melphalan and Pancreatic-Neoplasms

Developments in balloon catheter methodology have made hypoxic abdominal perfusion (HAP) with anti-tumour agents possible with only minimal invasive surgery. The initial reports on this modality and celiac axis stop-flow infusion for treatment of pancreatic cancer were very promising in terms of tumour response, median survival and pain reduction. Recent reports, however, have not been able to confirm these results and some have disputed the efficacy of these currently still applied treatment modalities.. Twenty-one patients with advanced pancreatic carcinoma were included in a phase I-II trial of HAP with MMC and Melphalan followed by celiac axis infusion (CAI) with the same agents six weeks later. Tumour response was assessed by abdominal-CT and by determining tumour markers. Effect on pain reduction was assessed by evaluation of pain registration forms.. HAP resulted in augmented regional drug concentrations. One patient died after CAI due to acute mesenterial ischaemia. One agent-toxicity related death was observed in the phase-I study. Significant hematological toxicity was observed after HAP and CAI at MTD. No patients were considered resectable after treatment. Median survival after HAP was 6 months (range 1-29). Pain reduction was experienced by only 5/18 patients and was short-lived.. In contrast to earlier reports HAP and CAI with MMC and Melphalan did not demonstrate any benefit in terms of tumour response, median survival and pain reduction, compared to less invasive treatment options. As this treatment was associated with significant toxic side-effects and even one procedure related death, we do not consider this a therapeutic option in patients with advanced pancreatic cancer.

Topics: Aged; Antineoplastic Agents; Balloon Occlusion; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Hypoxia; Infusions, Intra-Arterial; Male; Melphalan; Middle Aged; Mitomycin; Pain; Pain Measurement; Pancreatic Neoplasms; Remission Induction; Treatment Outcome

We report results of using isolated hepatic perfusion (IHP) in patients with advanced progressive liver metastases (LM) from pancreatic and gastrointestinal neuroendocrine neoplasms (NENs).. Thirteen patients with LM from NENs (mean percent hepatic replacement, 30; range, 10-60) were treated with a 1-hour hyperthermic IHP via a laparotomy with the use of 1.5 or 2.0 mg/kg melphalan and/or 1 mg tumor necrosis factor. An oxygenated extracorporeal circuit with inflow through the gastroduodenal artery and common hepatic artery, and outflow to a segment of the inferior vena cava was used. Portal flow and inferior vena cava flow were shunted to the axillary vein. Radiographic response, recurrence pattern, and survival were assessed.. Mean operative time was 9 hours (8-11 hours), and a median hospital stay was 10 days (6-64 days). Fifty percent of evaluable patients had a radiographic partial response in the liver (mean duration, 15 months; range, 6-26 months; 2 ongoing). Four had a marginal response (25%-49% reduction in the neoplasm). The median, hepatic, progression-free survival was 7 months (range, 3-27 months). The median actuarial survival was 48 months including 1 treatment mortality (median follow-up, 23 months).. For patients with advanced LM from NENs, IHP provides a reasonable response rate and duration with acceptable morbidity; continued clinical evaluation is important.

Topics: Adult; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Female; Gastrointestinal Neoplasms; Humans; Hyperthermia, Induced; Liver Neoplasms; Male; Melphalan; Middle Aged; Neoplasm Staging; Neuroectodermal Tumors; Pancreatic Neoplasms; Survival Analysis; Treatment Outcome; Tumor Necrosis Factor-alpha

Animal studies suggest less cardiovascular disturbance if the aorta and vena cava are occluded simultaneously. We set out to establish the effects of simultaneous clamping in humans, because oncologists suggested that perfusion for chemotherapy could be done under local anaesthesia without invasive haemodynamic monitoring.. We studied the cardiovascular effects of the onset and removal of simultaneous occlusion of the thoracic aorta and inferior vena cava, in seven ASA II patients. Two stop-flow catheters positioned in the aorta and in the inferior vena cava were inflated to allow hypoxic abdominal perfusion to treat pancreatic cancer. We measured the arterial pressure, heart rate (HR), right atrial pressure (RAP), pulmonary artery pressure (PAP), pulmonary artery wedge pressure (PAWP) and cardiac output (CO), and calculated systemic vascular resistance index (SVRi), pulmonary vascular resistance index (PVRi), left ventricular stroke work index (LVSWi) and right ventricular stroke work index (RVSWi). Three patients were studied with transoesophageal echocardiography.. Six patients needed intravenous nitroprusside during the occlusion because mean arterial pressure (MAP) increased to more than 20% of baseline (SVRi increased by 87%). One minute after occlusion release, all patients had a 50% decrease in MAP, and mPAP increased by 50%. The procedure had severe cardiovascular effects, shown by a 100% increase in cardiac index at occlusion release with increases in left and right ventricular stroke work indices of 75% and 147%. Left ventricular wall motion abnormalities were seen on transoesophageal echocardiography.. Serious haemodynamic changes occur during simultaneous occlusion of the thoracic aorta and inferior vena cava, which may need invasive haemodynamic monitoring.

