melphalan and Colorectal-Neoplasms

The Hepatic CHEMOSAT. Delcath Systems Inc., New York, NY, USA.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Hepatocellular; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Female; Humans; Liver Neoplasms; Male; Melanoma; Melanoma, Cutaneous Malignant; Melphalan; Middle Aged; Skin Neoplasms

Isolated pelvic perfusion (IPP) is a method of intra-arterial local-regional treatment using a simplified balloon occlusion technique. It achieved high-dose drug concentration in pelvis with the minimal adverse effects. Recently, this approach was improved with the use of a pressure-suit placed above the level of aortic and caval stop-flow. A better ratio between pelvic and systemic compartments was achieved. This stop-flow technique with low dose TNF-alpha and melphalan has shown promise in palliation of resectability of advanced cancer in patients not amenable to treatment with conventional chemo radiation in a comparable proportion to those obtained with isolated limb perfusions. A randomized study will start soon.

Topics: Animals; Antineoplastic Agents; Cattle; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Female; Genital Neoplasms, Female; Humans; Male; Melphalan; Pelvic Neoplasms; Tumor Necrosis Factor-alpha

Isolated hepatic perfusion (IHP) involves a method of complete vascular isolation of the liver to allow treatment of liver tumours with toxic systemic doses. The recent clinical studies mainly employed IHP with melphalan with or without tumour necrosis factor-alpha (TNF-alpha) and mild hyperthermia. The results of these studies show that high response rates and high survival rates can be achieved by IHP. In this article, the current status, recent developments and future perspectives of IHP are discussed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Humans; Hyperthermia, Induced; Liver Neoplasms; Melphalan; Treatment Outcome; Tumor Necrosis Factor-alpha

Metastatic or primary unresectable cancers confined to the liver are the sole or life-limiting component of disease for many patients with colorectal cancer, ocular melanoma, neuroendocrine tumors, or primary colangio- or hepatocellular carcinomas. Regional treatment strategies including infusional chemotherapy and local ablative therapy are under investigation, but have limitations with respect to the clinical conditions under which they can be employed. Isolated hepatic perfusion (IHP) was first clinically applied over 40 years ago, but because of its technical complexity, the attendant potential morbidity, and the lack of documented efficacy, it has not enjoyed consistent or widespread evaluation. In light of the antitumor activity with isolated limb perfusion with tumor necrosis factor (TNF) and melphalan in patients with unresectable extremity sarcoma or in transit melanoma, this regimen has been administered via IHP at several centers worldwide for patients with unresectable liver cancers. IHP with TNF and melphalan can result in significant regression of advanced refractory cancers from multiple histologies confined to the liver. Patient selection is important to ensure good results with minimal morbidity and mortality. Work to define the appropriate clinical groups is ongoing at many clinical centers.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Eye Neoplasms; Humans; Hyperthermia, Induced; Liver Neoplasms; Melanoma; Melphalan; Tumor Necrosis Factor-alpha

Progressive growth of unresectable metastatic or primary malignancies confined to the liver is a significant clinical problem. Approximately 25% of patients with colorectal cancer will develop metastatic disease exclusively or largely confined to liver, the vast majority of which are not amenable to surgical resection. Despite aggressive systemic or regional chemotherapy, survival is only 12 to 18 months. More than 80% of patients with ocular melanoma develop liver metastases as the first site of recurrent disease, and death from hepatic disease progression typically occurs 2 to 7 months after diagnosis. In addition, the liver is also the preferred site of metastatic disease for gastrointestinal or pancreatic neuroendocrine tumors. A number of physiological and anatomic features of the liver make it an ideal organ for regionally directed therapy to allow dose intensification to the cancer-burdened area while reducing or eliminating unnecessary systemic toxicity. To that end, complete vascular isolation and perfusion of the liver using a recirculating extracorporeal circuit, also called isolated hepatic perfusion (IHP), has been under clinical evaluation at our institution and others. In this article, we review the current results with IHP and its potential utility in the treatment of patients with unresectable hepatic malignancies.

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials as Topic; Colorectal Neoplasms; Combined Modality Therapy; Humans; Hyperthermia, Induced; Liver Neoplasms; Melanoma; Melphalan; Tumor Necrosis Factor-alpha

In an attempt to improve tumor response and survival among patients with colorectal cancer metastases confined to the liver, we developed an experimental (rats and pigs) and clinical isolated hepatic perfusion (IHP) technique to exploit maximally the steep dose-response relation of may anticancer drugs. In this overview we present our experimental and clinical results with mitomycin C (MMC) and melphalan (L-Pam). In rats, treatment with a four times higher maximally tolerated dose (MTD) of MMC during IHP compared to hepatic artery infusion (HAI) resulted in higher, more effective intratumoral concentrations of MMC. As a result, only in the IHP-treated rats were complete remissions observed and long-term survival achieved. Hepatotoxic side effects were minimal and transient in all animals. In the clinical phase I/II study with MMC 30 mg/m2 administered as a bolus in the isolated circuit, two of nine patients had a complete remission, with a median survival of 17 months. Four patients developed venoocclusive disease (VOD) of the liver, and as a result one patient died. Therefore we consider MMC unsuitable for further IHP studies. Meanwhile experiments in rats showed that IHP with the L-PAM MTD of 12 mg/kg was even more effective than MMC and did not cause hepatotoxic side effects. In the phase I/II dose-findings study with L-PAM in IHP, the MTD in humans was approximately 3.0 mg/kg. As in the rats, systemic toxicity was dose-limiting. The median survival of the whole group was 18 months. We have started a phase II study of L-PAM in IHP with a fixed dose of 200 mg L-PAM to determine if IHP can significantly increase the median survival and complete remission rate compared to other treatment modalities. Results from this study are expected by the end of 1997.

Topics: Animals; Antineoplastic Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Humans; Liver Neoplasms; Liver Neoplasms, Experimental; Melphalan; Mitomycin; Perfusion; Rats

Up to 66% of patients show local pulmonary disease progression after pulmonary metastasectomy. Regional treatment with isolated lung perfusion (ILuP) may improve local control with minimal systemic adverse effects. The aims of this study were to evaluate local and distant control after ILuP, determine the effect on overall survival compared with historical controls, and confirm the safety and feasibility of ILuP.. A total of 107 patients with resectable pulmonary metastases of colorectal carcinoma, osteosarcoma, and soft-tissue sarcoma were included in a prospective phase II study of pulmonary metastasectomy combined with ILuP with 45 mg melphalan at 37°C. Local and distant control, overall survival, lung function, and 90-day mortality and morbidity were monitored.. We report 0% mortality, low morbidity, and no long-term pulmonary toxicity. For colorectal carcinoma, median time to local pulmonary progression, median time to progression, and median survival time were 31, 14, and 78 months, respectively. Median time to local progression was not reached for sarcoma, whereas median time to progression and median survival time were 13 and 39 months, respectively. The 5-year disease-free rate and pulmonary progression-free rate were 26% and 44% for colorectal carcinoma and 29% and 63% for sarcoma, respectively.. ILuP with melphalan combined with metastasectomy is feasible and safe. Compared with historical controls, favorable results were obtained in this phase II study for local control. Further evaluation of locoregional lung perfusion techniques with other chemotherapeutic drugs is warranted.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Bone Neoplasms; Colorectal Neoplasms; Combined Modality Therapy; Disease Progression; Female; Historically Controlled Study; Humans; Lung Neoplasms; Male; Melphalan; Metastasectomy; Middle Aged; Perfusion; Prospective Studies; Sarcoma; Survival Analysis

Percutaneous hepatic perfusion (PHP) with melphalan is an effective treatment for patients with hepatic metastases, but associated with high rates of bone marrow depression. To reduce systemic toxicity, improvements have been made to the filtration system. In pre-clinical studies, the Delcath System's GEN2 filter was superior to the first-generation filters. In this clinical study, we analysed the pharmacokinetics and toxicity of PHP using the new GEN2 filter.. Starting February 2014, two prospective phase II studies were initiated in patients with hepatic metastases from ocular melanoma or colorectal cancer. In 10 PHP procedures performed in the first 7 enrolled patients, blood samples were obtained to determine filter efficiency and systemic drug exposure. PHP was performed with melphalan 3 mg/kg with a maximum of 220 mg. Complications were assessed according to CTCAE v4.03. Response was assessed according to RECIST 1.1.. Pharmacokinetic analysis of blood samples showed an overall filter efficiency of 86% (range 71.1-95.5%). The mean filter efficiency decreased from 95.4% 10 min after the start of melphalan infusion to 77.5% at the end of the procedure (p = 0.051). Bone marrow depression was seen after up to 80.0% of 10 procedures, but was self-limiting and mostly asymptomatic. No hypotension-related complications or procedure-related mortality occurred.. The GEN2 filter has a higher melphalan filter efficiency compared to the first-generation filters and a more consistent performance. PHP with the GEN2 filter appears to have an acceptable safety profile, but this needs further validation in larger studies.

