A clinical study of intraarterial infusion therapy with CDDP for primary osteosarcoma

Eleven patients with primary osteosarcoma were treated by intra-arterial infusion of cisplatin. Cisplatin (50-100 mg/m2) was infused slowly into tumor feeding artery or proximal-to-the-lesion artery. An antidote, sodium thiosulfate, was also administered intravenously in 10 cases and angiotensin II was simultaneously used in 2 cases. Symptoms of heat sensation and local pain were decreased or disappeared in almost all cases and histopathologic changes were observed in 7 cases. No viable tumor cells were seen in 3 cases.     

Systemic doxorubicin and intraarterial cisplatin preoperative chemotherapy plus postoperative adjuvant chemotherapy in patients with osteosarcoma

The role of adjuvant chemotherapy for osteosarcoma has been well defined. Recently, the use of preoperative chemotherapy has been further enhanced by the use of intraarterial cisplatin. The authors describe the use and results of systemic doxorubicin and intraarterial cisplatin as a preoperative regimen for eight pediatric patients with nonmetastatic osteosarcoma of an extremity. The therapy was well tolerated. Six patients achieved satisfactory local tumor control and were able to receive the surgical procedure to permit limb salvage. Two of these six patients subsequently developed metastatic disease. Of the two patients who did not achieve satisfactory local tumor control to permit a limb salvage procedure, both underwent amputation and one later developed metastatic disease. Five patients have remained continuously free of disease for a median of 18 months (range, 12-21 months). This report confirms the observations that intraarterial cisplatin and doxorubicin can be used as a safe and effective regimen preoperatively for pediatric patients with osteosarcoma of an extremity.     

Combined pre-operative chemotherapy with intra-arterial cisplatin and continuous intravenous adriamycin for high grade osteosarcoma

Osteosarcoma is one of the most common juvenile malignant tumors in Korea. Combined modality treatment (pre-operative chemotherapy + limb salvage surgery + adjuvant therapy) improved the patients' overall survival and quality of life. We evaluated the efficacy and feasibility of pre-operative chemotherapy with intra-arterial (IA) cisplatin plus continuous intravenous infusion (CI) of adriamycin. We assessed the rate of limb salvage, recurrence pattern and the survival impact based on the histologic response of pre-operative chemotherapy. Fourty-one patients with histologically-proven high grade osteosarcoma of the extremities were enrolled from January 1990 to June 1995. Pre-operative chemotherapy, cisplatin 120 mg/m2 IA and adriamycin 75 mg/m2/72 h CI was administered every 3 weeks for 3 cycles, followed by limb salvage surgery if possible or by amputation. According to the histologic tumor response, if the tumor necrosis was >90%, the same regimen was administered for 3 cycles as an adjuvant therapy. A salvage regimen (Ifosfamide 7.5 gm/m2/5 d IV + high dose MTX 10 gm/m2 IV+VP-16 360 mg/m2/3 d IV) was administered every 3 weeks for 6 cycles if the tumor necrosis was <90%. Of 41 patients, 37 patients were evaluable for efficacy and toxicities, because 4 patients refused chemotherapy after 1 or 2 cycles. Twenty-one patients were male and 16 were female with median age of 16 years (range 8-41). The tumor locations were: distal femur 20, proximal tibia 8, humerus 6, distal tibia 2 and 1 in proximal femur. All but one patient, who died of neutropenic sepsis, completed the planned pre-operative therapy. Of the 36 patients who received surgery, limb salvage surgery was possible in 30 patients (83.3%) and 27 patients (75%) showed a good response (grade III 10; 27.8%, grade IV 17; 47.2%). With a median follow-up of 23 months, 3-year disease-free survival rate was 54.7% and overall survival rate was 78.3%. Of the 15 patients who recurred, the major metastatic site was the lung. No operation-related mortality was observed. Most patients experienced grade III-IV nausea, vomiting and hematologic toxicities, which were reversible with supportive cares. Pre-operative chemotherapy with IA DDP+CI ADR followed by surgery showed 75% histologic tumor response rate, 83% limb salvage rate and 54.7% 3-year disease-free survival rate with tolerable side effects. To improve the survival rate, the possible role of good salvage chemotherapy with a non-cross resistance regimen in poor responders should be evaluated.     

