Mg Of Carboplatin Research Articles

Simulation of spatial diffusion of platinum from carboplatin-impregnated calcium sulfate hemihydrate beads by use of an agarose gelatin tissue phantom.

OBJECTIVE To characterize spatial release of platinum from carboplatin-impregnated calcium sulfate hemihydrate (CI-CSH) beads by use of an agarose tissue phantom. SAMPLE 3-mm-diameter beads (n = 60) containing 4.6 mg of carboplatin (2.4 mg of platinum)/bead. PROCEDURES 18 L of 1% agarose was prepared and poured into 36 containers (10 × 10 × 10 cm), each of which was filled half full (0.5 L/container). After the agarose solidified, 1, 3, 6, or 10 CI-CSH beads were placed on the agar in defined patterns. An additional 36 blocks of agar (0.5 L/block) were placed atop the beads, positioning the beads in the center of 1 L of agar. The experiment was replicated 3 times for each bead pattern for 24, 48, and 72 hours. At these times, representative agarose blocks were sectioned in the x-, y-, and z-planes and labeled in accordance with their positions in shells radiating 1, 2, 3, 4, and 5 cm from the center of the blocks. Agarose from each shell was homogenized, and a sample was submitted for platinum analysis by use of inductively coupled plasma-mass spectroscopy. RESULTS Platinum diffused from CI-CSH beads at predicted anticancer cytotoxic concentrations for 2 to 5 cm. CONCLUSIONS AND CLINICAL RELEVANCE Results provided information regarding the spatial distribution of platinum expected to occur in vivo. Agarose may be used as a diffusion model, mimicking the characteristics of subcutaneous tissues. Measured platinum concentrations might be used to guide patterns for implantation of CI-CSH beads in animals with susceptible neoplasms.

Gallbladder Cancer Showing a Great Response to Paclitaxel Plus Carboplatin Chemotherapy: A Case Report

Currently, complete surgical resection is the most effective and the only potentially curative treatment for gallbladder carcinoma (GBC). However, GBC frequently presents various manifestations as it progresses, including liver invasion, bile duct invasion, hepatoduodenal invasion, venous invasion, and lymphatic invasion. Although there is a clear need for effective chemotherapeutic methods in the management of GBC, no standard chemotherapeutic regimen for advanced GBC has been established to date, and the prognosis remains poor. Herein, we report a case of successful treatment in a patient with advanced GBC who showed a great response to combination chemotherapy and who was subsequently able to undergo curative resection. A 38-year-old Japanese woman was first diagnosed with unknown primary cancer with bilateral ovarian, hepatic, and peritoneal metastases. Combination paclitaxel plus carboplatin chemotherapy was started at a dose of 653 mg of carboplatin and 248 mg of paclitaxel once a week for 3 weeks. After 6 cycles, the tumor had shrunk in size and was detected as only a slightly contrasted lesion in Couinaud's hepatic segments 4 and 5. One month after the final cycle of chemotherapy, we performed cholecystectomy and right lobectomy of the liver with D2 lymph node dissection. The patient exhibited an uneventful postoperative course. Five months have passed since the operation, with no signs of recurrent disease. Our findings suggest that combination chemotherapy with paclitaxel and carboplatin may be effective against advanced GBC.

Elution of platinum from carboplatin-impregnated calcium sulfate hemihydrate beads in vitro.

OBJECTIVE To characterize the elution of platinum from carboplatin-impregnated calcium sulfate hemihydrate (CSH) beads in vitro. SAMPLE 60 carboplatin-impregnated CSH beads and 9 CSH beads without added carboplatin (controls). PROCEDURES Carboplatin-impregnated CSH beads (each containing 4.6 mg of carboplatin [2.4 mg of platinum]) were placed into separate 10-mL plastic tubes containing 5 mL of PBSS in groups of 1, 3, 6, or 10; 3 control beads were placed into a single tube of PBSS at the same volume. Experiments were conducted in triplicate at 37°C and a pH of 7.4 with constant agitation. Eluent samples were collected at 1, 2, 3, 6, 12, 24, and 72 hours. Samples were analyzed for platinum content by inductively coupled plasma-mass spectrometry. RESULTS The mean concentration of platinum released per carboplatin-impregnated bead over 72 hours was 445.3 mg/L. Cumulative concentrations of platinum eluted increased as the number of beads per tube increased. There was a significant difference in platinum concentrations over time, with values increasing over the first 12 hours and then declining for all tubes. There was also a significant difference in percentage of total incorporated platinum released into tubes with different numbers of beads: the percentage of eluted platinum was higher in tubes containing 1 or 3 beads than in those containing 6 or 10 beads. CONCLUSIONS AND CLINICAL RELEVANCE Carboplatin-impregnated CSH beads eluted platinum over 72 hours. Further studies are needed to determine whether implantation of carboplatin-impregnated CSH beads results in detectable levels of platinum systemically and whether the platinum concentrations eluted locally are toxic to tumor cells.

