Infusion Of Adriamycin Research Articles

Acute Effects of a Single Dose of Chemotherapeutic Agents Delivered to Swine through the Intraosseous Route

AbstractAbstract 4341 Introduction.The development and complexity associated with polychemotherapeutic protocols has increased the importance and the need for reliable vascular access. This study was designed to determine the safety of 3 different chemotherapeutic drugs delivered via the intraosseous tibial route in a swine model. Methods.Each of 4 groups of immature Yorkshire swine received different chemotherapeutic protocols which consisted of infusing known vesicants: Group 1-Mitomycin (n=6); Group 2-CHOP (comprising cyclophosphamide, doxorubicine hydrochloride, Oncovin, and prednisolone, (n=6); Group 3-Adriamycin standard dose (n=6); and Group 4-Adriamycin at different doses (n=3). For Groups 1–3, we investigated the effects of the standard maximum-allowed dose of drug delivered via the IO tibial route in swine (using the EZ-IO system, Vidacare Corporation, Shavano Park, TX). For Group 4, in one animal each, we investigated the effects of Adriamycin delivered via the IO tibial route at double maximum dose, maximum dose without a post-drug flush, and drug delivered with increased infusion pressure. As a control in all animals, normal saline was infused through the contra-lateral tibia. Animals were monitored for 7 days, followed by necropsy and histological analysis of the infused bone. Results.In the Mitomycin group, similar effects on marrow cells and bone spicules between the saline infused controls and the drug infused histology samples in half the group (n=3) were detected. In the other half of the group (n=3) there was a trend toward more loss of marrow cells and bone spicules in the drug infused limb. There were no differences in morphological changes between the drug infused limb and the saline control limb (p=.61). The CHOP infusion showed a trend toward loss of marrow cells, bone spicules, and some focal hemorrhage in the histology samples from the drug infused limb. Marrow cell loss was greater in the drug-infused limb (p<0.05). Adriamycin infusion caused significant morphological changes in the drug-infused limb (p<.05). For the Adriamycin/no flush protocol there was a reduction in marrow cells and loss of bone spicules in a focused area in the drug infused limb. Double-dose Adriamycin seemed to reduce marrow cells and bone spicules to the low normal range. Adriamycin high-pressure drug delivery caused a slight reduction of marrow cells and bone spicules. However, there were changes in tissue morphology at the injection site indicated by loss of bone marrow cells, and/or bone spicules, and focal hemorrhage represented by blood in the field. All changes detected were considered mild and not unexpected. There were no cases of osteomyelitis, significant necrosis of bone, or fat necrosis detected in the marrow samples. Conclusions.In this limited study, it appears that the IO route of infusing chemotherapy agents could be a safe alternative to IV infusion. Longer term studies are needed to more fully characterize the safety of IO delivery of chemotherapeutic agents. Disclosures:Hoskins:Vidacare Corporation: Research Funding. Philbeck:Vidacare Corporation: Employment. Miller:Vidacare Corporation: Employment, Equity Ownership. Kramer:Vidacare Corporation: Consultancy, Patents & Royalties, Research Funding.

Repeated Doses of Adriamycin Infused In Swine through the Intraosseous Route In the Same Bone May Result In Osteomyelitis

