Stop-flow in mediastinum and thorax for resistant lymphoma.

BACKGROUND/AIMS: Management of patients with heavily pretreated malignant lymphoma failing frontline treatment and salvage high-dose chemotherapy and autologous peripheral stem cell rescue, is problematic. A pilot study was conducted to evaluate isolated thoracic perfusion of drugs by means of stopflow technique. METHODOLOGY: Six patients were enrolled in the study; diagnoses included 4 advanced Hodgkin's disease, 1 primary mediastinal B-cell lymphoma, and 1 anaplastic large cell lymphoma. Patients were aged 18-37 years; 4 presented with bulky mediastinum. They had never achieved a complete response since all had progressed from front-line treatment, and 3 had even failed salvage high-dose chemotherapy with autologous peripheral stem cell rescue. Cisplatin (100 mg/m2) and melphalan (35 mg/m2) were used. Carmustine (100 mg/m2) were added to these 2 drugs and cytarabine (2000 mg/m2) in patients not previously treated by carmustine, etoposide, cytarabine, and melphalan. Epidoxorubicin (70 mg/m2) was added in patients who previously received a suboptimal dosage of antracycline. Drugs were delivered monthly via aortic perfusion performed by means of Aigner's stop-flow technique. RESULTS: Overall 13 cycles of perfusional chemotherapy were administered with a median number of 2 cycles. During the procedures there were no technical, hemodynamic, or vascular complications, and no deaths occurred during surgery. After 1 month, 6 (100%) objective responses after isolated thoracic perfusion were recorded, 3 (50%) of which were complete. Tolerance to therapy was excellent. Hematological toxicity was mild and transfusional support was needed only in one course. At the last follow-up, 2 patients are alive (1 complete response and 1 very good partial response, maintained). CONCLUSIONS: This new therapeutical approach seems very active in recurrent/refractory malignant lymphoma and may play an important role in this setting.

Pharmacokinetics of mitomycin C in pelvic stopflow infusion and hypoxic pelvic perfusion with and without hemofiltration: a pilot study of patients with recurrent unresectable rectal cancer.

This pilot study was conducted to evaluate the advantage in drug delivery for regional chemotherapy in patients with unresectable recurrent rectal carcinoma by different methods. For this research, the pharmacokinetic advantages of mitomycin C delivery by four different methods were compared: intraaortic infusion with aortic stopflow; intraaortic infusion with inferior vena cava stopflow; intraaortic infusion with aortic and inferior caval vein stopflow (hypoxic pelvic perfusion); and hypoxic pelvic perfusion with hemofiltration. The results of this study indicate that pelvic stopflow infusion followed by hypoxic pelvic perfusion significantly increases mitomycin C concentrations in the blood coming from the tumor site. Also, use of hemofiltration reduces mitomycin C levels in peripheral blood after high-dose regional chemotherapy. Further investigations involving more patients should be carried out in the future to validate these results.

Regional versus systemic chemotherapy for advanced pancreatic cancer: a randomized study.

BACKGROUND/AIMS: In an attempt to improve treatment protocols for advanced pancreatic cancer, the value of regional chemotherapy compared with systemic chemotherapy was investigated in this randomized study. METHODOLOGY: Fourteen patients with advanced non-resectable pancreatic adenocarcinoma were randomized receiving either systemic chemotherapy with mitomycin, mitoxanthrone and cisplatin (5pts.) or celiac axis infusion regional chemotherapy with SpherexR microembolization. In the systemic group one patient was stage III, four patients were stage IV, in the intraarterial group two patients were specified stage III and seven were stage IV. RESULTS: In the systemic group one stable disease and four progressive diseases were noted, in the regional group two stable diseases and seven partial responses were noted. Median survival was 11 weeks in the systemically treated patients versus 33 weeks in the patients treated with intraarterial infusion (p=0.001). One patient became resectable (R0). CONCLUSIONS: Performance status improved during regional chemotherapy whilst it steadily decreased in the patients treated systemically. The study was terminated at that point.

Intra-arterial infusion: overview and novel approaches.