Topics: Adult; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Eye Neoplasms; Female; Hemofiltration; Humans; Liver Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Prospective Studies; Treatment Outcome

The 5-year overall survival rate of patients undergoing complete surgical resection of pulmonary metastases (PM) from colorectal cancer (CRC) and sarcoma remains low (20-50%). Local recurrence rate is high (48-66%). Isolated lung perfusion (ILuP) allows the delivery of high-dose locoregional chemotherapy with minimal systemic leakage to improve local control.. From 2006 to 2011, 50 patients, 28 male, median age 57 years (15-76), with PM from CRC (n = 30) or sarcoma (n = 20) were included in a phase II clinical trial conducted in four cardiothoracic surgical centers. In total, 62 ILuP procedures were performed, 12 bilaterally, with 45 mg of melphalan at 37°C, followed by resection of all palpable PM. Survival was calculated according to the Kaplan-Meier method.. Operative mortality was 0%, and 90-day morbidity was mainly respiratory (grade 3: 42%, grade 4: 2%). After a median follow-up of 24 months (3-63 mo), 18 patients died, two without recurrence. Thirty patients had recurrent disease. Median time to local pulmonary progression was not reached. The 3-year overall survival and disease-free survival were 57% ± 9% and 36% ± 8%, respectively. Lung function data showed a decrease in forced expiratory volume in 1 second and diffusing capacity of the alveolocapillary membrane of 21.6% and 25.8% after 1 month, and 10.4% and 11.3% after 12 months, compared with preoperative values.. Compared with historical series of PM resection without ILuP, favorable results are obtained in terms of local control without long-term adverse effects. These data support the further investigation of ILuP as additional treatment in patients with resectable PM from CRC or sarcoma.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Alkylating; Bone Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Combined Modality Therapy; Female; Humans; Lung Neoplasms; Male; Melphalan; Metastasectomy; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Osteosarcoma; Survival Rate; Young Adult

To improve isolated hepatic perfusion (IHP), we performed a phase I dose-escalation study to determine the optimal oxaliplatin dose in combination with a fixed melphalan dose.. Between June 2007 and July 2008, 11 patients, comprising of 8 colorectal cancer and 3 uveal melanoma patients and all with isolated liver metastases, were treated with a one hour IHP with escalating doses of oxaliplatin combined with 100 mg melphalan. Samples of blood and perfusate were taken during IHP treatment for pharmacokinetic analysis of both drugs and patients were monitored for toxicity, response and survival.. Dose limiting sinusoidal obstruction syndrome (SOS) occurred at 150 mg oxaliplatin. The areas under the concentration-time curves (AUC) of oxaliplatin at the maximal tolerated dose (MTD) of 100 mg oxaliplatin ranged from 11.9 mg/L h to 16.5 mg/L h. All 4 patients treated at the MTD showed progressive disease 3 months after IHP.. In view of similar and even higher doses of oxaliplatin applied in both systemic treatment and hepatic artery infusion (HAI), applying this dose in IHP is not expected to improve treatment results in patients with isolated hepatic metastases.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemotherapy, Cancer, Regional Perfusion; Cohort Studies; Colorectal Neoplasms; Female; Humans; Liver Neoplasms; Male; Maximum Tolerated Dose; Melanoma; Melphalan; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Prospective Studies; Treatment Outcome; Uveal Neoplasms

To compare the median overall survival of patients with isolated nonresectable liver metastases in comparable groups of patients treated with either isolated hepatic perfusion (IHP) with melphalan or systemic chemotherapy.. Colorectal cancer patients with isolated liver metastases, who underwent IHP, were included in this study. The control group consisted of a subgroup of colorectal cancer patients with liver metastases only, who were enrolled in the randomized CApecitabine, IRinotecan, Oxaliplatin (CAIRO) phase III study.. Ninety-nine patients were treated with IHP, and 111 patients were included in the control group. All patient characteristics were comparable except for age. Median follow-up was 78.1 months for IHP versus 54.7 months in the control group. Median overall survival was 25.0 [95% confidence interval (CI) 19.4-30.6] months for IHP and 21.7 (95% CI 19.6-23.8) months for systemic treatment and did not differ significantly (P = 0.29). Treatment-related mortality was 2% for the systemic treatment and 6% for IHP (P = 0.11).. Compared with a patient group with comparable characteristics treated with systemic chemotherapy, IHP does not provide a benefit in overall survival in patients with isolated nonresectable colorectal liver metastases. Currently, the use of IHP cannot be advocated outside the scope of clinical studies.

Topics: Antineoplastic Agents, Alkylating; Case-Control Studies; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Female; Humans; Liver Neoplasms; Male; Melphalan; Middle Aged

Isolated hepatic perfusion for irresectable metastases confined to the liver has reported response rates of 50% to 75%. Magnitude, costs, and nonrepeatability of the procedure are its major drawbacks. We developed a less invasive, less costly, and potentially repeatable balloon catheter-mediated isolated hypoxic hepatic perfusion (IHHP) technique.. In this phase I and II study, 18 consecutive patients with irresectable colorectal or ocular melanoma hepatic metastases were included. Two different perfusion methods were used, both with inflow via the hepatic artery, using melphalan 1 mg/kg. In the first eight patients, the portal vein was occluded, and outflow was via the hepatic veins into an intracaval double-balloon catheter. This orthograde IHHP had on average 56% leakage. In next 10 patients, we performed a retrograde outflow IHHP with a triple balloon blocking outflow into the caval vein and allowing outflow via the portal vein. The retrograde IHHP still had 35% leakage on average.. Although local drug concentrations were high with retrograde IHHP, systemic toxicity was still moderate to severe. Partial responses were seen in 12% and stable disease in 81% of patients. The median time to local progression was 4.8 months.. We have abandoned occlusion balloon methodology for IHHP because it failed to obtain leakage control. We are presently conducting a study using a simplified surgical retrograde IHHP method, in which leakage is fully controlled, which translates into high response rates.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Catheterization; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Female; Humans; Liver Neoplasms; Male; Melphalan; Middle Aged; Survival Rate

Current 5-year survival after complete resection of pulmonary metastases is 20% to 40%, and many patients develop intrathoracic recurrences. Isolated lung perfusion is an experimental technique to deliver high-dose chemotherapy to the lung without systemic exposure. A phase I trial of isolated lung perfusion with melphalan (MN) combined with pulmonary metastasectomy for resectable lung metastases was conducted to define the dose-limiting toxicity and maximum tolerated dose.. From May 2001 to August 2003, 16 patients underwent isolated lung perfusion with MN, followed by surgical resection of lung metastases. Patients were treated with increasing MN doses (15, 30, 45, and 60 mg). For each dose level, normothermia (37 degrees C) and hyperthermia (42 degrees C) were evaluated (n = 3 per level). Serum samples were obtained during the procedure. Pulmonary, hematologic, and nonhematologic toxicities were recorded. The primary tumor was colorectal in 7 patients, renal in 5, sarcoma in 3, and salivary gland in 1. Isolated lung perfusion was performed unilaterally in 11 patients, and staged bilaterally in 5.. In total, 21 procedures of isolated lung perfusion with complete metastasectomy were performed without technical difficulties. Operative mortality was 0%, and no systemic toxicity was encountered. Grade 3 pulmonary toxicity developed at a dose of 60 mg of MN at 37 degrees C in 2 of 3 patients at this dose, terminating the trial.. Isolated lung perfusion with MN combined with pulmonary metastasectomy is feasible. Dose-limiting toxicity occurred at a dose of 60 mg of MN at 37 degrees C, and the maximum tolerated dose was set at 45 mg of MN at 42 degrees C.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Combined Modality Therapy; Female; Humans; Kidney Neoplasms; Lung Neoplasms; Male; Melphalan; Middle Aged; Pulmonary Surgical Procedures; Salivary Gland Neoplasms; Sarcoma

Isolated hepatic perfusion (IHP) involves complete vascular isolation of the liver to allow treatment with doses that would be toxic if delivered systemically. A phase II study of IHP in patients with colorectal metastases confined to the liver was performed.. Seventy-three patients with irresectable colorectal metastases underwent IHP with high-dose melphalan (200 mg) for 1 h. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria and tumour response was assessed according to World Health Organization criteria.. Seventy-one patients were perfused according to the protocol. Four patients died within 30 days after IHP, resulting in an operative mortality rate of 5.6 per cent. Sixteen patients (22.5 per cent) experienced grade 3-4 hepatotoxicity 1 week after IHP, which was transient and resolved within 3 months in all patients. The tumour response rate (complete or partial remission) was 59 per cent. Median time to progression was 7.7 (range 2.3-31.4) months. Overall median survival after IHP was 28.8 months with a 3-year survival rate of 37 per cent.. IHP for irresectable colorectal metastases confined to the liver resulted in good response rates and long-term survival in a selected group of patients.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Disease Progression; Female; Humans; Liver Neoplasms; Male; Maximum Tolerated Dose; Melphalan; Middle Aged; Survival Analysis; Treatment Outcome