AbstractAbstract 4343 Introduction:Intraosseous (IO) vascular access has been shown to be a safe and effective alternative to central venous lines for the use of emergency drugs, but its utility for the delivery of chemotherapy has not been determined. A 2007 study detected marginal changes in bone morphology after delivery of single doses of a variety of vesicant chemotherapeutic agents. However, Adriamycin in the previous study involved only a single dose and examined only acute effects to bone marrow morphology. This study was designed to determine the safety of multiple rounds of Adriamycin delivery via the IO route repeatedly in the same bone in a swine model. Methods:An IO needle (EZ IO, Vidacare Corporation, Shavano Park, TX) was aseptically placed into both tibias of 14 Yorkshire swine. On 3 occasions, 21 days apart, a dose of Adriamycin (60mg/m2) was delivered over 15 minutes followed by 2 minutes of saline infusion through a proximal tibia. For control purposes, the contra-lateral tibia received saline infusions. A radiologist reviewed films pre and post drug delivery. Bone samples were harvested 30 days post last drug delivery. Paired t-tests were used to compare changes between treated and saline controls. Two pathologists separately reviewed the slides of 14 animals. One pathologist scored the slides and both pathologists' comments were recorded in a masked fashion without knowledge of treatment groups, according to animal number and left or right limb. A one-way analysis of variance was used to evaluate the treatment effect (Adriamycin vs. saline control). A two-sided alpha level of 0.05 was used to define statistical significance. Results:After the 2nd infusion, visual examination revealed small dime-sized lesions over the injection site in 4 animals. After the third injection almost all animals developed some form of leg swelling and limping. Radiologically, osteomyelitis was detected in 6 animals (43%), 2 of which had fractures to the proximal head of the tibia. An additional 4 animals had fractures to the proximal head of the tibia without osteomyelitis. Of the 10 affected animals, half the complications occurred after the second Adriamycin dose and half occurred after the third dose. Histologically, there was no statistical significance for the parameters of marrow cell loss (p=0.85), bone spicule loss (p=1.0), blood in the field (p=0.20), or necrosis (p=0.33) between drug infused limbs and their paired controls. Matrix formation and scar formation were significantly greater in the drug limbs when compared to the saline control limbs (p<0.001 and p<0.05, respectively). There was no statistical significance for the parameters of hypocellularity (p=0.77), marrow degeneration (p=0.33), or blood (p=0.33) comparing drug limb to control limb. Severity of necrosis (p= 0.001) and fibrosis (p=0.001) formation were significantly higher for the drug limb compared to the control limb. Summary and Conclusions:Results suggest the repeated doses of Adriamycin in the same bone led to formation of osteomyelitis in 6 of 14. Two of the 6 swine had fracture confirmed at study end; 4 other pigs fracture were without signs of osteomyelitis while there was no evidence of osteomyelitis in saline-infused bones. The Adriamycin infusion in the same bone caused a significant increase in matrix and scar formation in histological samples taken from the drug limb compared to the saline control limb. In addition, there was a significant increase in necrosis and fibrosis in the drug infused limb. On the long-term evaluation, these increases suggest that Adriamycin has some direct effect on inducing bone pathology. Additionally, these complications may have been exacerbated by additional factors—including hurricane evacuation. A number of recommendations have been given to address these issues. The most important considerations could be the alternation of infusion limbs during drug delivery and increased post flush volumes. Disclosures:Hoskins:Vidacare Corporation: Research Funding. Philbeck:Vidacare Corporation: Employment. Miller:Vidacare Corporation: Employment, Equity Ownership. Kramer:Vidacare Corporation: Consultancy, Patents & Royalties, Research Funding.

Acute localized exanthematous pustulosis induced by docetaxel

To the Editor: A 44-year-old woman who was receiving chemotherapy after surgery for breast cancer complained of symmetric pustular skin lesions on an erythematous background on both cheeks (Fig 1). The lesions developed abruptly 2 days after the first infusion of docetaxel which began after four cycles of chemotherapy composed of adriamycin and cyclophophamide. The last infusion of adriamycin and cyclophophamide was 3 weeks earlier, and no medications were administered between the chemotherapies.