Intra-arterial infusion includes a variety of treatment modalities, adjusted selectively to chemosensitivity and vascularization. For most drugs, response behaviour of different tumors is concentration dependent and requires improved modes of application of cytotoxics. In the treatment of liver metastases from colorectal cancer and hepatocellular carcinoma, blood flow reduction by micro-embolization with starch microspheres has brought significant advantage in response. Balloon stopflow infusion combined with micro-embolization induced 83% complete remissions in a study including 100 patients with locally recurrent breast cancer. Stepwise increased local exposure demonstrated concentration-dependent response. Stopflow infusion of the celiac axis combined with microspheres for advanced Stage III and IV pancreatic cancer induced a 96% remission rate (n = 24 patients) at a median survival of 10 months. This was confirmed in a series of consecutive studies including 242 patients. Quality of life was significantly improved in all responding patients. Overall pain response was 80%. A prospective randomized trial in this patient group, comparing systemic vs. regional chemotherapy in the form of intra-arterial infusion with tumor adjusted concentrations, was stopped in an early phase because median survival time was significantly prolonged (P = 0.001) in the arterial group.

Abdominal stop flow infusion breaks drug resistance in systemically pretreated progressive FIGO IIIc and IV ovarian cancer.

Fourty-five patients with progressive FIGO IIIc (36/45 pts.) and IV (9/45 pts.) ovarian cancer, who were in progression under prior cisplatin-based chemotherapy, were submitted to aortic infusion and stop flow infusion with the same drugs. 36/45 patients (80%) had four-quadrant and 9/45 patients (20%) had two-quadrant peritoneal carcinosis, 33/45 with severe ascites. Overall clinical response was 93%: 5/45 CR (11%), 21/45 PR (47%), 16/45 MR (35%). Complete resolution of ascites occurred in 9/33 patients (27%), a substantial reduction of ascites of more than 50% in 14/33 patients (43%). Median survival time was 12.5 months, median time to progression 8.6 months. Toxicity was minimal and in most patients performance and quality of life improved shortly after therapy.

[Splenic rupture following arthroscopy]. / Milzruptur nach Arthroskopie.

Retroperitoneal bleeding from splenic rupture occurred after initially uneventful arthroscopy. The diagnosis was finally set up in CT-scan, whilst peritoneal lavage was negative. Since there was no incidence of previous abdominal trauma and no abnormal findings in histology, spontaneous perioperative splenic rupture has been discussed.

[Systemically administered regional tumor therapy. Regional hemi-body chemotherapy of metastatic malignant melanoma--an experimental therapy concept]. / Systemisch applizierte regionale Tumortherapie. Regionale Halbkörperchemotherapie des metastasierenden malignen Melanoms--eine experimentelle Therapiekonzeption.

Since systemic application of a high-dose chemotherapy is limited by the extent of intolerable toxicity and overall response rates so far are rather poor, the systemic mode of chemotherapy for metastatic melanoma appears to be of only limited benefit. On the other hand, results from isolated limb perfusion for satellitosis and in-transit metastasis suggest distinct dose-response correlations with tumoricidal properties of appropriate antineoplastic agents. This experience prompted the idea to pilot the anti-tumor action of a high-dose regimen confined to one hemibody compartment for targeted tumor therapy. After having standardized the surgical procedure this goal appeared to be achievable by expanding the perfused area and by simultaneously detoxifying toxic drug levels within the non-perfused compartment by venous filtration. Two initial causal experiences revealed impressive tumor regressions and are therefore reported on preceding subsequent evaluation within a controlled clinical trial being designed at different solid tumors.

[The course of blood glucose and electrolyte status in parenteral nutrition with a complete solution following intestinal resection]. / Blutzuckerverlauf und Elektrolyt-Status unter parenteraler Ernährung mit einer Komplettlösung nach Dickdarmresektion.

In 15 patients after resection of a part of the large intestine the efficacy of a complete solution for total parenteral nutrition was investigated. Glucose concentrations were 20 mg/dl higher than normal from the operation up to the fifth postoperative day. Electrolyte concentrations were normal during the investigation period. There was only a decrease in the total protein concentration to a lower normal range after the operation till the fifth postoperative day. No systemic or special side effects appeared after the infusion.

Diagnostic excision of the Rosenmüller's node. Screening for occult metastases before elective regional lymph node dissection in patients with lower limb melanoma?