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.. 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.. 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.. 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.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Floxuridine; Humans; Hyperthermia, Induced; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Radiography; Survival Analysis; Tumor Necrosis Factor-alpha

Isolated limb or liver perfusion with tumor necrosis factor (TNF) and melphalan results in regression of advanced cancers in the majority of treated patients. However, the contribution of TNF to the efficacy of isolation perfusion with melphalan has not been demonstrated conclusively in random assignment trials. Furthermore, TNF is an inflammatory cytokine and may be associated with significant systemic and regional toxicity. This study was conducted to characterize the toxicity and secondary cytokine production attributable to TNF by comparing these parameters in patients undergoing isolated hepatic perfusion (IHP) using melphalan with or without TNF.. Thirty-two patients with unresectable colorectal cancer confined to the liver underwent a 60-min hyperthermic IHP using 1.5 mg/kg melphalan alone (n = 17) or with 1.0 mg of TNF (n = 15) with inflow via the gastroduodenal artery and outflow via an isolated segment of inferior vena cava. Complete vascular isolation was confirmed using the I-131 radiolabeled albumin-monitoring technique. Post-IHP parameters of hepatic and systemic toxicity and cytokine levels [TNF, interleukin (IL)-6 and IL-8] in perfusate and serum were measured.. Levels of IL-6 and IL-8 in perfusate at the end of the 60-min IHP were significantly higher in TNF-treated patients (P < or = 0.001). Peak systemic IL-6 and IL-8 levels post-IHP were also significantly higher in TNF-treated compared with non-TNF-treated patients (P < 0.0001) by 28- and 268-fold, respectively. The peak levels of these cytokines were associated with significantly lower systolic blood pressure and higher heart rate and mean pulmonary artery blood pressure in TNF-treated patients during the first 48 h post-IHP (P < or = 0.03). Serum bilirubin levels were significantly higher (P = 0.017) and platelets lower (P = 0.03) in TNF-treated compared with non-TNF-treated patients. However, elevations in aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase were not significantly different between groups and returned toward baseline within 1 week after IHP.. Addition of TNF to melphalan during IHP results in significant differences in post-IHP production of IL-6 and IL-8 with associated changes in mean arterial blood pressure and greater regional toxicity, as reflected in higher levels of serum bilirubin. However, these measurable differences were transient and did not appear to be of major clinical consequence. Prior to its routine use, the benefit of TNF in isolation perfusion should be demonstrated in random assignment trials.

Topics: Adult; Aged; Analysis of Variance; Antineoplastic Agents, Alkylating; Colorectal Neoplasms; Female; Humans; Interleukin-6; Interleukin-8; Liver; Male; Melphalan; Middle Aged; Perfusion; Tumor Necrosis Factor-alpha

A phase I dose-escalation study was performed to determine whether isolated hepatic perfusion (IHP) with melphalan (L-PAM) allows exposure of the liver to much higher drug concentrations than clinically achievable after systemic administration and leads to higher tumour concentrations of L-PAM. Twenty-four patients with colorectal cancer confined to the liver were treated with L-PAM dosages escalating from 0.5 to 4.0 mg kg(-1). During all IHP procedures, leakage of perfusate was monitored. Duration of IHP was aimed at 60 min, but was shortened in eight cases as a result of leakage from the isolated circuit. From these, three patients developed WHO grade 3-4 leukopenia and two patients died due to sepsis. A reversible elevation of liver enzymes and bilirubin was seen in the majority of patients. Only one patient was treated with 4.0 mg kg(-1) L-PAM, who died 8 days after IHP as a result of multiple-organ failure. A statistically significant correlation was found between the dose of L-PAM, peak L-PAM concentrations in perfusate (R = 0.86, P< or =0.001), perfusate area under the concentration-time curve (AUC; R = 0.82, P<0.001), tumour tissue concentrations of L-PAM (R = 0.83, P = 0.011) and patient survival (R = 0.52, P = 0.02). The peak L-PAM concentration and AUC of L-PAM in perfusate at dose level 3.0 mg kg(-1) (n = 5) were respectively 35- and 13-fold higher than in the systemic circulation, and respectively 30- and 5-fold higher than reported for high dose oral L-PAM (80-157 mg m(-2)) and autologous bone marrow transplantation. Median survival after IHP (n = 21) was 19 months and the overall response rate was 29% (17 assessable patients; one complete and four partial remissions). Thus, the maximally tolerated dose of L-PAM delivered via IHP is approximately 3.0 mg kg(-1), leading to high L-PAM concentrations at the target side. Because of the complexity of this treatment modality, IHP has at present no place in routine clinical practice.

Topics: Antineoplastic Agents, Alkylating; Area Under Curve; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Humans; Liver Neoplasms; Melphalan; Survival Analysis; Treatment Outcome

To determine the toxicity and efficacy of isolated hepatic perfusion with tumour necrosis factor alpha (TNF-alpha) and melphalan (Alkeran) under mild hyperthermic conditions.. A phase I trial was performed. Eleven patients with unresectable metastatic malignancies in the liver were pre-treated with 3 x 10(6) U leukocyte IFN daily 2 days before the perfusion. The liver was isolated and inflow catheters inserted in the hepatic artery and the portal vein. The hepatic veins were drained via a catheter in the retrohepatic caval vein. The venous blood flow from the lower extremities and the splanchnic circulation was bypassed to the axillar vein. The liver circuit was perfused with oxygenated blood and 30-200 microg TNF-alpha was added. At 39 degrees C in the liver circuit 0.5 mg/kg melphalan was added and the perfusion was continued for 1 h.. Six patients underwent re-operation due to post-operative bleeding. Two patients died of coagulopathy or multiple organ failure within the first post-operative month. Three of six patients with liver metastases from malignant melanoma or leiomyosarcoma showed a partial response while no patients with liver metastases from colorectal cancer showed any response. The mean survival time was 20 months, which is within the same range as seen in previous isolated hepatic perfusion (IHP) studies.. IHP with this drug regimen is a method with a considerable toxicity, though it is hard to distinguish between toxicity from TNF-alpha and that from the perfusion procedure itself. The method was not effective in patients with colorectal liver metastasis, but the results in melanoma and leiomyosarcoma patients warrant further studies.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Extracorporeal Membrane Oxygenation; Female; Hepatic Artery; Humans; Hyperthermia, Induced; Leiomyosarcoma; Liver Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Radiography; Tumor Necrosis Factor-alpha

In this study, we have evaluated hepatotoxicity, secondary cytokine production and hepatic acute-phase response (APR) in patients who underwent isolated hepatic perfusion (IHP) with tumour necrosis factor (TNF) alpha and melphalan for irresectable colorectal liver metastases.. An extracorporeal veno-venous bypass was used to shunt blood from the lower body and intestines to the heart. Inflow catheters were placed in the hepatic artery and portal vein, and an outflow catheter in the inferior caval vein. The liver was perfused for 60 min with 0.4 mg of TNF-alpha plus 1 mg kg-1 melphalan (IHPTM group, n = 6) or 1 mg kg-1 melphalan (IHPM group, n = 3). The liver was washed with macrodex before restoring vascular continuity.. After the washout procedure, a TNF-alpha peak (169 +/- 38 pg mL-1) was demonstrated in the IHPTM group only. Both groups demonstrated peak levels of interleukin 6 (IL-6) in the perfusate as well as systemically. These were significantly higher in the IHPTM group. Acute-phase protein (APP) levels followed a similar pattern as has been demonstrated after major surgery, with no significant differences between both groups. The addition of TNF-alpha to the perfusate did not lead to a significant difference in APP levels and the time course between groups.. IHP with TNF and melphalan is followed by a transient systemic peak of TNF directly after liver washout. Secondary IL-6 induction was seen in the present study after IHP with and without TNF, which was highest when TNF was added. This phenomenon cannot be extrapolated to APP induction, which appeared unaffected by the addition of TNF, presumably because the surgical procedure itself already causes maximal stimulation of APP production.

