Circadian continuous chemotherapy of renal cell carcinoma with an implantable, programmable infusion pump

The authors treated 42 metastatic renal cell carcinoma (RCC) patients who had received no previous chemotherapy or radiation therapy with circadian venous continuous infusion of 5-fluoro-2-deoxyuridine (FUDR). The drug was delivered by Medtronic Synchromed implantable pump (Medtronic, Inc., Minneapolis, MN) in 14-day cycles alternating with 14-day intervals of heparinized physiologic saline infusion. In the course of 24 months 444 cycles of therapy have been given for a total of 12449 days of pump function. Of the patients observed for at least 3 months (range, 3 to 23 months; median, 7 months) three showed complete response (7%; 95% confidence interval, 0% to 15%), three partial response (7%; confidence interval, 0% to 15%), 18 stable disease, and 18 showed progression. Eighteen patients, all with advanced disease at the time of implantation, were living 6 months after treatment started. Circadian continuous central venous infusion of FUDR is minimally toxic. The FUDR can be delivered safely and conveniently in this way for long spans. This therapy is as active as any currently available treatment, is administered in an entirely outpatient setting, and is associated with a normal quality of life.     

Cancer chemotherapy by intra-arterial infusion with adriamycin

Adriamycin was given by arterial infusion to 32 patients with different types of advanced cancer. The drug was used for inducing the first remission. In responsive cases maintenance treatment was given with conventional agents. Twenty-six patients were adequately evaluable. Seventeen patients adequately treated showed objective improvement and 7/17 regression >50%. Head and neck cancer was the disease most sensitive to adriamycin by arterial infusion. Of 32 patients receiving adriamycin, 23 had one or more side effects, 14 had morbidity, and 2 patients died. In comparison with other conventional drugs, adriamycin by prolonged arterial infusion produces a higher percentage of side effects and not a higher percentage of therapeutic response.     

Intra-arterial infusion chemotherapy for locally advanced breast cancer using implantable reservoir connected with catheter inserted in recurrent radial artery

Intra-arterial infusion chemotherapy through a catheter incubated at the recurrent radial artery and connected to an implantable reservoir was performed in eight patients with supraclavicular lymph node metastasis including four locally advanced recurrent breast cancers and two inflammatory breast cancer. Clinical response in breast cancer patients was 1 CR, 3 PR, 1 NC, and 1 PD. There was no complication related with catheter insertion. Therefore from the aspect of quality of life, this system was considered useful for treatment of advanced breast cancer, especially locally advanced recurrent breast cancer.     

Continuous intra-arterial infusion chemotherapy for inoperable retroperitoneal liposarcoma--a case report

A case of an inoperable recurrent retroperitoneal liposarcoma, histologically diagnosed as being a mixed myxoid type and a round cell type, which was treated by continuous intra-arterial infusion chemotherapy, is reported. The authors applied this treatment method using adriamycin and 5-FU via the feeding arteries, i.e., the superior and the inferior mesenteric arteries. The tumor showed remarkable regression with no severe complications, even though general chemotherapy using adriamycin proved to be ineffective. This infusion method was thus evaluated as highly effective.     

Hepatic intra-arterial infusion chemotherapy using polymer-coated 2.9 Fr implantable catheter-port system--initial experience]

We developed a new 2.9 Fr implantable catheter-port system (reservoir) to perform arterial infusion chemotherapy in patients with unresectable liver tumors. This study was undertaken to evaluate the feasibility of placing this new reservoir system in patients in whom placement of a 5 Fr-reservoir system would seem to be difficult because of severe stricture, tortuosity or angulation of the hepatic artery. A new reservoir system was successfully implanted in 25 patients during 27 sessions. After a side hole was opened, a 2.9 Fr catheter was inserted in the distal hepatic artery or in the gastroduodenal artery in 24 sessions. The catheter tip was then fixed with coils to prevent catheter dislocation. In the other 3 sessions, a 2.9 Fr catheter was inserted without catheter fixation in the replaced right hepatic artery and a small sized collateral artery towards the liver. Arterial infusion chemotherapy was done without any trouble after 20 sessions. Catheter dislocation was found after 2 sessions in which the catheter tip was not fixed or inadequately fixed. Early arterial occlusion was found after placing a 2.9 Fr catheter in the replaced hepatic artery and the small sized-collateral artery after 4 sessions. In conclusion, although sequellae should be evaluated over a long-term period, implantation of a new 2.9 Fr reservoir system is technically feasible and useful in performing arterial infusion chemotherapy.     