Pharmacokinetic analyses of carboplatin in a patient with cancer of the fallopian tubes undergoing hemodialysis: A case report.

Opportunities for patients undergoing hemodialysis to receive chemotherapy are increasing. A combination of paclitaxel and carboplatin (TC) is first-line chemotherapy in patients with Müllerian cancer. However, the optimal dose and time interval between the end of carboplatin administration and initiation of hemodialysis remains to be elucidated. TC was administered to a patient with fallopian tube cancer undergoing hemodialysis. The paclitaxel regimen was determined to be 135 mg/m2 (total of 210 mg) over 3 h. After paclitaxel administration, 125 mg of carboplatin was administered over 1 h to achieve a target area under the concentration-time curve (AUC) of 5.0 mg•min/ml using the Calvert formula. The time interval between the end of carboplatin administration and hemodialysis initiation was 1 h at the first cycle, 16 h at the second cycle and 20 h at the third cycle, and the AUC obtained was 2.86, 4.16 and 6.0 mg•min/ml, respectively. The desired AUC of free platinum was demonstrated and only mild side effects were observed at the third cycle. Therefore, hemodialysis was initiated 20 h after completion of carboplatin infusion at cycles 4-6. The total chemotherapy planned was completed without severe adverse events. Measurement of the concentration of free platinum subsequent to administration is useful for determination of the optimal dose of carboplatin and time interval following administration to obtain an adequate AUC. The present study suggests that carboplatin can be administered to a patient undergoing hemodialysis, and that an adequate interval between the end of carboplatin administration and hemodialysis initiation may be ~20 h.

Dose calculation and tolerability of adjuvant AUC 7 carboplatin in 100 patients with stage I seminoma.

374 Background: Administration of carboplatin AUC 7 has become a standard adjuvant option to be discussed with pts following orchiectomy for stage I seminoma, as alternative to radiotherapy on retroperitoneal lymphnodes or observation. The toxicity of AUC 7 carboplatin appeared manageable in the pivotal trial by Oliver et al. (Lancet, 2005), but dose ranges were not reported. Oncologists use different methods to estimate GFR and to calculate this unusually high dosage of carboplatin, and fear of toxicity may induce arbitrary dose reductions and potentially compromise the outcome. Methods: In 9 Italian centers we conducted a retrospective review focusing on adjuvant carboplatin administration to stage I seminoma pts. Modality of dose calculation, dose reductions and toxicities were recorded. Results: Since August 2006, 100 pts have been treated, median age 35 years (range 26 to 58). Adverse prognostic factors were either T >4 cm (14% of pts) or rete testis invasion (32), both (36), none or unspecified (18). Glomerular Filtration Rated was estimated mainly by Cockroft-Gault formula (55% of pts), Jeliffe formula (27%), 24-hour urine collection (17%), MDRM (1%): median value was 106 ml/min (range 75 to 209). All Oncologists declared to use Calvert formula to calculate AUC 7 dose, and administered a median of 900 mg of carboplatin (range 690 to 1535). A dose reduction > 10% was prudentially applied to 15% of pts; a second cycle was delivered in 8 pts. Acute toxicities are outlined in table 1. After a median follow-up of 20 months, 6% of patients have relapsed (all in the retroperitoneum), none of whom had been treated with reduced dose. Conclusions: AUC 7 carboplatin dosage peaked 1,535 mg in our cohort of stage I seminoma patients with no infections and nephrotoxicity, moderate nausea-vomiting, but 5% of grade 3-4 thrombocytopenia. Prudential dose reductions appeared unfrequent and should be proscribed. [Table: see text]

Tumor Marker Rise during Second Course of High-Dose Chemotherapy in Cancer: Outcome Analysis