Topics: Acute-Phase Proteins; Aged; alpha 1-Antitrypsin; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Female; Humans; Interleukin-6; Liver Neoplasms; Male; Melphalan; Middle Aged; Orosomucoid; Recombinant Proteins; Time Factors; Transferrin; Tumor Necrosis Factor-alpha

We report our experience with isolated hepatic perfusion (IHP) with tumor necrosis factor (TNF) and melphalan in an experimental pig study and of a phase I study in humans. IHP was performed with inflow catheters in the hepatic artery and portal vein and an outflow catheter in eh caval vein. An extracorporeal venovenous bypass was used. IHP consisted of a 60-min perfusion with hyperthermia (> 41 degrees C). For the pig protocol rhTNF alpha 50 micrograms/kg alone (n = 5) or rhTNF alpha 50 micrograms/kg plus melphalan 1 mg/kg (n = 3) were added. In two control pigs no drugs were added. In the phase I study, patients received melphalan 1 mg/kg with 0.4 mg rhTNF alpha (n = 8) or 0.8 mg rhTNF alpha (n = 1). After the perfusion the liver was washed with Macrodex before vascular continuity was restored. All pigs but one survived the procedure. Systemic leakage was less than 0.02%. Transient, mild liver toxicity was seen in all pigs, including controls, as demonstrated by liver enzyme assays and histology. There was no significant hemodynamic, cardiopulmonary hematological, or renal toxicity. In the phase I clinical study there was leakage in one patient (cumulative leakage 20%). There were three perioperative deaths (one possibly drug-related). All patients demonstrated significant hepatotoxicity. Survival ranged from 6 to 26 months (median 10.3 months). All patients demonstrated a tumor response (partial response 5/6, 1/6 stable disease) with a median duration of 18 weeks. In contrast to our pig program, many problems were encountered in the phase I study. By using both the hepatic artery and portal vein for IHP we encountered more toxicity than expected based on data from the pig program, resulting in fatal coagulative disturbances in one patient who received the second rhTNF alpha dose. Furthermore, local control after one IHP with TNF alpha and melphalan is only temporary.

Topics: Acute-Phase Proteins; Animals; Antineoplastic Agents, Alkylating; Blood Coagulation; Colorectal Neoplasms; Humans; Interleukins; Liver Neoplasms; Melphalan; Perfusion; Receptors, Tumor Necrosis Factor; Solubility; Survival Rate; Swine; Treatment Outcome; Tumor Necrosis Factor-alpha

Tumor cell resistance against melphalan (LPAM) has been associated with increased cellular reduced glutathione (GSH) levels and glutathione S-transferase activity. Therefore, GSH conjugation of LPAM has been hypothesized to be a key factor in tumor cell resistance. In the present study, we evaluated GSH conjugation of LPAM by the perfused liver in patients with colorectal cancer metastases undergoing a Phase II study of isolated liver perfusion as well as in the rat. To evaluate whether LPAM-GSH conjugates were synthesized in the rat in vivo, LPAM was infused i.v. at a rate of 2.0 micromol/kg/min. In bile samples obtained during the infusion, two major GSH conjugates were identified by mass spectrometry: mono-hydroxy-mono-GSH-LPAM and di-GSH-LPAM. The maximum biliary excretion rate of these two conjugates accounted for only 1.3% of the LPAM infusion rate. In bile or perfusate samples from patients treated for 60 min initially with 0.3 mM LPAM in the perfusion medium via isolated liver perfusion (200 mg LPAM in approximately 2 liters perfusion medium), none of the above-mentioned conjugates were detected. When comparable rat liver perfusions were performed initially with 66 microM or 0.66 mM LPAM in the perfusion medium, bile samples did contain GSH-LPAM conjugates; the cumulative biliary excretion of the two conjugates amounted to 0.4 and 0.2% of the LPAM dose, respectively. These data suggest that both in rats and humans, hepatic GSH conjugation plays a very minor (if any) role in the elimination of LPAM and, therefore, that modulation of GSH levels is unlikely to affect the rate of elimination of this drug.

Topics: Animals; Antineoplastic Agents, Alkylating; Bile; Colorectal Neoplasms; Drug Resistance, Neoplasm; Glutathione; Humans; Infusions, Intravenous; Liver; Liver Neoplasms; Male; Melphalan; Rats; Rats, Wistar; Species Specificity

Relatively few studies have examined the activity of alkylating agents in the treatment of advanced colorectal adenocarcinoma. Recent reports have suggested possible therapeutic activity for high-dose intravenous melphalan administered with autologous bone marrow transplantation (BMT) support. We conducted a phase II study to determine the efficacy of administering intravenous melphalan at doses that do not require BMT support in patients with advanced colorectal adenocarcinoma.. Fifteen patients with histologically proven, bidimensionally measurable disease were treated. The starting dose of melphalan was 30 mg/m2, with dose escalation permitted.. No objective responses were observed. Toxic effects were primarily reversible granulocytopenia and thrombocytopenia. There were no treatment-associated deaths.. Melphalan's lack of efficacy at the doses administered does not disprove the steep chemotherapy dose-response relationship postulated for many solid tumors. However, we feel that it is unlikely that repetitive courses of high dose melphalan with autologous BMT support will be a practical approach to the management of advanced colorectal adenocarcinoma.

Topics: Adenocarcinoma; Aged; Colorectal Neoplasms; Female; Humans; Injections, Intravenous; Male; Melphalan; Middle Aged; Neoplasm Staging

Percutaneous hepatic perfusion with melphalan (M-PHP) is increasingly used in patients with liver metastases from various primary tumors, yet data on colorectal liver metastases (CRLM) are limited. The aim of this study was to prospectively evaluate the efficacy and safety of M-PHP in patients with CRLM.. Prospective, single-center, single-arm phase II study of M-PHP with hemofiltration in patients with unresectable CRLM. Proven, extrahepatic metastatic disease was one of the exclusion criteria. Primary outcomes were overall response rate (ORR) and best overall response (BOR). Secondary outcomes were overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.. A total of 14 M-PHP procedures were performed in eight patients between March 2014 and December 2015. All patients (median age 56 years, ranging from 46 to 68) had received (extensive) systemic chemotherapy before entering the study. The ORR was 25.0%, with two out of eight patients showing partial response as BOR. Median OS was 17.3 months (ranging from 2.6 to 30.9) with a one-year OS of 50.0%. Median PFS and hPFS were 4.4 and 4.5 months, respectively. No serious adverse events occurred. Grade 3/4 hematologic adverse events were observed in the majority of patients, though all were transient and well-manageable.. M-PHP is a safe procedure with only limited efficacy in patients with unresectable CRLM who already showed progression of disease after receiving one or more systemic treatment regimens.

Topics: Aged; Colorectal Neoplasms; Extracorporeal Circulation; Female; Hemofiltration; Humans; Liver; Liver Neoplasms; Male; Melphalan; Middle Aged; Perfusion; Progression-Free Survival

The role of hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is debated. Melphalan as a perfusion agent has also demonstrated survival benefit in other recurrent and chemoresistant malignancies. Thus, we hypothesize that melphalan as a HIPEC agent may improve overall survival (OS) and progression-free survival (PFS) in patients with PC from CRC.. A retrospective review of a prospective database of 48 patients who underwent optimal CRS (CC-0/1) and HIPEC from 2001-2016 was performed. Nineteen had CRS/HIPEC with melphalan (group I) and 29 with mitomycin-C (group II). Survival was estimated using the Kaplan-Meier method. Cox regression was used for multivariate analysis. Perioperative variables were compared.. Mean age at CRS/HIPEC was 53±10 years. Median peritoneal cancer index (PCI) was 17 vs 13 in groups I and II, respectively (p=0.86). PCI≥20 occurred in 9 (47%) and 13 (45%) patients in groups I and II, respectively. Positive lymph nodes were identified in 8/19 (42%) vs 12/29 (41%) in groups I and II, respectively (p=0.73). Multivariate analysis identified PCI≥20 as a predictive factor of survival (HR: 7.5). Median OS in groups I and II was 36 and 28 months, respectively (p=0.54). Median PFS in groups I and II was 10 and 20 months, respectively (p=0.05).. CRS/HIPEC with MMC had longer median PFS in PC from CRC. PCI≥20 was the only independent predictive factor for survival. Until longer follow-up is available, we recommend using MMC in CRS/HIPEC for PC from CRC. Further prospective randomized studies are necessary.

