Dose Of Bleomycin Research Articles

Enhancement of cancer chemotherapy in vitro by intense ultrawideband electric field pulses

Experiments have been performed to enhance the Jurkat cell-killing effects of the cancer chemotherapy agent bleomycin using electric field pulses of 50–200kV∕cm peak electric field strength, ∼150ns duration, and nanosecond rise time. Dramatic increases in cell killing (factors of ∼1000) were observed with a low dose of bleomycin after treatment with trains of ten or more pulses at all electric field strengths tested, compared to pulse-only or drug-only treatments. Cell death occurred within 24h for treated cells, with some evidence of membrane phosphatidylserine externalization at 6h postexposure but no significant increase in caspase activity, indicating that the primary mode of cell death was not caspase-mediated apoptosis.

Chromatin condensation and differential sensitivity of mammalian and insect cells to DNA strand breaks induced by bleomycin

Bleomycin (BLM) induces DNA damage in living cells. In this report we analyzed the role of chromatin compactness in the differential response of mosquito (ATC-15) and mammalian (CHO) cells to DNA strand breaks induced by BLM. We used cells unexposed and exposed to sodium butyrate (NaB), which induces chromatin decondensation. By nucleoid sedimentation assay and digestions of nuclei with DNAse I, untreated mosquito cells (no BLM; no NaB) were shown to have more chromatin condensation than untreated CHO cells. By alkaline unwinding ATC-15 cells treated with NaB showed more BLM-induced DNA strand breaks than NaB-untreated CHO cells. The time-course of BLM-induced DNA damage to nuclear DNA was similar for NaB-untreated mammalian and insect cells, but with mosquito cells showing less DNA strand breaks, both at physiological temperatures and at 4 °C. However, when DNA repair was inhibited by low temperatures and chromatin was decondensed by NaB treatments, differences in BLM-induced DNA damage between these cells lines were no longer observed. In both cell lines, NaB did not affect BLM action on cell growth and viability. On the other hand, the low sensitivity of ATC-15 cells to BLM was reflected in their better growth efficiency. These cells exhibited a satisfactory growth at BLM doses that produced a permanent arrest of growth in CHO cells. The data suggest that mosquito cells might have linker DNAs shorter than those of mammalian cells, which would result in the observed both greater chromatin condensation and greater resistance to DNA damage induced by BLM as compared to CHO cells.

Ginkgo biloba inhibits bleomycin-induced lung fibrosis in rats

Oxidative stress has been implicated in the pathogenesis of bleomycin-induced lung fibrosis and many antioxidant agents have been studied for prevention and treatment of the disease in animals and humans. We therefore examined whether Ginkgo biloba (Gb), a flavonoid-rich antioxidant, inhibits bleomycin-induced lung fibrosis in rats. Male Spraque–Dawley rats were given a single dose of bleomycin (2.5 mg/kg, intratracheally) in pulmonary fibrosis groups and saline in controls. First dose of Gb was given a day before the bleomycin injection and continued until sacrifice. At day 14, fibrotic changes in lung were estimated to occur by Aschoft's criteria and lung hydroxyproline content. Bleomycin challenge provoked severe pulmonary fibrosis with marked increase in hydroxyproline content of lung tissue and typical histological findings, which is prevented by Gb. Hydroxyproline level was significantly higher (13.51 ± 0.87 mg/g dried tissue) in bleomycin treated rats than controls (9.2 ± 1.33), and its level was remained to the control levels (7.38 ± 0.76) in rats treated with prophylactic Gb. On the other hand, bleomycin injection significantly reduced activities of glutathione peroxidase, superoxide dismutase and catalase in lung tissue which is prevented by Gb. Also, bleomycin injection resulted in a marked increase of malondialdehyde and nirite level which is attenuated by Gb. The data suggest that Gb has a potent antioxidant activity in the model of bleomycin-induced lung fibrosis in rats, and therefore has a potent antifibrotic activity against bleomycin-induced lung fibrosis model in rats.