Low-dose intermittent intra-arterial infusion chemotherapy

Arterial infusion chemotherapy is commonly-used modality for controlling cancers located in specific regions. Previously we described a new method of intra-hepatic arterial catheterization through the left subclavian artery using a subcutaneously-implanted silicone reservoir. In the present paper, we report our experience using a low dose-intermittent intraarterial (i.a.) infusion chemotherapy. Since February, 1982, 70 patients including 44 cases of metastatic liver cancer, 16 cases of primary hepatocellular carcinoma and 10 cases of other gastrointestinal malignancies, have been treated with this low dose-intermittent i.a. infusion chemotherapy, the drugs used being as follows. 1) MMC 4 mg, 5-FU 500 mg, AraC 40 mg/2w, 2) MMC 4 mg/w, 3) 5-FU 500 mg/w, MMC 4 mg/2w, ADM 30 mg/4w. Here, we briefly review the effectiveness of this modality for controlling regional diseases including liver metastases. The average hospital-free interval was 156 days and partial responses were observed in 43% (21/49) of cases. Side effects during the therapy were only mild bone marrow suppression and anorexia, which were tolerable in out-hospital care. We also studied the pharmacokinetics of i.a. infusion into the liver in comparison with i.v. infusion using 99mTc-RBC, and found that the ratio of i.a. to i.v. with regard to trans-arterial drug delivery to the liver was 10.0. From the viewpoints of first pass effect and increased local concentration theory, this ratio suggests that the effectiveness of a low-dose anti-tumor agent administered intraarterially is not so low. Accordingly, we believe that low dose-intermittent i.a. infusion chemotherapy is beneficial as an induction and maintenance chemotherapy for patients with regionally located cancers because it is effective, safer and prolongs the hospital-free interval.     

Home anti-cancer chemotherapy with continuous infusion of 5-FU combined with low-dose cisplatin injection via implantable venous port with portable balloon pump

Home anti-cancer chemotherapy was performed for patients with advanced cancer of the digestive plantable venous port placed beneath the skin via the subclavian vein. 128 patients under 75 years old (enrolled: 6 patients with esophageal, 65 with gastric, 44 with colorectal, 5 with cholangio, 5 with pancreatic, one with hepatic and one with ileal cancer) were treated. Continuous intravenous infusion of 5-FU (300-400 mg/body/day) combined with low-dose injection of cisplatin (5 mg/body/day) was continued for 10 days, and repeated 3 times for 6 weeks. The response rate was 23.6% in 72 patients with valuation of tumor mass. In 83 patients for whom a tumor marker evaluation was also performed, an effect was seen in 30.1%. No severe side effects such as renal dysfunction were observed, and no special infusions were needed. Therefore, a quality of life was maintained in which bathing was possible and patients were released from the hospital. Hyperalimentation through the venous port, and palliation during the terminal stage, is easily accomplished. It is useful method for surgery, chemotherapy and palliative therapy in the treatment of cancer.     

Two cases of stage IV breast cancer with locally advanced lesion treated by intra-arterial infusion chemotherapy using implantable reservoir

Intra-arterial infusion chemotherapy was used for 2 cases of Stage IV breast cancer with locally advanced lesions using implantable reservoir. The first case is a 64-year-old female who had multiple bone metastases with locally advanced breast lesion. A total dose of 220 mg ADM was injected via reservoir at outpatient department. The other case is a 66-year-old female who had multiple bone metastases with locally advanced breast lesions. A total dose of 235 mg ADM was injected via reservoir. After obtaining satisfactory response of local lesions, a standard radical mastectomy was performed for both cases. It was concluded that this method was useful for controlling locally advanced lesions of Stage IV breast cancer and beneficial for patient QOL.     

