Isolated Liver Perfusion With Oxaliplatin
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Publication
Journal: Biochemical Pharmacology
January/2/1997
Abstract
The present study was designed to explore the activity of platinum compounds in cisplatin-resistant cell lines, the unselected cell lines of the National Cancer Institute's Anticancer Drug Screen, and the potential for use in combination. The activities of four platinum compounds in cisplatin-resistant KB and A2780 cells were investigated. The cells were highly resistant to cisplatin and cross-resistant to carboplatin, but less than one-tenth as resistant to oxaliplatin and tetraplatin. Cellular accumulation of all platinum compounds was decreased in both resistant cell lines. When the activities of cisplatin and oxaliplatin were evaluated in the National Cancer Institute's Anticancer Drug Screen, marked differences were observed. Evaluation of the activity profile using the COMPARE program revealed a different pattern for both agents: the cisplatin activity profile was similar to those of other diamine-platinum compounds, alkylating agents including melphalan, and camptothecin analogs, whereas the activity profile of oxaliplatin resembled those of other "dach" (diaminocyclohexane) platinum compounds and of acridine derivatives. The sensitivity profiles are influenced by the target(s)/mechanism(s) of action and the mechanism(s) of resistance of a drug. The dissimilarity in profiles suggests that these two platinum compounds have a different target(s)/mechanism(s) of action, a different mechanism(s) of resistance, or most likely both. Studies evaluating combinations of cisplatin/oxaliplatin suggest that the activities of these two agents are at least additive and possibly synergistic. Oxaliplatin has a different spectrum of activity and low cross-resistance to cisplatin and should be valuable in cisplatin refractory patients or in combination with cisplatin.
Publication
Journal: Annals of Oncology
February/2/1999
Abstract
Of the new generation platinum compounds that have been evaluated, those with the 1,2-diaminocyclohexane carrier ligand-including oxaliplatin--have been focused upon in recent years. Molecular biology studies and the National Cancer Institute in vitro cytotoxic screening showed that diaminocyclohexane platinums such as oxaliplatin belong to a distinct cytotoxic family, differing from cisplatin and carboplatin, with specific intracellular target(s), mechanism(s) of action and/or mechanism(s) of resistance. In phase I trials, the dose-limiting toxicity of oxaliplatin was characterized by transient acute dysesthesias and cumulative distal neurotoxicity, which was reversible within a few months after treatment discontinuation. Moreover, oxaliplatin did not display any, auditory, renal and hematologic dose-limiting toxicity at the recommended dose of 130 mg/m2 q three weeks or 85 mg/m2 q two weeks given as a two-hour i.v. infusion. Clinical phase II experiences on the antitumoral activity of oxaliplatin have been conducted in hundreds of patients with advanced colorectal cancers (ACRC). Single agent activity reported as objective response rate in ACRC patients is 10% and 20% overall in ACRC patients with 5-fluorouracil (5-FU) pretreated/refractory and previously untreated ACRC, respectively. Synergistic cytotoxic effects in preclinical studies with thymidylate synthase inhibitors, cisplatin/carboplatin and topoisomerase I inhibitors, and the absence of hematologic dose-limiting toxicity have made oxaliplatin an attractive compound for combinations. Phase II trials combining oxaliplatin with 5-FU and folinic acid ACRC patients previously treated/refractory to 5-FU showed overall response rates ranging from 21% to 58%, and survivals ranging from 12 to 17 months. In patients with previously untreated ACRC, combinations of oxaliplatin with 5-FU and folinic acid showed response rates ranging from 34% to 67% and median survivals ranging from 15 to 19 months. Two randomized trials totaling 620 previously untreated patients with ACRC, comparing 5-FU and folinic acid to the same regimen with oxaliplatin, have shown a 34% overall response rate in the oxaliplatin group versus 12% in the 5-FU/folinic acid group for the first trial; and 51.2% vs. 22.6% in the second one. These statistically significant differences were confirmed in time to progression advantage for the oxaliplatin arm (8.7 vs. 6.1 months, and 8.7 vs. 6.1 months, respectively). A small but consistent number of histological complete responses have been reported in patients with advanced colorectal cancer treated with the combination of oxaliplatin with 5-FU/folinic acid, and secondary metastasectomy is increasingly done by oncologists familiar with the combination. Based on preclinical and clinical reports showing additive or synergistic effects between oxaliplatin and several anticancer drugs including cisplatin, irinotecan, topotecan, and paclitaxel, clinical trials of combinations with other compounds have been performed or are still ongoing in tumor types in which oxaliplatin alone showed antitumoral activity such as ovarian, non-small-cell lung, breast cancer and non-Hodgkin lymphoma. Its single agent and combination therapy data in ovarian cancer confirm its non-cross resistance with cisplatin/carboplatin. While the role of oxaliplatin in medical oncology is yet to be fully defined, it appears to be an important new anticancer agent.