Platinum concentrations in human tissue after administration of cisplatin

Using flameless atomic absorption spectrophotometry, platinum concentrations in tissue samples were determined to clarify the distribution and accumulation of platinum in the human tissue after administration of cisplatin. Tissue samples were obtained at the time of autopsies or operation from 14 patients who were given cisplatin 0.7-20.1 mg/kg. Platinum concentrations were highest in the liver and testicle, high in the kidney, lung, heart and spleen, and lowest in the brain. In most organs except the brain, the tissue platinum concentrations increased exponentially according to the total dose of cisplatin. Platinum concentrations in metastatic tumors were generally somewhat lower than those in the normal parts of the organs, with the exception of cerebral metastasis. However, some of the metastatic tumors in the lung and brain showed higher concentrations than those in normal parts of the lung and brain, respectively.     

Effect of preoperative chemotherapy by intraarterial infusion of cisplatin (cis-dichlorodiammineplatin) on primary osteosarcomas

Preoperative chemotherapy was conducted in seven cases of osteosarcoma by twice administering intraarterial infusions of cisplatin (100 mg/m2/day) and the effects were studied through evaluations of clinical symptoms, plane radiograms, angiographic findings, serum alkaline phosphatase levels determined prior to and after the intraarterial infusion, and the rate of necrosis of tumor cells in the resected material. Results of treatment were as follows: disappearance of pain in two cases; reduction of pain in five cases; reduction in tumor size in three cases; and an increase in tumor size in one case. Radiograms obtained after treatment showed a reduction of tumor shadow at the extraskeletal site in one case; no change in five cases; an increase in one case, a clearly defined lesion border in one case; and no change in six cases. The radiograms showed no significant change in many cases, but this is perhaps because the radiograms were taken only four weeks after the start of treatment. Angiograms obtained after the preoperative chemotherapy revealed the disappearance of neovascularity in neoplasms in three cases, reduction in two cases, and no change in two cases. Reductions in the rates of serum alkaline phosphatase levels were in the range of 8.3 to 93% (average, 47.8%); the rates of necrosis of the tumor cells in the resected materials were ranged from 53 to 95% (average, 82.1%). The present chemotherapy resulted in formation of a fibrous connective tissue in the reactive zone and in increase in thickness of its pseudo-capsule. From this, it may be said that, if a tumor is to be resected in the area a few of more centimeters distant from the newly formed tissue, the surgery can be conducted within a wide curative margin, or a safer surgical margin. Results obtained from an overall evaluation of the effects showed the chemotherapy to be markedly effective in one case, effective in four cases, slightly effective in one case, and to have no effect in one case. For making life prognostic evaluations, more case data and longer-range follow-up observations will be needed.     

Influence of infusion time on unchanged cisplatin disposition in patients with ovarian cancer

Summary The disposition of unchanged cisplatin in ten patients with ovarian cancer receiving 2-h infusions of 100 mg/m² was compared with that of ten patients receiving 6-h infusions. A high-performance liquid chromatographic assay specific for the unchanged drug was used and all collected samples were rapidly processed. Patients were catheterized for urine collections. Cisplatin renal clearance was significantly lower after 6-hour infusions (52.8±16.2 ml/min per m²) than after 2-h infusions (87.1±38.2 ml/min per m²) (P=0.026). Total clearance was also lower and less variable, although not significantly, in patients receiving the longer infusion. No differences in nonrenal clearance, volume of distribution, or half-life were observed between the two groups. There was only a poor relationship between cisplatin renal clearance and creatinine clearance after 2-h (r ²=0.02; P=0.66) and 6-h infusions (r ²=0.18; P=0.23). A single cisplatin plasma level obtained at the end of the infusion proved to be a good predictor of total cisplatin clearance after both 2-h (r ²-0.70; P=0.0096) and 6-h infusions (r ²=0.97; P=0.0001). This level was not significantly related to the relatively small changes in creatinine clearance that occurred after three courses of treatment.This study was supported by grants from the National Health and Medical Research Council of Australia and the Anti-Cancer Foundation of the Universities of South Australia     

Pharmacokinetics and tumor concentration of intraarterial and intravenous cisplatin in patients with head and neck squamous cancer