Effects of Ginkgo biloba on plasma oxidant injury induced by bleomycin in rats

Bleomycin is an anti-neoplastic agent and its clinical usage is limited by its toxicity, which is mostly induced by oxygen radicals. The aim of this study was to investigate the effect of Ginkgo biloba on plasma indices of oxidants induced by bleomycin in rats. Male Sprague-Dawley rats were divided into five groups: none medicated or 0.9% NaCl injected or only Ginkgo biloba (orally, 100 mg/kg per day for 14 days) or only a single dose of bleomycin (intratracheal, 2.5 U/kg) or Gingko biloba and bleomycin-treated groups. After 14 days, blood was taken before the rats were sacrificed. The plasma was removed and stored at -85 degrees C until the study day. Plasma superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and xanthine oxidase (XO) enzyme activities with malondialdehyde and nitric oxide (NO) levels were studied. The levels of malondialdehyde and NO with activity of XO were higher in plasma of bleomycin group than the other groups (P <0.05). The activities of SOD and GSH-Px were increased in the bleomycin plus Gingko biloba group in comparison with the bleomycin group (P <0.05). There was a positive correlation between malondialdehyde and NO levels in the bleomycin group (r =0.859, P <0.05). There were positive correlations between SOD and GSH-Px activities (r =0.760, P <0.05) and between XO activity and malondialdehyde level (r =0.822, P <0.05) in the bleomycin plus Gingko biloba group. In conclusion, it was thought that bleomycin induced oxidative stress can be prevented by Gingko biloba treatment via high anti-oxidant enzyme activity together with decreased radical production from XO.

DNA Strand Breaks Signal the Induction of DNA Double-Strand Break Repair in Saccharomyces cerevisiae

Genotoxic stress induces a checkpoint signaling cascade to generate a stress response. Saccharomyces cerevisiae shows an altered radiation response under different type of stress. Although the induction of repair has been implicated in enhanced survival after exposure to the challenging stress, the nature of the signal remains poorly understood. This study demonstrates that low doses of gamma radiation and bleomycin induce RAD52-dependent recombination repair pathway in the wild-type strain D-261. Prior exposure of cells to DNA-damaging agents (gamma radiation or bleomycin) equips them better for the subsequent damage caused by challenging doses. However, exposure to UV light, which does not cause strand breaks, was ineffective. This was confirmed by PFGE studies. This indicates that the strand breaks probably serve as the signal for induction of the recombination repair pathway while pyrimidine dimers do not. The nature of the induced repair was investigated by mutation scoring in special strain D-7, which showed that the induced repair is essentially error free.

Long-Term Effect of Bleomycin on Respiratory Function Tests in Pediatric Cancer Patients.

Abstract Chemotherapy and radiotherapy which are used in the management of cancer have acute and chronic adverse effects on various organs. Patients develop pulmonary damage due to mantle zone irradiation and bleomycin in the short or long-term. In this study, after the completion of treatment long-term pulmonary complications of the teatment were investigated in 30 pediatric patients (19 male, 11 female) with cancer aged between 72–229 months. Twelve of the patients used also chemotherapy in addition to 1020–3570 rad. of mantle zone irradiation (median 2177 rad.), whereas the remaining 18 had chemotherapy alone. All of the patients had completed their treatment approximately 3,8 years ago, and the total dose of bleomycin they used was 12–180 mg. (median 69,83). All of the patients underwent physical examination, and complete blood count, chest radiograph and spirometric tests to measure lung volumes were also performed. Additionally, in 20 patients single breath technique to measure the diffusing capacity for carbon monoxide was carried out. Physical examination of cardiopulmonary system revealed normal findings and none of our patients had a cardiopulmonary symptom. Chest radiograph was normal in 25 (83,3%) but it was abnormal in 5 patients. Lung volume measurements were normal in 21 (71%), but were abnormal in 9 (29%) patients. Of these 9 patients 23% had restrictive, 3% had combined and 3% had obstructive disorders. In our study, no correlation could be shown between the impaired respiratory function tests and irradiation and bleomycin doses used. In 3 (10%) out of 20 patients in whom the diffusing capacity test for carbon monoxide was performed, decreases in diffusing capacity for carbon monoxide were found. One of these patients had both high dose bleomycin (156 mg.) and mantle zone irradiation (2160 rad.), whereas the remaining 2 had low dose bleomycin (30–63 mg.) alone and received no radiotherapy. The diffusing capacity test for carbon monoxide which returns to normal values in short -term is less valuable than the measurement of lung volumes for the long-term follow-up evaluation of respiratory functions in these patients. Generally, in our late phase study (3,8 years after the completion of therapy), there was a low rate of impairment in diffusing capacity test for carbon monoxide, but the rate of impairment in lung volumes was much higher. This finding was compatible with most of the related literature. In conclusion, in pediatirc cancer patients respiratory function tests should be performed during the treatment and also after the completion of treatment in order to follow the course of pulmonary function impairment.