Leukocyte 8-oxo-7,8-dihydro-2′-deoxyguanosine and comet assay in epirubicin-treated patients

Epirubicin fights cancer through topoisomerase II inhibition, hence producing DNA strand breaks that finally lead to cell apoptosis. But anthracyclines produce free radicals that may explain their adverse effects. Dexrazoxane—an iron chelator—was proven to decrease free radical production and anthracycline cardiotoxicity.In this article, we report the concentrations of cellular 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dGuo) relative to 2′-deoxyguanosine (dGuo), and comet assay results from a study including 20 cancer patients treated with epirubicin. Plasma concentrations of vitamins A, E, C and carotenoids are also reported. All data were obtained before and immediately after epirubicin infusion. The ratios of 8-Oxo-dGuo to dGuo were measured in leukocyte DNA by HPLC-coulometry after NaI extraction of nucleic acids. Vitamins A and E and carotenoids were measured by HPLC-spectrophotometry. Vitamin C was measured by HPLC-spectrofluorimetry.Median 8-oxo-dGuo/dGuo ratios increased significantly from 0.34 to 0.48 lesions per 100,000 bases while per cent of tail DNA increased from 3.47 to 3.94 after chemotherapy 8-Oxo-dGuo/dGuo and per cent of tail DNA medians remained in the normal range. Only vitamin C decreased significantly from 55.4 to 50.3 μM Decreases in vitamins A, E, lutein and zeaxanthin were not significant, but concentrations were below the lower limit of the normal range both before and after chemotherapy. Only the correlation between comet assay results and vitamin C concentrations was significant ( ).This study shows that cellular DNA is damaged by epirubicin-generated free radicals which produce the mutagenic modified base 8-oxo-dGuo and are responsible for strand breaks. However, strand breaks are created not only by free radicals but also by topoisomerase II inhibition. In a previous study we did not find any significant change in urinary 8-oxo-dGuo excretion after adriamycin treatment. However, 8-oxo-dGuo may have increased at the end of urine collection as DNA repair and subsequent kidney elimination are relatively slow processes. In another study, authors used GC-MS to detect 8-oxo-dGuo in DNA and did not find any change after prolonged adriamycin infusion. Reasons for these apparent discrepancies are discussed.

Hepatic artery infusion of adriamycin combined with hemoperfusion in dogs

Hepatic artery infusion of adriamycin combined with hemoperfusion in dogs

Rapid-onset endothelial dysfunction with adriamycin: evidence for a dysfunctional nitric oxide synthase.

Adriamycin (ADR) is a commonly used chemotherapeutic agent that is believed to exert its effects through the generation of oxygen free radicals. We hypothesized that administration of a single dose of ADR results in endothelial nitric oxide synthase (eNOS)-dependent generation of superoxide (O2*-) and acute endothelial dysfunction. A single dose of ADR (10 mg/kg i.v.) administered to rabbits resulted in rapid attenuation of agonist-dependent responses to acetylcholine and calcium ionophore (A23187). In vitro exposure of ring segments to ADR for < 30 min resulted in O2*- generation measured by electron spin resonance (ESR) with the spin trap segments 5-tert-butoxycarbonyl-5-methyl-1-pyrroline N-oxide (BMPO) that was abolished by endothelial denudation and incubation with diphenyliodonium (DPI) (10 microM) but not L-NMMA (10 microM). Brachial artery flow-mediated dilation (FMD) in patients undergoing chemotherapy with ADR was markedly attenuated after a single dose of ADR (6.5 +/- 1.0 to 2.5 +/- 1.1% (p = 0.0004, time to end of infusion 27 +/- 8 min) while endothelial-independent dilatation with nitroglycerin was unchanged (16.3 +/- 3.1 and 14.33 +/- 2.1% respectively, p = 0.36). Serum nitrite and nitrate concentrations fell from 50 +/- 6 micromol/l pre-ADR to 33 +/- 6 micromol/l post-ADR infusion (p = 0.0005) while serum concentrations of CD141 thrombomodulin and von Willebrand factor (vWF) activity remained unchanged after ADR infusion (36 +/- 13 to 52 +/- 22% ng/ml versus 3.25 +/- 0.98 to 3.01 +/- 0.91%, respectively, p = NS for pre versus post for both). Doppler indices of diastolic function (IVRT, DT and E/A ratios) were not altered in response to ADR. In conclusion, ADR administration results in rapid depletion of systemic NO* levels and attenuation of agonist-dependent responses in rabbits and flow-mediated dilation in the brachial artery of humans. ESR measurements in rabbit ring suggest an endothelial origin for radical production via flavin-containing oxido-reductases such as eNOS or NADPH cytochrome P450 reductase. These findings may have implications for cardiovascular complications noted with ADR.