Evaluation of a totally implanted venous access port and portable pump in a continuous chemotherapy infusion schedule on an outpatient basis

In this study we evaluated the feasibility of a totally implanted vascular access port (VAP) and portable infusion pump for cytostatic drug administration on an outpatient basis, in a 21-day continuous infusion schedule with 4-epidoxorubicin (phase I and phase II study) and mitoxantrone (phase I study). Patients were instructed to dissolve their own drugs at home. Fifty patients were treated with 114 cycles (2394 infusion days). The complication rate was low. In one patient thrombosis of the subclavian and superior caval vein resulted in the termination of treatment. One patient developed pulmonary embolism during treatment. Needle dislocation was observed in two patients. No septicaemia and no irreversible catheter occlusion were seen. Pump functioning was efficient and pump arrest (9 ×) never lasted longer than 24 h. We conclude that a VAP and portable pump are a safe and reliable route of administration for cytostatic drugs on an outpatient basis and that patients are capable of preparing their own drugs at home without increase of complications.     

Chemotherapy response analysis for osteosarcom with intra-arterial chemotherapy by subcutaneous implantable delivery system

To summarize the experience in intraarterial neoadjuvant chemotherapy for extremity osteosarcoma. Between January 2002 and December 2007,111 patients with stage IIB extremity osteosarcoma received preoperative intraarterial therapy with subcutaneous implantation of chemotherapy pump as well as en bloc resection, and postoperative adjuvant chemotherapy. There were 63 males and 48 females with an average age of 18 (range, 14 ~ 39 years). The time from symptom onset to hospitalization varied from several days to 6 months. The induction chemotherapy regimen includes: epirubicin [50 ~ 70 mg/m² by 4-hour intraarterial infusion/day for 3 day] and cisplatin [100 ~ 120 mg/m² by 2-hour intraarterial infusion/day for 3 days] repetitively every 2 ~ 3 weeks. Among which 24 cases only received two cycles induction chemotherapy was set to nonstandard chemotherapy group and 87 cases received three to six cycles induction chemotherapy set to standard chemotherapy group. The number of preoperative chemotherapy-cycles of standard chemotherapy group depends on the clinical and radiographic evaluation of chemotherapy efficacy. Median follow-up time was 28(8 ~ 48) months. The rate of limb preservation surgery was 89.53% (77/86) in standard chemotherapy group,and was 37.5% (9/24) in nonstandard chemotherapy group. Kaplan-Meier survival analysis showed that the 3-year overall survival rate and disease free survival rate of all the 111 cases were 68.3% and 65.9% respectively. There were significant differences in overall survival rate (38.9%, 80.0%, P = 0.000), disease free survival rate (30.1%, 79.5%, P = 0.000), distant metastasis rate (66.67%, 16.09%, P = 0.0000) and local recurrence rate (58.33%, 13.79%, P = 0.0000) between nonstandard chemotherapy group and standard chemotherapy group. Standard intraarterial neo-adjuvant chemotherapy was more effective than nonstandard intraarterial induction chemotherapy to stage IIB extremity osteosarcoma.     

Consecutive intra-arterial infusion of cis-diamminedichloroplatinum with continuous intra-arterial infusion of 5-fluorouracil in locally advanced ovarian cancer

Consecutive intraarterial infusion of cis-diamminedichloroplatinum (CDDP) with continuous intraarterial infusion of 5-fluorouracil (5-FU) (250 mg/day) was administered to 10 patients with locally advanced (peritonitis carcinomatosa) ovarian cancer. The dose of CDDP was 10 mg/5 min/body/day and it was administered for about 10-20 consecutive days per one course. Each course was repeated at about 3-week intervals. The main dose-limiting factor was the number of peripheral leucocytes. The results were 6 PR, 1 MR and 2 NC out of 9 evaluable cases, all of whom had had previous therapy. The antitumor effect needed over 200 mg of intraarterial CDDP and the response lasted from 2 to more than 9 months. Among 6 patients who obtained PR, 4 had failed to respond to intravenous or intraperitoneal infusion of CDDP, which suggested that a high concentration and a critical drug gradient across the tumor cell membrane were more essential for a significant tumor cell kill, with CDDP, than the time of exposure. The toxic effects of intraarterial infusion of CDDP were almost absent as compared with those of intravenous infusion, which consisted of nausea and vomiting. Renal dysfunction was also mild. Other toxic effects were not different from those observed in intravenous infusion. Our results with intraarterial infusion of CDDP clearly indicate that this approach can deliver a high therapeutic efficacy in patients with advanced ovarian cancer with markedly less toxic effects.     