Purpose: To retrospectively analyze the frequency and outcome of hCG and AFP rise at start of or within 1 week after initiation of second course of high-dose carboplatin and etoposide chemotherapy (HDCE) in patients with relapsed or refractory germ cell cancer. Patients and methods: A single-institution review of 391 patients treated with HDCE and peripheral blood stem cell rescue from Feb 1996 to December 2010 was performed. Each patient received 2 consecutive courses of 700 mg of carboplatin per square meter of body-surface-area (BSA) and 750 mg of etoposide per square meter of BSA, each for 3 consecutive days, and each followed by autologous stem cell infusion. The second HDCE was administered 3-4 weeks after the first course. Weekly tumor markers were obtained. Results: 25 of 391 (6.4%) patients were noted to have rising hCG, AFP or both at initiation or within 1 week of second course of HDCE. Fourteen patients had hCG rise (median 48.7 mIU/mL; range 3.2 – 8.863) and 11 AFP rise (median 18.3 ng/mL; range 4.2 - 1,018.8). Twenty-four of 25 patients had a subsequent decline in tumor marker with second course HDCE. Seven of 25 (28%) patients are continuously disease-free at median followup of 69 months (range 28-124 months). Conclusion: Tumor marker rise during second course of HDCE is uncommon. Although it represents an adverse prognostic variable, cure is still possible with institution of second course of HDCE.

Retinal toxicity after repeated intravitreal carboplatin injection into rabbit eyes

The aim of this study was to assess retinal toxicity in a rabbit model after carboplatin delivered as repeated transcorneal intravitreal injection, in order to determine the highest possible safe dose for use in human retinoblastoma "seeding" tumor chemotherapy. We used six albino rabbits in an in vivo experiment and injected 0.008 mg of carboplatin intravitreally (iv) 4 times at two-week intervals. 0.08 mL saline was injected into the left eye. We recorded electroretinograms (ERGs) before the first carboplatin injection and after the fourth injection. Platinum concentration was measured 1 h after the fifth additional injection. We found reduced dark-adapted b-wave amplitudes and, light-adapted b-wave and a-wave amplitudes. The differences between right and left eyes was significant but we found no histopathologic retinal changes. 0.008 mg of carboplatin is probably the highest possible safe dose for the treatment of retinoblastoma patients. Questionable is direct extrapolation of retinal toxicity from the rabbit eye model to the human eye.

Tumor marker rise during second course high-dose chemotherapy in recurrent testicular cancer: Outcome analysis.

4612 Background: Metastatic germ cell tumors that cannot be successfully treated by platinum based initial chemotherapy regimen are potentially curable with salvage chemotherapy. Relapsed or refractory testicular cancer has been treated at Indiana University with two courses of high-dose carboplatin and etoposide chemotherapy (HDCE), each course followed by peripheral stem cell rescue. Einhorn et al published the result of 184 consecutive recurrent metastatic patients treated 1996-2004 with two cycles of HDCE. 63% of these 184 patients were continuously NED with median follow-up 48 months (NEJM 357,340 2007). Several patients were noted to have rising tumor markers—hCG and/AFP—during their second course of high-dose chemotherapy. Similar phenomenon has been noted in some patients treated subsequently. We present retrospective analysis of the frequency and outcome of a rising tumor marker at start of second course of HDCE or within 1 week after initiation of second course. Methods: 391 patients have been treated with HDCE and stem cell rescue from Feb 1996 to December 2010. Each patient received two consecutive courses of 700 mg of carboplatin per square meter of body-surface-area (BSA) and 750mg of etoposide per square meter of BSA, each for 3 consecutive days, and each followed by autologous stem cell infusion. The second HDCE was administered 3-4 weeks after the first course. Weekly tumor markers were obtained. Results: 25 of 391 (6.4%) patients were noted to have rising hCG, AFP or both at initiation or within one week of second course of HDCE. 14 patients had rising hCG (median 61.9 mIU/mL; range 3.2-8,863). 11 patient developed rising AFP (median 18.3 ng/mL; range 4.2-1,018.8). Six patients had increase in both hCG and AFP. 24 of 25 patients had a subsequent decline in tumor marker with second course HDCE. 7 of 25 (28%) patients are continuously disease free at median follow-up of 69 months (range 28-124 months). Conclusions: Tumor marker rise during second course of HDCE is uncommon. Although it represents an adverse prognostic variable, cure is still possible with institution of second course of HDCE.