Efficacy of Pre- and Postoperative Chemotherapy in Patients with Osteosarcoma of the Extremities.

We evaluated the treatment efficacy including survival and recurrence, and factors associated with recurrence in osteosarcoma patients treated with preoperative chemotherapy, surgery, and adjuvant chemotherapy. Forty nine patients with osteosarcoma were treated with preoperative chemotherapy with intra-arterial cisplatin and adriamycin infusion for 3 cycles, followed by surgery. According to the pathologic response, if tumor was necrotized more than 90%, the same adjuvant chemotherapy was reintroduced for 3 cycles, and if the response was not enough, then the salvage regimen was introduced. Plain chest film and chest CT scan were taken monthly and every 3 months, respectively. When tumor recurred, the metastasectomy was performed whenever possible. Forty three patients were evaluable with amedian follow up of 53 months. Five-year disease-free and overallsurvival rate was 47.0% and 66.9%, respectively. The recurrence was observed in 22 patients (51.2%) with median time of 12.5 months. Baseline alkaline phosphatase (ALP) was the only significant factor for recurrence (p=0.03) and the patients with the possibility of metastasectomy recurrence showed higher post-relapse survival compared to other treatment modalities (26 momths vs 5~12 months). These results indicates that pre- and postoperative chemotherapy with intra-arterial cisplatin and adriamycin infusion showed comparable treatment efficacy and acceptable toxicities.

Acute endothelial dysfunction with systemic adriamycin infusion Glenn Hirsch, Michael Schmidt, Robert Brook, Melvyn Rubenfire, Anne Schott, Zhenguo Han, Sanjay Rajagopalan. Section of Vascular Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI

Acute endothelial dysfunction with systemic adriamycin infusion Glenn Hirsch, Michael Schmidt, Robert Brook, Melvyn Rubenfire, Anne Schott, Zhenguo Han, Sanjay Rajagopalan. Section of Vascular Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI

Intrahepatic chemoembolization in unresectable pediatric liver malignancies

To determine the effectiveness of a new multidisciplinary approach using neoadjuvant intrahepatic chemoembolization (IHCE) and liver transplant (OLTx) in patients with unresectable hepatic tumors who have failed systemic chemotherapy. From November 1989 to April 1998, 14 children (2-15 years old) were treated with 50 courses of intra-arterial chemotherapy. Baseline and post-treatment contrast-enhanced CT and alpha-fetoprotein levels were performed. Seven had hepatoblastoma, and 7 had hepatocellular carcinoma (1 fibrolamellar variant). All patients had subselective hepatic angiography and infusion of cisplatin and/or adriamycin (36 courses were followed by gelfoam embolization). The procedure was repeated every 3-4 weeks based on hepatic function and patency of the hepatic artery. Six of 14 children received orthotopic liver transplants (31 courses of IHC). Pretransplant, 3 of 6 showed a significant decrease in alpha-fetoprotein, while only 1 demonstrated a significant further reduction in tumor size). Three of 6 patients are disease free at this time. Three of 6 patients died of metastatic tumor 6, 38, and 58 months, respectively post-transplant. One of 14 is currently undergoing treatment, has demonstrated a positive response, and is awaiting OLTx. Three of 14 withdrew from the program and died. Four of 14 patients developed an increase in tumor size, developed metastatic disease, and were not transplant candidates. Two hepatic arteries thrombosed, and one child had a small sealed-off gastric ulcer as complications of intrahepatic chemoembolization. The results of intrahepatic chemoembolization are promising and suggest that some children who do not respond to systemic therapy can be eventually cured by a combination of intrahepatic chemoembolization orthotopic liver transplant. Alpha-fetoprotein and cross-sectional imaging appear to be complementary in evaluating tumor response. IHCE does not appear to convert an anatomically unresectable lesion to a candidate for partial hepatectomy.