Neoadjuvant intra-arterial infusion chemotherapy for invasive thymoma

Four patients with stage III or IVa invasive thymoma successfully underwent surgical intervention and radiotherapy following neoadjuvant intra-arterial chemotherapy including 50 mg/m(2) of cisplatin and 20 mg/m(2) of adriamycin. Remarkable reduction rates (60% or more) of the tumor size were obtained without significant side effects. About 4 weeks after neoadjuvant chemotherapy, an extended thymectomy including invaded organs was easily performed with a small amount of intraoperative bleeding. All patients but one are currently alive and disease-free. This method may be a new therapeutic strategy in the management of invasive thymoma.     

Prolonged intracerebral convection-enhanced delivery of topotecan with a subcutaneously implantable infusion pump

Intracerebral convection-enhanced delivery (CED) of chemotherapeutic agents currently requires an externalized catheter and infusion system, which limits its duration because of the need for hospitalization and the risk of infection. To evaluate the feasibility of prolonged topotecan administration by CED in a large animal brain with the use of a subcutaneous implantable pump. Medtronic Synchromed-II pumps were implanted subcutaneously for intracerebral CED in pigs. Gadodiamide (28.7 mg/mL), with or without topotecan (136 μM), was infused at 0.7 mL/24 h for 3 or 10 days. Pigs underwent magnetic resonance imaging before and at 6 times points after surgery. Enhancement and FLAIR+ volumes were calculated in a semi-automated fashion. Magnetic resonance spectroscopy-based topotecan signature was also investigated. Brain histology was analyzed by hematoxylin and eosin staining and with immunoperoxidase for a microglial antigen. CED of topotecan/gadolinium was well tolerated in all cases (n = 6). Maximum enhancement volume was reached at day 3 and remained stable if CED was continued for 10 days, but it decreased if CED was stopped at day 3. Magnetic resonance spectroscopy revealed a decrease in parenchymal metabolites in the presence of topotecan. Similarly, the combination of topotecan and gadolinium infusion led to a FLAIR+ volume that tended to be larger than that seen after the infusion of gadolinium alone. Histological analysis of the brains showed an area of macrophage infiltrate in the ipsilateral white matter upon infusion with topotecan/gadolinium. Intracerebral topotecan CED is well tolerated in a large animal brain for up to 10 days. Intracerebral long-term CED can be achieved with a subcutaneously implanted pump and provides a stable volume of distribution. This work constitutes a proof of principle for the safety and feasibility for prolonged CED, providing a means of continuous local drug delivery that is accessible to the practicing neuro-oncologist.     

Continuous infusion of chemotherapy on an outpatient basis via a totally implanted venous access port

170 patients were treated with continuous infusion of epirubicin, mitoxantrone, carboplatin or 5-fluorouracil through an implanted venous access port with a portable infusion pump. A total of 440 cycles were given on an outpatient basis. The patients were instructed how to dissolve their drugs and to change the syringes. The complication rate was low. 10 patients developed a thrombosis of the subclavian vein, resulting in cessation of therapy in 5. Pulmonary embolism occurred twice, in 1 patient during a period of subclavian vein thrombosis. Needle dislocation occurred 6 times and catheter occlusion 20 times. Patency was restored with saline or urokinase. Local infection occurred 3 times and systemic infection only once. This technique is suitable for continuous infusion of different cytostatic drugs on an outpatient basis. Patients were able to prepare their drugs at home and the system can remain in situ for 3 weeks without increasing the complication rate.     

Continuous infusion chemotherapy: a critical review

With the development of reliable drug pumps and safe long-term venous access catheters, the continuous infusion of chemotherapeutic agents has become clinically feasible. The available studies on infusion therapy with 37 antineoplastic drugs are analyzed. With the majority of agents, infusion studies have either not been performed or the completed studies have failed to demonstrate improved effectiveness over bolus therapy. In some continuous infusion studies, effectiveness has been retained but with no apparent improvement in the therapeutic index. Several other drugs such as bleomycin, cytosine arabinoside, and doxorubicin have apparent improvement in the therapeutic index when given as a continuous infusion. The improved therapeutic index of the fluorinated pyrimidines when given via continuous infusion must be explored in randomized controlled studies using malignancies other than colorectal cancer. The cost effectiveness of such studies must be carefully assessed. Since this method of administration of chemotherapeutic agents offers the potential for less toxicity and retained antineoplastic effect, such investigations are highly desirable for improved patient care.