Summary Tumor-tissue platinum levels and major pharmacokinetic parameters were determined in 11 patients with head and neck squamous cancer (HNSC) who were given cisplatin (50 mg/m² daily x 2 days) and 5-fluorouracil (5-FU; 1000 mg/m², continuous infusion x 5 days) either i.a. or i.v. The plasma peak platinum concentrations (c _max) and the areas under the curve for total platinum concentration versus time (AUC) during i.a. infusions were lower than the i.v.c _max (mean, 1.92±0.28 and 4.08±2.80 mg/l, for i.a. and i.v. infusions, respectively) and AUC values (mean, 22.55±4.96 and 40.66±10.71 mg h^–1 l^–1 for i.a. and i.v. treatment, respectively), suggesting a first-passage extraction of the drug by the tumor mass during i.a. infusion. However, no statistically significant difference was found in platinum tumor concentrations after i.a. administration versus i.v. infusion. The lack of a difference in tumor platinum concentrations between the i.a. and the i.v. administration routes might be explained either by a relatively high blood supply to the tumor area, enabling efflux of the surplus free platinum from the tissue, or by the delay between drug infusion and biopsy. After three cycles of i.a. treatment good tumor remission was obtained with minimal local toxicity. Larger clinical studies testing the advantages of the i.a. administration route over i.v. infusion appear to be necessary.Abbreviations HNSC head and neck squamous cancer - AUC area under the total platinum concentration versus time curve - OS overall survival - 5-FU 5-fluorouracil - DFS disease-free survival - CR complete response - PR partial response - SD stable disease - PRO progression This study was supported by grants from the AIRC (Italian Association for Cancer Research) and by grant from the Regione Veneto. One of the Authors (P.A.) is the recipient of an MPI 40% grant     

Treatment of advanced and recurrent squamous carcinoma of the uterine cervix with constant intraarterial infusion of cisplatin

Twelve patients with primary or locally recurrent squamous carcinoma of the cervix were treated with constant internal iliac artery infusion of cisplatin (CDDP) via a totally implantable chemotherapy pump. Seven previously untreated patients received standard external and interstitial radiotherapy (RT) in conjunction with CDDP infusion. Five patients with isolated pelvic recurrences received CDDP therapy only. The chemotherapy pump was refilled weekly on an outpatient basis. All nine evaluable patients developed unilateral or bilateral lower extremity pain which responded to dosage reduction. No renal or marrow toxicity was seen. Both of the evaluable patients treated for recurrent tumor died 32 and 60 weeks after initiation of treatment. The seven patients treated primarily with RT + CDDP infusion include one who expired with persistent tumor and one with no evidence of disease (NED) after exenteration for a pelvic recurrence at 48 and 85 weeks respectively. The five remaining patients are NED at 12 to 60 weeks. Constant internal iliac artery infusion of CDDP via an implantable chemotherapy pump can be performed with acceptable toxicity. The preliminary results suggest that further study in previously untreated undergoing concurrent radiotherapy is warranted.     

MCNU delivery into malignant brain tumor and normal brain tissue by intravenous or intraarterial infusion

In 13 Fischer 344 rats transplanted intracerebrally with 9 L gliosarcoma, 13 normal Fischer 344 rats and 4 clinical cases of malignant glioma, a new water-soluble nitrosourea (MCNU) was given and the concentration was measured in blood, tumor tissues, normal brains around the tumors and normal hemispheres by intravenous or intraarterial infusion of MCNU. At 5 min. after administration of MCNU 20 mg/kg (4-5 mg/body) in 9 L gliosarcoma bearing Fischer rats, mean MCNU concentration in the blood was not different between 20 micrograms/ml intravenous and 23 micrograms/ml intraarterial administrations whereas that in the tumor tissues by intracarotid infusion of MCNU was 40 +/- 14.4 micrograms/g which was about two times as much as 22.9 +/- 8.13 micrograms/g by intravenous infusion of MCNU. Mean MCNU concentration of normal brains around tumor tissues was 2.49 micrograms/g in intravenous and 8.95 micrograms/g in intracarotid infusion. MCNU concentration of tumor tissues in 4 cases of malignant gliomas was higher by intracarotid administration than by intravenous administration compared to that in the blood. Maximum tumor/blood ratio of MCNU was 1.94 in intracarotid administration for the malignant glioma. It is suggested that intraarterial administration was more useful than intravenous infusion as an administration route for malignant brain tumors.     

国产长春瑞滨持续静脉输注治疗晚期食管癌的临床观察

目的：探讨小剂量国产长春瑞滨(NVB)持续静脉输注联合顺铂(PDD)治疗晚期食管癌的疗效与安全性。方法：NVB首剂10mg静脉推注,接用NVB 10mg静脉持续滴注24小时,第1～5天;PDD30mg／m^2静脉滴注2小时,第1～3天。21天为1周期,2周期后评价疗效。结果：27例共化疗61周期,平均2．3周期。食管原发病灶有效率为40．7％,吞咽功能得到改善的患占92．3％。转移病灶缓解率为42．0％,其中淋巴结转移的有效率较高(66．7％)。总的中位生存期为10个月(5-19个月)。主要不良反应为血液学毒性和消化道反应,Ⅲ-Ⅳ度白细胞下降为35．4％,恶心呕吐发生率41．3％,末梢神经炎10．2％。结论：NVB持续输注联合PDD方案治疗晚期难治性食管癌,近期疗效较好,毒副反应轻,值得进一步临床研究。     

