Administration Of Carboplatin Research Articles

Use of Single-Agent Carboplatin as Adjuvant or Neoadjuvant Therapy in Conjunction With Amputation for Appendicular Osteosarcoma in Dogs

Survival following amputation and administration of single-agent carboplatin for treatment of appendicular osteosarcoma (OSA) in dogs was retrospectively examined. Records of 155 dogs with appendicular OSA treated with amputation and single-agent carboplatin were included from 14 centers. Any carboplatin dosage, number of doses, and protocol schedule were eligible for inclusion. The median disease-free interval (DFI) was 256 days. The median overall survival time was 307 days. Similar prognostic survival factors were identified in this study as reported in prior studies of canine appendicular OSA. Median DFI and survival were comparable to those reported in the original Bergman et al publication. Carboplatin treatment improves the survival probability in dogs with appendicular OSA compared to amputation alone and remains an acceptable alternative to adjuvant treatment with cisplatin.

Efficacy of Pegylated Lyposomal Anthracyclines and of Intra-Arterial Carboplatin and Doxorubicin Combined with Local Hyperthermia in a Case of Malignant Endovascular Papillary Angioendothelioma

Malignant vascular tumors are exceedingly rare in childhood. Generally, their prognosis is dependent from a microscopically complete surgical resection. We observed the case of a 4-year-old boy affected by malignant endovascular papillary angioendothelioma, a rare vascular tumor of intermediate malignancy, involving all his left leg and partially the pelvis. Its very large size hampered any surgical intervention. However, we could demonstrate high sensitivity of the tumor to lyposomal anthracyclines and the child was eventually cured by the intra-arterial administration of carboplatin and doxorubicin coupled with local hyperthermia. This experience probably represents the first step toward an effective treatment of malignant vascular tumors in infancy.

カルボプラチン，パクリタキセル併用化学療法が奏功した耳下腺癌肺転移例

Patients with metastatic regions of carcinoma of the salivary gland have been treated with chemotherapy. Cisplatin, adriamycin and cyslophosphamide are the most active agents against adenocarcinoma-like salivary gland tumors; however, response rates to these agents have been low. Chemotherapy with carboplatin and paclitaxel is used for non-small cell lung cancer. It has been reported that the combination of carboplatin and paclitaxel was effective in some patients with recurrent or metastaic salivary gland malignancies. Weekly low-dose carboplatin and paclitaxel has been reported to have good activity with acceptable toxicity. A 47-year-old patient underwent total parotidectomy for carcinoma ex-pleomorphic adenoma of the parotid gland. He developed multiple lung metastases 5 months later. The lung metastases did not response to CAP (cisplatin, adriamycin, cyslophosphamide) and we therefore began administration of carboplatin and low-dose paclitaxel. One cycle of treatment consisted of carboplatin at an area under the curve of 1.5 and paclitaxel at 80 mg/m2 on days 1, 8 and 15 on a 28-day cycle. After 6 cycles of this treatment, lung metastases partially responded while maintaining good QOL.

MASPIN's prognostic role in patients with advanced head and neck carcinoma treated with primary chemotherapy (carboplatin plus vinorelbine) and radiotherapy: preliminary evidence

Conclusions: Our very preliminary results support the hypothesis that MASPIN expression in primary head and neck squamous cell carcinoma (HNSCC) may be a valuable parameter for predicting patients’ responses to a treatment based on carboplatin plus vinorelbine combined with radiotherapy. Objectives: The roles of induction chemotherapy and combined chemoradiotherapy in the treatment of locally advanced unresectable HNSCCs have evolved rapidly. MASPIN has a unique tumour-suppressing activity. Experimental evidence has shown that MASPIN suppresses tumour growth, angiogenesis, invasion and metastasis. We investigated the potential prognostic roles of MASPIN and p53 in a series of HNSCCs treated with carboplatin plus vinorelbine combined with radiotherapy. Patients and methods: Nineteen consecutive stage III or IV HNSCC patients were recruited. The treatment plan consisted of the administration of carboplatin on day 1 and vinorelbine on days 1 and 8. Four weeks later, carboplatin was administered concomitantly with radiation therapy. Expression of MASPIN and p53 was determined immunohistochemically in HNSCC diagnostic biopsies. Results: A significant inverse relation was found between MASPIN expression and cN staging (p=0.003). From a prognostic viewpoint, MASPIN expression was directly correlated with chemoradiotherapy response (p=0.041). Moreover, the log-rank test showed a significant relationship between higher MASPIN expression and longer disease-free survival (p=0.03), overall survival (p=0.006) and disease-specific survival (p=0.007).