Continuous antegrade infusion of adriamycin as adjuvant therapy for upper tract urothelial malignancies

Objectives. To evaluate the feasibility, efficacy, and toxicity of antegrade chemotherapy delivered continuously as adjuvant treatment for patients with upper tract transitional cell carcinoma. Methods. During a 6-year interval, 12 patients with upper tract transitional cell malignancies underwent continuous antegrade intraluminal infusion chemotherapy (CAIIC) with adriamycin. After placement of percutaneous access and surgical treatment of the primary lesion, patients received 5-day cycles of CAIIC. Patients received between two and four treatment cycles at 2-week intervals. After therapy, patients with no evidence of residual disease were then monitored long-term with retrograde pyelography and upper tract cytology. Results. Twelve patients underwent a total of 35 5-day cycles of CAIIC. No patient experienced hematologic and/or local/regional toxicity during or after drug infusion. Three patients were treated for upper tract carcinoma in situ, and 9 patients had discrete exophytic tumors. Two patients died (treatment unrelated) before a final assessment of therapeutic outcome, leaving 10 patients available for evaluation of the therapeutic response. One patient with carcinoma in situ and 5 of 7 patients with discrete upper tract tumors remained disease free after surgery and adjuvant therapy. Both patients with discrete tumors in whom therapy failed had residual gross disease after primary surgical treatment. Conclusions. CAIIC using adriamycin was well tolerated for periods of up to 5 days over multiple cycles. Early data suggest a limited efficacy in treating patients with gross residual disease. The efficacy of this approach in preventing the recurrence of upper tract disease after surgical ablation awaits further assessment.

A canine model of heart failure by intracoronary adriamycin injection: Hemodynamic and energetic results

Background: To eliminate the noncardiac toxicities associated with Adriamycin (Pharmacia Upjohn, Kalamazoo, MI) and to avoid the need for surgical implantation of a coronary artery catheter, we proposed serial intracoronary infusions of Adriamycin (Pharmacia Upjohn) with a Judkins catheter to develop a nonsurgical but selective model of dilated cardiomyopathy in dogs. Methods and Results: Twenty-two dogs were entered onto the study. Each dog received four weekly injections of Adriamycin (Pharmacia Upjohn; 15 mg/wk) through a Judkins catheter and verapamil orally (5 mg/kg twice daily) for 4 weeks. Dogs were evaluated with echocardiography, right-sided cardiac catheterization, and endomyocardial biopsy at times 0 and 10 weeks. The left ventricular ejection fraction decreased from 0.65 ± 0.04 to 0.48 ± 0.11 ( P = .0006). The left ventricular end-diastolic and end-systolic diameter indices increased from 42.00 ± 2.17 to 46.92 ± 5.81 mm ( P = .0029) and from 27.65 ± 2.59 to 35.00 ± 6.84 mm, respectively ( P = .0210). The mechanical cardiac efficiency decreased from 28.55% ± 13.30% at baseline and 15.64% ± 9.09% at 10 weeks ( P = .001). Cardiac myocyte vacuolation was present on histological examination at 10 weeks. The mortality rate was 41%. Minimal systemic Adriamycin (Pharmacia Upjohn) toxicity was noticed. Conclusion: Intracoronary injection of Adriamycin (Pharmacia Upjohn) in dogs induced a chronic dilated cardiomyopathy.