Topics: Aged; Antihypertensive Agents; Antineoplastic Combined Chemotherapy Protocols; Aorta, Thoracic; Chemotherapy, Cancer, Regional Perfusion; Constriction; Female; Hemodynamics; Humans; Hypertension; Male; Melphalan; Middle Aged; Mitomycin; Monitoring, Physiologic; Nitroprusside; Pancreatic Neoplasms; Vena Cava, Inferior

To test the hypothesis that 41.8 degrees C x 60 min whole body hyperthermia (WBH) induces increased serum levels of soluble necrosis factor receptors (sTNF-R).. We tested the serum of cancer patients for changes in sTNF-RI and RII levels, as a function of time, pre and post: (1) WBH alone, (2) WBH and chemotherapy, i.e., melphalan (L-PAM), and (3) L-PAM alone.. For sTNF-RI there was a marked increase (over pre-treatment values, i.e., 86%) in serum levels after WBH alone (n = 3), which peaked 2.5 h post-WBH; L-PAM (iv) only resulted in a dip in sTNF-RI seen 40 min postadministration; the combination (WBH + L-PAM), resulted in both the dip at 40 min and the increase at 2.5 h post-treatment. For sTNF-RII both WBH alone (n = 3) and WBH + L-PAM (n = 2), there was an increase in receptor serum levels of 25% and 30%, respectively, which peaked 5.5 h post-treatment, and remained elevated at 24 h. L-PAM alone resulted in a dip in levels only at 40 min post-treatment. sTNF-RI and RII levels returned to baseline values within 7 days post-treatment.. 41.8 degrees C WBH results in transient increases in TNF-RI and RII. These results may have therapeutic implications for the application of WBH to TNF mediated disease processes.

Topics: Adult; Antineoplastic Agents, Alkylating; Body Temperature; Cohort Studies; Female; Humans; Hyperthermia, Induced; Interleukin-10; Male; Melanoma; Melphalan; Middle Aged; Pancreatic Neoplasms; Receptors, Tumor Necrosis Factor; Rheumatic Diseases; Skin Neoplasms; Solubility; Tumor Necrosis Factor-alpha

Topics: Adult; Aged; Biliary Tract Diseases; Clinical Trials as Topic; Colonic Neoplasms; Drug Evaluation; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Male; Melphalan; Middle Aged; Pancreatic Neoplasms; Rectal Neoplasms; Stomach Neoplasms

Whereas surgical resection is the only curative treatment for liver tumors, effective treatment for isolated unresectable lesions when there is tumor progression in spite of several lines of chemotherapy remains to be found. We report herein two cases of patients treated by a 1-hour Hyperthermic Isolated Liver Perfusion (HILP) with a combination of melphalan and bevacizumab leading to complete response. The first patient had liver metastases secondary to previously resected malignant glucagonoma and the second, recurrent hepatocellular carcinoma. We used bevacizumab in association with melphalan for HILP because of the additional effect of an anti-VEGF antibody in these highly vascularized tumors and its locally restricted delivery to the isolated hepatic vascular compartment despite of its classic contraindication in association with surgery. The protocol was approved by the Ethics Committee. Enhanced CT scans during follow-up showed complete tumor necrosis as early as the second postoperative day. Patients had 27 and 7 months disease-free survival and 48 and 41 months overall survival after HILP, for neuroendocrine liver metastases and HILP plus liver transplantation for HCC respectively. Under very specific conditions, bevacizumab in HILP can provide excellent tumor response in hopeless clinical cases of liver tumors.