The treatment of stage A testicular seminoma by carboplatin monochemotherapy

Although radiotherapy is considered to be a standard treatment of stage A testicular seminoma, an increasing number of studies have reported encouraging results of the treatment by carboplatin monochemotherapy (CBDCA). The aim of this study was to analyse the treatment results of patients with clinical stage A seminoma treated by CBDCA on daily basis in the period June 1999 to September 2008. A total of 124 patients, mean age 36.63 years (20-62 years), with stage A testicular seminoma were treated, upon radical orchiectomy, by adjuvant CBDCA (400 mg/m2 on day 1 and 22). Chemotherapy was well tolerated, except moderate nausea on the day of the drug administration and the following day. No patient had any serious disorders in blood cells count requiring substitutional treatment. During the mean follow-up period of 37.5 (range 6-111) months, three relapses were noted (2.41%) and none neoplasm of contralateral testicle or any other organ. Simple and easy carboplatin administration with excellent treatment results, along with good tolerance and absence of comorbidity, poses itself as a new "gold standard" of treatment for stage A testicular seminoma.

Neoadjuvant chemoradiation followed by surgery versus surgery alone for patients with adenocarcinoma or squamous cell carcinoma of the esophagus (CROSS)

BackgroundA surgical resection is currently the preferred treatment for esophageal cancer if the tumor is considered to be resectable without evidence of distant metastases (cT1-3 N0-1 M0). A high percentage of irradical resections is reported in studies using neoadjuvant chemotherapy followed by surgery versus surgery alone and in trials in which patients are treated with surgery alone. Improvement of locoregional control by using neoadjuvant chemoradiotherapy might therefore improve the prognosis in these patients. We previously reported that after neoadjuvant chemoradiotherapy with weekly administrations of Carboplatin and Paclitaxel combined with concurrent radiotherapy nearly always a complete R0-resection could be performed. The concept that this neoadjuvant chemoradiotherapy regimen improves overall survival has, however, to be proven in a randomized phase III trial.Methods/designThe CROSS trial is a multicenter, randomized phase III, clinical trial. The study compares neoadjuvant chemoradiotherapy followed by surgery with surgery alone in patients with potentially curable esophageal cancer, with inclusion of 175 patients per arm.The objectives of the CROSS trial are to compare median survival rates and quality of life (before, during and after treatment), pathological responses, progression free survival, the number of R0 resections, treatment toxicity and costs between patients treated with neoadjuvant chemoradiotherapy followed by surgery with surgery alone for surgically resectable esophageal adenocarcinoma or squamous cell carcinoma. Over a 5 week period concurrent chemoradiotherapy will be applied on an outpatient basis. Paclitaxel (50 mg/m2) and Carboplatin (Area-Under-Curve = 2) are administered by i.v. infusion on days 1, 8, 15, 22, and 29. External beam radiation with a total dose of 41.4 Gy is given in 23 fractions of 1.8 Gy, 5 fractions a week. After completion of the protocol, patients will be followed up every 3 months for the first year, every 6 months for the second year, and then at the end of each year until 5 years after treatment. Quality of life questionnaires will be filled out during the first year of follow-up.DiscussionThis study will contribute to the evidence on any benefits of neoadjuvant treatment in esophageal cancer patients using a promising chemoradiotherapy regimen.Trial registrationISRCTN80832026