Myocardial Oxygen Consumption Is Affected by Dynamic Cardiomyoplasty in Dogs with Adriamycin-Induced Cardiomyopathy

The purpose of the study was to investigate a possible myocardial sparing effect by dynamic cardiomyoplasty. We directly measured cardiac work and myocardial oxygen consumption after dynamic cardiomyopathy in dogs with adriamycin-induced cardiomyopathy. Ten dogs with cardiomyopathy induced by 4 weekly intracoronary infusions of adriamycin were studied. Five dogs underwent right latissimus dorsi cardiomyoplasty with progressive myostimulation, and five served as controls. Right heart and coronary sinus catheterizations were performed at 0, 10, and 15 weeks. Four and two dogs, respectively, the cardiomyoplasty and the control group, survived until 15 weeks. Cardiac work was not different between the control and the cardiomyoplasty groups (p = 0.42). Myocardial oxygen consumption was less in the cardiomyoplasty group (185.70 +/- 37.22; 165.75 +/- 25.86; 161.40 +/- 54.14 J/min at 0, 10, and 15 weeks, respectively) compared to the control group (147.80 +/- 70.99; 275.00 +/- 103.24; 263.50 +/- 52.75 J/min at 0, 10, and 15 weeks, respectively, p = 0.019). Mechanical cardiac efficiency was not meaningfully different between the cardiomyoplasty group (16.08% +/- 5.39%; 20.51% +/- 5.89%; 20.67% +/- 11.98% at 0, 10, and 15 weeks, respectively) compared to the control group (15.29% +/- 8.06%; 9.40% +/- 1.22%; 13.40% +/- 2.29% at 0, 10, and 15 weeks, respectively, p = 0.093). Acute changes of the cardiosynchronization ratio (2:1, 1:1, OFF) did not affect myocardial oxygen consumption or cardiac work within the cardiomyoplasty group. Dynamic cardiomyoplasty reduced myocardial oxygen consumption in dogs with adriamycin-induced cardiomyopathy.

Continuous infusion of adriamycin + cyclophosphamide + 5-fluorouracil in disseminated breast cancer

Continuous infusion of adriamycin + cyclophosphamide + 5-fluorouracil in disseminated breast cancer

A case of resection under the IVC-atrial venovenous bypass of a hepatoblastoma after intraarterial chemotherapy

An 11-month-old infant with a huge hepatoblastoma occupying almost the entire liver was admitted to the hospital. Serum alpha fetoprotein (AFP) level was elevated to 685,120 ng/mL. Combination chemotherapy with continuous arterial infusion of tetrahydropyranyl Adriamycin (THP-Adriamycin) and cisplatin based on the 91B1 protocol of the Japanese Study Group For Pediatric Liver Tumor (JPLT) was administered as the adjuvant chemotherapy. The tumor responded to three courses of chemotherapy and shrank in size, although venocavography showed that the inferior vena cava (IVC) was completely occluded below the entry of the hepatic veins. Right hepatic trisegmentectomy was performed with an IVC-atrial venovenous bypass that prevented massive bleeding. In this case, it was recognized that the IVC-atrial venovenous bypass was advantageous in an infant. The procedure is very simple and the blood flow obtained by the bypass was sufficient. Two weeks postoperatively, three courses of chemotherapy were initiated after the protocol. The patient remains well without signs of recurrence 39 months postoperatively, and the AFP value has remained within 10 ng/mL.

Balloon-occluded arterial infusion as a useful neoadjuvant chemotherapy for bladder cancer.

To evaluate the balloon-occluded arterial infusion (BOAI) of cisplatin and adriamycin as a preoperative adjuvant chemotherapy in patients with bladder cancer of stage > or = T2 or in those with stage T1 and multiple large tumours. The study comprised 120 patients with bladder cancer who underwent BOAI from November 1984 to December 1995. BOAI chemotherapy (adriamycin and cisplatin) was administered under ischaemia through a 7 F torque-control balloon catheter, both sides of which were inserted into the contralateral internal iliac artery. The regression rate of tumours and any improvement in tumour stage was assessed. The clinical response rate (complete or partial) was 66% and the tumour stage improved in 39% of the patients after BOAI. Of 26 patients with stage T3 a diagnosed before BOAI, 12 were diagnosed as T2 or less after treatment. Of 27 patients who underwent total cystectomy because the tumour was diagnosed as T2 after BOAI, the post-operative histopathological examination showed that 22 (82%) were stage pT1 or below. The features associated with a good response to BOAI in patients with up to pT3a disease were grade 3, non-papillary tumours with a diameter of < 3 cm. In patients diagnosed as stage T2 and T3a, or stage T1 with multiple large tumours difficult to be treat by transurethral resection, BOAI should be considered as the first choice to decrease the stage or to confirm the pathological staging.