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Hepatocellular; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Fatal Outcome; Female; Glucagonoma; Humans; Hyperthermia, Induced; Liver Neoplasms; Male; Melphalan; Middle Aged; Pancreatic Neoplasms

Topics: Adenocarcinoma; Animals; Autophagy; Cell Line, Tumor; Cell Proliferation; Chloroquine; Humans; Immunoglobulin G; Macrolides; Melphalan; Mice; Oxidative Phosphorylation; Pancreatic Neoplasms; Reactive Oxygen Species; Xenograft Model Antitumor Assays

Sunitinib demonstrating efficacy in pancreatic islet cell carcinomas will pave the way for further trials in other neuroendocrine tumor types such as carcinoid, poorly differentiated neuroendocrine disease, and several other endocrine tumors that are dependent on VEGF/VEGFR for angiogenesis. In addition, other drugs with distinct mechanisms of action, such as mTOR inhibitors, currently investigated in phase III trials, may also supply novel options in those diseases to control tumor growth and metastasis.

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoid Tumor; Cell Line, Tumor; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Indoles; Kidney Neoplasms; Lung Neoplasms; Melphalan; Neovascularization, Pathologic; Neuroendocrine Tumors; Pancreatic Neoplasms; Procarbazine; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyrroles; Sunitinib; Vinblastine; Xenograft Model Antitumor Assays

We have recently demonstrated that cytolysis of human melanoma cells by immune effectors (both NK and T cells) is associated with release of the nuclear chromatin protein, high mobility group box I (HMGB1). Extracellular HMGB1 mediates a number of important functions including endothelial cell activation, stromagenesis, recruitment and activation of innate immune cells, and also dendritic cell maturation that, in the setting of cancer, lead to a chronic inflammatory response. This reparative inflammatory response promotes tumor cell survival, expansion, and metastases. Release of HMGB1 after chemotherapy-induced cytotoxicity has not been well characterized. We measured the release of HMGB1 after chemotherapy or immune cytolysis and demonstrated that this did not correlate with conventional markers of apoptosis and necrosis in several human colorectal, pancreatic, and melanoma tumor cell lines. Rather, we observed that tumor cells incubated with the platinating agent oxaliplatin, retained HMGB1 within the nucleus for significantly longer periods than other agents used at comparable cytotoxic concentrations or even with potent cytolytic cells. Thus, release of HMGB1 from dying tumor cells treated with chemotherapy or cells with lymphokine activated killer cell activity is not dependent solely on the mode of cell death. Sequestration of the damage associated molecular pattern molecule, HMGB1, may play a role in the clinical efficacy of platinating agents and suggests this as a superior agent for coupling with immunotherapeutic strategies, possibly enhancing their effectiveness.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Nucleus; Colonic Neoplasms; Combined Modality Therapy; HMGB1 Protein; Humans; Immunotherapy; Killer Cells, Lymphokine-Activated; Melanoma; Melphalan; Microscopy, Confocal; Necrosis; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms

BRCA2, FANCC, and FANCG gene mutations are present in a subset of pancreatic cancer. Defects in these genes could lead to hypersensitivity to interstrand cross-linkers in vivo and a more optimal treatment of pancreatic cancer patients based on the genetic profile of the tumor.. Two retrovirally complemented pancreatic cancer cell lines having defects in the Fanconi anemia pathway, PL11 (FANCC-mutated) and Hs766T (FANCG-mutated), as well as several parental pancreatic cancer cell lines with or without mutations in the Fanconi anemia/BRCA2 pathway, were assayed for in vitro and in vivo sensitivities to various chemotherapeutic agents.. A distinct dichotomy of drug responses was observed. Fanconi anemia-defective cancer cells were hypersensitive to the cross-linking agents mitomycin C (MMC), cisplatin, chlorambucil, and melphalan but not to 5-fluorouracil, gemcitabine, doxorubicin, etoposide, vinblastine, or paclitaxel. Hypersensitivity to cross-linking agents was confirmed in vivo; FANCC-deficient xenografts of PL11 and BRCA2-deficient xenografts of CAPAN1 regressed on treatment with two different regimens of MMC whereas Fanconi anemia-proficient xenografts did not. The MMC response comprised cell cycle arrest, apoptosis, and necrosis. Xenografts of PL11 also regressed after a single dose of cyclophosphamide whereas xenografts of genetically complemented PL11(FANCC) did not.. MMC or other cross-linking agents as a clinical therapy for pancreatic cancer patients with tumors harboring defects in the Fanconi anemia/BRCA2 pathway should be specifically investigated.