High Resolution Computed Tomography of Bleomycin-Induced Lung Injury in Hodgkin Lymphoma.

Bleomycin is the chemotherapeutic agent most commonly associated with pulmonary toxicity in about 4–20% of treated patients. The diagnosis of bleomycin-induced lung disease is primarily clinical and there is no true gold standart test available. In this study, we aimed to evaluate the role of high resolution computed tomography (HRCT) in monitoring patients for drug toxicity.We prospectively evaluated the HRCT scans of 18 newly diagnosed hodgkin lymphoma patients baseline, after the fourth and the eight cycle of ABVD (Adriamycin-bleomycin-vinblastine-dacarbazine) chemotherapy. The age ranges of the patients was 17–69 years (mean, 35 years). Serial PFTs and arterial blood gases were obtained in addition to imaging studies during bleomycin therapy. The parenchymal abnormalities on HRCT were grouped into different categories according to the dominant pattern and distribution of disease: diffuse alveolar damage (DAD), nonspecific interstitial pneumonitis (NSIP), bronchiolitis obliterans organizing pneumonia (BOOP), interstitial pneumonitis and fibrosis and hypersensitivity reaction. Pulmonary parenchymal abnormalities were detected on HRCT in 5 of 18 patients (27.8%). Patient details, cumulative doses of bleomycin and patterns of lung injury are presented in table. Arterial O2 pressure (p<0.01), O2 saturation (p<0.01) and carbon monoxide diffusing capacity (DLCO) (p<0.01) were decreased after bleomycin therapy compared to baseline values in 18 patients.Our results indicate that HRCT is useful in the diagnosis of bleomycin-induced lung disease by better characterization of the nature of the abnormality and assessment of extent and distribution of disease.Bleomycin-induced lung diseaseNoAgeSexDosePattern of lung injury146M234 mgBOOP230M128 mgNSIP369F210 mgNSIP426M162 mgBOOP551M256 mgNSIP

The Need for Routine Bleomycin Test Dosing in the 21st Century

To review the clinical evidence for routine use of bleomycin test dosing. English-language review articles, references from retrieved articles, case reports, and clinical trials were identified from a MEDLINE literature search (1966-July 2005). Key search terms included bleomycin, test dose, anaphylactic reactions, and hypersensitivity. Information from an unpublished E-mail survey, the manufacturer, and the Internet was also used. Early clinical trials and isolated case reports suggest that bleomycin-induced acute hypersensitivity reactions occur in 1% of patients with lymphoma and <0.5% of those with solid tumors. The reactions are mainly characterized by high-grade fever, chills, hypotension, and in a few cases, cardiovascular collapse, which can lead to death. The exact mechanism of these reactions is unclear, but is thought to be related to the release of endogenous pyrogens from the host cells. Evidence does not suggest any correlation between doses and the onset or severity of the reactions. Supportive care, including hydration, steroids, antipyretics, and antihistamines, may resolve the symptoms. However, it may not completely prevent recurrences. The incidence of acute hypersensitivity or hyperpyrexic reactions associated with bleomycin is very low, but the reaction is potentially fatal. Clinicians should monitor their patients for any signs and symptoms of acute hyperpyrexic reactions during bleomycin administration. Since the onset of the reactions can occur with any dose of bleomycin and at any time, routine test dosing does not seem to predict when drug reactions may occur.

Acute arterial occlusion after chemotherapy for testicular cancer

910 http://oncology.thelancet.com Vol 6 November 2005 A 40-year-old man who had been diagnosed with IGCCG (International Germ-Cell Cancer Collaborative Group stage II) non-seminoma of the testis and had a good outlook, had nearly completed three planned courses of 30 mg bleomycin on days 2, 9, and 16, 100 mg/m etoposide on days 1–5, and 20 mg/m cisplatin on days 1–5 every 3 weeks when he was referred to the emergency department because of severe pain in his right lower leg and a cold, pale right foot. After each course of chemotherapy he had developed cold, pale, painful feet, alternating between the left and right foot. He had never smoked and he did not have a family history of cardiovascular disease. Physical examination showed intact sensory and motor functions, but no palpable pulses of the popliteal artery and distal artery in the right leg. Angiography showed occlusion of the distal popliteal artery (figure, arrow), a filling defect in the truncus tibiofibularis artery, and collateral filling of the proximal fibularis posterior artery and proximal tibialis posterior artery. The aorta, iliacal arteries, and proximal femoral arteries were unaffected. Thrombolysis and mechanical thrombectomy were unsuccessful. Because the foot was not threatened clinically and pain had diminished, treatment with 10 mg nifedipine 3 times daily and acenocoumarol resulting in an international normalised ration of 2·0–3·0 was started, which resulted in a full recovery. Since investigations of thrombophilia showed no abnormalities, we concluded that the acute arterial occlusion was associated with the chemotherapy. The final dose of bleomycin was withheld because the toxic effects posed a potential threat to the leg. Histological assessment of the germcell tumour showed a complete remission. Given the possible life-threatening nature of chemotherapyassociated vascular side-effects in patients with a potentially curable disease, clinical signs of this nature always demand further thorough investigation, even in the absence of any risk-factors, as in our patient.