Increased distribution of carboplatin, an anti-cancer agent, to rat brains with the aid of hyperbaric oxygenation

1. The distribution of an anti-cancer agent carboplatin to brains was investigated in combination with hyperbaric oxygenation treatment in rats.2. After intravenous administration of carboplatin (30 mg kg−1) to male Wistar rats, elimination curves of plasma drug concentrations plotted against a time of 45 min were not different with or without hyperbaric oxygenation (at 0.20–0.25 MPa for last 20 min) treatments.3. Carboplatin concentrations of livers, lungs and kidneys in each group were similar at the endpoint of hyperbaric oxygenation treatment.4. Under these atmosphere conditions (at 0.10 MPa), carboplatin concentration was at an undetectable level in rat brains (<0.1 µg g−1 tissue, n = 6). On the contrary, carboplatin was detected in all brains tested at the levels of 0.5 ± 0.3 µg g−1 tissue (mean and standard deviation (SD), n = 6), 0.8 ± 0.5 µg g−1 tissue, and 0.4 ± 0.2 µg g−1 tissue in combination with hyperbaric oxygenation at 0.20, 0.22, and 0.25 MPa, respectively, at the endpoint of hyperbaric oxygenation treatment.5. The results suggest that carboplatin could be uptaken into rat brains at the detectable levels by the aid of hyperbaric oxygenation, consistently with the reported findings of enhanced transendothelial permeability and improved clinical efficacy of carboplatin combined hyperbaric oxygenation therapy.

The Stage of Offspring of Female Rats after Treatment with Cytostatics of Various Groups

We examined the offspring of female rats that were mated with intact males in the delayed period after administration of cytostatic drugs Farmorubicin, platidiam, carboplatin, etoposide, and paclitaxel (1, 3, and 6 months post-treatment). Toxicity of these drugs in the offspring decreased in the following order: paclitaxel > etoposide > carboplatin > platidiam > Farmorubicin. The toxic effect depended not only on the type of cytostatic treatment, but also on the period of conception.

A prospective study on the incidence of delayed nausea and vomiting following administration of carboplatin containing regimens for treatment of cancer without prophylactic aprepitant

20626 Background: Delayed nausea and vomiting following administration of carboplatin containing chemotherapy regimen remains a clinically significant problem for patients with cancer despite administration of standard antiemetic prophylaxis (a 5-HT3 antagonist & dexamethasone). Methods: We report here preliminary results of an ongoing prospective study to evaluate the incidence of delayed chemotherapy-induced nausea and vomiting (CINV) after the first cycle of treatment. Previously untreated patients with newly diagnosed cancer scheduled to receive carboplatin containing regimen (AUC 5 or above) (but no prophylactic aprepitant) are eligible to participate. Primary endpoint is the incidence of CINV after cycle 1 of chemotherapy. Secondary endpoints include the incidence of CINV after the third cycle & the gender differences in incidence of CINV. Patients completed the Functional Living Index Emesis (FLIE) questionnaires 24, 48, 72 and 96 hours after receiving chemotherapy. Telephone interviews were conducted 24–48 hours following chemotherapy to assess the severity & need for breakthrough medications for CINV. Results: The characteristics of 50 patients enrolled thus far: 54% male, mean age 63.2 years (range 42.2 - 79.6 years) and 86% diagnosed with lung cancer. Thirty six percent of patients reported moderate to severe CINV 72 hours after chemotherapy, with symptoms persisting as long as 96 hours in 33% of the patients after cycle 1. Women had only a slightly higher incidence of CINV (38%) than men (35%) at 72 hours following cycle 1, but a significantly higher incidence of emesis was seen in women (31%) compared to men (8%) (P=0.047) at 72 hours following cycle 3. Conclusions: Without prophylactic aprepitant administration, one third of cancer patients receiving carboplatin containing regimen had moderate to severe delayed CINV. Percentage of patients with delayed CINV 24 hrs 48 hrs 72 hrs 96 hrs Cycle 1 13.51% 24.32% 36.11% 33.34% Cycle 3 3.85% 21.74% 20.00% 23.08% No significant financial relationships to disclose.