Elective radical groin dissection was performed on 297 consecutive patients with high-risk melanoma of the leg, Anderson Stages I, IIA, IIIA. By separate histologic examination of the so-called "Rosenmüller's node," the other inguinal, and the external iliac lymph nodes, the diagnostic excision of the Rosenmüller's node was tested as a suitable mode of screening for metastases before a planned elective regional lymph node dissection. Eighty patients (27%) presented with what was histologically determined to be occult groin metastases. Rosenmüller's node was involved in 30 of these cases; in the remaining 50, however, it was not affected; that is, 63% of the cases were false-negative. Thus, the involvement of Rosenmüller's node is not representative of metastases in the other ilioinguinal lymph nodes, but is rather a matter of chance. In women with superficial spreading melanoma the rate of occult lymph node metastases was significantly lower than that in men with melanomas of the other type. Iliac lymph node involvement was observed in 18 patients (22%) depending on clinical stage and depth of invasion of the primary tumor.

Inhibition of proteases during extracorporeal extremity perfusion experimental and clinical results.

In an experimental and clinical study a significant reduction of the postoperative edema after extracorporeal extremity perfusion under addition of Aprotinin was observed. Together with reduction of edema usually expected complications like pain and peripheral nerve damage could be reduced significantly. Preliminary, yet unpublished data on cytostatic infusion of the pancreas also indicate that intraarterial Aprotinin when given simultaneously may prevent pancreatitis. It is mandatory Aprotinin to be given early enough in sufficiently high dose and there seems to be an advantage when the arterial route is used.

Concentration and time dependence of the toxicity of fluorinated pyrimidines to HT 29 colorectal carcinoma cells.

To determine the optimal concentration time factors for the fluoropyrimidines 5-fluorouracil (FU), 5-fluorouridine (FUR), and 5-fluoro-2'-deoxyuridine (FUdR) in regional chemotherapy, we tested these drugs against the colorectal carcinoma cell line HT 29 at various dosages and exposure times. The measure of cytotoxicity used was the degree of inhibition of colony formation in soft agar after drug treatment compared with untreated control cells. Colonies were visible after 6 days of growth in soft agar, so the initial evaluation of toxicity was done at this time. Additional colonies were found 10 and 16 days after the first evaluation, so the dishes containing the treated cells were also evaluated for this delayed growth phenomenon ("regrowth"), which we considered to be due to a cell growth inhibition effect of the drugs rather than a cytocidal effect. Exposure times of the cells to the drugs ranged from 5 min to 24 h and the doses, between 0.01 and 1000 micrograms/ml. The toxicity of FUdR was concentration-dependent, but its time dependence ceased after a relatively short exposure time. There was a cell population that was not susceptible to FUdR regardless of dose and exposure time; consequently, FUdR treatment was always accompanied by substantial regrowth of colonies. With FU and FUR, conditions could be achieved that resulted in complete cell death (no regrowth), but high concentrations and long exposure times were required with FU. With FUR, on the other hand, both cytostasis and cytotoxicity could be achieved with substantially lower doses and shorter exposure times than with FU. These results indicate that FUR has the potential to be an effective drug in chemotherapy protocols not involving systemic administration.

Prospective correlative chemosensitivity testing in high-dose intraarterial chemotherapy for liver metastases.

Clinical response of liver metastases treated by high-dose intraarterial chemotherapy (HDIAC) delivered via the hepatic artery was predicted by a modification of the human tumor colony-forming assay (HTCFA) originally described by Hamburger and Salmon [Science (Wash. DC), 197:461-463, 1977. In a first set of experiments, the immediate clinical response to HDIAC was determined in 12 patients with colorectal liver metastases. Biopsies were taken immediately before and after HDIAC, and cells were plated in the HTCFA. Three patients received intraoperative 4-epidoxorubicin and another 9 received mitomycin C by 15-min intraarterial infusions. Sensitivity in the HTCFA was defined as 50% inhibition of colony formation in tumors exposed to the chemotherapeutic agent, compared to the untreated controls. Clinical response was accurately predicted by the HTCFA in 11 of 12 cases. Eight patients had a regression of disease following HDIAC treatment with mitomycin C, as evidenced by either greater than 50% reduction in carcinoembryonic antigen serum level (7 patients) or regression of tumor by computed tomography scan (1 patient). Three patients had no evidence of clinical response to epidoxorubicin, and their tumors were resistant to epidoxorubicin in the HTCFA. One tumor was sensitive to mitomycin C in the HTCFA, but serum carcinoembryonic antigen in the patient continued to increase following HDIAC. The HTCFA was also performed on untreated biopsies following incubation in vitro with the drug used for HDIAC. Results correlated with clinical response in all 12 cases. In a second set of experiments, the HTCFA was used to predict the long-term clinical response to HDIAC of 30 patients with liver metastases. One patient had breast cancer metastases, one patient had carcinoid liver metastases, 4 had liver metastases of malignant melanoma, and 24 patients had colorectal liver metastases. All 21 of the patients whose tumors were sensitive in vitro had clinical response, while 6 of 9 patients predicted by the HTCFA to be resistant had no clinical response. Our results demonstrate a high correlation between the HTCFA and clinical response.