Clinical Dose-Volume Histogram Analysis in Predicting Radiation Pneumonitis in Hodgkin’s Lymphoma

Purpose/Objective: Very few studies have focused exclusively on radiation pneumonitis in Hodgkin’s Lymphoma (HL). A seminal paper from the lung cancer literature (1Graham M.V. et al.Clinical dose-volume histogram analysis for pneumonitis after 3D Treatment for non-small cell lung cancer (NSCLC).IJROBP. 1999; 45: 323-329Google Scholar) predicts for a 13% incidence of grade 2 or greater radiation pneumonitis (RP) if the V20 (volume of lung receiving 20Gy) is 32–40%, increasing to 36% for V20 >40%. Moreover if the mean lung dose (MLD) is >20Gy, the rate of RP was 24%. The objectives of this study were firstly to quantify the incidence of RP in a modern Hodgkin’s Lymphoma cohort; and secondly to attempt to identify a clinically relevant parameter to determine the risk of RP in lymphoma patients. Materials/Methods: From January 2003 to February 2005, 65 consecutive HL patients receiving radical mediastinal radiotherapy (RT) were retrospectively reviewed. Clinical parameters collected included disease stage, site and extent of nodal involvement, smoking status, respiratory co-morbidities, and pulmonary function tests. Treatment parameters including RT dose, field dimensions, RT induced esophagitis, chemotherapy regime (primary and/or salvage), number of cycles, and cumulative bleomycin dosage were reviewed. Results: There were 65 patients (37 females, 28 males) median age 29 years (range 11.9 – 63.1 years). Stage of disease was: IA-IB 11%, IIA 49%, IIB 29%, IIIA-B 8%, IVB 3%. ABVD chemotherapy was given in 86%, with a median of 6 cycles. Post-chemotherapy RT was given in 58 pts, and 7 had RT post autologous stem cell transplant. Median cumulative bleomycin dose was 162 units. Three patients developed bleomycin related pulmonary toxicity, with 2 additional suspected cases. RT dose was 35Gy/20 fractions in 74% (range 15–40Gy). The median V20 was 31.1% (range 0–53%) and mean lung dose (MLD) was 12.4Gy (range 2.9–19.6Gy). No obvious relationship was found between RP and any of the clinical or treatment parameters tested. Actuarial survival at 2 years is 100% with a median follow up of 1.7 years. Two cases of RP occurred at 1.5 and 2.7 months post RT, for an overall incidence of 3%. Both were SWOG grade 2 in severity, occurred in females who received 6 cycles of ABVD, and who experienced progressive disease and underwent RT (dose 35Gy/20 fractions) in the post transplant setting. The first case was in an ex-smoker with IA disease and a 9cm initial mediastinal mass who had developed bleomycin toxicity with a restrictive lung defect (DLCO of 48% predicted) prior to RT. The other case occurred in a non-smoker with IIIB disease and a 12cm mediastinal mass. Both responded clinically to a tapering schedule of prednisone. The RP cases with V20 values of 47% and 41% respectively fell into the highest quartile (range 37–53%), corresponding to a risk of 2/18 (11% among cases in the 4th quartile). Their mean lung doses of 17.6Gy and 16.4Gy were also in the highest quartile (range 14.8–19.6Gy). Conclusions: Despite relatively high V20 values in this cohort, the incidence of radiation pneumonitis was lower than predicted based upon the lung cancer literature. We report that a V20 value of 37% or greater is associated with a RP incidence of 11%, suggesting that a higher V20 cutoff may apply to HL patients. Moreover our study found that a MLD of >15Gy, in comparison to >20Gy in lung cancer, may be used to determine the risk of RP in lymphoma patients, which may in part reflect the lower absolute prescribed RT dose in this setting.