Topics: Animals; Antineoplastic Agents; Apoptosis; BRCA2 Protein; Caspases; Cell Cycle; Cell Line, Tumor; Cell Survival; Chlorambucil; Cisplatin; Cross-Linking Reagents; Deoxycytidine; Dose-Response Relationship, Drug; Doxorubicin; Etoposide; Fanconi Anemia Complementation Group C Protein; Fanconi Anemia Complementation Group G Protein; Fanconi Anemia Complementation Group Proteins; Female; Fluorouracil; Gemcitabine; Humans; Inhibitory Concentration 50; Melphalan; Mice; Mice, Nude; Mitomycin; Mutation; Paclitaxel; Pancreatic Neoplasms; Time Factors; Vinblastine; Xenograft Model Antitumor Assays

Recent studies have demonstrated that various tumors express enhanced levels of the radical scavenger glutathione (GSH). Moreover, there are grounds for claiming that GSH plays a crucial role in cell proliferation and tumor resistance. In the current study, we investigated the relation between cell growth and GSH levels in the pancreatic adenocarcinoma cell line, AsPC-1, and the significance of GSH in tumor resistance to chemotherapy.. Cell growth in AsPC-1 was initiated through transforming growth factor-alpha (TGF-alpha) or fetal calf serum (FCS). Then, cell cycle, cell proliferation, and cellular GSH content were analyzed at different times in the presence or absence of buthionine sulfoximine (BSO). The impact of GSH on chemotherapy-induced apoptosis was studied using 5-fluorouracil or melphalan in the presence or absence of BSO. Finally, we compared the GSH content of 15 pancreatic tumor specimens with 10 normal pancreatic tissue specimens.. Analysis of GSH in pancreatic tissues demonstrated increased GSH levels in cancerous compared with normal tissue (17.5 +/- 2.3 vs. 8. 8 +/- 1.4 nmol/mg protein; P < 0.004). Incubation of AsPC-1 with TGF-alpha or FCS resulted in cell proliferation and cell cycle activity, whereas GSH content was not altered. Incubation of GSH-depleted cells with TGF-alpha did not stimulate cell growth. In addition, GSH-depletion resulted in an increased rate of apoptosis after melphalan (6.3 +/- 0.3 % vs. 11.2 +/- 0.3 %; P < 0.001), but not after 5-fluorouracil treatment.. Taken together, our results show enhanced GSH levels in pancreatic carcinoma and an essential role of GSH in cell proliferation and in resistance of AsPC-1 cells. Therefore, GSH-depletion may improve the efficacy of adjuvant therapy in pancreatic carcinoma.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Apoptosis; Cell Division; Drug Resistance, Neoplasm; Female; Fluorouracil; Glutathione; Humans; Male; Melphalan; Middle Aged; Pancreatic Neoplasms

Cultured cell populations derived from the refractory murine pancreatic ductal adenocarcinoma (Panc 02) were propagated in modified Eagle's minimal essential medium supplemented with 20% fetal bovine serum and had a doubling time of 19.1 +/- 4.7 hours (mean +/- SD). The Panc 02 cell populations were tested against 8 antitumor agents and exhibited different sensitivities to the agents in a 24-hour growth-inhibition assay. The concentration that inhibits the growth of the test culture by 50% relative to the growth of the control culture (IC50) in micromolars was determined for each agent. The IC50 values were: doxorubicin (ADR), 0.055; vincristine (VCR), 0.042; 5-fluorouracil, 1.92; cytarabine, 5.35; melphalan, 10.5; cisplatin, 17.0; carmustine (BCNU), 46.2; and lomustine (CCNU), 52.6. These IC50's were estimated to be pharmacologically attainable concentrations in mice. On a micromolar basis, the Panc 02 cells were the most sensitive to VCR and ADR and the least sensitive to BCNU and CCNU. By the use of a colony-forming assay and a 24-hour exposure period and the evaluation of each agent at 1/3 X IC50, 1 X IC50, and 3 X IC50, the degree of cell killing was greater than predicted on the basis of the IC50's determined in the growth-inhibition assay. The use of a 1-hour exposure period resulted in a very minimal reduction in viability of the cell populations except for BCNU and CCNU. It was concluded that the degree of cell killing was a function of drug concentration and time of exposure and that the pancreatic tumor in vivo should be sensitive to these agents, provided effective concentrations and exposure periods can be achieved at the tumor target sites.

Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents; Cell Cycle; Cell Survival; Cells, Cultured; Cisplatin; Doxorubicin; Melphalan; Mice; Nitrosourea Compounds; Pancreatic Neoplasms; Vincristine

The effects of melphalan were studied in rats fed raw soya flour and injected with azaserine in order to determine the suitability of this experimental model for testing drugs potentially useful for the treatment of pancreatic cancer. While melphalan did not prevent or delay the development of pancreatic cancer in these rats, the drug significantly lessened the number and size of the premalignant proliferative lesions in the pancreas. It seems that the model is useful both for testing potentially useful therapeutic agents and for analysing some of the processes involved in the development of pancreatic cancer.

Topics: Animals; Azaserine; Body Weight; Disease Models, Animal; Male; Melphalan; Nucleic Acids; Organ Size; Pancreas; Pancreatic Neoplasms; Proteins; Rats; Rats, Inbred Strains

We administered melphalan by the intraperitoneal route to investigate its toxicity and pharmacokinetics. The drug was instilled with 2 litres of fluid and allowed to dwell in the peritoneal cavity for 4 hours. No local toxicity was detected by clinical examination, laboratory tests, or histologic examination. The intraperitoneal route allowed the dose to be increased to approximately three times the maximum dose tolerated intravenously before drug leaking into the systemic circulation produced dose-limiting myelosuppression. The peak peritoneal concentration averaged 93-fold greater than the plasma concentration, and total drug exposure for the peritoneal cavity averaged 63-fold greater than that for plasma. Tumor regressions were observed in patients with ovarian carcinoma and gastrointestinal adenocarcinomas. This study shows that from the pharmacologic point of view, if any portion of the tumor can be reached by intraperitoneal instillation, then there is a very strong rationale for the administration of melphalan by the intraperitoneal route, rather than the oral or intravenous route, for the treatment of tumors confined to the peritoneal cavity.

Topics: Adult; Aged; Ascites; Ascitic Fluid; Bone Marrow Diseases; Colonic Neoplasms; Female; Humans; Infusions, Parenteral; Kinetics; Laparotomy; Male; Melphalan; Middle Aged; Models, Biological; Neoplasms; Ovarian Neoplasms; Pancreatic Neoplasms; Peritoneal Cavity; Stomach Neoplasms

Topics: Altretamine; Animals; Antineoplastic Agents; Cell Line; Cisplatin; Cyclophosphamide; Hindlimb; Humans; Melphalan; Mice; Mice, Inbred CBA; Neoplasm Transplantation; Pancreatic Neoplasms; Semustine; Streptozocin; Transplantation, Heterologous; Vinblastine

Topics: Anuria; Cholestasis; Diagnosis, Differential; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Pancreatic Neoplasms

Topics: Antineoplastic Agents; Breast Neoplasms; Busulfan; Carcinogens; Cyclophosphamide; Humans; Leukemia, Myeloid; Lung Neoplasms; Melphalan; Methotrexate; Neoplasms; Pancreatic Neoplasms; Rectal Neoplasms; Triaziquone; Urinary Bladder Neoplasms

Topics: Adenine; Carbon Isotopes; Culture Techniques; Female; Hemangiosarcoma; Humans; Lysine; Melphalan; Mesenchymoma; Neoplasm Proteins; Ovarian Neoplasms; Pancreatic Neoplasms; RNA, Neoplasm; Stomach Neoplasms; Uridine

Topics: Abdomen; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Colonic Neoplasms; Cyclophosphamide; Female; Geriatrics; Hodgkin Disease; Humans; Hypothermia; Hypothermia, Induced; Leiomyosarcoma; Mechlorethamine; Melanoma; Melphalan; Neoplasms; Ovarian Neoplasms; Pancreatic Neoplasms; Pelvis; Rectal Neoplasms; Retroperitoneal Neoplasms; Uterine Cervical Neoplasms; Vaginal Neoplasms