockcroft-Gault equation using diverse weight descriptors. This study indicated that lean body mass was the best weight descriptor in underweight and normal weight patients, while adjusted ideal body weight was the best weight descriptor in overweight and obese patients. However, a flat dose based on the population carboplatin clearance performed better in all weight categories than the use of the Cockcroft-Gault equation with diverse weight descriptors. These results suggest that in overweight and obese patients, with a normal renal function, a flat carboplatin dose should be administered, based on the population carboplatin clearance (8.38 l/h = 140 mL/min). Thus, in case an AUC of 5 mg min/mL is desired, the appropriate dose for carboplatin would be 5 x 140 = 700 mg.

Carboplatin and oral cyclophosphamide combination after temozolomide failure in malignant gliomas

Temozolomide is a novel cytotoxic agent for malignant gliomas. However, treatment failure occurs approximately in half of patients, and the optimal regimen in this setting has yet to be defined. In the present study, we assessed retrospectively the efficacy and toxicity of the combination of carboplatin and oral cyclophosphamide in temozolomide-resistant patients. We evaluated the medical records of 30 patients with malignant gliomas. After failure of temozolomide therapy, patients were treated with a combination of carboplatin and oral cyclophosphamide. Treatment consisted of intravenous carboplatin AUC 6 (based on the Calvert Formula) on day 1 and oral cyclophosphamide 75 mg/m2 daily on days 1 to 14, followed by 14 days of rest, with the treatment repeated every 4 weeks. All patients were evaluated for response and toxicity. The objective response rate was 30%, including 9 partial responses. Median time to disease progression and median overall survival was 7 months and 8 months, respectively. Clinically responsive patients had statistically significant longer progression-free survival and overall survival than unresponsive patients. Hematological side effects were commonly observed toxicities, with neutropenia the most frequent. Our data suggest that carboplatin and oral cyclophosphamide therapy is a convenient regimen after failure of temozolomide therapy in patients with malignant gliomas because of its activity, feasibility and tolerability. Further prospective studies are needed in this setting.

A Study of the Predictive Method of 24-Hour Creatinine Clearance in Calculating the Appropriate Dosage of Carboplatin

The carboplatin (CBDCA) dosage is usually calculated using the formula of Calvert. Instead of the glomerular filtration rate (GFR), 24-h creatinine clearance (24 CLcr) is often used in this formula, which is calculated based on 24-h urine collection in clinical practice. We studied the adequacy of 24 CLcr in calculating the appropriate dosage of CBDCA using the formula of Calvert and compared CLcr and GFR using various substitutable predictive formulas (the formulae of Cockcroft and Gault, Yasuda, Orita, Jellife, Mawer, MDRD, and modified MDRD) when we were not able to use 24 CLcr. We retrospectively studied 193 patients who received CBDCA as chemotherapy during the period April 2004 through November 2006. We evaluated the adequacy of 24-h urine collection for measurement of creatinine production and excretion. We also evaluated the appropriate urine collection within a 15% range of the difference. The correlation between the appropriate 24 CLcr resulting in the urine collection and the CLcr or GFR was examined using past predictive formulae in the patients with appropriate urine collection. The accuracy of 24 CLcr was evaluated in 83 patients (43%). There was a significant correlation between CLcr or GFR using various predictive formulas and the appropriate 24 CLcr. There was an especially close and significant correlation with the formulae of Cockcroft and Gault and Yasuda (r>0.950, p<0.001). When using the Calvert formula, the accuracy of 24 CLcr should be evaluated. Patients evaluated as having inaccurate urinary collection should use the formulae of Cockcroft and Gault and Yasuda.

Evaluation of carboplatin dosage based on a body surface area adjusted 4-variable modification of diet in renal disease (MDRD) equation