Percutaneous hepatic venous isolation and extracorporeal charcoal hemoperfusion for high-dose intraarterial chemotherapy in patients with colorectal hepatic metastases.

The results of treating 12 consecutive patients with unresectable colorectal hepatic metastases with a hepatic arterial infusion of high-dose Adriamycin, 100-120 mg/m2, using hepatic venous isolation (HVI) and charcoal hemoperfusion (CHP) are reported herein. Adriamycin was administered over 5-15 min under extracorporeal drug elimination by HVI-CHP. HVI was percutaneously accomplished by either the double-balloon technique using a Fogarty occlusion catheter (8/22F) or a balloon-tipped catheter (16F). During the infusion, isolated hepatic venous blood was filtered by CHP and pumped into the left axillary vein. There were no lethal complications, and good hemodynamic tolerance to HVI-CHP was confirmed. Tumor liquefaction accompanied by a sharp decrease in serum carcinoembryonic antigen levels by more than 50% of pretreatment levels was observed in 6 of the 12 patients 1 month after treatment. Apart from chemical hepatitis, which developed in 11 (92%) of the patients, the Adriamycin toxicities were well controlled following the development of nausea and vomiting in 2 patients (17%), leukopenia < 2,000/mm3 in 3 (25%), and gastric ulcer in 1 (8%). These results indicate that this method is a safe and useful procedure for otherwise hazardous high-dose intra-arterial chemotherapy in patients with unresectable hepatic tumors.

Effects of anthracyclin-based chemotherapy on total plasma antioxidant capacity in small cell lung cancer patients

Plasma total peroxyl radical trapping antioxidant parameters (TRAP) and their main antioxidant components (vitamin E, uric acid, protein sulfhydryl groups, and unidentified antioxidant proportions) were measured in 12 small cell lung cancer (SCLC) patients receiving combined chemotherapy consisting of vincristine, adriamycin and cyclophosphamide for SCLC. Plasma samples were collected ten times during the first two cycles of chemotherapy. There is previous evidence that many anticancer drugs exert their cytotoxity via free oxygen radicals. We hypothesized that adriamycin-induced, increased oxygen free radical production should decrease plasma TRAP as a consequence of oxidative stress. A statistically significant reduction of plasma TRAP was noted 8 hours after the first adriamycin infusion. A reduction of calculated TRAP (TRAP calc)—the sum of concentrations of individual antioxidants, corrected by their experimentally-determined stochiometric factors—appeared 3 hours after the first adriamycin infusion and continued for up to 1 week afterwards. This decrease was due to the reduction of ascorbate and urate concentrations. Total TRAP, however, recovered to initial levels after 20 hours, due to an increase in unidentified antioxidants. The second course of chemotherapy yielded a decrease in unidentified antioxidant proportions only 20 hours following the second infusion of adriamycin. These results are in accordance with previous studies showing the formation of oxidants with the use of anthracyclines. Evidence suggests that the as yet unidentified component of TRAP (UNID) increases during the oxidative stress caused by anthracycline based chemotherapy.