[Reduction of postoperative edema following isolated hyperthermic perfusion of the extremities with prophylactic administration of aprotinin. Preliminary results]. / Reduktion des postoperativen Odems nach der isolierten hyperthermen Extremitätenperfusion durch prophylaktische Anwendung von Aprotinin. (Vorläufige Ergebnisse).

Experience from more than 380 operations resulted in the standardisation of isolated hyperthermic perfusion with cytostatic drugs for the treatment of malignancies of the extremities. A side-effect of this procedure is postoperative oedema in varying degrees of severity. The influence of prophylactic intraoperative administration of aprotinin (Trasylol) was investigated under experimental and clinical conditions. In these preliminary studies aprotinin distinctly reduced maximum extent and duration of the postoperative oedema. An investigation concerning interaction of aprotinin with the cytotoxic activity of the drugs used in perfusion showed only minor inhibition which does not limit clinical usefulness.

[Isolated hyperthermic extremity perfusion with vindesine, dacarbazine and cisplatin in the treatment of malignant melanomas]. / Die isolierte hypertherme Extremitätenperfusion mit Vindesin, Dacarbazin und Cis-Platin bei der Behandlung maligner Melanome.

A three drug combination consisting of dacarbazine, vindesine and CDDP (DVP) was used for isolated extremity perfusion in 26 patients with stage I, II and III melanomas of the limbs. Dosages of 100 mg/l dacarbazine, 0.4 mg/l vindesine and 20 mg Cis-Platinum/l extremity volume have been tolerated without major side effects. All perfusions of bulky tumors or metastases resulted in more than 50% tumor-size reduction (8 patients stage III A, 6 patients stage III AB). In five stage III patients relapse occurred 2, 3, 5, 6 months after isolated DVP perfusion.

[Isolated liver perfusion in advanced metastases of colorectal cancers]. / Die isolierte Leberperfusion bei fortgeschrittenen Metastasen kolorektaler Karzinome.

A special cannulation system was developed in order to completely isolate the liver in an extracorporeal circuit. Isolated hyperthermic liver perfusion at 40 degrees C with an average dosage of 1000 mg 5-FU was performed in 32 patients with liver metastases (29 colorectal carcinomas, 2 carcinoids, 1 primary hepatoma). 12 patients who had an overall 45% tumor invasion of the entire liver-volume as measured in CT-scan were treated exclusively by isolated liver perfusion. In that group median survival was 8 months and death occurred in the presence of extrahepatic metastases. Better results are achieved with isolated liver perfusion followed by intraarterial short-time infusions (Mitomycin C/5-FU) via an Implantofix catheter. Median actual survival in this group is 12 months, the longest follow-up period is 23 months.

Regional perfusion of VX 2 carcinoma with cis-DDP.

High dose effect of regionally applied cis-DDP was studied using VX 2 carcinoma as a tumor model. The tumors were transplanted on both hind limbs of New-Zealand rabbits. After strict standardization of the methods, treatment with cis-DDP systemically was compared to regional treatment with cis-DDP by isolated perfusion on extremities. These results were related to untreated controls. Therapeutic effect was determined by comparing the average tumor diameters at various time points after the end treatment. Remission could be induced for a short period by systemic treatment. After isolated perfusion, remission was continuous during the observation period. There was no therapeutic benefit by a dose increase from 20 to 40 mg cis-DDP/kg limb weight.