13524 Background: Calculations of carboplatin dose are based on the Calvert formula, which incorporates glomerular filtration rate (GFR). In everyday practice, creatinine clearance (CrCl) as calculated by Cockroft-Gault, Jelliffe or other formulas is commonly substituted for GFR in the Calvert formula. More recently, a new formula, originally devised by the MDRD research group for estimating GFR (eGFR), has been promulgated. In this study the impact of interchanging CrCl with eGFR when calculating carboplatin dose was investigated. Allied to this we highlight the importance of taking body surface area (BSA) into account when using eGFR, known as ‘absolute GFR’. Methods: We conducted a retrospective analysis of patients (pts) receiving carboplatin at our institution from December 2005 to October 2006. Serum creatinine and CrCl according to the Cockcroft-Gault and the Jelliffe formulas were recorded. Calvert formula derived carboplatin dose using the CrCl was compared to eGFR and absolute GFR. Results: 92 carboplatin treatment episodes were recorded. The average serum creatinine was 70.5μmol/l (47% male, mean age 53years {range 33–74 years} and 53% women, mean age 60 years {range 41–82 years}). eGFR and CrCl correlated reasonably well with a correlation coefficient (r) of 0.88. The correlation was weakest at lower levels of serum creatinine. While the Cockroft-Gault and Jelliffe formulas are estimates of actual CrCl, the eGFR is an estimate of GFR per 1.73m2 BSA. This affected the correlation at extremes of BSA. Correcting eGFR for BSA resulted in a tighter correlation (r = 0.94) with the CrCl. Even using absolute GFR, significant scatter still occurs at lower serum creatinine levels, as the MDRD equation was originally formulated for usage in pts with impaired renal function. Correlation of carboplatin dosage as derived using CrCl or absolute GFR showed a correlation coefficient of 0.95. Conclusions: Absolute GFR calculated using the MDRD equation corrected for BSA correlates well with CrCl as calculated by Cockroft-Gault and Jelliffe formulas. While this means that either parameter is valid in the majority of pts, care should be taken when applying MDRD-derived estimates of GFR when serum creatinine is within the normal reference range. No significant financial relationships to disclose.

Gemcitabine and carboplatin in the treatment of transitional cell carcinoma of the urothelium

16136 Background: In advanced transitional cell carcinoma (TCC) of the urothelium gemcitabine plus cisplatin (GC) is considered a gold standard chemotherapy regimen. However, treatment with cisplatin is associated with significant toxicity and requires intravenous hydration. Carboplatin is an analogue of cisplatin which at standard doses is less toxic, and does not require hydration. From July 2003 to June 2007, 15 consecutive patients with metastatic TCC of the urothelium were treated with gemcitabine plus carboplatin (GCarbo). Patients were not selected on the basis of poor renal function, poor performance status (PS) or any other adverse feature. Methods: All cases of metastatic TCC of the urothelium referred to a single consultant at Velindre Cancer Centre, South East Wales from July 2003 to date were treated using 3-weekly cycles of gemcitabine 1,200 mg/m2 i.v. days 1 and 8 plus carboplatin AUC 5–6 i.v. day 1. Creatinine clearance was estimated using the Cockroft-Gault formula. Carboplatin dose was calculated using the Calvert formula. All patients were required to have a histological diagnosis of TCC. Survival was calculated from the start of chemotherapy to the date of last contact or death using the Kaplan-Meier method. Treatment was continued for up to 6 cycles. Granulocyte-colony stimulating factors were not routinely used. Patients were transfused if the haemoglobin fell below 9g/dl, or if significant symptoms developed. Results: The median age of all patients was 67 years. In 10/15 (67%) patients the urinary bladder was the primary site. All patients had stage 4 disease. In total, 4/15 (27%) patients had a PS of 0, 8/15 (53%) patients had a PS of 1 and 3/15 (20%) had a PS of 2. Grade 3 or 4 toxicity included neutropenia (47%), anaemia (27%) and thrombocytopenia (20%). Red blood cell transfusions were given to 6/15 (40%) patients. No platelet transfusions were given. No patients required admission for neutropenic pyrexia/sepsis, and there were no treatment-related deaths. The overall response rate was 67%. The median survival was 9 months (95% CI 7.4–10.6), and 1-year survival 42%. Conclusions: GCarbo is well tolerated, and has activity as first- line treatment in metastatic TCC of the urothelium. Results are comparable to other studies using this regimen. No significant financial relationships to disclose.