Publication
Journal: Annals of Oncology
August/21/2002
Abstract
OBJECTIVE
This article reports the pharmacokinetics (PK) of heated intra-operative intraperitoneal oxaliplatin and its tolerance profile. Oxaliplatin has demonstrated significant activity in advanced colorectal cancer, and this is the first publication concerning its intraperitoneal administration.
METHODS
Twenty consecutive patients with peritoneal carcinomatosis (PC) of either gastrointestinal or uniquely peritoneal origin underwent complete cytoreductive surgery followed by intra-operative intraperitoneal chemo-hyperthermia (IPCH) with increasing doses of oxaliplatin. We performed IPCH using an open procedure (skin pulled upwards), at an intraperitoneal temperature of 42-44 degrees C, with 2 l/m2 of 5% dextrose instillate in a closed circuit. The flow-rate was 2 l/min for 30 min. Patients received intravenous leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2) just before the IPCH to maximize the effect of oxaliplatin. We treated at least three patients at each of the six intraperitoneal oxaliplatin dose levels (from 260 to 460 mg/m2) before progressing to the next. We analysed intraperitoneal, plasma and tissue samples with atomic absorption spectrophotometry.
RESULTS
The mean duration of the entire procedure was 8.4 +/- 2.7 h. Half the oxaliplatin dose was absorbed in 30 min at all dose levels. Area under the curve (AUC) and maximal plasma concentration (Cmax) increased with dose. At the highest dose level (460 mg/m2), peritoneal oxaliplatin concentration was 25-fold that in plasma. AUCs following intraperitoneal administration were consistently inferior to historical control AUCs after intravenous oxaliplatin (130 mg/m2). Intratumoral oxaliplatin penetration was high, similar to absorption at the peritoneal surface and 17.8-fold higher than that in non-bathed tissues. Increasing instillate volume to 2.5 l/m2 instead of 2 l/m2 dramatically decreased oxaliplatin concentration and absorption. There were no deaths, nor severe haematological, renal or neurological toxicity, but we observed two fistulas and three deep abscesses.
CONCLUSIONS
Heated intraperitoneal chemotherapy gives high peritoneal and tumour oxaliplatin concentrations with limited systemic absorption. We recommend an oxaliplatin dose of 460 mg/m2 in 2 l/m2 of 5% dextrose for intraperitoneal chemo-hyperthermia, at a temperature of 42-44 degrees C over 30 min. We may be able to improve these results by increasing the intraperitoneal perfusion duration or by modifying the instillate composition.
Publication
Journal: Annals of Surgery
December/16/1983
Abstract
A prospective phase II evaluation of regional FUDR chemotherapy using a totally implantable drug infusion pump was conducted in 81 patients with colorectal metastases to the liver. The survival results were compared to a historical control group of 129 patients with isolated liver metastases. The two groups were comparable with respect to their dominant prognostic factors. The pump patients received their continuous chemotherapy on an outpatient basis and had an 88% response rate, as evidenced by a fall in their serum CEA levels by one-third or greater after two cycles of chemotherapy. By four criteria, the regional chemotherapy patients had an improved survival rate compared to the control series. First, the 1 year survival and median survival was better for the entire group of pump patients vs. controls (82% vs. 36%, 26 months vs. 8 months, p less than 0.0001). The survival for the regional chemotherapy patients was not influenced by the extent of tumor involvement, whether previous systemic 5-FU was given, or whether the patient had symptomatic disease. Second, the entire group of regional chemotherapy patients (including nonresponders) had a greater 1 year survival compared to the most favorable subgroup of control patients with the following characteristics: normal liver function tests, no symptoms, and only one lobe involved (82% vs. 66%, p = 0.009). Third, a subgroup of 49 pump patients, whose initial treatment for metastatic disease was regional chemotherapy (within 3 months of diagnosis) had a better 1 year survival than an exactly matched group of 49 control patients (67% vs. 30%, p = 0.000003). Fourth, the actuarial survival for all 81 pump patients was significantly better than predicted by a mathematical model constructed to predict the patient's clinical course based upon the seven dominant prognostic variables identified in a multifactorial analysis (82% survival at 1 year vs. 33% predicted survival). While liver metastases could be controlled in most patients, the major cause of death was tumor progression in extrahepatic sites, particularly lung metastases and abdominal carcinomatosis. Although it appears that regional chemotherapy with an implantable pump appears to prolong life by 12 to 18 months more than matched historical controls, these results must be confirmed by a randomized (phase III) prospective clinical trial.