Combination chemotherapy of intraperitoneal carboplatin and intravenous taxane in advanced endometrial cancer: A pilot study

16560 Background: This is a pilot study to assess the efficacy and safety of combination chemotherapy of intraperitoneal (IP) carboplatin and intravenous (IV) taxane (paclitaxel or docetaxel) in advanced endometrial cancer for the future trial. Methods: The patients eligible for this study had histologically confirmed endometrial cancer with peritoneal carcinomatosis and/or positive for peritoneal cytology. A Bard IP port system was placed within the subcutaneous fat when the primary surgery was underwent. IV Paclitaxel 175 mg/m2 or IV docetaxel 60 mg/m2 was administered followed by IP carboplatin administration based on an area under the curve 6. Chemotherapy was repeated every 3 weeks for at least 3 courses depending on the purpose of the therapy. The toxicity grade was determined by National Cancer Institute common toxicity criteria version 2. Results: During April 2000 and March 2005, 13 patients were entered in this study. The distribution of stage was IIIA, 7; IIIB, 1; IIIC, 3; IVB, 2. There were 5 endometrioid adenocarcinoma grade 1, 7 endometrioid adenocarcinoma grade 2 and 1 endometrioid adenocarcinoma grade 3. Seven patients received IP carboplatin with IV paclitaxel and 6 patients received IP carboplatin with IV docetaxel. The incidences of grade 3/4 toxicities were 77% for neutrocytopenia, 23% for thrombocytopenia, and 15% for anemia. No grade 3/4 non-hematological toxicity was observed. No patient encountered catheter problems. Median follow up period was 61 months. Two patients with stage IVB and 2 patients with stage IIIC recurred and died of disease. No patient with stage IIIA recurred. Conclusions: The combination of IP carboplatin and IV taxane is an effective and safe for advanced endometrial cancer. Further evaluation particularly targeted on stage IIIA endometrial carcinoma is warranted. No significant financial relationships to disclose.

Use of alternating administration of carboplatin and doxorubicin in dogs with microscopic metastases after amputation for appendicular osteosarcoma: 50 cases (1999–2006)

To evaluate the efficacy and toxicity of an alternating carboplatin and doxorubicin chemotherapy protocol in dogs with putative microscopic metastases after amputation for appendicular osteosarcoma and assess patient-, tumor-, and treatment-related factors for associations with prognosis. Retrospective case series. 50 client-owned dogs. Records of dogs that underwent amputation for appendicular osteosarcoma and received an alternating carboplatin and doxorubicin chemotherapy protocol were reviewed. Dogs had full staging and were free of detectable metastases prior to chemotherapy. Data on disease-free interval (DFI), survival time, and toxicoses were retrieved from medical records and owner or referring veterinarian communications. Median DFI was 202 days. Median survival time was 258 days. Twenty-nine (58%) dogs completed the protocol as planned, and the rest were withdrawn typically because of metastases or toxicoses. Grade 3 or 4 myelosuppression was reported in 9 of 50 (18%) dogs and grade 3 or 4 gastrointestinal toxicosis in 6 of 50 (12%) dogs. There were no chemotherapy-related fatalities. Univariate factors associated with significant improvement in DFI included tumor location (radius), receiving doxorubicin as the first drug, starting chemotherapy more than 14 days after amputation, and no rib lesions on preamputation bone scans. Multivariate factors associated with a significant improvement in survival time were tumor location (radius) and completing chemotherapy. Alternating administration of carboplatin and doxorubicin resulted in DFI and survival time similar to those reported for single-agent protocols. Clients should be counseled regarding the likelihood of toxicoses. Relevance of sequence and timing of starting chemotherapy should be further evaluated.