Evaluation of toxicity after periocular and intravitreal administration of carboplatin in rabbit eyes

The aim of this study was to characterize the extent of toxicity of focal carboplatin administration and to identify the dose limiting toxicity in rabbit eyes depending on administered concentrations. New Zealand white male rabbits (n = 18) were treated with 1 of 3 regimens: a single periocular injection of 15 mg of carboplatin (group I), a single periocular injection of 30 mg of carboplatin (group II) and a single transcorneal intravitreal injection of 0.05 mg of carboplatin (group III). Ophthalmologic examinations and vitreous samplings were performed under dissociative anaesthesia at regular intervals during next 2 (groups I and III) or 3 (group II) weeks. Carboplatin concentrations in vitreous samples were assessed by atomic absorption spectroscopy. At the end of experiments, all rabbit eyes were obtained for histopathologic examination. Clinical and histological evidence of toxicity was graded into four grades according to anatomical structures of the rabbit eye. The dose limiting toxicity was reached in group II after periocular injection of 30 mg of carboplatin and in group III after intravitreal injection of 0.05 mg of carboplatin. No systemic toxicity was observed in any group. Focal carboplatin administration may decrease systemic exposure to this cytotoxic drug in the retinoblastoma treatment. This moreover suggests that focal carboplatin administration is a promising approach and challenge for advanced retinoblastoma chemotherapy.

Unresectable gastric cancer with gastric outlet obstruction and distant metastasis responding to intraperitoneal and folfox chemotherapy after palliative laparoscopic gastrojejunostomy: report of a case

BackgroundGastric outlet obstruction (GOO) caused by unresectable gastric cancer is a challenging aspect of patient care. There have been no reports involving patients with obstructing gastric cancer and several incurable factors curatively treated by multimodal treatments.Case presentationWe report a case of 55-year-old man who was diagnosed with a poorly differentiated adenocarcinoma in the pre-pyloric antrum with GOO by gastroscopy. An abdominal computed tomography (CT) scan revealed thickening of the gastric wall and adjacent fat infiltration, and a large amount of food in the stomach suggesting a passage disturbance, enlarged lymph nodes along the common hepatic and left gastric arteries, and multiple hepatic metastases. The serum carcinoembryonic antigen (CEA) level was 343 ng/ml and the carbohydrate antigen (CA) 19-9 level was within normal limits. The patient underwent a laparoscopic gastrojejunostomy for palliation of the GOO. On the 3rd and 12th days after surgery, he received intraperitoneal chemotherapy with 40 mg of docetaxel and 150 mg of carboplatin. Simultaneously, combined chemotherapy with 85 mg/m2 of oxaliplatin for the 1st day and 600 mg/m2 of 5-FU for 2 days (FOLFOX regimen) was administered from the 8th post-operative day. After completion of nine courses of FOLFOX, the patient achieved a complete response (CR) with complete disappearance of the primary tumor and the metastatic foci. He underwent a radical subtotal gastrectomy with D3 lymph node dissection 4 months after the initial palliative surgery. The pathologic results revealed no residual primary tumor and no lymph node metastasis in 43 dissected lymph nodes. He has maintained a CR for 18 months since the last operation.ConclusionCombination chemotherapy with systemic and intraperitoneal chemotherapy following laparoscopic bypass surgery showed marked efficacy in the treatment for unresectable advanced gastric cancer with GOO.

Intravitreal Carboplatin Concentration and area under Concentration versus Time Curve after Intravitreal and Periocular Delivery

To determine platinum (Pt) concentrations and area under the concentration versus time curve (AUC) of the vitreous humor after periocular or transcorneal intravitreal administration of carboplatin in rabbits. Eighteen albino rabbits were included in an in vivo experiment. Each animal received a single dose of either 30 mg of carboplatin by periocular injection (POI30 group: n = 6) or 15 mg by periocular injection (PI15 group: n = 6), or 0.05 mg by transcorneal intravitreal injection (TII group: n = 6), respectively, into the right eye. Vitreous humor from the right eyes and plasma samples were collected post dose at 1, 2, 6, 24, 48, 168, and 336 hours or 448 hours, respectively. Flameless atomic absorption spectroscopy was employed to analyze total platinum concentrations in blood and vitreous humor. AUC was calculated using the trapezoidal rule. Pt concentration was mostly < 1 mg/L (0-3.15 mg/L) in the vitreous humor samples and > or = 2 mg/L (2.33-7.3 mg/L) in the blood samples 1 hour after administration in POI groups. Markedly higher Pt concentrations were found 1 hour after intravitreal (TII) administration (10.285-66.759 mg/L) and decreased below 1 mg/L no less than 168 hours after administration. The mean AUC for Pt in vitreous humor was significantly lower (p = 0.0001) after both POI30 and P0I15 administration compared to TII route (8.955 +/- 2.464 mg/L/min). These findings proved that intravitreal carboplatin delivery enables the achievement of relatively stable concentrations and AUC of platinum in the rabbit vitreous humor. This moreover suggests that transcorneal intravitreal delivery of carboplatin aiming to treat retinoblastoma vitreous seeding is a promising mode of chemotherapy.