Abstract LB-245: Local drug delivery to the breast: A Phase I study of breast intraductal cytotoxic agent administration prior to mastectomy

Abstract Background: Intraductal administration of cytotoxic agents has been shown to inhibit the development of breast cancer in Her-2/neu over-expressing mouse and MNU rat models (Murata S, et al. Cancer Res 2006;66:638-45). This dose escalation study was performed to demonstrate the safety of this approach in women prior to mastectomy. Methods: The study was performed in the Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China, where the standard of care includes a long preoperative hospital stay prior to mastectomy. Two drugs, pegylated liposomal doxorubicin (PLD) and carboplatin were administered at 3 dose levels (PLD: 10, 20, and 50 mg; carboplatin: 60, 120, and 300 mg) with the highest dose approximating the clinical intravenous dose. There were five subjects in each group with 15 subjects treated with each drug. Study drug was administered once per subject. Upon obtaining informed consent, subjects underwent a local nipple block and cannulation of 5-8 ducts with intraductal instillation of the drug. Venous blood samples were obtained for pharmacokinetic analysis. The total dosage was divided by the number of cannulated ducts to yield a dose per duct. The breast was removed surgically as planned 2-5 days post treatment and the treated ducts were marked to enable identification on pathological evaluation. Results: Intraductal administration was generally well-tolerated with mild, transient breast discomfort upon administration associated with the rate of infusion. Clinically significant laboratory adverse events were limited to decreases in hemoglobin following mastectomy, consistent with blood loss. Neither leucopenia nor thrombocytopenia were observed in the study. In the carboplatin arm, three women at the 300 mg dose experienced mild nausea and vomiting. In the PLD arm most women had mild erythema and swelling of the breast over the 72 hours following the drug administration while the women receiving the highest dose experienced local erythema until the time of surgery. Pharmacokinetic analysis showed that carboplatin rapidly entered systemic circulation with an early peak time (tmax~30 min) with a resultant PUF AUC consistent with the Calvert Formula using estimated GFR. Total plasma doxorubicin had delayed peak concentration times (tmax&amp;gt;36 hours) with a linear dose response and peak concentrations substantially lower than expected from equivalent iv dosing. No doxorubicinol metabolite was detected in the plasma. Pathological examination showed the drugs were widely distributed throughout the ductal systems reaching terminal duct lobular units, and there was a significant although variable dose-related epithelial cell loss in ducts with dye indicating drug effect. While dye was seen in or near the cancer areas, the effect of drug treatment on the disease could not be distinguished. Conclusions: This study demonstrates that cytotoxic drugs can be easily administered into breast ducts with minimal toxicity. [This research was sponsored by Windy Hill Medical. Both S.M.L. and J.R. are consultants to WHM and S.M.L. is a founder, Board Member, and share holder.]

Carbamazepine induces bioactivation of cyclophosphamide and thiotepa

We report a patient with metastatic breast cancer who received three cycles of high-dose chemotherapy with cyclophosphamide [1,000 mg/(m(2) day)], thiotepa (80 mg/(m(2) day) and carboplatin (dose calculated based on modified Calvert formula with 3.25 mg min/ml as daily target AUC) over 4 days, followed by peripheral blood progenitor cell support. During the first two cycles the patient concomitantly used carbamazepine for the treatment of epilepsy. Due to severe nausea and vomiting the patient was unable to ingest carbamazepine; therefore, this was discontinued after the second cycle. Blood samples were drawn on 2 days (day 1 and 2, 3 or 4) of each cycle and plasma levels of cyclophosphamide, its active metabolite 4-hydroxycyclophosphamide, thiotepa, its main, active metabolite tepa and carboplatin were determined. Exposure to 4-hydroxycyclophosphamide and tepa on day 1 was increased in the presence of carbamazepine (58 and 75%, respectively), while exposure to cyclophosphamide and thiotepa was reduced (40 and 43%, respectively). Since increased exposure to the active metabolites is associated with an increased risk of toxicity, it is important to be aware of this drug-drug interaction.

Peritoneal disseminated recurrence and lung metastasis after surgery for stage IA uterine papillary serous carcinoma of the endometrium: a case report

We describe a case of synchronous peritoneal dissemination and multiple lung metastases after surgery for stage IA primary uterine papillary serous carcinoma (UPSC) of the endometrium, revealed by an uncontrollable retention of ascites. She was initially treated with a hysterectomy, bilateral salpingo-oophorectomy and pelvic lymphadenectomy after initial presentation. Tumor recurrence, diagnosed 12 months later, has been treated with six cycles of Paclitaxel 175 mg/m(2) and Carboplatin [area under the curve 5 (Calvert Formula)] every 3 weeks and showed an advantage of this regimen. Early recurrences of the stage IA UPSC can occur and continued close surveillance is recommended. We report herein the case about this entity.