Effect of intraarterial versus intravenous cisplatin in addition to systemic doxorubicin, high-dose methotrexate, and ifosfamide on histologic tumor response in osteosarcoma (study COSS-86)

In osteosarcoma, intraarterial (IA) administration of systemic treatment has been advocated to improve local tumor response preparing for, or even obviating, definitive surgery. Because data from the literature did not unequivocally support the local superiority of IA infusion, a comparative study was started in 1986. Preoperative chemotherapy consisted of 45 mg/m2 of doxorubicin on days 1 and 2; 12 g/m2 of high-dose methotrexate on days 15 and 22; and 3 g/m2 of ifosfamide on days 29, 30, 50, and 51 followed on days 31 and 52 by intravenous (IV) versus IA tourniquet infusion of cisplatin (DDP). A strict randomization of patients was not feasible. A balanced distribution of risk factors was strived for by stratifying and allocating the appropriate patients centrally. The infusion time was prolonged from 1 to 5 hours in the IV group, and the DDP dose was reduced from 150 to 120 mg/m2 in both arms when intolerable ototoxicity became apparent. A multivariate analysis was performed to exclude a bias on the response rates from risk factor distribution and from modifications of DDP infusion time and dosage. The overall fraction of histologic good responders (greater than 90% necrosis) was not found to be different after IA versus IV treatment (34/50 [68%] vs. 41/59 [69%]). Intraarterial instead of IV use of DDP within an aggressive systemic treatment does not seem to improve the local tumor response.     

Continuous intraarterial infusion chemotherapy for early lip cancer

Most lip cancers are usually diagnosed and can be treated with good prognosis at an early stage. This study reports our experience of treating seven, previously untreated, patients with lip cancer in stage I or II using intraarterial infusion chemotherapy with a single agent. They were all males with ages ranging from 37 to 69 years. An implantable port-catheter system was used for catheterization. Methotrexate 50mg was infused continuously to the external carotid artery every 24h using a portable pump. Methotrexate was given continuously for a mean period of 7 days (range, 4-10 days) and the total administrated dose of methotrexate for intraarterial infusion ranged from 200 to 500 mg (mean, 350 mg). These seven patients were then given weekly bolus of methotrexate (25mg) via intraarterial route for a range of 6-12 weeks. In every case the tumor regressed dramatically and disappeared completely after treatment within a mean period of 2.5 months. Only one patient died, of non-disease related pneumonia 3 years after infusion therapy. The remaining patients are still alive and no recurrence of carcinoma has been observed at a median follow-up period of 28 months. There was no catheter-related complication. The side effects of infusion chemotherapy were mild and tolerable. Our technique of continuous intraarterial infusion therapy for treatment of early lip cancers seems to be as effective as other standard techniques such as surgery or radiation therapy. This modality achieves good tumor response rates, an excellent cosmetic result, preservation of function and minimal side effects.     

Clinical pharmacokinetics of intraarterial cisplatin in humans

The pharmacokinetics of intraarterially administered cisplatin (DDP) were studied in three patients with large hepatic tumors, and one patient with a fibrous histiocytoma in the thigh, using an assay sensitive to only those forms of non-protein bound DDP capable of reacting with the nucleophilic ligand diethyldithiocarbamate. Each patient received continuous intravenous and intraarterial infusions at various dose rates, with and without concurrent infusion of the neutralizing agent sodium thiosulfate. Steady-state DDP concentrations were achieved within two hours, and the mean (+/- SEM) plasma clearance at infusion rates of 5-15 mg/m2 per hour was 345 +/- 45 mL/m2 per minute. Apparent plasma clearance did not vary significantly with route of infusion. Based on the plasma clearance, predicted values for the relative advantage of an intraarterial infusion (Rt) were less than two for hepatic infusion; observed values averaged 1.9 +/- 0.5 (+/- SEM). The infusion of thiosulfate did not significantly increase plasma clearance. The mean (+/- SEM) extraction ratio for hepatic infusions was 0.24 +/- 0.09, and for infusion of the peripheral soft tissue sarcoma it was 0.27 +/- 0.03. These data indicate that from the point of view of both the tumor and the systemic circulation there is only a limited pharmacologic advantage for intraarterial infusion of DDP into organs with plasma flows of greater than 350 mL/m2 per minute.     