Publication
Journal: Journal of Clinical Oncology
April/11/1984
Abstract
A multifactorial analysis was used to identify the dominant prognostic variables predicting survival rates of 175 patients with hepatic metastases from colorectal carcinoma. Seven of 22 parameters examined simultaneously were found to independently influence the median survival rate in these patients: (1) elevated alkaline phosphatase (p = 0.0004), (2) elevated serum bilirubin level (p = 0.0005), (3) location of hepatic metastases (unilateral or bilateral, p = 0.0022), (4) number of metastatic nodes involved (0, 1-5, greater than 5; p = 0.0148), (5) depressed serum albumin (p = 0.0217), (6) whether or not the primary colorectal tumor was resected (p = 0.0013), and (7) chemotherapy (given or withheld, p = 0.0439). The prothrombin time, serum lactic dehydrogenase, and the number of hepatic metastases also correlated with survival, but they did not independently predict survival rates after other more dominant factors were accounted for. A mathematical equation for predicting an individual patient's clinical course once they developed hepatic metastases was derived from this statistical analysis. In addition, a simple and clinically useful guide for predicting outcome was developed that integrated the two most important risk factors, alkaline phosphatase and bilirubin.
Publication
Journal: Journal of Clinical Oncology
May/11/1998
Abstract
OBJECTIVE
To evaluate the efficacy and systemic and regional toxicities of hyperthermic isolated hepatic perfusion (IHP) using tumor necrosis factor (TNF) and melphalan for the treatment of unresectable primary or metastatic cancers confined to the liver.
METHODS
Thirty-four patients (18 men and 16 women; mean age, 49 years) underwent a 60-minute hyperthermic (39.5 degrees to 40.0 degrees C) IHP performed by laparotomy that used TNF 1.0 mg and melphalan 1.5 mg/kg. Perfusion inflow was through the gastroduodenal artery and outflow was from a cannula positioned in an isolated segment of retrohepatic inferior vena cava (IVC). Infrahepatic IVC and portal venous blood flow were shunted to the axillary vein using an external venoveno bypass circuit. Complete vascular isolation of the liver was confirmed by an I-131-labelled human serum albumin monitoring technique.
RESULTS
There was no operative mortality. Seventy-five percent of patients had reversible grade III or IV (National Cancer Institute Common Toxicity Criteria) hepatic toxicity with one treatment-related mortality (3%) because of hepatic venoocclusive disease. In 33 assessable patients, the overall response rate was 75% (complete response, one patient [3%]; partial response, 26 patients [72%]). With a median potential follow-up of 15 months, the mean duration of response was 9 months (range, 2 to 30 months).
CONCLUSIONS
IHP with TNF and melphalan results in significant regression of bulky hepatic cancers confined to the liver in the majority of patients. Based on these initial results, further refinement of this treatment technique is warranted; perhaps by the combination of IHP with other regional treatment strategies to provide long-term control of unresectable cancers confined to liver.
Publication
Journal: Clinical Cancer Research
December/27/2000
Abstract
There are no satisfactory treatment options for patients with ocular melanoma metastatic to liver, and after liver metastases are identified, median survival is only between 2 and 7 months. Because liver metastases are the sole or life-limiting component of disease in the vast majority of patients who recur, we reasoned that complete vascular isolation and perfusion of the liver might result in clinically meaningful regression of disease. Between September 1994 and July 1999, 22 patients (13 women and 9 men; mean age, 49 years) with ocular melanoma metastatic to liver were treated with a 60-min hyperthermic isolated hepatic perfusion (IHP) using melphalan alone (1.5-2.5 mg/kg, n = 11) or with tumor necrosis factor (TNF, 1.0 mg, n = 11). Via a laparotomy, IHP inflow was via the hepatic artery alone (n = 17) or hepatic artery and portal vein (n = 5) and outflow from an isolated segment of inferior vena cava. Most patients had advanced tumor burden with a mean percentage of hepatic replacement of 25% (range, 10-75%) and a median number of metastatic nodules of 25 (range, 5 to >50). Complete vascular isolation was confirmed in all patients using a continuous intraoperative leak monitoring technique with 131I radiolabeled albumin. There was one treatment mortality (5%). The overall response rate in 21 patients was 62% including 2 radiographic complete responses (9.5%) and 11 partial responses (52%). The overall median duration of response was 9 months (range, 5-50) and was significantly longer in those treated with TNF than without (14 versus 6 months, respectively; P = 0.04). Overall median survival in 22 patients was 11 months. These data indicate that a single 60-min IHP can result in significant regression of advanced hepatic metastases from ocular melanoma. TNF appears to significantly prolong the duration of response.