High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors: Einhorn LH, Williams SD, Chamness A, Brames MJ, Perkins SM, Abonour R, Division of Hematology-Oncology, Indiana University School of Medicine, Indianapolis, IN

Metastatic testicular tumors that have not been successfully treated by means of initial chemotherapy are potentially curable with salvage chemotherapy. We conducted a retrospective review of 184 consecutive patients with metastatic testicular cancer that had progressed after they received cisplatin-containing combination chemotherapy. We gave 173 patients 2 consecutive courses of high-dose chemotherapy consisting of 700 mg of carboplatin per square meter of body-surface area and 750 mg of etoposide per square meter, each for 3 consecutive days, and each followed by an infusion of autologous peripheral-blood hematopoietic stem cells; the other 11 patients received a single course of this treatment. In 110 patients, cytoreduction with 1 or 2 courses of vinblastine plus ifosfamide plus cisplatin preceded the high-dose chemotherapy. Of the 184 patients, 116 had complete remission of disease without relapse during a median follow-up of 48 months (range, 14–118). Of the 135 patients who received the treatment as second-line therapy, 94 were disease-free during follow-up; 22 of 49 patients who received treatment as third-line or later therapy were disease-free. Of 40 patients with cancer who were refractory to standard-dose platinum, 18 were disease-free. A total of 98 of 144 patients who had platinum-sensitive disease were disease-free, and 26 of 35 patients with seminoma and 90 of 149 patients with nonseminomatous germ-cell tumors were disease-free. Among the 184 patients, there were 3 drug-related deaths during therapy. Acute leukemia developed in three additional patients after therapy. Testicular tumors are potentially curable by means of high-dose chemotherapy plus hematopoietic stem-cell rescue, even when this regimen is used as third-line or later therapy or in patients with platinum-refractory disease.

High-Dose Chemotherapy and Stem-Cell Rescue for Metastatic Germ-Cell Tumors

Metastatic testicular tumors that have not been successfully treated by means of initial chemotherapy are potentially curable with salvage chemotherapy. We conducted a retrospective review of 184 consecutive patients with metastatic testicular cancer that had progressed after they received cisplatin-containing combination chemotherapy. We gave 173 patients two consecutive courses of high-dose chemotherapy consisting of 700 mg of carboplatin per square meter of body-surface area and 750 mg of etoposide per square meter, each for 3 consecutive days, and each followed by an infusion of autologous peripheral-blood hematopoietic stem cells; the other 11 patients received a single course of this treatment. In 110 patients, cytoreduction with one or two courses of vinblastine plus ifosfamide plus cisplatin preceded the high-dose chemotherapy. Of the 184 patients, 116 had complete remission of disease without relapse during a median follow-up of 48 months (range, 14 to 118). Of the 135 patients who received the treatment as second-line therapy, 94 were disease-free during follow-up; 22 of 49 patients who received treatment as third-line or later therapy were disease-free. Of 40 patients with cancer that was refractory to standard-dose platinum, 18 were disease-free. A total of 98 of 144 patients who had platinum-sensitive disease were disease-free, and 26 of 35 patients with seminoma and 90 of 149 patients with nonseminomatous germ-cell tumors were disease-free. Among the 184 patients, there were three drug-related deaths during therapy. Acute leukemia developed in three additional patients after therapy. Testicular tumors are potentially curable by means of high-dose chemotherapy plus hematopoietic stem-cell rescue, even when this regimen is used as third-line or later therapy or in patients with platinum-refractory disease.