Preventive effect of melatonin on bleomycin‐induced lung fibrosis in rats

Oxidative stress has an important role in the pathogenesis of idiopathic pulmonary fibrosis. Melatonin has direct and indirect free radical-detoxifying activity. The present study investigated whether melatonin treatment attenuates bleomycin-induced lung fibrosis in rats. A group of rats was given one dose of bleomycin while the control animals were given saline. The first dose of melatonin (4 mg/kg/day) was given 2 days before the bleomycin injection. At day 14, fibrotic changes were evaluated using Aschoft's criteria and lung hydroxyproline content. Bleomycin produced a 2.7-fold rise in the fibrosis score that was decreased 65% by melatonin (P < 0.05) and a 1.4-fold increase in hydroxyproline content which was completely prevented by melatonin. Protein carbonyl and thiobarbituric acid reactive substances levels, which were significantly elevated in the bleomycin treated rats, were significantly attenuated by melatonin. Bleomycin administration significantly reduced the activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in lung tissue. The reduction in CAT activity was prevented by melatonin but SOD and GSH-Px were not influenced. These results revealed that melatonin may prevent the development of bleomycin-induced lung fibrosis via the repression of protein and lipid peroxidation.

Successful application of targeted electrochemotherapy using novel flexible electrodes and low dose bleomycin to solid tumours

Electroporation is the application of very brief electric pulses to cells or tissues to render the cell membranes transiently and reversibly permeable, facilitating cellular uptake of otherwise impermeant molecules. Flexible electrode arrays were developed which may be used with endoscopic and laparoscopic devices for delivery of therapeutic electroporation. Their efficacy in enhancing the delivery of bleomycin, an impermeant drug, was assessed in vitro and in vivo in both human and murine cancer cell lines, and growing tumours (xenografts). These flexible electrodes consistently and predictably deliver the permeabilising electric pulses requisite for in vivo electroporation, and would be suitable for electrochemotherapy of endoluminal tumours when incorporated into an endoscopic delivery system.

Unrelated bone marrow transplantation for high‐risk anaplastic large cell lymphoma in pediatric patients: a single center case series

The use of allogeneic stem cell transplantation in NHL patients is not yet clearly defined, especially in children and adolescents, but this option offers the advantages of a tumor-free graft and the possible induction of a graft-vs.-tumor effect. We report the results of four consecutive pediatric patients affected by anaplastic large cell lymphoma (ALCL) and treated with allogeneic stem cell transplantation from an unrelated donor. The conditioning regimen was based on total body irradiation given in association with etoposide in three patients, and with thiotepa and cyclophoshamide in one patient. Graft-vs.-host disease (GVHD) prophylaxis consisted of cyclosporin, a short course of methotrexate and rabbit antithymocyte globulin. All patients had rapid engraftment within 3-4 wk for neutrophils and platelets, and achieved a stable full donor chimerism that has been maintained to the last follow-up visit. One patient later developed a restrictive pneumonopathy. This patient had been heavily pretreated during the course of the disease having suffered four relapses and had received a cumulative dose of bleomycin of 160 mg/m(2). After a follow-up of 11-42 months, all patients are alive in complete hematological and molecular remission; and three of them without any chronic GVHD. The increasing number of volunteer bone marrow donors and the reduced toxicity of unrelated stem cell transplantation, especially in children, make this therapeutic option worth more extensive investigation in the treatment of high-risk failure ALCL, although more data is needed to evaluate the long-term benefits. In this regard, the presence of factors predictive of worst outcome such as an early relapse (within 12 months from diagnosis), a refractory or relapsing ALCL and the persistent detection on blood or bone marrow of nucleophosmin-anaplastic lymphoma kinase protein (NPM-ALK) transcript may help select the patients eligible to allogeneic related or unrelated stem cell transplantation.

Genetic variation in the bleomycin hydrolase gene and bleomycin-induced pulmonary toxicity in germ cell cancer patients