Publication
Journal: Annals of Oncology
December/3/2001
Abstract
BACKGROUND
To determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of oxaliplatin administered as hepatic arterial infusion.
METHODS
Patients with isolated hepatic metastases from colorectal cancer were treated every three weeks with increasing doses of oxaliplatin (4 hours; starting dose 25 mg/m2, escalation in steps of 25 mg/m2) in combination with folinic acid (1 hour, 200 mg/m2) and 5-fluorouracil (2 hour, 600 mg/m2).
RESULTS
Twenty-one patients (median age, 61 years) have been entered all of whom are fully evaluable. The DLT has been observed at dose level 6, i.e., at 150 mg/m2/cycle and consisted of leucopenia, obliteration of the hepatic artery, and acute pancreatitis. Overall, toxicity mainly consisted of nausea/vomiting (16 of 21 patients), anemia (16 of 21), upper abdominal pain (15 of 21), sensory neuropathy (10 of 21), diarrhea (9 of 21), and thrombocytopenia (9 of 21). The mean PK parameters were: terminal half-life of ultrafiltrable platin, 17.75 +/- 9.29 hours; renal elimination, 48.7% +/- 14.1% of the applied dose; renal clearance 135.55 +/- 45.32 ml/min. The mean area under the plasma-concentration curve (AUC) increased linearly from 3.22 +/- 0.61 microg x h/ml to 18.45 +/- 8.90 microg x h/ml through the first five dose levels (P = 0.0004). Ten of eighteen evaluable patients achieved a complete or partial response (59%).
CONCLUSIONS
The recommended dose for phase II studies is 125 mg/m2 oxaliplatin.
Publication
Journal: International Journal of Hyperthermia
July/29/2002
Abstract
It has been established that hyperthermia can enhance cytotoxicity of some chemotherapeutic agents. This has led to various clinical trials of thermochemotherapy, although many questions remain unanswered. The effects of various agents have been studied on animal tumours with different histopathology at elevated temperatures. These studies indicated that alkylating agents were most effective to all tumours at a moderately elevated temperature. Cisplatin was also effective to all tumours, but its effectiveness at 41.5 degrees C was less than that of alkylating agents. To quantitatively study these findings, the magnitude of thermal enhancement of melphalan, an alkylating agent, and that of oxaliplatin, a new platinum compound, were studied at 37-44.5 degrees C by the colony formation assay. The dose of each agent was kept constant, and cell survival was determined as a function of treatment time. The cell survival curve was exponentially related with treatment time at all test temperatures, and the T(0) (the time to reduce survival from 1 to 0.37) decreased with an increasing temperature. These results suggested that the cytotoxic effect of these agents occurred with a constant rate at 37 degrees C, and the rate was facilitated with an increasing temperature. This suggests that heat can accelerate the cytotoxic chemical reaction, leading to substantial thermal enhancement. The thermal enhancement ratio (TER, the ratio of the T(0) at 37 degrees C to the T(0) at an elevated temperature) increased with an increase in the temperature. The activation energy for melphalan at moderately elevated temperatures was largest among the agents tested in the laboratory and that for oxaliplatin was approximately half of the melphalan activation energy. This suggests that the thermal enhancement for the cytotoxicity of melphalan or alkylating agents might be the greatest. Potential mechanisms of thermal enhancement of cytotoxicity were discussed.
Publication
Journal: Surgery
March/14/2001
Abstract
BACKGROUND
Unresectable colorectal liver metastases are a significant clinical problem. Isolated hepatic perfusion (IHP) is a regional treatment technique that delivers high dose chemotherapy, biologic agents, and hyperthermia via a completely isolated vascular recirculating perfusion circuit as a means of regionally treating liver tumors. This study presents our results of IHP with tumor necrosis factor (TNF) plus melphalan or IHP with melphalan alone followed by infusional floxuridine (FUDR) and leucovorin in patients with advanced or refractory unresectable hepatic colorectal metastases.