Calculating carboplatin doses using the 4-variable modification of diet in renal disease (4-v MDRD) estimate of glomerular filtration rate (GFR) in the Calvert formula

2521 Background: The dose of carboplatin is usually calculated using the Calvert formula, with various bedside estimates utilized rather than directly measured GFR. The 4-v MDRD equation (Levey AS, et al. Ann Intern Med 2006; 145: 247–254) is now advocated as the routine method of estimating renal function from serum creatinine in all patients. Adoption in clinical practice is occurring despite lack of validation in oncology patients. The aim of this study was to compare carboplatin doses derived from the Calvert formula using measured GFR and the estimates of the 4-v MDRD equation and other established estimates. Methods: GFR was determined using technetium-99m diethyl triamine penta-acetic acid (Tc99mDTPA) clearance. Serum creatinine (Jaffe method) was measured and GFR estimates calculated using 4-v MDRD, Cockcroft and Gault formula (CGF), Wright, Martin, and Jelliffe (JF) formulae. Carboplatin doses were calculated using the Calvert formula, targeting an area under the curve of 7mg.ml- 1.min-1. Results: GFR was measured in 510 adult oncology patients (323 male, 187 female, mean age 63 years, range 17–87 years, mean GFR 84 mL/min, range 16–205 mL/min). The mean (range) carboplatin dose was 765 mg (287–1,610 mg), 681 mg (237–1,306 mg), 674 mg (249–2,044 mg), 721 mg (261–1,536mg), 741 mg (261–2,128mg), 620 mg (244- 1,329 mg) for measured GFR, 4-v MDRD, CGF, Wright, Martin, and JF formulas respectively. The accuracy (% within 20% of ‘true’ dose) was 58%, 63%, 73%, 72% and 49% for 4-v MDRD, CGF, Wright, Martin, and JF formulas respectively. Carboplatin doses derived using the 4-v MDRD estimate of GFR become increasingly less accurate with increasing GFR (see table ). All other formulas performed similarly. Conclusions: The 4-v MDRD equation resulted in an imprecise estimation of carboplatin doses with the degree of variability dependant on the level of renal function. [Table: see text] No significant financial relationships to disclose.

Intraperitoneal carboplatin in icodextrin 4% as first-line treatment for epithelial ovarian cancer: A phase I/II trial

5522 Background: First line intraperitoneal (IP) chemotherapy improves survival in epithelial ovarian cancer (EOC). Problems with IP delivery are not uncommon; in the GOG 172 study, 34% of patients discontinued IP therapy due to catheter complications. Icodextrin 4% is a high molecular weight solution for IP use, which produces a prolonged pharmacological ascites and reduces both post-surgical and post-chemotherapy adhesions. Methods: This phase I study investigated IP carboplatin in icodextrin 4% in optimally debulked EOC. Immediately post operatively, 1.5L Icodextrin 4% was infused IP. This was repeated on a weekly basis. Carboplatin was added 3-weekly, over 6 cycles. Carboplatin target AUC started at 5 mg/ml.min based on 51Cr EDTA clearance and the Calvert formula, and increased by increments of 1 mg/ml.min until dose limiting toxicity (DLT) was reached. Three to 6 patients were treated per dose level. IP fluid samples and blood samples were obtained immediately prior and after IP administration of carboplatin in icodextrin 4% and 1, 2, 4, 8, 12, 24, 48 h and 1 week after. Results: Fourteen patients were treated; 4 at AUC 5, 3 at AUC 6, 3 at AUC 7, 4 at AUC 8. DLT was reached at AUC 8. Myelosuppression was the DLT. The mean AUCs, measured in plasma ± SEM (and peritoneal fluid ± SEM), were: 5.8 ± 0.80 (55.2 ± 14.3), 4.9 ± 0.92 (43.0, 1 sample), 5.3 ± 1.3 (74.4 ± 25.3) and 7.5 ± 0.28 (135.3 ± 9.48) mg/ml.min for the target AUCs of 5, 6, 7 and 8 respectively. Two patients were withdrawn at the start of the 2nd cycle due to vaginal leaking of the IP installed icodextrin. The other 12 patients completed all 6 cycles without significant catheter problems or abdominal pain. Conclusions: The pharmacokinetic data suggest that carboplatin in icodextrin 4% is associated with a considerable IP pharmacokinetic advantage. Compared to data obtained on IP carboplatin in 5% glucose, icodextrin 4% does not seem to alter the pharmacokinetics of IP installed carboplatin. Icodextrin 4% appears to be an excellent carrier solution for IP carboplatin, with the potential to reduce catheter associated complications. To complete the phase II part of the study, 20 further patients will be treated at the maximum tolerated dose (MTD), AUC 7 mg/ml.min. No significant financial relationships to disclose.