Accumulation, Fractionation, and Analysis of Platinum in Toxicologically Affected Tissues after Cisplatin, Oxaliplatin, and Carboplatin Administration

Antitumoral Pt-containing drugs present side effects like nephrotoxicity and ototoxicity. Several systematic experiments have been carried out with Wistar rats treated with cisplatin, carboplatin, and oxaliplatin to study Pt-drugs accumulation and elimination, and Pt-biomolecule distribution in the cells and cytosols of ear, kidney, and liver. Inductively coupled plasma-mass spectrometry (ICP-MS) analysis shows a cisplatin accumulation capability between oxaliplatin (the highest) and carboplatin (the lowest). The maximum concentration of Pt in all the organs studied was achieved around the first week after cisplatin treatment. During the first 30 days, the elimination was very fast, decreasing in the subsequent 60 days in all the organs. Analysis of cytosols by liquid chromatography (LC)-ICP-MS showed an analogous behavior. In most samples, the distribution of the three drugs in the cellular and cytosolic fractions was similar for all the tissues. For kidney and ear, approximately 60% and 30%, respectively, of the metal accumulated was present in the cytosol, the cytosolic fractions smaller than 50 KDa being especially important. Cisplatin-biomolecule interaction strength under denaturing conditions was evaluated by LC-ICP-MS and showed a quite strong bond.

Randomized, Phase III Study of Weekly Paclitaxel in Combination With Carboplatin Versus Standard Every-3-Weeks Administration of Carboplatin and Paclitaxel for Patients With Previously Untreated Advanced Non–Small-Cell Lung Cancer

To compare the efficacy and safety of weekly paclitaxel in combination with carboplatin administered every 4 weeks to the standard regimen of paclitaxel and carboplatin administered every 3 weeks for the treatment of patients with advanced non-small-cell lung cancer (NSCLC). Four hundred forty-four patients with previously untreated stage IIIB/IV NSCLC were randomly assigned to either arm 1 (n = 223), paclitaxel 100 mg/m(2) weekly for 3 of 4 weeks with carboplatin area under the curve (AUC) = 6 mg/mL x min on day 1 of each 4 week cycle, or arm 2 (n = 221), paclitaxel 225 mg/m(2) and carboplatin AUC = 6 on day 1 of each 3-week cycle. After four cycles of therapy, patients in both treatment arms were eligible to continue weekly paclitaxel (70 mg/m(2), 3 of 4 weeks) as maintenance therapy until unacceptable toxicity or disease progression. The objective response rate was 27.6% for arm 1 and 19.2% for arm 2. Median time to progression (TTP) was 18.4 and median survival (MS) was 38.6 weeks for arm 1. For arm 2, the median TTP and MS were 16.7 weeks and 42.9 weeks respectively. Grade 3/4 anemia was more common with arm 1, although grade 2/3 neuropathy and arthralgia were less common. The remainder of the toxicities were similar between the two arms. All efficacy parameters were similar between the two treatment arms. The favorable nonhematologic toxicity profile of arm 1 makes this an alternative treatment option for patients with advanced NSCLC.

Determination of carboplatin dose by area under the curve in combination chemotherapy for senile non-small cell lung cancer

To preliminarily determine the appropriate dosage of carboplatin (CBP) at AUC of 5 mg.Ml(-1).min(-1) in the combination chemotherapy for Chinese senile patients with non-small cell lung cancer (NSCLC). Thirty-five Chinese senile patients with NSCLC in advanced stage (III/IV) were given 96 cycles of combination chemotherapy. Chemotherapy schedules included Taxol+CBP, Gemzar+CBP and NVB+CBP. The dose of CBP was at 5 mg.mL(-1).min(-1) of area under the concentration-time curve (AUC). Side effects and quality of life were observed before and after the chemotherapy. Myelosuppression was severe and commonly observed. Grade 3/4 of granulocytopenia was found in 47.9% (46/96) of the patients and grade 3/4 of thrombocytopenia was noted in 28.1% (27/96) of the subjects. However, other side effects were slight. The mean score of quality of life (QOL), according to the criteria of QOL for Chinese cancer patients had reduced 6.8. At 5 mg.mL(-1).min(-1) by AUC, the hematological toxicity of CBP was severe and it had some negative effects on the QOL. The administration of CBP at 5 mg.mL(-1).min(-1) by AUC may be too high for Chinese senile patients with non-small cell lung cancer.