Use of bleomycin as a cytotoxic agent is limited by its pulmonary toxicity. Bleomycin is mainly excreted by the kidneys, but can also be inactivated by bleomycin hydrolase (BMH). An 1450A>G polymorphic site in the BMH gene results in an amino acid substitution in the C-terminal domain of the protein. Deletion of this domain, including the polymorphic site, reduces enzymatic activity. We investigated the relation between the BMH genotype and the risk of bleomycin-induced pneumonitis (BIP). From male germ cell cancer patients, treated with bleomycin-containing chemotherapy at the University Hospital Groningen, The Netherlands, between 1977 and 2003, data were collected on age, cumulative bleomycin dose, pretreatment creatinine clearance, pulmonary metastases, lung function parameters, and occurrence of BIP. BIP was defined as: death due to BIP, or presence of clinical and/or radiographic signs of BIP during or following treatment. Polymerase chain reaction and restriction fragment length polymorphism were used to determine the BMH genotype. BIP developed in 38 (11%) of 340 patients; four of these cases were fatal. BMH genotype distribution did not differ between patients with and those without BIP. Patients with BIP were older and had a lower pretreatment creatinine clearance. Changes in pulmonary function tests were similar in patients with different genotypes. The BMH genotype was not associated with the development of BIP nor with changes in pulmonary function tests. Since renal function is important for bleomycin pharmacokinetics, variations in renal clearance may have obscured significant effects of the BMH genotype.

Pulmonary epithelial permeability in patients treated with bleomycin containing chemotherapy detected by technetium-99m diethylene triamine penta-acetic acid aerosol (99mTc-DTPA) scintigraphy

To evaluate pulmonary epithelial permeability using 99mTc-DTPA scintigraphy in patients treated with bleomycin-containing regimens. Twelve non-smoking chemotherapy-naïve patients with no clinical or radiological evidence of pulmonary disease and treated with bleomycin-containing chemotherapy were tested with 99mTc-DTPA scintigraphy before the first cycle and every 3 weeks until the third month after the end of chemotherapy (total cumulative dose of bleomycin 347.9 mg). Pretreatment values (T1/2 74.93 minutes) of 99mTc-DTPA scintigraphy were significantly higher than those obtained after the total dose of bleomycin (T1/2 51.00 minutes) (p < 0.001). This difference was more important in the later evaluations especially, on the third week and third month measures after discontinuing treatment (p < 0.001). All the tests of Within-Subjects Effects were significant (p < 0.001). Comparing pretreatment and post-treatment scintigraphies the mean T1/2 99mTc-DTPA values decreased as the bleomycin dose increased. We conclude that cumulative bleomycin doses are related to increased pulmonary epithelial permeability at a dose of 256.5 mg. However, whether this is related to clinical toxicity is uncertain and large, multi-center prospective studies are needed.

G-CSF Administration Increases Pulmonary Toxicity for Hodgkin's Disease Patients Treated with Bleomycin-Containing Chemotherapy.

Background: In Hodgkin's Disease (HD), G-CSF has been used to maintain maximum dose intensity by avoiding neutropenia and treatment delays. Pre-clinical data and anecdotal reports have shown an association between G-CSF administration and bleomycin pulmonary toxicity (BPT). This complication may cause access morbidity and have a detrimental impact on survival in this otherwise good prognosis population. We embarked on a retrospective analysis to determine if G-CSF increased the incidence of this complication or had an impact on outcomes.Methods: We reviewed all patients managed for HD at Mayo Clinic, Rochester, from January 1986 to February 2003. BPT was defined by the presence of pulmonary symptoms, bilateral interstitial infiltrates, and no evidence for an infectious etiology. Patients who received G-CSF support with one or more of their bleomycin-containing chemotherapy cycles were considered as being treated with G-CSF.Results: A retrospective review identified 141 patients with HD treated with a bleomycin-containing regimen. The mean age of patients at diagnosis was 34 years. Fifty four percent were males. The histology was nodular sclerosing in 85%. The Hasenclever index was 0 in 15%, 1 in 35%, 2 in 24%, 3 in 16%, 4 in 9%, and ≥ 5 in 1%. The G-CSF and non G-CSF groups were balanced for poor prognosis risk factors including Hasenclever index. Frontline chemotherapy included ABVD in 57%, MOPP-ABV(D) in 33%, COPP-ABV in 8%, BEACOPP in 3%, and Stanford V in 2%. Forty one percent of patients received radiation. The 5-year overall survival (OS) and progression free survival (PFS) for all patients were 87% and 79% respectively. G-CSF was administered to 52% (74/141) of patients. BPT occurred in 18% of patients (25/141). A higher rate of BPT was observed in patients receiving G-CSF, 26% (19/74) versus 9% (6/67) in non G-CSF patients (p=0.0141). In this population, G-CSF administration was the only factor associated with an increased risk of BPT. There was no difference between the two groups for BPT associated risk factors including radiation, bleomycin dose, renal insufficiency, smoking history, and underlying lung disease. Additionally these risk factors showed no correlation with the development of BPT. The mortality from BPT was 4.2% (6/141) in all patients and 24% (6/25) in patients who developed the pulmonary syndrome. Of the 6 patients who died acutely, 83% (5/6) received G-CSF. CR rates were equal between the G-CSF and non G-CSF groups at 92% and 94% respectively. Five year OS and PFS were equal between the G-CSF and non G-CSF groups at 82% versus 89% (p=0.473) and 74% versus 84% (p=0.152) respectively.Conclusion: G-CSF administration increases the incidence of pulmonary toxicity in HD patients treated with bleomycin based chemotherapy. The major impact was on treatment related morbidity as 5-year OS and PFS were equal between the G-CSF and non G-CSF groups.