Topics: Antineoplastic Agents, Alkylating; Colorectal Neoplasms; Combined Modality Therapy; Cytoreduction Surgical Procedures; Female; Humans; Hyperthermia, Induced; Male; Melphalan; Middle Aged; Mitomycin; Peritoneal Neoplasms; Retrospective Studies; Survival Rate; United States

Topics: Animals; Antineoplastic Agents, Alkylating; CD4-Positive T-Lymphocytes; Cell Differentiation; Cell Line, Tumor; Colorectal Neoplasms; Dendritic Cells; Disease Models, Animal; Drug Therapy, Combination; Fibrosarcoma; Humans; Killer Cells, Natural; Lymphocyte Activation; Lymphocyte Depletion; Melphalan; Mice; Mice, Inbred BALB C; Recombinant Fusion Proteins; T-Lymphocytes, Cytotoxic; Tumor Burden

Unresectable liver metastases of colorectal cancer can be treated with systemic chemotherapy, aiming to limit the disease, extend survival or turn unresectable metastases into resectable ones. Some patients however, suffer from side effects or progression under systemic treatment. For patients with metastasized uveal melanoma there are no standard systemic therapy options. For patients without extrahepatic disease, isolated liver perfusion (IHP) may enable local disease control with limited systemic side effects. Previously, this was performed during open surgery with satisfying results, but morbidity and mortality related to the open procedure, prohibited a widespread application. Therefore, percutaneous hepatic perfusion (PHP) with simultaneous chemofiltration was developed. Besides decreasing morbidity and mortality, this procedure can be repeated, hopefully leading to a higher response rate and improved survival (by local control of disease). During PHP, catheters are placed in the proper hepatic artery, to infuse the chemotherapeutic agent, and in the inferior caval vein to aspirate the chemosaturated blood returning through the hepatic veins. The caval vein catheter is a double balloon catheter that prohibits leakage into the systemic circulation. The blood returning from the hepatic veins is aspirated through the catheter fenestrations and then perfused through an extra-corporeal filtration system. After filtration, the blood is returned to the patient by a third catheter in the right internal jugular vein. During PHP a high dose of melphalan is infused into the liver, which is toxic and would lead to life threatening complications when administered systemically. Because of the significant hemodynamic instability resulting from the combination of caval vein occlusion and chemofiltration, hemodynamic monitoring and hemodynamic support is of paramount importance during this complex procedure.

Topics: Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Humans; Liver Neoplasms; Melphalan

In order to determine the applicability of oxaliplatin in isolated liver perfusion, we identified the interaction between combinations of oxaliplatin and melphalan in 13 human colorectal cancer cell lines.. Cytotoxic activity was determined by the MTT-assay. Three different administration schedules of the two drugs were compared and median effect isobologram analysis was applied to the results, to determine the presence of synergism, additive effects, or antagonism as described by Chou and Talalay.. Resistance to melphalan did not correspond to resistance to oxaliplatin. All combinations of melphalan and oxaliplatin showed synergistic or additive interaction in the majority of the cell lines. One hour of oxaliplatin followed by 1h of melphalan showed the lowest percentage of cell viability, with synergy in 10 out of 13 cell lines at 50% cell viability. Simultaneous treatment showed the highest cell viability, with antagonism in six cell lines, additivity in two cell lines, synergism in five cell lines at 50% cell viability. One hour of melphalan followed by 1h of oxaliplatin showed synergy in six cell lines, antagonism in another six, and additivity in one cell line.. Our findings suggest a schedule-dependent synergistic interaction between melphalan and oxaliplatin. Therefore, oxaliplatin should be considered as a new, potentially valuable additional agent to the currently commonly used melphalan in isolated hepatic perfusion in colorectal cancer patients.

Topics: Adenocarcinoma; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms; Drug Administration Schedule; Drug Interactions; Drug Resistance, Neoplasm; Drug Synergism; Drug Therapy, Combination; Humans; In Vitro Techniques; Melphalan; Organoplatinum Compounds; Oxaliplatin; Time Factors

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Humans; Liver Neoplasms; Melphalan; Prognosis

Isolated hepatic perfusion with high-dose chemotherapy is a treatment option for patients with irresectable metastases confined to the liver. Prolonged local control and impact on survival have been claimed. Major drawbacks are magnitude and costs of the procedure. We developed an isolated hypoxic hepatic perfusion (IHHP) with retrograde outflow without the need for a heart-lung machine.. Twenty-four consecutive patients with irresectable metastases of various origins were treated. IHHP inflow was via the hepatic artery, outflow via the portal vein with occlusion of the retrohepatic caval vein. Radiolabeled albumine was used for leakage monitoring. Melphalan was used at 1-2 mg/kg. A 25-minute perfusion period was followed by a complete washout. Local and systemic melphalan concentrations were determined.. Compared with oxygenated classical IHP, the IHPP procedure reduced operation time from >8 h to 4 hours, blood loss from >4000 to 900 cc and saved material and personnel costs. Leakage was 0% with negligible systemic toxicity and 0% perioperative mortality. Tumor response: complete response (CR) in 4%, partial response (PR) in 58%, and stable disease (SD) in 13%. Median time to progression was 9 months (2-24 months); pharmacokinetics demonstrated intrahepatic melphalan concentrations more than 9 fold higher than postperfusion systemic concentrations.. IHPP is a relatively simple procedure with reduced costs, reduced blood loss, no mortality, limited toxicity, and response rates comparable to classic IHP. The median duration of 9 months of tumor control should be improved. Hereto, vasoactive drugs, will be explored in further studies.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Disease Progression; Eye Neoplasms; Female; Follow-Up Studies; Gas Chromatography-Mass Spectrometry; Hepatic Artery; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Male; Melphalan; Middle Aged; Neoplasms, Unknown Primary; Portal Vein; Sarcoma; Survival Rate; Treatment Outcome

The aim of this study was to identify prognostic factors for local and systemic failure after isolated hepatic perfusion (IHP) with 200 mg melphalan in patients with colorectal liver metastases.. Hundred and fifty-four patients were selected for IHP and underwent laparotomy. Patients were monitored for response, toxicity and survival. Univariate and multivariate analyses were carried out to identify prognostic factors for hepatic response and progression-free and overall survival.. Hepatic response rate was 50% with a median progression-free and overall survival of, respectively, 7.4 and 24.8 months. In multivariate analyses, absence of ability to perfuse through the hepatic artery (P = 0.003), severe postoperative complications (P = 0.048) and >10 liver metastases (P = 0.006) adversely influenced overall survival and no adjuvant chemotherapy adversely influenced progression-free survival.. This is the first study to report prognostic factors for survival after IHP. Possibly, overall and disease-free survival can increase if preoperative screening is improved. In future studies on IHP, adjuvant chemotherapy should be considered.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Female; Humans; Liver Neoplasms; Male; Melphalan; Middle Aged; Prognosis; Retrospective Studies; Survival Analysis; Treatment Outcome

Isolated hepatic perfusion (IHP) offers the advantage of high local drug exposure with limited systemic toxicity. To increase local drug exposure, we administered melphalan at a reduced flow in the hepatic artery during IHP (hepatic artery infusion, hepatic artery-portal vein perfusion, HI-HPP). Between December 2001 and December 2004, 30 patients with colorectal cancer liver metastases underwent HI-HPP with 200mg melphalan. Samples of the perfusate were taken for pharmacokinetic analysis. Patients were monitored for response, toxicity and survival. Perfusion was aborted prematurely in 2 patients due to leakage. During melphalan administration in the hepatic inflow cannula a mean flow rate of 121.3 mL/min and mean pressure of 62.5mm Hg were achieved. One patient died within 30 days after HI-HPP. Four patients developed veno-occlusive disease (VOD), while 2 patients showed signs of VOD. Twelve patients showed hepatic response, with a median duration of response of 11.5 months, according to WHO criteria. Although HI-HPP results in high perfusate melphalan concentration levels, it is associated with a relatively high level of hepatotoxicity and a limited response rate. We believe that the low flow and pressure rates found in this study can result in reduced drug penetration of the tumour and thus limited tumour response.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Colorectal Neoplasms; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Hepatic Artery; Humans; Infusion Pumps; Infusions, Intra-Arterial; Liver Neoplasms; Male; Melphalan; Middle Aged; Netherlands; Perfusion; Retrospective Studies; Survival Rate; Treatment Outcome

Irinotecan given with 5-fluorouracil and leucovorin is currently used as first-line therapy for patients with metastatic colorectal cancer (CRC). However, the response duration is <1 year, and second-line systemic chemotherapy has limited efficacy. We analyzed the efficacy of isolated hepatic perfusion (IHP) for patients with progressive CRC liver metastases after irinotecan.. Between March 1993 and February 2003, 124 patients with CRC liver metastases underwent IHP on institutional review board-approved protocols. The overall treatment mortality was 4% (5 of 124). Twenty-five patients (10 women and 15 men; mean age, 53 years) were identified who had progressive liver metastases by carcinoembryonic antigen, imaging studies, or both after irinotecan. A 1-hour hyperthermic IHP (mean hepatic temperature, 40.0 degrees C) with melphalan 1.5 mg/kg (mean total dose, 100 mg) was administered via laparotomy. Perfusion with an oxygenated extracorporeal circuit was established with inflow via a cannula in the gastroduodenal artery and common hepatic artery inflow occlusion. Outflow was via a cannula in an isolated segment of the inferior vena cava. During IHP, portal and inferior vena caval flow were shunted to the axillary vein. Patients were assessed for radiographical response, recurrence pattern, and survival.. The mean number of prior irinotecan cycles in 25 patients was 6 (range, 2-14), and it was given primarily as second-line therapy. The median number of liver metastases before IHP was 10 (range, 1-50), and the median percentage of hepatic replacement by tumor was 25%. The mean operative time was 9 hours (range, 6-12 hours), and the median hospital stay was 11 days (range, 8-76 days). There was 1 complete response and there were 14 partial responses in 25 patients (60%), with a median duration of 12 months (range, 5-35 months). Disease progressed systemically in 13 of 25 patients at a median of 5 months (range, 3-16 months). The median overall survival was 12 months (range, 1-47 months), and the 2-year survival was 28%.. For patients with progressive CRC liver metastases after irinotecan, IHP has good efficacy in terms of response rate and duration. Continued evaluation of IHP with melphalan as second-line therapy in this clinical setting is justified.