Neoadjuvant treatment of gastric cancer with peritoneal dissemination

Aims To report our experience of neoadjuvant intraperitoneal and systemic chemotherapy (NIPS) for patients having a complete resection of the primary gastric cancer and peritoneal carcinomatosis (PC). Patients and methods Patients with advanced peritoneal dissemination of primary gastric cancer had the placement of a peritoneal port system. For intraperitoneal chemotherapy, 40 mg of docetaxel and 150 mg of carboplatin were introduced in 1000 ml of saline on a weekly basis. Simultaneously, 100 mg/m 2 of methotrexate and 600 mg/m 2 of 5-fluorouracil were infused via a peripheral vein. A minimum of two cycles and up to six cycles of NIPS were used prior to cancer resection. At surgery a complete removal of the primary gastric cancer and the peritoneal implants by peritonectomy was attempted. Results Sixty-one patients were enrolled in the study. Thirty-nine had positive intraperitoneal cytology which reverted to negative cytology after treatment in 22. Thirty-eight showed a partial response. Thirty patients came to resection and 14 patients could be made disease-free. Median survival time of all patients was 14.4 months. Patients who received a complete resection had a median survival time of 20.4 months. Grade III/IV toxicities were not found after two courses of NIPS, but did develop in seven patients after more than three courses of NIPS. Conclusion NIPS can downstage large volume peritoneal dissemination of gastric cancer. When combined with gastrectomy including peritonectomy a complete surgical resection was possible in one-quarter of the patients and resulted in a prolonged survival. This combined intraperitoneal and systemic chemotherapy for PC from gastric cancer is worthy of consideration for phase III clinical investigations.

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

New approach to tumor therapy for inoperable areas of the brain: chronic intraparenchymal drug delivery.

Because the brainstem has little functional redundancy, diffuse lesions have been regarded as inoperable. To determine whether local drug therapy can prolong survival in a rodent model of a tumor in such eloquent tissue, lethal doses of F98 and 9L tumor cells were injected into the brainstems of Fischer 344 rats. Five days after inoculations, 0.5 mg/ml solutions of carboplatin were infused at 1 microl/h for 7 days. Compared to control groups that survived 13-17 days with F98 tumors and 22-23 days with 9L tumors, animals locally infused with 0.1 mg of carboplatin survived 27-30 days (Prob > Chi Sq = 0.0003), and 32 days (Prob > Chi Sq = 0.01), respectively. Measurements of tissue platinum levels at autopsy suggested that infusions distributed pharmacologically relevant levels of carboplatin through a volume of tissue at least 0.5 cm in diameter. The results suggest that chronic low-flow infusions provide a promising approach to therapy for CNS lesions in tissues considered to be inoperable.

Concurrent radiochemotherapy for patients with stage III non-small–cell lung cancer (NSCLC): long-term results of a phase II study

Purpose: To investigate the feasibility and activity of concurrent radiochemotherapy in patients with Stage III nonsmall-cell lung cancer (NSCLC).Materials and Methods: Forty-one patients were treated with hyperfractionated radiation therapy (HfxRT) using 1.2 Gy bid, to a total of 69.6 Gy and concurrent low-dose daily chemotherapy (CHT) consisting of 30 mg of carboplatin (CBDCA) and 30 mg of etoposide (VP-16) given Mondays to Fridays during the RT course. On Saturdays and Sundays during the RT course, CBDCA and VP-16 were both given in a daily dose of 100 mg each.Results: Median survival time was 25 months, and 3- and 5-year survival rates were 34% and 29%, respectively. Median relapse-free survival time was 22 months, and 3- and 5-year relapse-free survival rates were 32%, and 29%, respectively. Median time to local recurrence was 24 months and 3- and 5-year local recurrence-free survival rates were 41% and 38%, respectively. Median time to distant metastasis was 28 months, and 3- and 5- year distant metastasis-free survival rates were 44% and 44%, respectively. Acute high-grade (≥ 3) toxicity was mostly hematological (30%), esophageal (15%), and bronchopulmonary (12%). Late high-grade toxicity was infrequent.Conclusion: This combined radiochemotherapy regimen produced promising results and warrants further studies with more patients before testing it in a prospective randomized fashion.