METHODS
Fifty-one patients with unresectable colorectal hepatic metastases underwent a 60-minute IHP with 1.5 mg/kg melphalan and hyperthermia (39 degrees C to 40 degrees C). Thirty-two patients received IHP with 1 mg TNF with melphalan and 19 patients had IHP with melphalan alone followed by monthly hepatic intra-arterial infusional (HAI) FUDR (0.2 mg/kg/day) and leucovorin (15 mg/M(2)/day) for 14 days monthly for up to 12 months. Twenty-six patients failed 1 or more previous treatment regimens for established hepatic metastases and 27 had greater than 25% hepatic replacement (PHR) by tumor. Patients were monitored for response, toxicity, and survival.
RESULTS
There was 1 perioperative death (2%), and only 2 patients (4%) had measurable perfusate leak during IHP (both less than 4%). In the 32 patients treated with IHP alone there were no detectable systemic TNF or melphalan levels during perfusion. The overall objective radiographic response rate (all partial [PR]) was 76% (38 of 50 assessable patients) with a median duration of 10.5 months (range, 2 to 21 months). Twenty-four of 31 patients (77%) had a PR after IHP alone and 14 of 19 (74%) after IHP with postperfusion HAI. Median duration of response was 8.5 months after IHP alone and 14.5 months after IHP and HAI; median survival was 16 and 27 months, respectively. There were 18 PRs in 26 patients (69%) whose prior therapy had failed and 18 PRs in 27 patients (67%) with PHR of 25 or greater.
CONCLUSIONS
IHP can be performed with acceptably low morbidity and has significant antitumor activity in patients with unresectable hepatic metastases from colorectal cancer including those with refractory disease or PHR of 25 or greater. HAI appears to prolong the duration of response after IHP, and this combined treatment strategy deserves additional clinical evaluation as a therapeutic modality in this setting.
Publication
Journal: Current Problems in Surgery
June/12/1995
Abstract
Current data indicate that liver resection is the only available treatment that regularly produces long-term survival with possible cure in patients with metastatic colorectal carcinoma to the liver. Although a number of clinical or pathologic factors predicts a poor outcome, the only absolute contraindications to liver resection are general health incompatible with recovery from major hepatic resection or clear evidence of wide dissemination of disease. Important areas for future study include the potential role of adjuvant regional chemotherapy after resection and cryoablation of "close" margins. For patients with unresectable disease, operative therapy also plays an important role. Multiple operative modalities hold promise in palliative treatment in the setting of clinically incurable disease. It is imperative that a large randomized trial of regional chemotherapy be performed allowing no crossover and with mortality as an endpoint. Additionally, the role of cryoablation begs systematic investigation to ensure proper use of this modality.
Publication
Journal: Journal of Cancer Research and Clinical Oncology
February/2/1997
Abstract
The cytotoxicity of cisplatin and cisplatin-DNA adduct formation in vitro and in vivo is clearly enhanced by hyperthermia. We investigated whether cytotoxicity and platinum-DNA adduct formation of two promising new third-generation platinum derivatives, lobaplatin [1,2-diamminomethylcyclobutane platinum(II) lactate] and oxaliplatin [oxalato-1,2-diaminocyclohexane platinum(II)], are also enhanced by hyperthermia. Cisplatin was used for comparison. SW 1573 cells were incubated with cisplatin, lobaplatin or oxaliplatin at different concentrations for 1 h at 37 degrees, 41 degrees and 43 degrees C. The reproductive capacity of cells was determined by cloning experiments. Immunocytochemical detection of platinum-DNA adducts was performed with the rabbit antiserum NKI-A59. At 37 degrees C, cisplatin was the most cytotoxic, followed by oxaliplatin and lobaplatin. Hyperthermia clearly enhanced the cytotoxicity of cisplatin, lobaplatin and oxaliplatin. There was no further increase in cytotoxicity at 43 degrees C compared to 41 degrees C for cisplatin and oxaliplatin. A further increase in cytotoxicity at 43 degrees C was observed for lobaplatin. At 43 degrees C thermal enhancement was higher for lobaplatin than for oxaliplatin, with the reverse pattern at 41 degrees C. For both drugs, thermal enhancement of cytotoxicity was lower than observed for cisplatin. Immunocytochemical detection of platinum-DNA adducts was feasible for all the drugs. Adduct formation was enhanced at 43 degrees C for cisplatin, lobaplatin and oxaliplatin with a relative increase of 410%, 170% and 180%. These results seem to confirm that an increase in platinum-DNA adduct formation is involved in the in vitro thermal enhancement of cytotoxicity. The observed thermal enhancement of cytotoxicity of lobaplatin and oxaliplatin in vitro warrants further in vivo investigations.