动脉及静脉注射化疗药物的血浆及组织药物浓度变化特征

目的 探讨不同化疗药物经动脉及静脉途径注射后血浆及组织内药物浓度的变化规律。方法 10只成年新西兰雌兔随机平均分为两组（动脉组和静脉组。一组经髂内动脉,另一组经耳缘静脉注射顺铂（DDP）,5-氟脲嘧啶（5-Fu)和依托泊甙（Vp-16)。注射后于不同时间采血样及子宫耳缘静脉注射顺铂（DDP）,5-氟脲嘧啶（5-Ru)和依托泊甙（Vp-16)。注射后于不同时间采血样及子宫组织标本,以HPLC法测定血浆及子宫组织中药物浓度,所得数据用3P97软件处理,计算药代动力学参数。结果 动脉及静脉注射3种药物后,在血浆及靶组织中的浓度均呈现了规律性的变化,其变化过程均可两室模型来描述,动脉注射3种药物的药代动力学数与静脉主射的药代动力学参数不同,动脉组注射药物后,血浆药物峰浓度均低于静脉组,而靶组织内药物峰浓度均高于静脉组,靶组织内药物AUC（药时曲线下面积）值均明显高于静脉组。结论 动脉注射DDP,5-Fu和Vp-16较静脉注射有不同程度的优势,这种优势与药物的药理特性有关。     

Combined therapy consisting of intraarterial cisplatin infusion and systemic interferon-alpha for hepatocellular carcinoma patients with major portal vein thrombosis or distant metastasis

BACKGROUND: Hepatocellular carcinoma (HCC) patients with major vascular involvement or extrahepatic metastasis are not good candidates for surgery or transarterial chemoembolization (TACE). In this study, the authors evaluated the efficacy of combined therapy with intraarterial cisplatin infusion and systemic administration of interferon-alpha (IFN-alpha) as a palliative treatment for these patients. METHODS: Sixty-eight HCC patients with major portal vein thrombosis (n = 47) or distant metastasis (n = 27) were randomly allocated to 1 of 3 groups. Group I (n = 19) received combined therapy consisting of intraarterial cisplatin infusion and systemic IFN-alpha, Group II (n = 23) received intraarterial cisplatin infusion, and Group III (n = 26) was managed with only supportive care. Cisplatin 2 mg/kg was infused through the proper hepatic artery every 8 weeks, and IFN-alpha 3 million IU/m2 was administered subcutaneously 3 times a week. RESULTS: The partial response (defined as a 50% or greater reduction in the product of the 2 longest perpendicular tumor measurements) rate of Group I was significantly higher than that of Group II (33% vs. 14%; P < 0.05). Also, the 1-year survival rate of Group I (27%) was higher than that of Group II (9%) or Group III (0%) (P < 0.05 and P < 0.01, respectively). The median survival period of Group I was 19 weeks, which was significantly longer than that of Group II (11 weeks) or Group III (5 weeks) (P < 0.05 and P < 0.01, respectively). CONCLUSIONS: These results suggest that combined therapy consisting of intraarterial cisplatin infusion and systemic IFN-alpha may be useful as a palliative treatment for HCC patients with major vascular involvement or extrahepatic metastasis.     

A report on the comparative response of sheep epidermal squamous-cell carcinoma to intraarterial versus intravenous Cisplatin infusion

There is an apparent lack of randomised clinical trials demonstrating a therapeutic advantage for intra-arterial, versus systemic, cisplatin administration as cancer treatment. A spontaneous, head and neck epidermal squamous cell carcinoma in sheep was used to compare intra-arterial and equivalent dose intravenous cisplatin infusion. The objective response rate for intra-arterially infused lesions was 73%, with a mean tumour regression for all carcinomas of 70% +/- 6 (sem). In comparison, 27% of intravenously treated carcinomas showed an objective response, the mean volume reduction being 42% +/- 6 (sem). Statistical comparison of the number of objective response lesions was significantly in favour of intra-arterial cisplatin therapy (p<0.05), as was the difference in the mean tumour response for both groups (p<0.005). The experimental data suggest that further study of the clinical application of intra-arterial induction cisplatin therapy is warranted.     

Treatment of lung cancer with bronchial artery infusion of cisplatin and intravenous sodium thiosulfate rescue

Forty-nine patients with primary lung cancer were treated with bronchial artery infusion of cisplatin and intravenous injection of and antidote, sodium thiosulfate. More than 50% reduction of tumor size (PR) was observed in 8 of 9 small cell carcinomas (SCLC) and in 16 of 40 non-small cell carcinomas (NSCLC). In NSCLC patients PR was obtained in 71% (12/17) after repeated infusion (greater than or equal to 200 mg cisplatin) and in 17% (4/23) after a single infusion (less than or equal to 150 mg cisplatin). There was a significant linear relationship between cisplatin dose and tumor reduction in this group. No severe adverse effects were encountered.