Bleomycin Pulmonary Toxicity Does Impact on Hodgkin's Disease Outcome.

Background: Bleomycin-containing chemotherapy regimens have become the mainstay of treatment in Hodgkin's Disease (HD). The risk of bleomycin pulmonary toxicity (BPT) ranges from 0–46% and mortality rates range from 0–27%. Although there is no excepted standard treatment for BPT, corticosteroid treatment, withholding bleomycin from subsequent chemotherapy, and proceeding with a non-bleomycin containing regimen is the most common approach. We reviewed our experience to better delineate outcome and appropriate treatment in these patients.Methods: We reviewed all patients managed for HD at Mayo Clinic, Rochester, from January 1986 to February 2003. BPT was defined by the presence of pulmonary symptoms, bilateral interstitial infiltrates, and no evidence for an infectious etiology.Results: A retrospective review identified 141 patients with HD treated with a bleomycin-containing regimen. The mean age of patients at diagnosis was 34 years. Fifty four percent were males. The histology was nodular sclerosing in 85%. The Hasenclever index was 0 in 15%, 1 in 35%, 2 in 24%, 3 in 16%, 4 in 9%, and >5 in 1%. Frontline chemotherapy included ABVD in 57%, MOPP-ABV(D) in 33%, COPP-ABV in 8%, BEACOPP in 3%, and Stanford V in 2%. Forty one percent of patients received radiation. The 5-year overall survival (OS) and progression free survival (PFS) for all patients were 87% and 79% respectively. BPT was observed in 18% of patients (25/141). There was a significant decrease in OS, 63% in patients with BPT versus 90% in non-BPT patients at 5 years (p=0.0013). The mortality from BPT was 4.2% (6/141) in all patients and 24% (6/25) in patients who developed the pulmonary syndrome. These 6 patients all died within 9 months of their HD diagnosis from BPT. The Hasenclever index was 3 or less in 5 of these 6 patients. CR rates were equal at 91% and 93% in BPT and non-BPT patients respectively (p=0.299). Twenty two percent (31/141) of patients, either symptomatic or asymptomatic, had bleomycin omitted at any time from their regimen with no difference in OS or PFS, 83% versus 88% (p=0.369) and 82% versus 78% (p=0.853) respectively. The mean bleomycin dose was 84 mg/m2 (range of 20–180 mg/m2). Bleomycin dose had no impact on OS or PFS. In BPT patients subsequent non-bleomycin therapy included AVD 44%, MOPP-AV 31%, or no further chemotherapy 25%. The five-year OS was equal between the AVD and MOPP-AV groups at 91%. However in patients who received no further chemotherapy 5-year OS was 30% (p=0.0001).Conclusion: Bleomycin pulmonary toxicity (BPT) results in a significant decrease in OS survival at 5 years in patients being treated for Hodgkin's Disease. In patients who do not die acutely from pulmonary toxicity both OS and PFS appear equal despite the omission of bleomycin.

Sonographically guided small-bore chest tubes and sonographic monitoring for rapid sclerotherapy of recurrent malignant pleural effusions.