Topics: Adult; Aged; Antineoplastic Agents; Camptothecin; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Disease Progression; Female; Humans; Hyperthermia, Induced; Irinotecan; Liver Neoplasms; Male; Melphalan; Middle Aged; Neoplasm Staging; Treatment Failure; Treatment Outcome

Isolated lung perfusion is an experimental technique for the treatment of lung metastases. Single-agent isolated lung perfusion does not result in complete remission. We studied the in vivo and in vitro efficacy of combinations of gemcitabine, cisplatin, and melphalan.. In vitro, using the sulforhodamine B assay, CC531s cells were incubated with cisplatin, gemcitabine, or melphalan or with a combination of these drugs. One drug was added at concentrations causing 25% growth inhibition, whereas the second drug was added at variable concentrations. In vivo, left pulmonary metastases were induced in Wag/Rij rats by means of intravenous injection of CC531s adenocarcinoma cells. At day 7, rats underwent left isolated lung perfusion with gemcitabine (n = 7), cisplatin (n = 9), melphalan (n = 7), gemcitabine-cisplatin (n = 6), melphalan-gemcitabine (n = 6), and cisplatin-melphalan (n = 7). Death by means of metastatic disease was the end point. Survival and differences in survival were assessed by using Kaplan-Meier and log-rank testing.. In vitro synergistic activity was observed for melphalan-gemcitabine, whereas other combinations showed additive or antagonistic activity. In vivo treated rats lived longer compared with control animals ( P < .0001). In isolated lung perfusion melphalan resulted in longer survival compared with gemcitabine ( P = .0016) and cisplatin ( P = .046). Isolated lung perfusion with melphalan-gemcitabine resulted in 67% survival of the rats after 90 days versus 0% in other groups.. Isolated lung perfusion monotherapy or combination therapy with gemcitabine, cisplatin, or melphalan resulted in significantly longer survival compared with that seen in control animals. Isolated lung perfusion combination therapy with melphalan-gemcitabine resulted in the best survival either in vitro or in vivo.

Topics: Adenocarcinoma; Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Colorectal Neoplasms; Deoxycytidine; Dose-Response Relationship, Drug; Gemcitabine; In Vitro Techniques; Inhibitory Concentration 50; Lung Neoplasms; Male; Melphalan; Rats; Rats, Inbred Strains; Tumor Cells, Cultured

Melphalan is a chemotherapeutic drug that exerts its cytotoxic effect mainly through the formation of DNA adducts. We report the specific immunohistochemical detection and visualisation of melphalan-DNA adducts using the monoclonal antibody MP5/73 in cultured tumour cells and solid tumour tissue from colorectal liver metastases from patients treated with melphalan. The human colon cancer cell lines HT29, SW480 and SW1116, and the rat colon cancer cell line CC531 were exposed to different concentrations of melphalan. In addition, tumour samples from 17 patients with colorectal liver metastases treated by isolated hepatic perfusion with high dose melphalan (200mg) were collected. Cell lines and tumour samples were stained with the MP5/73 antibody against melphalan-DNA adducts and cell viability was determined by an MTT assay. Melphalan-DNA adducts could be visualised by immunohistochemistry in both cultured cells and solid tumour tissue. A correlation between melphalan exposure concentration, the subsequent melphalan-DNA adduct staining intensity, and melphalan cytotoxicity existed for each individual cell line, but the level of both parameters independently differed between cell lines. Specific staining for melphalan-DNA adducts also was feasible in the human solid tumour tissue. There was considerable variation in melphalan-DNA adduct staining, staining intensity, and distribution in the tumour stroma and the tumour epithelium among the different patients. Melphalan-DNA adducts appeared to be more intense in tumour cells at the border of the tumour nodules than in tumour cells in the centre. Thus, visualisation of melphalan-DNA adducts by immunohistochemistry allows the study of distribution of melphalan-DNA adducts in solid tumours.

Topics: Animals; Antigens, CD34; Antineoplastic Agents, Alkylating; Biomarkers, Tumor; Carrier Proteins; Colonic Neoplasms; Colorectal Neoplasms; DNA Adducts; Enzyme-Linked Immunosorbent Assay; Humans; Immunohistochemistry; Laminin; Leukocyte Common Antigens; Liver Neoplasms; Melphalan; Rats; Receptors, Cell Surface; Tumor Cells, Cultured

Increasing the drug concentration in tumors may produce massive tumoral response. By using a variety of hepatic vascular isolation techniques, high concentrations of chemotherapeutic drugs may be achieved in the hepatic vascular bed.. Complete percutaneous isolated hepatic perfusion (IHP) is feasible and safe.. Case series.. The hepatobiliary unit of a university hospital.. Ten patients with irresectable and chemoresistant hepatic tumors were eligible for study participation; 4 patients with hepatic metastases of breast cancer, gastric cancer, colorectal cancer, and cholangiocarcinoma were included.. Patients received 3 successive courses of chemotherapy by IHP. The first course was given at laparotomy, and the next 2 courses were given percutaneously. The interval between courses was 3 to 6 weeks. Each course involved IHP of the liver for 15 to 30 minutes, without oxygenation, with 1 to 3 boluses of melphalan (15 mg).. Morbidity and mortality.. Ten IHPs were performed (4 at laparotomy and 6 percutaneously). Concentrations of melphalan in the extracorporeal circulation were 10 times higher than those in the systemic circulation. Percutaneous IHPs had more leakage than those at laparotomy. However, hepatotoxicity was minimized. One patient experienced hepatic artery thrombosis, and 3 had severe neutropenia. Minor complications included ascites and pleural effusion. No deaths were observed 2 months after the last IHP. One partial response was observed (hepatic metastases of breast cancer).. Percutaneous IHP for intensive chemotherapy is less aggressive and less hepatotoxic than IHP at laparotomy and may be iterative.

Topics: Adenocarcinoma; Antineoplastic Agents; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Breast Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Cholangiocarcinoma; Colorectal Neoplasms; Fatal Outcome; Female; Humans; Laparotomy; Liver Neoplasms; Male; Melphalan; Middle Aged; Radiography, Interventional; Stomach Neoplasms

Many patients with colorectal carcinoma develop unresectable metastases confined to the liver that remain the life-limiting component of disease despite best available systemic or regional chemotherapy. In the current study, the authors present their results using vascular isolation and perfusion of the liver for individuals with progressive, unresectable liver metastases from colorectal carcinoma that were refractory to both previous systemic and regional chemotherapy.. Seven patients with refractory, progressive, unresectable colorectal carcinoma metastases confined to the liver underwent a 60-minute hyperthermic (39-40 degrees C) isolated hepatic perfusion (IHP) and were followed for toxicity, response, and survival.. There was no surgical- or treatment-related mortality; all patients experienced transient Grade 3-4 (according to National Cancer Institute common toxicity criteria) hepatic toxicity. At a median potential follow-up of 16 months, the overall objective radiographic response rate (all partial responses) was 71% (5 of 7 assessable patients). It is interesting to note that two patients who were treated with tumor necrosis factor (TNF) alone demonstrated no response to therapy compared with all five patients who were treated with melphalan and TNF (three patients) or melphalan alone (two patients). For the 5 patients who responded to treatment, the median duration of response was 10 months (range, 10-13 months) and in all 7 patients the mean overall survival was 19.7 months (range, 2-33 months), including 5 months and 7.5 months, respectively, for the 2 patients treated with TNF alone.. The results of the current study demonstrate that IHP using melphalan with or without TNF has significant antitumor activity in this patient population. IHP deserves continued clinical evaluation as a therapeutic modality for patients with unresectable colorectal carcinoma metastases to the liver.