Effect Of N‐Acetylcysteine on Carboplatin‐Induced Ototoxicity and Nitric Oxide Levels in a Rat Model

The aim of the present study is to investigate the effect of N-acetylcysteine (NAC) given 30 minutes before carboplatin administration on carboplatin-induced ototoxicity and nitric oxide (NO) levels in a rat model. Animal study. Eighteen Sprague-Dawley rats were divided into three groups that each contained six animals. Intraperitoneal injection of physiologic saline was performed in group 1 twice with an interval of 30 minutes. Group 2 was treated with a single bolus administration of carboplatin at a dose of 256 mg/kg 30 minutes after the intraperitoneal injection of physiologic saline. Group 3 was treated with a single bolus administration of carboplatin at a dose of 256 mg/kg 30 minutes after the intraperitoneal injection of NAC at a dose of 400 mg/kg. Pretreatment and posttreatment distortion product otoacoustic emissions (DPOAE) were performed in rats from all groups. Then, the animals were sacrificed on the fourth day, and cochlear tissue NO and glutathione peroxidase (GSH-Px) levels were measured. The comparison of pre- and posttreatment DPOAE responses did not demonstrate any significant changes for groups 1 and 3. Results of group 2 showed a decrease of the DPOAE amplitude. Cochlear NO levels were significantly higher in rats treated with carboplatin than in controls and in those treated with carboplatin plus NAC (P < .05). Cochlear GSH-Px levels were higher in rats treated with carboplatin plus NAC than in those treated with carboplatin, but the difference did not reach statistical significance (P = .079). The present study showed that carboplatin at higher doses induced hearing loss and increased NO levels in the cochlea of rats. NAC appears to have a protective effect against carboplatin-induced ototoxicity, which may be related to its inhibitory effect on NO production.

A Phase I Dose Escalation Study of Biweekly Gemcitabine and Carboplatin in Completely Resected Stage IB-IIIA Nonsmall Cell Lung Cancer

We conducted a phase I dose escalation study to determine the maximum tolerated dose, recommended dose, and safety profile of a biweekly gemcitabine and carboplatin combination regimen in the treatment of patients with completely resected nonsmall cell lung cancer (NSCLC). Patients with completely resected pathologically documented stage IB, II, or IIIA NSCLC, performance status (ECOG) 0-1, with adequate bone marrow, renal, liver, and cardiac functions, were treated with gemcitabine and carboplatin. The starting dose was gemcitabine 800 mg/m2 on days 1 and 15 and carboplatin area under the time-concentration curve (AUC) 4 mg/mL/min on day 1. Gemcitabine was increased to 1000 mg/m2 (level 3). Carboplatin was increased to AUC 5 (level 2, 3). The regimen was performed every 4 weeks. The dose-limiting toxicity of the regimen was assessed during the first chemotherapy cycle. Nine patients were enrolled in this study. All patients were assessed for safety. Grade 3 leukopenia occurred in 1 patient (11%) and grade 3/4 neutropenia occurred in 3 patients (33%). No other grade 3/4 toxicity was observed. No dose-limiting toxicity was experienced at dose levels 1, 2, and 3 of this schedule. Maximum tolerated dose was not reached in this study. Considering treatment continuation, the recommended dose for a phase II study is gemcitabine 1000 mg/m2 on days 1 and 15 and carboplatin AUC 5 on day 1, every 4 weeks. Biweekly administration of gemcitabine and carboplatin is a feasible and well-tolerated regimen for the treatment of patients with completely resected NSCLC as adjuvant chemotherapy.