Adjuvant Chemoimmunotherapy for Hepatocellular Carcinoma Patients

To determine improved postresection survival in patients with hepatocellular carcinoma, two postoperative protocols were compared: adoptive chemoimmunotherapy versus chemotherapy. Following resection, 24 patients were allocated at random to receive (1) arterial infusion of Adriamycin, recombinant interleukin-2 and lymphokine-activated killer cells or (2) arterial infusion of Adriamycin alone. The spleen was removed at operation and used to prepare lymphokine-activated killer cells. Each group had 12 patients. They were followed until signs of recurrence appeared. The overall survival rates of the patients were 91.7%, 82.9%, and 72.5% at 1, 2, and 3 years, respectively, and slightly higher than would be expected with surgery alone. No statistically significant difference was found between the two groups either in the survival rate (generalized Wilcoxon test, P = .936) or in the cumulative disease free rate (P = .182). However, when patients who had had hepatic resection with negative margin (> or = 1 cm) were separated, the 2-year cumulative disease-free rate in the adoptive chemoimmunotherapy was higher (83.3%, n = 6) than that in chemotherapy (37.5%, n = 8). Toxicity to adoptive chemoimmunotherapy was moderate; no severe side effects were observed. Totally no statistical difference between the two groups was found. Although only one of six patients in adoptive chemoimmunotherapy experienced recurrence after hepatic resection with negative margin, it was not feasible to determine the role of interleukin-2 and lymphokine-activated killer cells. We conclude that the adoptive chemoimmunotherapy in this study is not an ideal adjuvant protocol after hepatic resection.

Clinical pilot study on high-dose intraarterial chemotherapy with direct hemoperfusion under hepatic venous isolation in patients with advanced hepatocellular carcinoma

We recently developed a novel system of direct hemoperfusion under hepatic venous isolation in an attempt to achieve high-dose intraarterial chemotherapy for patients with malignant liver tumors. We report here the results of treatment of these patients with advanced hepatocellular carcinoma. Adriamycin (100 to 150 mg/m2) was administered into the hepatic artery of 15 patients, under conditions of extracorporeal drug elimination by direct hemoperfusion under hepatic venous isolation. Hepatic venous isolation was accomplished mainly by the double-balloon technique with an occlusion catheter and a balloon catheter. The isolated hepatic venous blood was filtered by direct hemoperfusion and pumped to the left axillary vein. During 5 minutes of adriamycin infusion, the mean drug extraction ratios of the direct hemoperfusion filters were 91% +/- 9% (mean +/- SD). The amount of drug removed by the system was 26.4% +/- 16.0% of the amount of drug administered. Two patients died, one of necrotizing pancreatitis and the other of hepatic arterial thrombosis. Both deaths were related directly to the hepatic arterial catheter. Other side effects included hemolysis related to the system of hemoperfusion (87%), chemical hepatitis (80%), leukopenia less than 3000/mm3 (67%), alopecia (33%), and nausea and vomiting (20%). Nine (64%) of 14 evaluable patients had objective tumor responses, with a median duration of response of 6.2 months. This approach offers an effective therapeutic option for patients with advanced hepatocellular carcinoma.

Regional chemotherapy in the canine liver.

Using a fluorometric assay, mean drug levels of Adriamycin were significantly higher in the normal canine liver following bolus injection of this drug via the hepatic artery or portal vein as compared to hepatic tissue levels following systemic intravenous administration (P < 0.001). However, the variations in tissue levels observed after hepatic artery (+/- 16.8 mcg/gm tissue) or portal vein (+/- 21.1 mcg/gm) infusion were significantly wider than those observed after systemic (+/- 1.3 mcg/gm) administration (P = 0.03). Using C14-labeled drugs, regional infusion of Adriamycin through the hepatic artery or portal vein resulted in significantly higher mean drug levels in the liver than after systemic intravenous administration, but the difference was more pronounced with bolus infusion of the drug than 1-hour infusion. 5-FU bolus or 1-hour infusion in the hepatic artery resulted in significantly higher mean drug levels in the liver compared to peripheral intravenous administration, but this was not so with the 3-hour infusion. The above experiments confirm previous studies that regional chemotherapy results in higher drug levels in the regional tissues compared to systemic administration. They also: (1) demonstrate the spotty drug distribution in the regional tissues after regional administration, a potentially correctable problem, and (2) suggest that the advantage of intra-arterial infusion may be more pronounced within a certain range of infusion times.