Topics: Aged; Antineoplastic Agents; Carcinoma; Chemotherapy, Cancer, Regional Perfusion; Cohort Studies; Colorectal Neoplasms; Drug Resistance, Neoplasm; Hepatic Veins; Humans; Liver Neoplasms; Male; Melphalan; Middle Aged; Tumor Necrosis Factor-alpha

We compared two prospective trials of intra-arterial cytokine/chemotherapeutic infusion plus chemoembolization in the treatment of inoperable colorectal liver metastases.. One hundred and three patients with disseminated inoperable colorectal liver metastases received intra-arterial chemotherapy with 5-FU and granulocyte-macrophage colony-stimulating factor (GM-CSF) plus chemoembolization via an angiographically positioned hepatic artery catheter. Two different regimens were used in two consecutive studies. Group A: short-term i.a. infusion of 550 mg/m(2)5-FU (days 1-4) plus 80 microg/m(2)GM-CSF (day 1+2) combined with chemoembolization with 25 mg/m(2)melphalan plus Lipiodol and Gelfoam (day 5). Group B: continuous circadian intra-arterially administered 1400 mg/m(2)5-FU infusion plus 60 mg/m(2)i.v. leucovorin and 80 microg/m(2)GM-CSF (day 1+2) combined with chemoembolization with 25 mg/m(2)melphalan plus Lipiodol and Gelfoam (day 3).. One hundred and three patients (62 male/41 female) with a median age of 59.9 and a median Karnofsky index of 88.5 were treated with 447 cycles of immuno-chemoembolization (group A 299, group B 148 cycles). Fifty-seven percent of these patients had received prior systemic chemotherapy. Side-effects were seen in all patients, mainly upper abdominal pain lasting 1-4 days and grade 1 or 2 vomiting. Systemic side-effects were mild and transient with a very low rate of leukopenia. Using World Health Organization response criteria, the following responses could be demonstrated: group A: CR 2.7%, PR 32.4%, MR 21.6%, SD 12.7%, NR 16.2%; group B: CR 1.0%, PR 42.4%, MR 24.2%, SD 18.2%, NR 12.1%. Time to progression was 7 as compared to 8 months. Median survival was 17 months in group A, whereas it has not been reached after 28 months (P=0.0095) in group B. There was no statistically significant difference between chemo-naive patients and patients who had received prior systemic therapy.. Immuno-chemoembolization combined with 2-day circadian administration of 5-FU is an effective tool in the treatment of disseminated colorectal liver metastases. This regimen is also effective as second-line treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemoembolization, Therapeutic; Colorectal Neoplasms; Combined Modality Therapy; Dendritic Cells; Female; Fluorouracil; Granulocyte Colony-Stimulating Factor; Humans; Infusions, Intravenous; Liver Neoplasms; Male; Melphalan; Middle Aged; Prospective Studies; Statistics, Nonparametric; Survival Rate

The theoretical advantage of regional vs. systemic chemotherapy was calculated, based on pharmacokinetic considerations. The relevance of exposure time and high local concentrations of chemotherapeutic drugs for regional chemotherapy was elucidated in time dependent concentration response curves with two human cell lines. The theoretical pharmacological advantage of regional vs. systemic chemotherapy was defined by the formula Rd = (AUCi. a. 1 + AUCi. a. 2)/(AUCi. v.) and in hepatic artery infusion is for adriamycin (ADM) 5.8-.6, cis-platinum (CDDP) 8, epirubicine (EPI) 6.3, 5-fluorouracil (5-FU) 22-58, mitomycin C (MMC) 4.6, mitoxantrone (NOV) 6.3. All drugs but 5-FUDR exerted concentration response behaviour in the cell line-experiments. In the cell lines cytotoxicity depended on exposure time so that concentration chi time products at (IC50), (c chi t (IC50)), were calculated to determine an optimal in vitro exposure time. Based on these results and clinical considerations, optimal clinical exposure times could be defined for regional chemotherapy. The results may be of high relevance for e.g. hepatic artery infusion at the lower and chemoembolization or intraperitoneal instillation at the higher test concentration, respectively.

Topics: Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Carcinoma; Cisplatin; Colorectal Neoplasms; Doxorubicin; Epirubicin; Floxuridine; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Melphalan; Mitomycin; Mitoxantrone; Tumor Cells, Cultured

Glutathione (GSH) plays an important role in the resistance of tumors to cytostatics. Therefore, depletion of GSH by the GSH synthesis inhibitor buthionine sulfoximine (BSO) has been proposed to enhance the efficacy of certain anticancer agents. We studied the effect of BSO in rats bearing intrahepatically implanted tumors of the CC531 colorectal cancer cell line on the antitumor activity of melphalan (L-PAM). Since these liver tumors tend to derive most of their blood supply from the hepatic artery, we evaluated whether delivery of BSO into the hepatic artery would more selectively decrease GSH levels in the implanted tumor tissue as compared with normal liver and extrahepatic tissues.. Tumor-bearing rats were treated with a 24-h continuous infusion of 0.375 mmol/ kg BSO via the jugular vein, immediately followed by a bolus L-PAM (15 micromol/kg; 4.5 mg/kg) infusion via the hepatic artery. Laparotomy was performed on day 14 and 28 after treatment for measurement of the liver tumors. For the evaluation of locoregional administration of BSO, a 24-h continuous infusion of 0.375 mmol/kg BSO was delivered into either the hepatic artery, the portal vein, or the jugular vein in freely moving rats and GSH levels in the tumor, liver, kidney, lung, heart, bone marrow, and blood were measured.. BSO infusion via the jugular vein increased the antitumor efficacy of L-PAM injected into the hepatic artery 2-fold as determined at 14 days after treatment. Although infusion of BSO via the hepatic artery depleted GSH more severely in the tumor as compared with jugular vein or portal vein administration, the additional effect was only slight (10%). No difference was observed in any other tissue.. GSH depletion increased the cytostatic efficacy of L-PAM 2-fold in vivo as determined at 14 days after treatment. Hepatic artery infusion of BSO translated into a statistically significant, but probably not therapeutically relevant, increase in tumor GSH depletion as compared with the other routes of BSO administration.

Topics: Animals; Buthionine Sulfoximine; Colorectal Neoplasms; Drug Synergism; Glutathione; Infusions, Intra-Arterial; Liver Neoplasms, Experimental; Male; Melphalan; Rats

Intracellular levels of glutathione have been shown to affect the sensitivity of cells to cell death-inducing stimuli, as well as the mode of cell death. We found in five human colorectal cancer cell lines (HT-29, LS-180, LOVO, SW837, and SW1116) that GSH depletion by L-buthionine-[S,R]-sulfoximine (BSO) below 20% of control values increased L-phenylalanine mustard (L-PAM; Melphalan) cytotoxicity 2- to 3-fold. Effects on kinetics of both cell cycle progression and cell death were further investigated in the HT-29 cell line. BSO treatment alone had no effect on cell cycle kinetics, but did enhance the inhibition of S phase progression as induced by L-PAM; at high concentration of of L-PAM, BSO pretreatment resulted in blockage in all phases of the cell cycle. Yet, BSO pretreatment did not affect the intracellular L-PAM content. L-PAM induced apoptosis in both normal and GSH-depleted cells. A combination of annexin V labeling and propidium iodide staining revealed that even the higher concentration of L-PAM (420 microM) did not induce apoptosis until 48 hr after treatment, but that induction of cell death was markedly accelerated as a result of GSH depletion: 48 hours after L-PAM (420 microM) treatment, GSH-depleted cells showed a 4-fold increase in DNA fragmentation and a 7-fold increase in the fraction of apoptotic (annexin V-positive) cells as compared to cells with normal GSH levels. Various antioxidant treatment modalities could not prevent this potentiating effect of GSH depletion on L-PAM cytotoxicity, suggesting that reactive oxygen species do not play a role. These data show that after BSO treatment the mode of L-PAM-induced cell death does not necessarily switch from apoptosis to necrosis.

Topics: Antineoplastic Agents, Alkylating; Antioxidants; Apoptosis; Buthionine Sulfoximine; Cell Cycle; Cell Line; Colorectal Neoplasms; Glutathione; HT29 Cells; Humans; Melphalan; Tumor Cells, Cultured

Loss of DNA mismatch repair is a common finding in hereditary non-polyposis colon cancer as well as in many types of sporadic human tumours. We compared the effect of loss of DNA mismatch repair on drug sensitivity as measured by a clonogenic assay with its effect on the ability of the same drug to enrich for mismatch repair-deficient cells in a proliferating tumour cell population. Mixed populations containing 50% DNA mismatch repair-deficient cells constitutively expressing green fluorescent protein and 50% mismatch repair-proficient cells were exposed to different chemotherapeutic agents. 6-Thioguanine, to which DNA mismatch repair-deficient cells are known to be resistant, was included as a control. The results in the cytotoxicity assays and in the enrichment experiments were concordant. Treatment with either carboplatin, cisplatin, doxorubicin, etoposide or 6-thioguanine resulted in enrichment for mismatch repair-deficient cells, and clonogenic assays demonstrated resistance to these agents, which varied from 1.3- to 4.8-fold. Treatment with melphalan, paclitaxel, perfosfamide or tamoxifen failed to enrich for mismatch repair-deficient cells, and no change in sensitivity to these agents was detected in the clonogenic assays. These results identify the topoisomerase II inhibitors etoposide and doxorubicin as additional agents for which loss of DNA mismatch repair causes drug resistance. The concordance of the results from the two assay systems validates the enrichment assay as a rapid and reliable method for screening for the effect of loss of DNA mismatch repair on sensitivity to additional drugs.