Pharmacodynamic model for chemotherapy-induced anemia in rats

Anticancer agents often cause bone marrow toxicity resulting in progressive anemia which may influence the therapeutic effects of erythropoietic-stimulating agents. The objective of this study was to develop a pharmacodynamic (PD) model to describe chemotherapy-induced anemia in rats. Anemia was induced in male Wistar rats with a single intravenous (i.v.) injection of 60 mg/kg carboplatin. Hematological responses including reticulocytes, red blood cells (RBC), hemoglobin, and endogenous rat erythropoietin (EPO) were measured for up to 4 weeks. A catenary, lifespan-based, indirect response model served as a basic PD model to represent erythroid cellular populations in the bone marrow and blood involved in erythropoiesis. The model assumed that actively proliferating progenitor cells in the bone marrow are sensitive to anti-cancer agents and subject to an irreversible removal process. The removal rate of the target cells is proportional to drug activity concentrations and the cell numbers. An additional RBC loss from the circulation resulting from thrombocytopenia was described by a first-order process. The turnover process of rat EPO and EPO-mediated feedback inhibition mechanism regulated by hemoglobin changes were incorporated. Reticulocyte counts decreased rapidly and reached a nadir by day 3 after administration of carboplatin and returned to the baseline by day 13. This was followed by a gradual increase and the rebound peak occurred at about day 15. The hemoglobin nadir was approximately 9 g/dl observed at about 11-13 days compared to its normal value of 13 g/dl and hemoglobin returned to the baseline by day 30. The increase in endogenous rat EPO mirrored inversely hemoglobin changes and the maximum increase was observed soon after the hemoglobin nadir. The carboplatin-treated rats exhibited progressive anemia. The proposed model adequately described the time course of hematological changes after carboplatin in rats and can be a useful tool to explore potential strategies for the management of anemia caused by chemotherapy.

Enhanced Survival and Cure of F98 Glioma–Bearing Rats following Intracerebral Delivery of Carboplatin in Combination with Photon Irradiation

The goal of the present study was to evaluate the efficacy of intracerebral (i.c.) administration of carboplatin by means of convection-enhanced delivery (CED) in combination with fractionated, external beam photon irradiation for the treatment of F98 glioma-bearing rats. Carboplatin (20 microg/20 microL) was administrated i.c. by CED to F98 glioma-bearing rats, 13 days after stereotactic implantation of 10(3) tumor cells. One day following initiation of CED, a 24-Gy X-ray dose was administered in three daily fractions of 8 Gy each. Photon irradiation was carried out using either a conventional (6 MV) linear accelerator or a monochromatic synchrotron source (80 keV) at the European Synchrotron Radiation Facility. The primary end point of this study was overall survival. The median survival times were 79 and 60 days and the corresponding percent increase in life spans were 182% and 114%, respectively, for the combination of carboplatin chemotherapy and irradiation with either 6-MV or 80-keV photons. A subset of long-term survivors (>200 days) were observed in both chemoradiotherapy groups: 16.6% and 8.3% for 6 MV and 80 keV, respectively. In contrast, the median survival times for 6-MV or 80-keV irradiated controls, chemotherapy alone, and untreated controls were 42, 51, 45, and 28 days, respectively. Our results convincingly show the therapeutic efficacy of i.c. administration of carboplatin by means of CED in combination with either 6-MV or 80-keV photons. Further studies are warranted to optimize this combination of chemoradiotherapy for malignant gliomas.