To evaluate the role of sonographically guided small-bore chest catheters and sonographically based monitoring of fluid evacuation in rapid sclerotherapy of malignant pleural effusions. In 50 patients with recurrent malignant pleural effusions, a 9F catheter was inserted into the pleural space under sonographic guidance. When sonography documented complete fluid evacuation, bleomycin (0.75 mg/kg) was injected via the tube. Fluid drainage was monitored for 12 hours; if fluid output was less than 100 mL, the pleural catheter was removed; otherwise, a second dose of bleomycin was administered after 24 hours. If loculations or fluid reaccumulations due to tube malfunctioning were detected, they were evacuated by sonographically guided thoracentesis, and bleomycin (1.5 mg/100 mL of fluid) was injected through the thoracentesis needle. All patients were monitored for fluid recurrence with thoracic sonography. Twenty-nine patients received 1 dose of bleomycin, and 21 received 2 doses. In 11 patients with residual loculations, sonographically guided thoracentesis was performed, and bleomycin was injected into the loculations. In 29 patients, pleurodesis was completed within 24 hours; in 21, it was completed within 48 hours. The 30-day response was 84%; the long-term response was 60%. No complications or serious side effects were observed. Rapid pleurodesis can be accomplished within 24 to 48 hours, with good short- and long-term responses. Thoracic sonography plays a pivotal role. It guides placement of the pleural catheter and is valuable in the monitoring of fluid evacuation for determining the right time for sclerosing agent administration and in the detection and treatment of loculations or residual pleural fluid due to tube malfunctioning.

Use of pharmacogenomics in predicting bleomycin-induced pulmonary toxicity in testicular cancer patients

4531 Background:Use of bleomycin, important for treatment efficacy in testicular cancer, is limited by its pulmonary toxicity. Bleomycin is mainly excreted by the kidneys, but can also be inactivated by bleomycin hydrolase (BLH). An A1450G polymorphic site in the BLH gene results in an amino acid substitution in the C-terminal domain of the protein. Deletion of this domain reduces enzymatic activity. We investigated whether the homozygote polymorphic BLH genotype increases sensitivity to bleomycin and risk of bleomycin-induced pulmonary toxicity (BIP) in testicular cancer patients. METHODS: For all patients with testicular cancer treated with bleomycin combination chemotherapy at our institution between 1977 and 2003, data were collected on age, pretreatment creatinine clearance, and occurrence of BIP, which was defined as: death due to BIP, or clinical and/or radiographic signs of BIP either following treatment or during treatment leading to cessation of bleomycin administration. PCR and restriction fragment length polymorphism were used to determine A/A (wild-type), A/G, and G/G (two polymorphic alleles, possibly reduced enzymatic activity)genotypes. RESULTS: Both genotype and clinical data were available for 246 patients (60% of cohort; median age 29 yrs, range 16-64; median cumulative bleomycin dose 270 mg, range 60-360; median pretreatment creatinine clearance 122 ml/min, range 64-202), of whom 27 (11%) had BIP. A/A, A/G, and G/G genotype frequencies were 41.9%, 48.4% and 9.7%. G/G genotype distribution did not differ between patients with and without BIP (7.4% versus 10.0%; odds-ratio G/G versus A/A genotype: 0.53, 95% confidence interval 0.11-2.51). Patients with BIP had a lower creatinine clearance. CONCLUSIONS: Compared with patients without BIP, patients with BIP were not more likely to have a G/G than an A/A genotype. However, effects of BLH genotype may become visible in patients with markedly reduced creatinine clearance. Supported by grants from the Dutch Cancer Society and the University Hospital Groningen. No significant financial relationships to disclose.

Bleomycin lung toxicity detected by technetium-99m diethylene triamine penta-acetic acid aerosol (99mTc-DTPA) scintigraphy

4600 Background: To investigate lung toxicity in patients treated with chemotherapy containing bleomycin using 99mTc-DTPA scintigraphy Methods: Twelve non-smokers chemo-naïve patients (10 testis cancer, 1 ovary germ cell tumor, 1 Hodgkin's Disease) with no clinical or radiological evidence of pulmonary disease treated with bleomycin-based chemotherapy were tested with 99mTc-DTPA scintigraphy and pulmonary function tests before the first cycle and every 3 weeks until the third month after the end of chemotherapy (bleomycin's total cumulative dose 347.9 mg). Results: The descriptive statistics for the tests is shown in the table below. The pretreatment values of scintigraphy (T1/2 74.93 minutes) were significantly higher than those obtained after total dose bleomycin (T1/2 50.38 minutes) (P<0.001). Comparing pretreatment and post-treatment scintigraphies, the mean values decreased mainly after 256.5 mg of bleomycin's total dose. There were no difference in diffusing lung carbon monoxide (DLCO), Forced vital capacity (FVC), forced inspiratory volume at 1st second (FEV1), total lung capacity (TLC), and residual volume (RV). Conclusions: We conclude that cumulative bleomycin doses are related to increasing lung toxicity in every cycle of chemotherapy and that 99mTc-DTPA scintigraphy is able to quantify pulmonary toxicity even before the development of clinical signs and earlier than the pulmonary function tests or the CO diffusing. No significant financial relationships to disclose.