Carboplatin (Cb) clearance (Cl) in elderly and young patients with advanced non-small cell lung cancer (ANSCLC): An exploratory analysis of the Calvert’s formula

18047 Background: It seems that elderly lung cancer patients (p) respond better to combination chemotherapy than to single-agent therapy. Application of pharmacokinetic (pk) modelling to the routine therapeutic drug monitoring in elderly p help to individualize the dosage of anticancer drugs. The aim of this study was to explore the Calvert′s formula usefulness for calculating the Cb dose in elderly p by means of the predicted AUC/actual AUC ratio. Creatinine (Cr) Cl was calculated by Cockdroft-Gault equation. Methods: Between December 2005 and September 2006, 20 chemonaive ANSCLC p were included in two groups: 10 adults p ≤ 65 years and 10 aged p ≥ 75 years. Treatment consisted in Cb day 1 and gemcitabine 1250 mg/m2 days 1 and 8 every 21 days. Cb dose was calculated for a foreseen AUC = 5 in young adults and AUC = 4 in aged p. Three blood samples were collected at 1–2 hours(h), 3–5 h, 12–24 h postinfusion. Total and ultrafiltrated Cb was determined using a flameless atomic absortion spectrometer. For pk analysis non lineal effects models implemented in NONMEM program were used. Individual pk parameters were calculated and predictors in the structural model were analized. Results: Table 1 shows mean and variation coefficient of some biometric characteristics. Pk parameters analysis: ClAUC5 p = 137 mL/min; Clfactor (parameter for measuring Cl changes according to age) = 0.44; Cl AUC4 p = 59.7 mL/min. Cb Cl in elderly p was 43.55% with respect to younger p. In younger p estimated Cb Cl was 5.69% higher than Cb Cl calculated using the Calvert equation. In elderly p, the opposite effect was achieved, estimated Cb Cl was 26.85% lower than Cb Cl calculated Conclusions: The Cb Cl calculation by means of Calvert formula showed underestimation of the dose in younger p and upperestimation of the dose in elderly p. It is necessary to investigate the covariates which contribute to take away the strength of the Calvert equation, which could to affect the efficacy and toxicity of Cb. [Table: see text] No significant financial relationships to disclose.

Chemoradiation therapy using radiotherapy, systemic chemotherapy with 5-fluorouracil and nedaplatin, and intra-arterial infusion using carboplatin for locally advanced head and neck cancer – Phase II study

To improve the treatment results for locally advanced head and neck cancer, chemoradiation therapy by radiotherapy, systemic chemotherapy with 5-fluorouracil (5FU) and nedaplatin (NDP), and intra-arterial therapy using carboplatin (CBDCA) was performed. Thirty-two patients were entered into the study between July 1997 and August 2002. According to the TNM staging (1997), 14 patients had stage III lesions, and 19 patients had stage IV (M0) lesions. Alternating chemoradiotherapy was performed by the following regimen. Initially, systemic chemotherapy was administered, followed by 4 weeks of radiotherapy (36Gy/20 fractions; wide field irradiation) starting 2 days after chemotherapy, a second course of systemic chemotherapy 2 days after radiotherapy, and a second course of a reduced field radiotherapy (30Gy/15 fractions) 2 days after chemotherapy. Arterial injection therapy was administered in the latter half of radiotherapy after the end of the second course of systemic chemotherapy. For systemic chemotherapy, 5FU at 3500mg/m(2)/120h was intravenously administered for 5 days (Days 1-5), and NDP at 120mg/m(2)/6h was administered on Day 6. An intra-arterial agent using CBDCA was continuously infused by a portable electrical pump for 4 (to 6) weeks. The total dose of CBDCA was AUC 6 as established by Calvert's formula. The 5-year local control rate was 59%. The 5-year overall survival rate was 51%. There were no clinically significant adverse effects. Chemoradiation therapy by radiotherapy, systemic chemotherapy, and intra-arterial chemotherapy for locally advanced head and neck cancer may be useful for improving treatment results.