Comparative phase II study of intraperitoneal (IP) versus intravenous (IV) carboplatin administration with IV paclitaxel in patients with bulky residual disease after primary debulking surgery for epithelial ovarian or primary peritoneal cancer: A Sankai Gynecology Study Group (SGSG) study

5584 Background: To assess the anti-tumor effect and safety of IP carboplatin (C) administration comparing with IV C administration in combination with IV infusion of paclitaxel (P). Methods: This is a non-randomized comparative phase II trial. Eligible patients were those with histologically confirmed epithelial ovarian or primary peritoneal cancer who received initial surgery and ended up with residual disease &gt;= 2 cm. They must have reasonable hematological, hepatic, renal function before receiving chemotherapy. The patients received either of the following treatment arms; IP Arm: IV P 175 mg/m2 over 3h followed by IP C AUC6, IV Arm: IV P 175 mg/m2 over 3h followed by IV C AUC6. The treatments were scheduled to repeat 6–8 cycles. Interval debulking surgery was allowed after 3 to 5 cycle of treatment. Each participating institution had to declare, before the study was opened, which of the treatment arms the patients from the institution would be entered. Primary endpoint was a response. Secondary endpoints were toxicity and progression-free survival (PFS) and overall survival (OS). Target accrual was 30 patients in each arm. Results: Total accrual was 26 patients for IP arm and 30 patients for IV arm between 2001 and 2005. The study was closed early, because of the conflict of protocols for IP treatment. Eligible patients were 24 in IP Arm and 25 for IV arm. Median number of treatment cycle was 6 for both arms. Although the difference was not statistically significant, response rate was better in the IP Arm. Response rates were 83.3% (95%CI: 62.6%-95.3%) for IP Arm and 60.0% (95%CI: 38.7%-78.9%) for IV Arm. As of median followup of 31 months, median PFS is 25 months for IP Arm and 21 months for IV Arm,. Median OS is not reached for IP Arm, and 52 months for IV arm. Incidences of hematological and non-hematological toxicities were essentially the same on both arms. Conclusions: IP administration of C may be a better treatment strategy for epithelial ovarian and primary peritoneal cancer patients. A randomized phase III trial including bulky residual disease for comparison of IP and IV carboplatin treatment. No significant financial relationships to disclose.

A randomized phase II trial comparing pulsed erlotinib before or after carboplatin and paclitaxel in patients with stage IIIB or IV non-small cell lung cancer

7619 Background: A randomized phase 3 trial failed to show any improvement in response rate (RR) or overall survival (OS) when erlotinib was added to carboplatin and paclitaxel (TRIBUTE). However, preclinical data suggested that administration of erlotinib before or after chemotherapy may improve efficacy of chemotherapy [Gumerlock et al ASCO 2003, Solit et al Clin Can Res 2005]. We designed this trial to test the hypothesis that administration of pulsed erlotinib prior to or following chemotherapy would improve the response rate in patients with advanced NSCLC. Methods: All patients had chemotherapy naive, stage IIIB or IV NSCLC and were former or current smokers. All patients received carboplatin (AUC 6) and paclitaxel (200 mg/m2). Patients were randomly assigned to one of three arms: erlotinib 150 mg days 1,2, and chemotherapy on day 3; erlotinib 1500 mg days 1, 2 and chemotherapy on day 3; or chemotherapy on day 1 and erlotinib 1500 mg on days 2,3. Patients received up to six 21-day cycles of treatment. The primary endpoint was overall RR (CR+PR) using RECIST. We planned to enroll 29 patients to each arm in a “pick the winner” design comparing arms to the chemotherapy alone arm of TRIBUTE (RR 19%) with a desirable RR of 50%. Results: Eighty-seven patients were randomized to 3 arms. Accrual is complete. The most common grade 3/4 toxicities were neutropenia (39%), fatigue (15%), and anemia (12%). Grade 3/4 rash or diarrhea were uncommon. Conclusions: Treatment with erlotinib before (150 mg on days 1 and 2 or 1500 mg on days 1 and 2) or after (1500 mg on days 2 and 3) administration of carboplatin and paclitaxel failed to improve response rates compared to TRIBUTE. The benefit of pulsatile administration of erlotinib predicted by preclinical models was not evident in this clinical trial. Supported by Genentech, Inc. [Table: see text] [Table: see text]