Topics: Adenocarcinoma; Antineoplastic Agents; Carboplatin; Cell Separation; Cisplatin; Colorectal Neoplasms; Cyclophosphamide; DNA Repair; DNA, Neoplasm; Doxorubicin; Enzyme Inhibitors; Etoposide; Humans; Melphalan; Paclitaxel; Tamoxifen; Thioguanine; Tumor Cells, Cultured; Tumor Stem Cell Assay

In this study we determined the level of tumour necrosis factor alpha (TNF-alpha) in liver and tumour tissue samples obtained from patients with colorectal metastases confined to the liver, who were treated with isolated liver perfusion with TNF-alpha and melphalan. We adapted a standard enzyme-linked immunosorbent assay kit for the quantification of TNF-alpha in serum to measure the amount of this cytokine in solid tissue. For this purpose, we developed a buffer that lysed the tissues without affecting the TNF-alpha present. The minimum detection level was about 2 pg of TNF-alpha per mg tissue. Using this technique, we found a significant increase in the TNF-alpha level after perfusion in the liver tissue of all evaluable patients, which may explain the transient liver toxicity we observed in all patients. In tumour tissue, a significant TNF-alpha increase was observed in one out of five patients. The level of TNF-alpha in all liver tissue samples and some of the tumours after treatment by isolated liver perfusion was much higher than the peak serum concentrations obtained after systemic administration of the maximum tolerated dose of TNF-alpha. Furthermore, we demonstrated that the level of TNF-alpha in the liver tissue samples was about seven to eight times higher than in tumour tissue. We concluded that regional liver treatment resulted in a relatively high local level of TNF-alpha, but also that this cytokine did not preferentially accumulate in tumour tissue.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Colorectal Neoplasms; Enzyme-Linked Immunosorbent Assay; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Liver; Liver Neoplasms; Male; Melphalan; Middle Aged; Perfusion; Tumor Necrosis Factor-alpha

Loss of DNA mismatch repair is a common finding in many types of sporadic human cancers as well as in tumors arising in patients with hereditary nonpolyposis colon cancer. The effect of the loss of DNA mismatch repair activity on sensitivity to a panel of commonly used chemotherapeutic agents was tested using one pair of cell lines proficient or deficient in mismatch repair due to loss of hMSH2 function and another due to loss of hMLH1 function. 6-Thioguanine and N-methyl-N'-nitro-N-nitrosoguanidine, to which these cells are known to be resistant, were included in the panel as controls. The results were concordant in both pairs of cells. Loss of either hMSH2 or hMLH1 function was associated with low level resistance to cisplatin, carboplatin, and etoposide, but there was no resistance to melphalan, perfosfamide, 5-fluorouracil, doxorubicin, or paclitaxel. The results are consistent with the concept that the DNA mismatch repair proteins function as a detector for adducts produced by 6-thioguanine, N-methyl-N'-nitro-N-nitrosoguanidine, cisplatin, and carboplatin but not for melphalan and perfosfamide. They also suggest that these proteins play a role in detecting the DNA damage produced by the binding of etoposide to topoisomerase II and propagating signals that contribute to activation of apoptosis.

Topics: Adaptor Proteins, Signal Transducing; Adenocarcinoma; Antineoplastic Agents; Carboplatin; Carrier Proteins; Cisplatin; Colorectal Neoplasms; Cyclophosphamide; DNA Adducts; DNA Damage; DNA Repair; DNA-Binding Proteins; DNA, Neoplasm; Doxorubicin; Drug Resistance, Neoplasm; Endometrial Neoplasms; Etoposide; Female; Fluorouracil; Humans; Melphalan; Methylnitronitrosoguanidine; Mutagenesis; MutL Protein Homolog 1; MutS Homolog 2 Protein; Neoplasm Proteins; Nuclear Proteins; Paclitaxel; Proto-Oncogene Proteins; Thioguanine; Tumor Cells, Cultured

Human anti-mouse antibody (HAMA) response was determined in the serum of 67 patients who received subcutaneously administered radiolabelled murine monoclonal antibodies (MoAb) (50 micrograms-3 mg) for immunolymphoscintigraphy and of 10 patients with advanced colorectal cancer who received murine MoAb-N-acetyl melphalan (MoAb-N-AcMEL) conjugates (amount of MoAb ranged from 120 mg/m2 body surface area to 1000 mg/m2 body surface area) as therapy. A pre-existing low level of apparent human anti-mouse antibody reactivity could be detected in the serum of normal subjects and patients prior to administration of murine MoAb. Subcutaneous administration of low doses of murine MoAb, as used in immunolymphoscintigraphy, was associated with a low incidence (4/67 or 6%) of elevated HAMA response; the use of F(ab')2 fragments was associated with the development of elevated HAMA response in one of three patients. By contrast, therapy with hepatic artery infusion of murine MoAb-N-AcMEL conjugates in three repetitive daily doses (each infusion lasting 2 h) elicited elevated HAMA responses in 10/10 (100%) patients, usually 1-3 weeks after the start of therapy. The HAMA response of patients in the therapy group was higher than those in the immunolymphoscintigraphy study and the use of steroids did not prevent the development of the HAMA response. Further administration of MoAb-N-AcMEL conjugates to a patient, who had already developed HAMA, led to 'serum sickness'-type symptoms and a transient reduction in the HAMA titres. The elevated HAMA response was polyclonal, containing increased levels of both immunoglobulin M and G (IgM and IgG) and was directed against mouse-specific determinant, the isotype (presumed to be the Fc portion), the F(ab')2 and the 'idiotype' of mouse immunoglobulins.

Topics: Animals; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Breast Neoplasms; Colorectal Neoplasms; Enzyme-Linked Immunosorbent Assay; Epitopes; Humans; Immunoglobulin Fab Fragments; Immunoglobulin Fc Fragments; Immunoglobulin Fragments; Immunotoxins; Infusions, Intra-Arterial; Injections, Subcutaneous; Lymphatic Metastasis; Melphalan; Mice; Radionuclide Imaging; Time Factors

Based on the high response rates seen among patients with colon cancer receiving high dose Melphalan with autologous marrow infusion, the Southwest Oncology Group conducted a Phase II trial of the compound at a conventional dose. The initial starting dose of 40 mg/m2 was reduced to 30 mg/m2 after severe myelotoxicity was encountered in the first five patients. Toxicity was primarily myeloid and was moderate to severe in most patients with one treatment related death. There were two complete and one partial response among 43 patients. Melphalan at 30 mg/m2 has little activity among patients with metastatic colorectal carcinoma.

Topics: Adult; Aged; Colorectal Neoplasms; Drug Evaluation; Female; Humans; Infusions, Intravenous; Male; Melphalan; Middle Aged

Melphalan (MEL), an alkylating agent, has been modified to a derivative, N-acetylmelphalan (N-AcMEL), which can be conjugated to anticolon cancer monoclonal antibodies (MoAbs 30.6, I-1, and JGT) and used for immunochemotherapy. The final immunoconjugates possess potent cytotoxicity and specificity in preclinical studies. In a phase I clinical study, N-AcMEL-MoAb conjugates were administered via the hepatic artery to 10 patients, nine of whom had disseminated colorectal cancer (including the liver) and one of whom had Dukes' C colon cancer that had been resected. The selection of MoAb was based on the immunoperoxidase staining of the primary colon cancer tissue. Thus far doses of 1000 mg/m2 MoAb conjugated to 20 mg/m2 of N-AcMEL have been administered with no significant side effects, whereas MEL unconjugated to monoclonal antibodies would have caused myelosuppression in a proportion of patients at the same dosage. Serum antimouse antibody responses were noted in all of the patients; febrile reactions were noted with higher doses but were easily controlled with antipyretics, antihistamines and, if necessary, steroids. Serum sickness developed in one patient who was given a second course of treatment in the presence of human antimouse antibody, but the episode was self-limiting. Eight of the 10 patients had evaluable disease. Subjective improvement was noted in almost all of the patients examined, and 33%, or 3 of 9, of the treatments (nine courses of treatment in eight patients with evaluable disease; one of the patients had two courses of treatment) led to antitumor responses (minor response) by objective assessment with computed tomography of the liver. It is important to note that treatment with N-AcMEL-MoAb conjugates was safe at a dose of 20 mg/m2 of N-AcMEL, whereas the efficacy of such a form of treatment remains to be determined.

Topics: Adult; Antibodies, Monoclonal; Antineoplastic Agents; Carcinoembryonic Antigen; Carcinoma; Colorectal Neoplasms; Drug Evaluation; Female; Humans; Immunohistochemistry; Immunotoxins; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Tomography, X-Ray Computed