Publication
Journal: Cancer Chemotherapy and Pharmacology
February/1/1995
Abstract
Plasma ultrafiltrates are routinely used in pharmacokinetic studies of carboplatin. Experiments were performed to detect and quantitate artifactual decreases in the platinum concentration of ultrafiltrates prepared from plasma samples stored at -20 degrees C and -70 degrees C. Carboplatin was added to anticoagulated, whole human blood to produce a 20 microgram/ml concentration. Plasma produced from the blood was stored frozen at either -20 degrees C or -70 degrees C. Aliquots from each storage condition were thawed and ultrafiltered once a week for up to 100 days. Platinum concentrations in ultrafiltrates and plasma were determined by flameless atomic absorption spectrometry. There was no loss of ultrafilterable platinum in plasma samples stored at -70 degrees C, whereas there was a steady decrease in free platinum concentration in ultrafiltrates prepared from plasma samples stored at -20 degrees C. These results imply that pharmacokinetic studies of carboplatin should use ultrafiltrates prepared immediately or that plasma for such studies should be stored at -70 degrees C. Storage of carboplatin-containing plasma at -20 degrees C and subsequent ultrafiltration is not acceptable, because measurement of platinum in such ultrafiltrates will be artifactually low.
Publication
Journal: Liver transplantation and surgery : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society
February/10/1999
Abstract
Although the liver is the most common site of metastatic disease from a variety of tumor types, isolated hepatic metastases most commonly occur from colorectal cancer and, less frequently, from neuroendocrine tumors, gastrointestinal sarcoma, ocular melanoma, and others. Complete evaluation of the extent of metastatic disease, both intrahepatically and extrahepatically, is important before considering treatment options. Based on a preponderance of uncontrolled studies for hepatic metastatic colorectal carcinoma, surgical resection offers the only potential for cure of selected patients with completely resected disease, with 5-year survival rates of 25% to 46%. Systemic and hepatic arterial infusion chemotherapy may be useful treatment options in patients with unresectable disease and possibly as an adjuvant treatment after liver resection. Other techniques of local tumor ablation, including cryotherapy and radiofrequency ablation, although promising, remain unproved. Management of hepatic metastases from neuroendocrine tumors and other noncolorectal primary tumors should be individualized based on the patient's clinical course, extent of disease, and symptoms.
Publication
Journal: Seminars in surgical oncology
February/17/1997
Abstract
The technique of isolated limb perfusion for treatment of extremity melanoma has been used in the United States for almost 40 years. The treatment is based upon the ability to isolate the circulation of the afflicted extremity from the systemic circulation, thereby allowing dose-intensive delivery of anti-cancer agents to the limb while eliminating systemic exposure and toxicity. A number of agents have been used in ILP, however, the bulk of clinical experience has been with the alkylating agent melphalan, typically used under conditions of mild hyperthermia. Despite considerable clinical experience, there has been a lack of agreement about the role of ILP in the prophylaxis against or the treatment of recurrent extremity melanoma. Recently there has been renewed interest in the use of ILP based upon the very promising results using a combination of tumor necrosis factor, melphalan, and interferon-gamma which have produced complete response (CR) rates of almost 90%. The utility of this regimen in extremity melanoma is actively being evaluated by clinical trials in the United States and Europe.
Publication
Journal: Cancer treatment reports
October/27/1983
Abstract
Floxuridine (5-FUDR) was administered by continuous venous infusion using an ambulatory portable pump in a phase I study designed to establish the optimal (maximal) daily dose rate to deliver a minimum of 14 days of drug therapy. The major determinant of toxicity was dose rate rather than cumulative dose. Patients receiving greater than 0.15 mg/kg/day developed dose-limiting diarrhea at 7-14 days (median, 10), while patients receiving 0.1-0.125 mg/kg/day were treated for 18-78 days without adverse effects. The recommended daily dose rate for continuous-infusion schedules of 14 days is 0.15 mg/kg/day.
Publication
Journal: Cancer Journal
July/13/2000