In Vivo Adenovirus Vector-Mediated Transfer of the Human Thrombopoietin cDNA Maintains Platelet Levels During Radiation- and Chemotherapy-Induced Bone Marrow Suppression

Thrombopoietin (TPO, c-mpl ligand) has emerged as a major hematopoietic cytokine stimulating megakaryocyte proliferation, endomitosis, and platelet production. This study shows that a single administration of an adenovirus (Ad) vector encoding TPO (AdCMV.TPO) abrogates thrombocytopenia induced in mice by carboplatin and irradiation. Normal Balb/c mice receiving the vector had increased platelet counts peaking at 7 days and returning to baseline by day 15. Mice rendered pancytopenic with 500 rads and 1.2 mg of carboplatin had a nadir platelet count of five percent of the baseline. Mice receiving AdCMV.TPO 3 days before receiving irradiation and chemotherapy achieved a platelet nadir fourfold higher, and had significant reduction in duration of thrombocytopenia, than mice receiving the control Ad vector. Introduction of AdCMV.TPO the same day of chemotherapy and irradiation was equally effective in acceleration of platelet recovery, but administration of AdCMV.TPO 3 days after chemotherapy-radiation had little effect on platelet recovery. At 30 days after therapy bone marrow and spleen of mice treated with AdCMV.TPO were populated with a large number of polyploid megakaryocytes, but there was no evidence of circulating megakaryocytes in the liver or lungs and no pathologic bone abnormalities such as osteosclerosis or myelofibrosis. These observations suggest that an Ad vector may be an excellent delivery system to provide adequate TPO production to maintain platelet levels in circumstances associated with life-threatening thrombocytopenia.

In vivo adenovirus vector-mediated transfer of the human thrombopoietin cDNA maintains platelet levels during radiation-and chemotherapy- induced bone marrow suppression

Thrombopoietin (TPO, c-mpl ligand) has emerged as a major hematopoietic cytokine stimulating megakaryocyte proliferation, endomitosis, and platelet production. This study shows that a single administration of an adenovirus (Ad) vector encoding TPO (AdCMV.TPO) abrogates thrombocytopenia induced in mice by carboplatin and irradiation. Normal Balb/c mice receiving the vector had increased platelet counts peaking at 7 days and returning to baseline by day 15. Mice rendered pancytopenic with 500 rads and 1.2 mg of carboplatin had a nadir platelet count of five percent of the baseline. Mice receiving AdCMV.TPO 3 days before receiving irradiation and chemotherapy achieved a platelet nadir fourfold higher, and had significant reduction in duration of thrombocytopenia, than mice receiving the control Ad vector. Introduction of AdCMV.TPO the same day of chemotherapy and irradiation was equally effective in acceleration of platelet recovery, but administration of AdCMV.TPO 3 days after chemotherapy-radiation had little effect on platelet recovery. At 30 days after therapy bone marrow and spleen of mice treated with AdCMV.TPO were populated with a large number of polyploid megakaryocytes, but there was no evidence of circulating megakaryocytes in the liver or lungs and no pathologic bone abnormalities such as osteosclerosis or myelofibrosis. These observations suggest that an Ad vector may be an excellent delivery system to provide adequate TPO production to maintain platelet levels in circumstances associated with life-threatening thrombocytopenia.

Successful desensitization to carboplatin in patients with systemic hypersensitivity reactions

Carboplatin is the drug of choice for the treatment of nonresectable astrocytomas in children, but patients who are intolerant may require cranial irradiation which is associated with significant morbidity. Hypersensitivity reactions, including urticaria, bronchospasm, and hypotension, have been reported in 1% to 30% of patients treated with carboplatin. Although a few patients have attempted to continue therapy following pretreatment with antihistamines and corticosteroids, most have had recurrent severe reactions and have discontinued therapy. Two children with a history of severe systemic reactions to carboplatin were pretreated with 1 to 2 mg/kg of oral prednisolone the night before and the morning of their infusion. The initial desensitization was carried out in the intensive care unit (ICU) using doses of 1, 2.5, 5, 10, 25, and 50 mg of carboplatin infused at 1 mg/min every 15 minutes. This was well-tolerated and the remainder of the dose was infused at the standard rate of 200 mg/hr. One patient continued to receive infusions in the clinic without any difficulty. The other patient tolerated a second infusion, but during his third he experienced a systemic reaction that required discontinuation of the infusion and treatment with diphenhydramine. Desensitization was repeated in the ICU with pretreatment with prednisolone, diphenhydramine, and ranitidine, starting with 0.1 mg of carboplatin, and increasing more slowly than in the first protocol. This was well-tolerated, and subsequent infusions have been administered beginning with 1 mg doses without adverse effects. Both boys continued therapy with carboplatin; their astrocytomas are stable and they are clinically well. The use of the desensitization protocol enabled them to avoid cranial irradiation and improved their chances for normal neurologic development.